The new insight of prostate-specific antigen reduction during finasteride therapy in aging men

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上海市第一人民医院国家临床重点专科申报书——泌尿外科

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彩色超声波诊断仪彩色超声波诊断仪单光子发射扫描仪直线加速器治疗计划系统（TBS）模拟机核磁共振仪 64 排 CT 扫描机高压液相色谱仪图像传输与存储系统数字化 X 光机 CR 计算机成像系统移动式 C 臂 X 光机 C 臂 X 光机肺功能测定仪肌电图仪麻醉机流式细胞仪（BD）分选监护除颤仪心输出量测定仪血气分析仪电动呼吸机带显示器手术无影灯
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二膦酸盐类药物对转移性骨肿瘤作用研究进展

济宁医学院学报ＪＯＵＲＮＡＬＯＦＪＩＮＩＮＧＭＥＤＩＣＡＬＵＮＩＶＥＲＳＩＴＹＶ０１．３２Ｎｏ．６２００９４４５二膦酸盐类药物对转移性骨肿瘤作用研究进展徐兴华王建礼（济宁医学院基础学院．山东日照２７６８２６）关键词二膦酸盐；转移性骨肿瘤中图分类号：Ｒ７３０．５３文献标志码：Ａ文章编号：１０００—９７６０（２００９）１２—０４４５－０３二膦酸盐是１８６５年首次在德国合成的一类焦膦酸类似物，与焦膦酸不同的是以Ｐ－Ｃ－Ｐ键代替焦膦酸盐中Ｐ—ｏＰ键，这种变化改变了二膦酸盐的体内代谢过程，使其可以抵抗水解酶的作用而不被降解，在体内保持一定的稳定性。

１９６８年开始利用其具有显著的抑制烃基磷酸钙结晶溶解的生物特性，用于骨代谢疾病的治疗。

目前二膦酸盐类药物广泛用于治疗恶性骨疾病（如骨质疏松，骨肿瘤性疾病，ＰＡＧＡＥＴｓ病，高钙血症等）的治疗。

尤其是骨质疏松和转移性骨肿瘤的治疗。

现就二膦酸盐类药物对转移性骨肿瘤作用方面的研究进展做一综述。

１二膦酸盐类药物的分类二膦酸盐类药物常依它们的化学结构和作用机制而分成两类，其中一类被称作含氮二膦酸盐类药物，它包括阿仑膦酸钠（ａｌｅｎｄｒｏｎａｔｅ）、伊班膦酸钠（ｉｂａｎｄｒｏｎａｔｅ）、帕米膦酸二钠（ｐａｍｉｄｒｏｎａｔｅ）、利塞膦酸钠（ｒｉｓｅｄｒｏｎａｔｅ）和唑来膦酸（ｚｏｌｅｄｒｏｎｉｃａｃｉｄ）；另一类称之为非含氮二膦酸盐类药物，它包括氯屈膦酸钠（ｃｌｏｄｒｏｎａｔｅ）和依替膦酸钠（ｅｔｉｄｒｏｎａｔｅ）等。

在这两类二膦酸盐类药物中，含氮二膦酸盐类药物因能抑制法尼基二膦酸合成酶，故其作用较不含氮二膦酸盐类药物更强。

法尼基二膦酸合成酶是朋固醇生物合成途径中的一种酶。

通过抑制破骨细胞中的法尼基二膦酸合成酶．含氮二膦酸盐类药物可以干扰脂质粘着到调控蛋白上，进而引致破骨细胞的灭活。

２二膦酸盐对转移性骨肿瘤的作用目前所了解和掌握的恶性肿瘤发生骨转移的机制主要涉及三个方面：肿瘤细胞自身所固有的内在特性，即它具有离开原发病灶迁移到远处骨骼组织中的能力；骨骼系统的特定部位所具有的解剖学特性允许其接受并容纳播散的肿瘤细胞；受累骨骼对转移的肿瘤细胞所产生的各种生物学反应．使得瘤细胞能够在宿主骨骼中繁殖、生长并破坏正常骨组织的形态和结构。

新gre练习题

新gre练习题GRE填空题1. Though the volume of radioactive waste produced by nuclear power plants is________, the problem of how to dispose of that waste is not: rather, it is of major importance. [单选题] *A.unmanageableB.troublingC.significantD.small(正确答案)E.deceptive2. Investors are grateful that the attorney general has stepped in to pursue inquiries into the misfeasance in the financial markets, given that the regulators officially charged with policing the industry have been________. [单选题] *A.tenaciousB.diffident(正确答案)C.meticulousD.implacableE.straightforward3. The author suggests that cinema archives should become more like museums, justifying their existence by selecting, grouping and commenting on important films. By thus (i)________films,archives would not only serve as repositories, but would provide (ii)________as well.*A. improvingB. restoringC. interpreting(正确答案)D. conservationE. education(正确答案)F. income4. “Argument” may be an overly (i)________word to apply to the gossamer contrivance that is A summer of Humming birds. In what seems a self-conscious (ii)________ of its mascot, the book flits from one subjects or moment in history to another, following the various whims of its authors.*A. archaicB. impreciseC. strong(正确答案)D. repudiationE. emulation(正确答案)F. misrepresentation5. The skin of the poison dart frog contains deadly poison called batrachotoxins. But the(i)of the toxins has remained an enigma, as the frog does not (ii)________them. Now an analysis suggests that the melyrid beetle is the source. Collected beetle specimens all contained batrachotoxins, suggesting that these beetles are(iii)________ by the frogs.*A. effectB. origin(正确答案)C. purposeD.pressureE. produce(正确答案)F.suffer fromG. eaten(正确答案)H. neutralizedI. poisoned6. When a new scientific model emerges, research studies (i)________that paradigm tend to dominate in the scientific literature: the process of selecting articles for publication is tilted towardpositive results. But once the paradigm (ii)________, the academic incentives shift in the opposite direction: research results are more likely to be consideredworthy of publication when they(iii)________what has become the established view.*A. tweakingB. affirming(正确答案)C. controvertingD. is initially articulatedE. has become entrenched(正确答案)F. is about to be attackedG. bolsterH. circumventI. undermine(正确答案)7. The beauty of the scientific approach is that even when individual researchersdo________bias or partiality, others can correct them using a framework of evidence on which everyone broadly agrees. *A.overreact toB.deviate fromC.succumb to(正确答案)D.recoil fromE.yield to(正确答案)F.shrink from8.The initial, widely shared pessimism turned out to be________, because it ignored the many things that would be done with resources left behind. *A.unimportantB.unintelligibleC.unfathomableD.unfounded(正确答案)E.unimaginativeF.unjustified(正确答案)9. Despite a tendency to be overtly________, the poetry does not consist solely of pious sentiments: It sparks the imagination and provides lively entertainment. *A.preachy(正确答案)B.querulousC.insincereD.sanctimonious(正确答案)E.plaintiveF.disingenuous10. Though it may seem as if more than a century of________has made the electrical grid an all-encompassing web connecting the whole of the continent, many vast and beautiful areas remain without power. *A.refinementB.expansion(正确答案)C.ubiquityD.augmentation(正确答案)E.omnipresenceF.isolation11. With the numerous opponents of the controversial new taxation measure in such a fury, anyone who publicly advocated the measure did not fail to meetwith________usage. [单选题] *A.politicB.severe(正确答案)C.soberD.respectfulE.dejected12. The paleontologist examined the problem afresh, believing that the accepted classification________the essential continuity of the specimens by making specious distinctions among them. [单选题] *A.disprovedB.belied(正确答案)C.conflatedD.divulgedE.relaxed13.Invention was (i)________the work of the ancient Greek historians, whose writings were filled with long and often purely fictitious speeches by great historical figures. The animating force in historical writing was rhetoric rather than (ii)________. Even well into the eighteenth century, not a few historians continued to understand themselves as artists, given a license to invent.*A. discouraged inB. a hallmark of(正确答案)C. exceptional inD. eloquenceE. evidence(正确答案)F. imagination14. Scholars have marveled over the (i)________that Shakespeare displays in his works, noting that such broad learning is all the more remarkable given that books were relatively (ii)________ in Shakespeare's time.*A. meticulousnessB. humorC. erudition(正确答案)D. edifyingE. scarce(正确答案)F. inexpensive15.She was never (i)________: she was nothing if not discreet, so she (ii)________ for the present to declare her passion.*A. precipitate(正确答案)B. tactfulC. thoughtfulD. pretendedE. decidedF. forbore(正确答案)16.The slow pace of job creation was without precedent for the period of recovery from a recession,but the conditions that conspired to cause the recession were also (i)________. The stock market declined sharply, and rampant business investment slumped. Then an ensuing spate of scandals (ii)________ public trust in the way companies were run. And yet,despite these powerful (iii)________ to growth, the recession proved surprisingly mild.*A. hearteningB. atypical(正确答案)C. ambiguousD. weakened(正确答案)E. illuminatedF. consolidatedG. counterforce(正确答案)H. stimulantsI. concomitants17.A cure for the common cold has been so elusive that it has become a modern symbol of______. *A.dangerB.futility(正确答案)C.uneaseD.pointless(正确答案)E.slothF.apathy18.The dictators gleaming military uniform and imperial paraphernalia sharply contrast with the________fashion favored by most other contemporary political leaders. *A.unostentatious(正确答案)B.modest(正确答案)C.augustD.majesticE.formalF.casual19. Despite her rather________choices, Moreland was neither a rebellious spirit nor someone who saw herself as anything out of the ordinary. *A.unconventional(正确答案)B.impracticalC.quirky(正确答案)D.flamboyantE.successfulF.lucrative20. His premiership, seemingly cast-iron a year ago, is now so vulnerable that even a good day at the office does no more than buy him a few weeks of________from rebels within his own party. *A.controversyB.reproachC.respite(正确答案)D.relief(正确答案)E.blameF.deference21.In the last two hundreds years, the practice of archaeology has changed greatly, from digging up ancient artifacts for use by wealthy individuals as art objects to analyzing the detritus of everyday life in the laboratory, and thus from________to data collection. [单选题] *A.suppositionB.theorizingC.fact-findingD.treasure hunting(正确答案)E.scientific discovery22.The identity of hominid remains found in a cave in the Altai Mountainswas________until Paabo and his colleagues ended the speculation by showing that DNA sequences indicated the bones belonged to Neanderthals. [单选题] *A.extraneousB.conjectural(正确答案)C.improbableD.demonstrableE.consistent23. The documentation of Earth’s biodiversity is complicated by the(i)________taxonomists. Those experts in classifying species tent to be (ii)________ North America and Europe, whereas most of the undocumented biodiversity is likely in the tropics.*A. uneven distribution of(正确答案)B. theoretical commitments ofC. professional rivalries amongD. clustered in(正确答案)E. oblivious toF. exported from24. For decades, economic ideas have been (i)________ political purpose. Economists, for example, have peddled their theories as a way of gaining public prominence or political appointment, while politicians have (ii)________economic doctrines as possible solutions to the nation’s social problems.*A. undermined byB. inspired byC. exploited for(正确答案)D. rejectedE. ignoredF. promoted(正确答案)25. Computers make it spectacularly easy to search for particular pieces of information in downloaded texts. And doing research in this strategic, targeted manner can feel(i)________. Instead of (ii)________ the organizing logic of the book you are reading, you can approach the book with your own questions and (iii)________. You, not the author, are the master.*A. disorientingB. humblingC. empowering(正确答案)D. disregardingE. surrendering to(正确答案)F. imitatingG. begin to discern the author’s intentH. glean precisely what you want from it(正确答案)I. evaluate the book on its own terms26.There are two opposing theories about mountain formation and climate over the past 40 million years: either the surge of mountain building (i)________the global cooling, or vice versa. The first of these two theories asserts that widespread mountain buildingcooled the earth as a result of the(ii)________mountains and climate. For example, mountain glaciers tent to be (iii)________: once established, they increase the reflectivity of the surface, thus lowering temperatures and allowing more ice to form.*A. supersededB. haltedC. caused(正确答案)D. disparity betweenE. feedback between(正确答案)F. complexity ofG. unpredictableH. staticI. self-perpetuating(正确答案)27. If giant x-ray flares churn circumstellar disks enough to keep newborn planets, such as Earth once was, from spiraling into their suns, it would be an ironic twist on our conception of x-ray flares as ______ . *A.dangerous(正确答案)B.predictableC.ancientD.ephemeralE.perilous(正确答案)F.foreseeable28. Despite their cultural and social significance, rapid growth, and widespread appeal in China, video game—unlike traditional media—have received________attention from international communication researches. *A.undueB.scant(正确答案)C.excessiveD.focusedE.limited(正确答案)F.dwindling29. Although Wynne claims to recognize that________evidence is available to make definitive statements, she offers them nonetheless, arriving at some sweeping generalizations. *A.concreteB.finiteC.insufficient(正确答案)D.indirectE.conclusiveF.meager(正确答案)30.Although the biography never explicitly assesses what role the dynamic between Mr. Merrills parents might have played in the development of his personality, the author offers plenty of _____ *A.mystificationB.elucidationC.speculation(正确答案)D.reflectionE.obfuscationF.conjecture(正确答案)GRE阅读题GRE阅读题【1】At a certain period in Earth’s history, its atmosphere contained almost no oxygen, although plants were producing vast quantities of oxygen. As a way of reconciling these two facts, scientists have hypothesized that nearly all of the oxygen being produced was taken up by iron on Earth’s surface. Clearly, however, this explanation is inadequate. New studies show that the amount of iron on Earth’s surface was not sufficient to absorb anywhere near as much oxygen as was being produced. Therefore, something in addition to the iron on Earth’s surface must have absorbed much of the oxygen produced by plant life.1. In the argument given, the two portions in boldface play which of the following roles? [单选题] *A. The first is a claim made by the argument in support of a certain position; the second is that position.B. The first is a judgment made by the argument about a certain explanation; the second is that explanation.C. The first expresses the argument’s dismissal of an objection to the position it seeks to establish; the second is that position.D. The first sums up the argument’s position with regard to a certain hypothesis; the second provides grounds for that position.(正确答案)E. The first is a concession by the argument that its initial formulation of the position it seeks to establish requires modification; the second presents that position in a modified form.Rain-soaked soil contains less oxygen than does drier soil. The roots of melon plants perform less efficiently under the low-oxygen conditions present in rain soaked soil. When the efficiency of melon roots is impaired, the roots do not supply sufficient amounts of the proper nutrients for the plants to perform photosynthesis at their usual levels. It follows that melon plants have a lower-than-usual rate of photosynthesiswhen their roots are in rain-soaked soil. When the photosynthesis of the plants slows, sugar stored in the fruits is drawn off to supply the plants with energy. Therefore, ripe melons harvested after a prolonged period of heavy rain should be less sweet than other ripe melons.2. In the argument given, the two portions in boldface play which of the following roles? [单选题] *A. The first states the conclusion of the argument as a whole; the second provides support for that conclusion.B. The first provides support for the conclusion of the argument as a whole; the second provides evidence that supports an objection to that conclusion.C. The first provides support for an intermediate conclusion that supports a further conclusion stated in the argument; the second states that intermediate conclusion.(正确答案)D. The first serves as an intermediate conclusion that supports a further conclusion stated in the argument; the second states the position that the argument as a whole opposes.E. The first states the position that the argument as a whole opposes; the second supports the conclusion of the argument.Columnist: Until very recently, Presorbin and Veltrex, two medications used to block excess stomach acid, were both available only with a prescription written by a doctor. In an advertisement for Presorbin, its makers argue that Presorbin is superior on the grounds that doctors have written 200 million prescriptions for Presorbin, as compared to 100 million for Veltrex. It can be argued that the number of prescriptions written is never a worthwhile criterion for comparing the merits of medicines, but that the advertisement’s argument is absurd is quite adequately revealed by observing that Presorbin was available as a prescription medicine years before Veltrex was.3. In the columnist’s argument, the two highlighted portions play which of the following roles? [单选题] *A. The first is a claim that the columnist’s argument seeks to clarify; the second states a conclusion drawn about one possible interpretation of that claim.B. The first identifies the conclusion of an argument that the columnist’s argument is directed against; the second states the main conclusion of the columnist’s argument.(正确答案)C. The first states the main conclusion of the columnist’s argument; the second states a conclusion that the columnist draws in defending that conclusion against an objection.D. The first identifies an assumption made in an argument that the columnist's argument is directed against; the second states the main conclusion of the columnist’s argument.E. The first is a claim that has been offered as evidence to support a position that the columnist opposes; the second states the main conclusion of the columnist’s argument. Politician: The number of traffic deaths in our region has increased over the past several years. Because the poor condition of our roads and highways has caused a number of fatal accidents, the road commission recommended that, to reduce traffic deaths, the budget for road maintenance should be increased. Many major traffic deaths, however, are attributed to traffic congestion than to poor road condition, and better road will encourage people to drive more, worsen traffic congestion. So a better strategy for the road commission to recommend would be to reduce traffic congestion, though the best means for doing so remains to be determined. Improving mass transit is only one possibility.4. In the politician’s argument, the two highlighted portions play which of the following roles? [单选题] *A. The first introduce the position that the politician seeks to establish, the second provides evidence to support that position.B. The first introduces the position that the politician seeks to establish, the second is evidence that was cited in support of the position that the politician opposes.C. The first introduces the position that the politician seeks to establish, the second is an intermediate conclusion that is made in order to support that position.D. The first introduces a problem, the response to which is presented in the argument, the second provides evidence that is aimed at arguing that a proposed response to this problem will turn out to be counterproductive.(正确答案)E. The first introduces a problem, the response to which is presented in the argument, the second is evidence that was cited in support of a response that the politician opposes. Stylistic evidence and laboratory evidence strongly support the claim that the magnificent painting Garden of Eden is a work of the Flemish master van Eyck. Nevertheless, the painting must have been the work of someone else, as anyone with a little historical and zoological knowledge can tell merely by looking at the painting. The animals in the painting are all vivid representations of actual animals, including armadillos. Yet armadillos are native only to Americas, and van Eyck died decades before Europeans reached the Americas.5. In the argument given, the two highlighted portions play which of the following roles? [单选题] *A. The first is a position that the argument seeks to reject, the second is evidence that the argument uses against that position.B. The first and the second are each pieces of evidence that have been used to support the position that the argument opposes.C. The first presents the main conclusion of the argument; the second provides evidence in support of that conclusion.(正确答案)D. The first is a judgment that serves as the basis for the main conclusion of the argument; the second states that main conclusion.E. The first is an intermediate conclusion drawn in order to support a further conclusion stated in the argument; the second provides evidence in support of that intermediate conclusion.GRE阅读题【2】A ten-year comparison between the United States and the Soviet Union in terms of crop yields per acre revealed that when only planted acreage is compared, Soviet yields were equal to 68 percent of United States yields. When total agricultural acreage (planted acreage plus fallow acreage) is compared, however, Soviet yield was 114 percent of United States yield.1. From the information above, which of the following can be most reliably inferred about United States and Soviet agriculture during the ten-year period? [单选题] *A. A higher percentage of total agricultural acreage was fallow in the United States than in the Soviet Union.(正确答案)B. The United States had more fallow acreage than planted acreage.C. Fewer total acres of available agricultural land were fallow in the Soviet Union than in the United States.D. The Soviet Union had more planted acreage than fallow acreage.E. The Soviet Union produced a greater volume of crops than the United States produced.New methods developed in genetic research have led taxonomists to revise their views on the evolutionary relationships between many species. Traditionally the relatedness of species has been ascertained by a close comparison of their anatomy. The new methodsinfer the closeness of any two species’ relationship to each other directly from similarities between the species’ genetic codes.2. Which of the following conclusions is best supported by the information? [单选题] *A. The apparent degree of relatedness of some species, as determined by anatomical criteria, is not borne out by their degree of genetic similarity.(正确答案)B. When they know the differences between two species’ genetic codes, taxonomists can infer what the observable anatomical differences between those species must be.C. The degree to which individuals of the same species are anatomically similar is determined more by their genetic codes than by such environmental factors as food supply.D. The traditional anatomical methods by which taxonomists investigated the relatedness of species are incapable of any further refinement.E. Without the use of genetic methods, taxonomists would never be able to obtain any accurate information about species’ degrees of relatedness to one another.Years ago, consumers in Frieland began paying an energy tax in the form of two Frieland pennies for each unit of energy consumed that came from nonrenewable sources. Following the introduction of this energy tax, there was a steady reduction in the total yearly consumption of energy from nonrenewable sources.3. If the statements in the passage are true, then which of the following must on the basis of them be true? [单选题] *A. There was a steady decline in the yearly revenues generated by the energy tax in Frieland.(正确答案)B. There was a steady decline in the total amount of energy consumed each year in Frieland.C. There was a steady increase in the use of renewable energy source in Frieland.D. The revenues generated by the energy tax were used to promote the use of energy from renewable sources.E. The use of renewable energy sources in Frieland greatly increased relative to the use of nonrenewable energy sources.GRE阅读题【3】During the day in Lake Constance, the zooplankton D. hyalina departs for the depths where food is scarce and the water cold. D. galeata remains near the warm surface wherefood is abundant. Even though D. galeata grows and reproduces much faster, its population is often outnumbered by D. hyalina.1. Which of the following, if true, would help resolve the apparent paradox presented above? [单选题] *A. The number of species of zooplankton living at the bottom of the lake is twice that of species living at the surface.B. Predators of zooplankton, such as whitefish and perch, live and feed near the surface of the lake during the day.(正确答案)C. In order to make the most of scarce food resources,D. hyaline matures more slowly than D. galeata.D. D. galeata clusters under vegetation during the hottest part of the day to avoid the Sun’s rays.E. D. galeata produces twice as many offspring per individual in any given period of time as does D. hyalina.In the past ten years, there have been several improvements in mountain-climbing equipment. These improvements have made the sport both safer and more enjoyable for experienced climbers. Despite these improvements, however, the rate of mountain climbing injuries has doubled in the past ten years.2. Which of the following, if true, best reconciles the apparent discrepancy presented in the passage? [单选题] *A. Many climbers, lulled into a false sense of security, use the new equipment to attempt climbing feats of which they are not capable.(正确答案)B. Some mountain-climbing injuries are caused by unforeseeable weather conditions.C. Mountain climbing, although a dangerous sport, does not normally result in injury to the experienced climber.D. In the past ten years there have been improvements in mountain-climbing techniques as well as in mountain-climbing equipment.E. Although the rate of mountain-climbing injuries has increased, the rate of mountain-climbing deaths has not changed.Despite the fact that the health-inspection procedure for catering establishments are more stringent than those for ordinary restaurant, more of the cases of food poisoning reported to the city health department were brought on by banquets served by catering services than were brought on by restaurant meals.3. Which of the following, if true, helps explain the apparent paradox in the statement above? [单选题] *A. A significantly larger number of people eat in restaurants than attend catered banquets in any given time period.B. Catering establishments know how many people they expect to serve, and therefore are less likely than restaurants to have, and serve, leftover foods, a major source of food poisoning.C. Many restaurant provide catering services for banquets in addition to serving individual meals.D. The number of reported food-poisoning cases at catered banquets is unrelated to whether the meal is served on the caterer’s or the client’s premises.E. People are unlikely to make a connection between a meal they have eaten and a subsequent illness unless the illness strikes a group who are in communication with one another.(正确答案)Despite a dramatic increase in the number of people riding bicycles for recreation in Parkville, a recent report by the Parkville Department of Transportation shows that the number of accidents involving bicycles has decreased for the third consecutive year.4. Which of the following, if true during the last three years, best reconciles the apparent discrepancy in the facts? [单选题] *A. The Parkville Department of Recreation confiscated abandoned bicycles and sold them at auction to any interested Parkville residents.B. Increased automobile and bus traffic in Parkville had been the leading cause of the most recent increase in automobile accidents.C. Because of the local increase in the number of people bicycling for recreation, many out-of-town bicyclists ride in the Parkville area.D. The Parkville Police Department enforced traffic rules for bicycle riders much more vigorously and began requiring recreational riders to pass a bicycle safety course.(正确答案)E. The Parkville Department of Transportation canceled a program that required all bicycles to be inspected and registered each year.Although initially symptomless, glaucoma can eventually cause blindness when not properly treated. Tests under laboratory conditions of the traditional treatment, daily administration of eyedrops, show it to be as effective in relieving the internal ocular pressure that causes glaucoma as is a new laser-surgical procedure. Yet glaucoma-related blindness occurs in a significantly smaller percentage of patients who have had the surgery than of patients for whom only the eyedrop treatment was prescribed.5. Which of following, if true, most helps to explain the low rate glaucoma-related blindness among patients who had the surgery? [单选题] *A. Glaucoma-related blindness is no more common among patients who have had only the surgery than it is among patients who had the surgery after using the eyedropsB. Doctors rarely recommend the surgery for glaucoma patients who have already started the traditional course of treatmentC. There is no known physiological cause of glaucoma other than increase in pressure inside the eyeD. A significant percentage of the people for whom the eyedrop treatment has been prescribed fail to follow the prescribed daily regimen, because the eyedrops have unpleasant side effects.(正确答案)E. The eyedrops traditionally prescribed to treat glaucoma are normally prescribed to treat other disease of the eye.GRE阅读题【4】In 1998 the United States Department of Transportation received nearly 10,000 consumer complaints about airlines; in 1999 it received over 20,000. Moreover, the number of complaints per 100,000 passengers also more than doubled. In both years the vast majority of complaints concerned flight delays, cancellations, mishandled baggage, and customer service. Clearly, therefore, despite the United States airline industry’s serious efforts to improve performance in these areas, passenger dissatisfaction with airline service increased significantly in 1999.1. Which of the following, if true, most seriously weakens the argument? [单选题] *A. Although the percentage of flights that arrived on time dropped slightly overall, from77 percent in 1998 to 76 percent in 1999, some United States airlines’ 1999 on-time rate was actually better than their 1998 on-time rate.B. The number of passengers flying on United States airlines was significantly higher in 1999 than in 1998.C. Fewer bags per 1,000 passengers flying on United States airlines were lost or delayed in 1999 than in 1998.D. The appearance in 1999 of many new Internet sites that relay complaints directly to the Department of Transportation has made filing a complaint about airlines much easier for consumers than ever before.(正确答案)E. Although the number of consumer complaints increased for every major United States airline in 1999, for some airlines the extent of the increase was substantial, whereas for others it was extremely small.。

A biomedical engineering approach to mitigate the errors of prostate biopsy

IntroductionThe current diagnostic pathway that is employed to both detect and rule out pros-tate cancer involves serum PSA testing and transrectal ultrasonography (TRUS)-guided biopsy. The role of PSA screening in the underdetection of clinically significant prostate cancer, overdiagnosis of clinically insignificant disease and limitations in risk stratification has been discussed in great detail, but little has been written regarding the contribution of TRUS-guided biopsy to these errors.1,2We believe that the inherent limitations of TRUS-guided biopsy confer most of the error that has hitherto been attributed to PSA testing. Indeed, the blind spot we have for TRUS-guided biopsy is even reflected in the terms that we use to describe it: it is often referred to as ‘systematic’ or ‘random’.However, as a method of sampling a volumeof tissue, the reality is that it is neither trulyrandom nor reliably systematic in nature.Randomness is not achieved because ofoperator preferences for certain parts ofthe prostate and the accessibility of someparts of the organ compared with others—a systematic sampling of the whole prostateis a near impossibility, owing to anatomicalconstraints if the point of access is trans-rectal. The result is oversampling of someareas and undersampling of others.Ultimately, TRUS-guided biopsy per-forms poorly because it is conductedwithout knowledge of the cancer l o cation—ultrasonography is used simply to deter-mine that the needle has targeted prostatetissue. Until novel imaging modalities,such as multiparametric MRI or ultrasono-graphic tissue characterization, are shownto be reproducible outside single expertcenters, we continue to seek improvementsto the traditional TRUS-guided biopsy. Wehave started this search with a bio m edicalengineering evaluation of the currentassumptions that underlie TRUS-guidedbiopsy, leading to the modeling of a strat-egy that could address the short c omings.We propose corrections to the protocolthat could reduce the types of error result-ing from a procedure that is undertakenalmost a million times per year in the USA.This plethora of biopsies, which are oftenperformed on men only nominally at risk,materially affect patient welfare, introduceadded morbidity, and substantially increasesocietal costs.Current biopsy strategy is flawedCurrently, a man with an unexplained risein PSA is advised to undergo TRUS-guidedbiopsy, and 10 or 12 core samples are col-lected from throughout the peripheral zoneof the prostate. The results of such biop-sies are most often negative and, therefore,inconclusive. One in five men with a nega-tive biopsy will have clinically significantprostate cancer if verified using a more accu-rate test such as template prostate mappingbiopsy, which samples the gland every5 mm.3 Even when the results are positive,biopsy performs poorly as a histological testto rule in or rule out clinically significantprostate cancer. Given this poor attributionof status, it follows that the process of riskstratification is also compromised by the testperformance. About half of those men whoare diagnosed as “low-risk” following biopsyare shown to harbor a cancer of either highergrade or higher burden than originallydetermined when the sample is subjectedto some method of reclassification.3 Thisattribu t ion error will result in inappropriatetreat m ent al l ocation—men with high-riskdis e ase will be recommended conservativemanagement in contrast to radical therapyand men with low-risk disease are recom-mended radical therapy ‘just in case’.4,5 Theburden of overtreatment has always beenrecognized in prostate cancer therapy buthas only recently been quantified. Large-scale randomized studies have generatedmetrics such as ‘number needed to treat’(NNT)—the number of patients who mustbe treated in order to save one life. For a manin a screened versus nonscreened popu-lation, the NNT for prostate cancer rangesfrom 12 to 48.6,7The stability of the negative biopsy statuswas tested formally in the Reduction byOPINIONA biomedical engineering approachto mitigate the errors of prostate biopsyHashim Uddin Ahmed, Mark Emberton, Gordon Kepner and Jeremy KepnerAbstract | The current protocol for detecting and ruling out prostate cancer involvesserum PSA testing followed by sampling of the prostate using a transrectalultrasonography (TRUS)-guided biopsy. Many specialists have discussed how PSAscreening has contributed to underdetection of clinically significant prostate cancer,overdiagnosis of clinically insignificant disease and poor risk stratification; however,little consideration has been given to the role of TRUS-guided biopsy in these errors.The performance of TRUS-guided biopsy is constrained by the biomechanical attributesof the sampling strategy, resulting in suboptimal detection efficiency of each core. Byusing a biomedical engineering approach, a uniform grid sampling strategy could beused to improve the detection efficiency of prostate biopsy. Moreover, the calibrationof the sampling can be adjusted by altering the distance between needle deployments.Our model shows that for any given number of needle trajectories, a uniform gridapproach will be superior to a divergent, nonuniform strategy for the detection ofclinically important disease. This is an important message that should result in a moveaway from divergent sampling to a uniform grid approach for prostate biopsy.Ahmed, H. U. et al.Nat. Rev. Urol.9, 227–231 (2012); published online 7 February 2012;doi:10.1038/nrurol.2012.3Competing interestsH. U. Ahmed and M. Emberton declareassociations with the following companies:Advanced Medical Diagnostics, GSK, Oncura,Steba Biotech, USHIFU, and USHIFU/FocusedSurgery/Misonix Inc. See the article online for fulldetails of the relationships. The other authorsdeclare no competing interests.PERSPECTIVESDutasteride of Prostate Cancer Events (REDUCE) study,8 in which men with a nega t ive biopsy were eligible for randomiza-tion to receive either dutasteride or placebo. Men underwent two planned, protocol-directed biopsies and a for-cause biopsy if indicated. At the end of the study, one-quar-ter of men in the placebo group had tested positive for cancer. The sobering implication of this result is that men who are classified as ‘at risk’ prior to TRUS-guided biopsy have about a one-in-four chance of the result being positive. A negative biopsy result does little to change this risk if men undergo another TRUS-guided biopsy using the same protocol on two further occasions. In other words, the probability of being diagnosed with prostate cancer is the same for a man awaiting biopsy as it is for a man who has just been informed that his biopsy is negative. The true extent of the errors generated by TRUS-guided biopsy and the costs and harms that result from them are, at present, impossible to quantify because of the effects of selection and verification biases. These biases occur as a result of several practices. The first, and probably most important, is the management of the man with a nega-tive biopsy result. Men who test negative for prostate cancer are either discharged to the community for yearly PSA testing or kept under review for planned repeat biopsies triggered by subsequent PSA rises.The second form of bias relates to the most commonly used reference test (radical prostatectomy specimens), which are used to validate the accuracy of TRUS-guided biopsy. In other words, only men who are diagnosed with prostate cancer who then choose to have extirpative surgery (as opposed to radiation therapy or active surveil l ance) are used to validate the accu-racy of TRUS-guided biopsy. Consequently, the false-negative rate of TRUS biopsy is never tested and the positive is verified in a very select population, inviting the influ-ence of spectrum bias when the results are inevit a bly generalized.Evolution of TRUS biopsyThe current protocol for placing TRUS-guided biopsy needles is based on a series of clinical studies demonstrating that 10 or 12 tissue cores were better at detecting prostate cancer than six and that needle trajectories directed obliquely to the prostate were again better at detecting prostate cancer than those directed perpendicular to the posterior surface of the prostate.9 Biopsy studies claim-ing that the frequency of tumors is greater in one part of the peripheral compared toanother conflict with data showing a homo-geneous distribution of tumors within azone.10,11 Nonetheless, the probability ofdetection is not necessarily the same at everypoint in a prostatic zone because tumors atthe periphery of the prostate, especi a lly inthe apex, are more easily detected owing tothe ‘edge effect’, which means that these areasare more easily sampled, because the periph-eral zone at these points has less volume soa tumor is more likely to be detected by abiopsy needle.12Furthermore, the current samplingapproach limits comparison betweenstudies, as it is not known precisely wherebiopsy needles were placed nor the distri-bution and risk stratification of cancer indifferent cohorts.Multifocality of prostate cancerProstate cancer is often multifocal with twoor three tumors of different volumes beingpresent in a single patient.13 Most men withprostate cancer will have a dominant tumorthat has the greatest volume and the highestgrade. Evidence sug g ests that this dominanttumor is the index lesion—the lesion thathas the immediate potential to pro g ress andmetastasize within the patient’s remain-ing lifetime—and the smaller, lower gradelesions are deemed indolent or clinicallyinsignificant.14,15 It has also been arguedthat the index lesion must meet a thresholdvolume for this potential to be realized,16 butthe exact value for this threshold remainsthe sub j ect of con s ider a ble disagreementand uncer t ainty.17 Values of 0.2 cm3, 0.5 cm3and 1.3 cm3 have been pro p osed.18 However,such a thres h old is unlikely to be absoluteand might differ from one man to the nextdepending on comor b idity, age and esti-mates of life expec t ancy. Thus, the role ofthe biopsy may not necessarily be to findevery lesion. Instead, when positive, itshould be used to locate and characterizethe index lesion grade and volume. Whennegative, it should pro v ide an estimate,bounded by known levels of certainty, ofthe largest volume of any lesion that couldhave escaped detection. This knowledgewould confer some clinical utility to a nega-tive test result, where currently none exists.So, instead of the rather glib—and factu-ally incorrect—‘all clear’, clinicians couldtell their patients that the biopsy resultis negative, mean i ng that there is a 95%chance that they do not have any clinicallysignificant prostate cancer. It is likely thatthe patient would walk away just as relievedand the clini c ian would feel considerablyless anxious than they would having toldtheir patients something that has a one-in-three chance of not being true if based onthe result of a TRUS-guided biopsy.Modeling a new biopsy strategyThe ideal biopsy strategy should detectcancer greater than a specified volume with95% certainty and rule out prostate cancervolumes that are greater than a specifiedthreshold volume with 95% certainty.19,20Studies of radical prostatectomy specimenshave shown that the great majority of bothperipheral and transition zone tumors areless than 2 cm3 in volume and are confinedto their zone of origin, whereas a smallfraction of tumors are 2–4 cm3 in volume,found in both zones, and are confined tothe prostate.21,22 Assume for one momentthat the radical prostatectomy specimensinvestigated are representative of othermen diagnosed and treated for presumedorgan-confined disease. Using the distribu-tion of cancers within removed prostates asthe reference standard, we can begin to testsome sampling theories. Thus, one methodfor evaluating the effectiveness of a biopsystrategy would be to assess how effectivelyit detects prostate tumor foci within thesetwo volume ranges (<2 cm3 and 2–4 cm3)and how well it rules them out if the biopsyresult is negative.Tumor model assumptionsIn order to develop the model we requireone other assumption—that tumor foci<4 cm3 conform to a sphere.12 However, weknow that many tumor foci are not spheri-cal when viewed in cross section on whole-mount specimens—some are curvilinear,others are fusiform. Despite this, for thepurposes of modeling, the assumption of asphere works well for generating samplingprobabilities, in that certain geometries willbe over-represented on any detection strat-egy and others will be under-represented.As the sphere has the lowest surface:volumeratio, its morphology is, therefore, hardestto detect per unit volume. Thus, by usingspheres the modeling we describe is a‘worst-case scenario’. In addition, thedetection of a sphere should be orientation-independent to any sampling regimen—transrectal or transperineal. Tumors withdiameters of 1–2 cm yield tumor volumesbetween 0.5 and 4.0 cm3, suggesting that theprimary focus of a biopsy approach shouldbe to detect tumors 1–2 cm in diameter,while minimizing the detection of tumorsPERSPECTIVES<1.0 cm in diameter, as very few men are likely to benefit from the detection and treatment of such small tumors.Uniform grid of coresImagine, instead of the currently used random location of the biopsy cores, a 3D perspective on the relationship between a uniform grid of cores and its ability to detect a spherical tumor volume (Figure 1). The unit grid is four parallel biopsy cores placed S cm apart (Figure 2). The unit grid uses four parallel point cores to create the detection square, with sides of length S cm. The circumscribed circle of diameter D rep-resents the model spherical tumor in cross-section. It is the largest tumor that just fits inside the detection square cores. There is a set volume for the largest spherical tumor that could, theoretically, be positioned pre-cisely inside these four points without being detected. This is calculated in the following way: first, sphere dia m eter, D, is the product of S and √2. Second, sphere volume is the product of π/6 and D3. In this way, if S is known, the maximum tumor volume that could avoid detection (by fitting into the space delineated by S) can be derived. Forexample, if the core spacing S is 1.0 cm and D is 1.41 cm, then V is 1.46 cm3. There are hundreds of different positions, all equally likely, for the center point of this tumor within the unit grid of four cores. At every one of these positions (except the position shown in Figure 2) the tumor would inter-sect at least one core. Effectively, the prob-ability of detection for this tumor volume is almost 100%. A detailed analysis on the probability of detection for spherical tumors by the unit grid of cores was pre-viously summarized for different values of S.12 Decreasing S decreases the size of the largest tumor that could go undetected. To do so requires increasing the sampling intensity, in other words increasing the number of cores. This uniform grid analysis has many useful attributes. It is independent of the number of tumors within each zone that is sampled. It is also independent of tumor location because a uniformly spaced biopsy strategy will sample the whole gland as opposed to preferentially sampling a particular zone or area of the prostate. For instance, TRUS-guided biopsy has one par-ticular area that is always avoided (called the ‘no-fly zone’). This is the midline in which the urethra is positioned. By sampling either side of the urethra, the operator will have an estimate of what volume tumor, if any, might lie behind the urethra.Negative biopsy limits tumor sizeWhen a biopsy conducted with the uniformgrid approach is negative, the cliniciancan estimate the largest spherical tumorvolume that could escape detection with, forexample, 95% or 99% probability.12 In theidealized setting, if S is 1.0 cm, then thereis a 99% probability of detecting a 1.0 cm3tumor. In real-life practice the small needledeviations that take place will be randomand over many deployments should canceleach other out. The swelling of the prostatethat occurs during any sampling proce-dure will have the effect of systematicallyclustering some needle deployments as aresult of tissue swelling on a fixed samp-ling frame, but this error should be smallover the 10 min or so that is required tocomplete the sampling.Uniform grid versus TRUS-guided biopsyVarious nonuniform TRUS-guided biopsyprotocols involving 6–20 cores, or some-times more, have been reported.23–25 Forease of visualization, a 14-core patternis used for the example presented here(Figure 3). In the TRUS-guided biopsysetting, one can see the difficulty of placingthe second biopsy needle deployments inoptimal positions, given the uncertaintyof the needle placements during the firstround of sampling. Furthermore, the place-ment of biopsies inevitably leads to unsam-pled areas, which could allow larger tumorsto escape detection (Figure 3).Figure 1 | Relation of the spherical tumor model volume to the detection grid formed by the four parallel cores. a | A 3D cut-out view of the prostate shows the maximum size of a spherical tumor that can avoid detection in a uniform grid of cores with spacing, S, between core centers.b | Gray quarter-cylinders denote the volume in which a small spherical tumor of diameter DT would be detected. The volume of the four quarter-cylinders (one cylinder of diameter D2Tand height h), is (π/4)(DT)2h. When divided by the total volume of the sampling space, S2h, it calculates the probability of detection.12 This figure was modified from Kepner, G. & Kepner, J. Theor. Biol. Med. Model.7, 23 (2010), which is published under an open-access license by Biomed Central.SFigure 2 | Four evenly spaced parallel pointcores spaced S cm apart, with thecircumscribed circle of diameter Drepresenting the model spherical tumor incross-section. It is the largest tumor that justfits inside the detection square cores. Thereis a set volume for the largest sphericaltumor that could, theoretically, be positionedprecisely inside these four points withoutbeing detected.PERSPECTIVESBy contrast, needles deployed as part of a uniform grid approach sample tissue volumes that are essentially equal, with uniform and minimal overlap (Figure 4). This approach maximizes detection effi-ciency because the value of S is constant throughout the entire prostate volume sampled and is minimized to produce a higher probability of detection for the volume of cancer lesion that would be important in a particular man.12DiscussionTRUS biopsy performs poorly.26,27 Its perfor-mance is constrained by the bio m echanical attributes of the sampling strategy, resulting in suboptimal detection efficiency of each core. Greater detection efficiencies can be gained by using a uniform grid sampling strategy, which can be calibrated according to the specific risk of a particular man har-boring clinically significant cancer and the volume of tumor that defines clinical sig-nificance for his particular situation, taking into account preoperative biomarker levels and competing risks of mortality.Methodological limitationsMuch of the theory supporting these con-clusions is derived from idealized models that are unlikely to exactly replicate the real-life situation. In creating biomedical engineering models we have been careful not to underestimate the performance of the standard test, TRUS-guided biopsy. If anything, the performance of TRUS-guided biopsy has been overestimated in our model, by assuming that it samples the whole prostate—most clinicians are aware that the needle trajectories employed duringTRUS-guided biopsy mean that parts of the prostate such as the apex and the anterior prostate are difficult to sample effectively. We have assumed otherwise. Our aim was to develop a new strategy that maximized the detection efficiency of each needle.We accept that tumor grade is not evalu a ted within our model. In order to inform models of the grade within indivi-dual lesions, whole-mount specimens are required in order to map Gleason grade within the whole tumor, as areas of vary-ing grade are heterogeneously distrib-uted through o ut the lesion. We have not been able to obtain such datasets. How-ever, there is a strong correlation between tumor volume and grade. Only 5% of lesions <0.2 cm 3 in volume have elements of Gleason pattern 4. In other words, our assump t ion is that if one detects a lesion of volume above a clinically acceptable volume threshold, then the highest grade will also have been detected in the majority of cases.Clinical implicationsOur modeling shows that for any given number of needle trajectories, a uniform grid approach will be superior to a diver-gent, nonuniform strategy for the detec-tion of clinically important disease. This is an important message that we hope will prompt a move away from divergent sam-pling to a uniform grid approach. Moreover, the uniform grid approach is amenable to a user-defined calibration for detecting, or ruling out, cancer foci of a given volume. In other words, the distance between needles can be altered and set to rule out a tumor focus with a volume above what the clini-cian would consider significant for a par-ticular man, taking into account all other clinical parameters such as age, serum PSA level, family history of prostate cancer and rectal examination findings. The 5 mm needle distance, advocated by Barzell 28 for transperineal sampling is the most accurate biopsy test we have, and could be adjusted to 10 mm or 15 mm for any revised defi-nition of tumor volume significance, or for biopsy in the older man. Our use of the term ‘uniform grid’ might imply that the parallel sampling strategy requires a transperineal approach.12 This is not the case. Novel, commercially available needle tracking and biopsy guidance platforms mean that optimal sampling strategies can be constructed independent of the point of access to the prostate. As well as construct-ing a needle-by-needle sampling strategy, unlike a fixed template, the biopsy protocolcan be adjusted to account for random needle deflection and for gland swelling.29,30 Although the expert user might be able to carry out such uniform grid sampling trans-rectally, it is unlikely that the average user will be able to do so without a commercial platform. Thus, for the average user and in order to facilitate dissemination of uni-form grid sampling, either a transperineal approach will have to be adopted or such software platforms will be needed. Either way, such a change in the biopsy protocol is likely to transform the diagnostic pathway, while also providing the necessary correc-tions to the problems of risk stratification and treatment allocation that are inherent in TRUS-guided biopsy.In addition, our biopsy modeling does not take into account progress being made in imaging and detection and measurement of biomarkers in the blood and urine. For instance, multiparametric MRI incorpo-rates T2-weighted, diffusion-weighted, and dynamic-contrast-enhanced imaging and spectroscopy to obtain detailed anatomical and functional information. Early studies using multiparametric MRI for prostate cancer diagnosis demonstrate promising results in detecting and ruling out clinically significant lesions.31 In addition, tissue bio-markers such as PCA3, serum kallikrein and single nucleotide polymorphism panels might have utility as triage tests.32Future researchThe optimal biopsy strategies can only be designed once the urological communitydecides what they hope to detect in termsFigure 3 | A typical TRUS-guided biopsyapproach, showing the 14-core sample sites (pink dots) in the initial biopsy and the 14-core rebiopsy sites (blue dots). A largespherical tumor could just escape detection (dashed circle), even after two biopsies whenthis “random systematic” approach is used.Figure 4 | A potential uniform grid pattern for the 28 cores—biopsy and rebiopsy—distributed throughout the entire prostatevolume. The largest spherical tumor that could just escape detection by the uniform gridpattern (dashed circle) is substantially smaller than that which could escape detection using a TRUS-guided biopsy. The dotted partial circle illustrates the edge effect.PERSPECTIVESof cancer volume and grade and, more importantly given the near universality of prostate cancer in the older man, what it is in terms of tumor volume and grade that we are content for our tests to overlook. Once optimal strategies are in place and refined, the next challenge will focus on the role of triage tests to assist in identifying which man should undergo biopsy, and on exploit-ing the negative predictive value of imaging in order to deploy fewer needles in those who do.Division of Surgery and Interventional Science, 4th Floor, Medical School Building, University College London, 74 Huntley Street, London WC1E 6AU, UK (H. U. Ahmed, M. Emberton). Membrane Studies Project, PO Box 14180, Minneapolis, MN 55414, USA (G. Kepner). MIT Computer Science and Artificial Intelligence Laboratory, The Stata Center, Building 32,32 Vassar Street, Cambridge, MA 02139, USA (J. Kepner).Correspondence to: H. U. Ahmedhashim.ahmed@1. Strope, S. A. & Andriole, G. L. Prostate cancerscreening: current status and futureperspectives. Nat.Rev.Urol.7, 487–493(2010).2. Esserman, L. & Thompson, I. Solving theoverdiagnosis dilemma. J.Natl Cancer Inst.102, 582–583 (2010).3. Onik, G., Miessau, M. & Bostwick, D. G. Three-dimensional prostate mapping biopsy has apotentially significant impact on prostatecancer management. J.Clin.Oncol.27,4321–4326 (2009).4. Taira, A. V. et al. Performance of transperinealtemplate-guided mapping biopsy in detectingprostate cancer in the initial and repeat biopsysetting. Prostate Cancer Prostatic Dis. 13,71–77 (2010).5. Barqawi, A. B. et al. The role of 3-dimensionalmapping biopsy in decision making fortreatment of apparent early stage prostatecancer. J.Urol.186, 80–85 (2011).6. Schröder, F. H. et al. ERSPC Investigators.Screening and prostate-cancer mortality in arandomized European study. N.Engl.J.Med.360, 1320–1328 (2009).7. Hugosson, J. et al. Mortality results from theGöteborg randomised population-basedprostate-cancer screening trial. Lancet Oncol.11, 725–732 (2010).8. Andriole, G. L. et al. REDUCE Study Group.Effect of dutasteride on the risk of prostatecancer. N.Engl.J.Med.362, 1192–1202(2010).9. Heidenreich, A. et al. EAU guidelines onprostate cancer. Part 1: screening, diagnosis,and treatment of clinically localised disease.Eur.Urol.59, 61–71 (2011).10. Brossner, C. et al. Distribution of prostatecarcinoma foci within the peripheral zone:analysis of 8062 prostate biopsy cores. WorldJ.Urol.21, 163–166 (2003).11. Djavan, B. & Margreiter, M. Biopsy standardsfor detection of prostate cancer. World J.Urol.25, 11–17 (2007).12. Kepner, G. & Kepner, J. Transperineal biopsy:analysis of a uniform core sampling patternthat yields data on tumor volume limits innegative biopsies. Theor.Biol.Med.Model.7,23 (2010).13. Wise, A. M., Stamey, T. A., McNeal, J. E. &Clayton, J. L. Morphologic and clinicalsignificance of multifocal prostate cancers inradical prostatectomy specimens. Urology60,264–269 (2002).14. Ahmed, H. U. The index lesion and the origin ofprostate cancer. N.Engl.J.Med.361,1704–1706 (2009).15. Liu, W. et al. Copy number analysis indicatesmonoclonal origin of lethal metastatic prostatecancer. Nat. Med.15, 559–565 (2009).16. Netto, G. Tumor volume threshold ofinsignificant prostate cancer—was Dr. Stameyright all along? J.Urol.185, 10–11 (2011).17. Ploussard, G. et al. The contemporary conceptof significant versus insignificant prostatecancer. Eur.Urol.60, 291–303 (2011).18. Stamey, T. et al. Localized prostate cancer.Relationship of tumor volume to clinicalsignificance for treatment of prostate cancer.Cancer71, 933–938 (1993).19. Karavitakis, M., Ahmed, H. U., Abel, P. D.,Hazell, S. & Winkler, M. H. Tumor focality inprostate cancer: implications for focal therapy.Nat.Rev.Clin.Oncol.8, 48–55 (2011).20. Ahmed, H. U. et al. Characterizing clinicallysignificant prostate cancer using templateprostate mapping biopsy. J.Urol.186, 458–464(2011).21. Bouye, S. et al. Transition zone and anteriorstromal prostate cancers: zone of origin andintraprostatic patterns of spread athistopathology. Prostate69, 105–113 (2009).22. Haffner, J. et al. Peripheral zone prostatecancers: location and intraprostatic patterns ofspread at histopathology. Prostate69,276–282 (2009).23. Delongchamps, N. & Hass, G. Saturationbiopsies for prostate cancer: current usesand future prospects. Nat.Rev.Urol.6,645–652 (2009).24. Patel, A. & Jones, S. Optimal biopsystrategies for the diagnosis and staging ofprostate cancer. Curr.Opin.Urol.19,232–237 (2009).25. Scattoni, V. et al. Biopsy schemes with thefewest cores for detecting 95% of theprostate cancers detected by a 24-corebiopsy. Eur.Urol.57, 1–8 (2010).26. Singh, P., Ahmed, H. U. & Emberton, M. Activesurveillance: Is there a need for better riskstratification at the outset? J.Clin.Oncol.28,e513 (2010).27. Wei, J. Limitations of a contemporary prostatebiopsy: The blind march forward. Urol.Oncol.28, 546–549 (2010).28. Barzell, W. E. & Melamed, M. R. Appropriatepatient selection in the focal treatment ofprostate cancer: the role of transperineal3-dimensional pathologic mapping of theprostate--a 4-year experience. Urology70(Suppl. 6), 27–35 (2007).29. Megwalu, I. I. et al. Evaluation of a novelprecision template-guided biopsy system fordetecting prostate cancer. BJU Int.102,546–550 (2008).30. Ukimura, O., Hung, A. & Gill, I. Innovations inprostate biopsy strategies for activesurveillance and focal therapy. Curr.Opin.Urol.21, 115–120 (2011).31. Ahmed, H. U. et al. Is it time to consider a rolefor MRI before prostate biopsy? Nat.Rev.Clin.Oncol.6, 197–206 (2009).32. Mikolajczyk, S. D., Song, Y., Wong, J. R.,Matson, R. S. & Rittenhouse, H. G. Aremultiple markers the future of prostatecancer diagnostics? Clin.Biochem.37,519–528 (2004).AcknowledgmentsH. U. Ahmed and M. Emberton receive funding fromthe Medical Research Council, National Institute ofHealth Research-Health Technology Assessmentprogramme, Pelican Cancer Foundation, ProstateAction, St Peter’s Trust, Prostate Cancer ResearchFoundation, Prostate Cancer Charity and ProstateCancer Research Centre. Mark Emberton receivesfunding in part from the UK National Institute ofHealth Research UCLH/UCL ComprehensiveBiomedical Research Centre.Author contributionsH. U. Ahmed and G. Kepner researched data for thearticle. All authors contributed to discussion ofcontent, writing the manuscript, and review andediting of the article before submission.PERSPECTIVES。

优质护理在脑梗死患者护理中的应用效果评价

review[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2012,156:186-199.[12] Lubiński J,Lener MR,Marciniak W,et al.Serum essential elements andsurvival after cancer diagnosis[J].Nutrients,2023,15(11):2611.[13] Schenk JM,Till C,Neuhouser M,et al.Differential biopsy patternsinfluence associations between multivitamin use and prostate cancer risk in the selenium and vitamin e cancer prevention trial[J].Cancer Epidemiol Biomarkers Prev,2022,31:2063-2069.[14] Crowe FL,Appleby PN,Travis RC,et al.Endogenous hormones,nutritionalbiomarkers and prostate cancer collaborative group. Circulating fatty acids and prostate cancer risk: Individual participant meta-analysis of prospective studies[J].J Natl Cancer Inst,2014,106(9):dju240.[15] Parra-SS,Ahumada D,Petermann-Rocha F,et al.Association ofmeat,vegetarian,pescatarian and fish-poultry diets with risk of 19 cancer sites and all cancer:findings from the UK Biobank prospective cohort study and meta-analysis[J].BMC Med,2022,20:79.[16] Birney E.Mendelian randomization[J].Cold Spring Harb PerspectMed,2022,12(4):a041302.[17] Davey SG,Hemani G.Mendelian randomization:genetic anchors for causalinference in epidemiological studies[J].Hum Mol Genet,2014,23:89-98.[18] Dong H,Kong X,Wang X,et al.The causal effect of dietary compositionon the risk of breast cancer: A mendelian randomization study[J].Nutrients,2023,15(11):2586.[19] Yan H,Jin X,Zhang C,et al.Associations between diet and incidencerisk of lung cancer: A Mendelian randomization study[J].Front Nutr,2023,10:1149317.[20] Yin L,Yan H,Chen K,et al.Diet-derived circulating antioxidants andrisk of digestive system tumors: A mendelian randomization study[J].Nutrients,2022,14(16):3274.[21] Brasky TM,Darke AK,Song X,et al.Plasma phospholipid fatty acidsand prostate cancer risk in the SELECT trial[J].J Natl Cancer Inst,2013,105:1132-1141.[22] Outzen M,Tj ønneland A,Christensen J,et al.Fish consumption andprostate cancer risk and mortality in a Danish cohort study[J].Eur J Cancer Prev,2018,27:355-360.[23] Fu YQ,Zheng JS,Yang B,et al.Effect of individual omega-3 fatty acids onthe risk of prostate cancer: A systematic review and dose-response meta-analysis of prospective cohort studies[J].J Epidemiol,2015,25:261-274.[24] Burgess S,Swanson SA,Labrecque JA.are mendelian randomizationinvestigations immune from bias due to reverse causation[J].Eur J Epidemiol,2021,36:253-257.[25] Guo JZ,Xiao Q,Gao S,et al.Review of Mendelian Randomization Studieson Ovarian Cancer[J].Front Oncol,2021,11:681396.[2024-01-07收稿]脑血管疾病是指脑血管病变所引起的脑功能障碍。

前列腺癌靶向超声造影剂的研究进展

前列腺癌（PCa ）是男性泌尿生殖系统最常见的恶性肿瘤之一，在西方国家发病率极高，在美国和欧洲的癌症死因中位居第2［1］。

据美国癌症协会统计，2020年新诊断的PCa 患者超过190000人，因PCa 死亡的人数高达3万人以上［2］。

近年来PCa 的发病率在大多数亚洲国家呈上升趋势［3］。

随着我国居民生活习惯的改变，检查技术的提高以及人口进入老龄化，PCa 的发病率也逐年升高，故对于高危群体进行及时干预具有非常重要的意义。

超声分子成像技术使用特定抗体或配体标记成像化合物，生成能够结合特定组织或病变的靶向超声造影剂，静脉给药后，这些分子探针通过血液循环在靶组织中特异性聚集，经超声检查可在分子或细胞水平上对病变区域进行特异性成像。

本文就靶向超声造影技术在PCa 的诊断与治疗方面的研究进展进行综述。

1靶向超声造影剂在PCa 诊断方面的研究进展靶向超声造影剂是将靶向生物标记物添加到分子显像剂中的一种技术，配体被设计成黏附在外壳上的内皮生物标志物［4］。

靶向造影剂将通过配体-受体黏附到靶组织，在微血管中积累。

给药几分钟后进行影像学检查，大部分游离造影剂通过呼吸道排出，靶区的造影剂将会显影，信号强度与生物标志物的表达程度成正比［5］。

目前在超声造影剂中常用的PCa 靶向配体有以下几种。

1.1前列腺素1（STEAP-1）STEAP-1是一种细胞表面蛋白，具有组织特异性，在原发性PCa 细胞中高表达，与细胞之间的通讯有关［6］。

该抗原有339个氨基酸残基，并以蛇形方式折叠成2个Advances in targeted ultrasound contrast agents for prostate cancerWANG Huijie 1,2,HONG Hua 2,LIANG Danyan 21Inner Mongolia Clinical College,Inner Mongolia Medical University,Hohhot 010110,China;2Department of Ultrasound Medicine,People's Hospital of Inner Mongolia Autonomous Region,Hohhot 010017,China摘要：前列腺癌是泌尿系统常见的恶性肿瘤之一，在我国前列腺癌的发病率逐年升高。

RECSIT1[1].1中英文对照全文

New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)新版实体瘤疗效评价标准：修订的RECIST指南（1.1版本）Abstract摘要Background背景介绍Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews.临床上评价肿瘤治疗效果最重要的一点就是对肿瘤负荷变化的评估：瘤体皱缩（目标疗效）和病情恶化在临床试验中都是有意义的判断终点。

Advances in biomarkers for the early diagnosis of prostate cancer

窑Review 窑Prostate cancer(PCa)is a common tumor that poses a significant threat to men's health.Currently,serum prostate specific antigen(PSA)is the most important marker for screening patients for PCa.However,the sensitivity and specificity of PSA in the early detection of PCa are not satisfactory 1,2 ,particularly when PSA falls within the range of410ng/mL.The detection rate of PCa is merely25%,while the rate of negative biopsy was about70%80% 2 .Some studies have demonstrated that negative biopsy results could not completely exclude the possibility of malignant tumors 3 .In addition,not only do inappropriate needle biopsies put patients at risk for prostate complications and increase their mental burden,but also it increases medical cost. Therefore,there is urgent demand for early diagnostic evidence of PCa,so that we can identify significant PCa to the extent possible,reduce the detection of latent and clinically insignificant tumors,and avoid inappropriate clinical treatment.Recently,numerous molecular markers have been reported to be useful for early diagnosis of PCa or prognostic prediction in PCapatients.Tumor biomarkers often signal the existence of tumors before other detection approaches,and thereby contribute to the diagnosis of tumors at early stages.That makes them an effective method to diagnose PCa earlier and is also a critical step in improving prognosis.At present,among studies that are exploring for more specific tumor biomarkers than PSA to improve the early diagnosis capacity of PCa,the most interesting tumor markers are PSA derivatives,hereditary prostate cancer1 (HPC1),prostate cancer antigen3(PCA3),the TMPRSS2:ETS fusion gene,glutathione stransferase π 1(GSTP1), α methylacylCoA racemase(AMACR),Golgi phosphoprotein2 (GOLPH2),early prostate cancer antigen(EPCA),andsarcosine.The PSA gene is located on chromosome19(19q13.41)and encodes a261aminoacid preprotein.When a leader sequence at the end of the amino acid chain is cleaved,it becomes a proenzyme without catalyzing activity(ProPSA).When another 7aminoacid leader sequence is cleaved from the terminal of ProPSA,it becomes a237aminoacid enzyme with catalyzing activity(PSA).There are various forms of PSA in the bloodstream,including free PSA(fPSA)and complex PSA (cPSA).Furthermore,fPSA includes nicked PSA,intact PSA,and ProPSA,while cPSA mostly refers to the PSA binding to琢 1 antichymotrypsin(PSAACT)and less frequently the PSA binding to琢 2 macroglobulin(PSAA2M)and琢 1protease inhibitorAdvances in biomarkers for the early diagnosis ofprostate cancerDaLong Cao 1,2 ,XuDong Yao 1,21 Department of Urology,Cancer Hospital,Fudan University,Shanghai200032,P.R.China;2 Department of Oncology,Shanghai Medical College, Fudan University,Shanghai200032,P.R.China揖Abstract铱Key words:Correspondence to:Xu鄄Dong Yao;Tel:+86013817811836;Email: yaoxudong67@This paper was translated from Chinese into English by Guangzhou Liheng Medical Translation and edited by Hope fferty on 20091030.The Chinese version of this paper is avaiable at /cn/article .asp?id=16207.Received:20090520;Accepted:20090908(PSAAPI).A recent metaanalysis including66studies showed that% fPSA[fPSA/total PSA(tPSA)]and cPSA had better diagnostic capacity than tPSA 4 .However,Bratslavsky . 5 expanded the biopsy scope in their study but failed to reveal any statistically significant difference between the diagnostic capacity of%fPSA, tPSA,and cPSA.The reasons for this may be that fPSA in the bloodstream is unstable,that PSA is not specific to PCa,and that a prostate with a larger volume may dilute tPSA.Benign PSA(BPSA)is formed when the internal peptide bonds between145and146amino acids and between182and 183amino acids are ruptured.It is mainly related to the volume of the transition zone in the prostate.As cleavaged by human kallikrein2(hk2),ProPSAs with leader peptides of2,4,5,and7 amino acids were named[2]ProPSA,[4]ProPSA,[5]ProPSA, and[7]ProPSA,respectively.Sokoll . 6 illuminated the practical value of this change in a confirmative study in the Early Detection Research Network by the United States National Cancer Institute(NCI).When PSA fell within the range of2 ng/mL10ng/mL,the areas under the curve(AUCs)of%[2] ProPSA([2]ProPSA/fPSA),a logistic regression model(with the combination of PSA,BPSA,%fPSA,%[2]ProPSA,[2] ProPSA/BPSA,and testosterone),and%fPSA were0.73,0.73, and0.53,respectively.All these findings indicate that the substantially altered PSA metabolic pathway in the occurrence and development of PCa,as well as relevant PSA mathematical models,may aid in the early recognition of PCa.Currently,the kinetic parameters of PSA,such as PSA velocity(PSAV),PSA doubling time(PSADT),and PSA halflife (PSAHL),are mainly used in monitoring treatment response and disease progression and prognosis 7 .Their significance in the early detection of PCa has yet to be developed.For the time being,serum PSA is still the most important parameter in PCa diagnosis and posttreatment followup.Therefore,it is extremely necessary to further study the metabolic pathway of PSA, relevant mathematical models for PSA,and PSA kinetics and their relationships with other tumor biomarkers,to optimize the early detection ofPCa.Hereditary prostate cancer1(HPC1),an important andsusceptible gene in PCa,is located on chromosome1(1q2425).The RNASEL(25Adependent ribonuclease)gene is located atthe lq25site.RNASEL interferes with the antiviral andantiproliferative activities mediated by the25A pathway,which,alternately,is regulated by interferon.The E265X mutation inRNASEL results in significantly reduced activity of RNASEL.Therefore,based on the linkage and segregation phenomenaidentified between PCa and the deletion mutation(E265X)andthe mutation in the initiation code(M1I)in two families carryingHPC1,RNASEL is considered a candidate allele for HPC1 8 .Inaddition,Rokman . 9 revealed in their study that deletionmutation E265X and missense mutation R462Q in RNASEL wereassociated with an increased risk for PCa.HPC1is probablyinvolved in the initiation of hereditary PCa.Yet,Rennet . 10failed to identify the association between the mutations of theRNASEL gene and PCa risk in Asian(Indian)patients with PCa.Such inconsistency may derive from the heterogeneity ofhereditary factors.Despite all this,the significance of thesestudies is not limited to illustrating the important role of geneticfactors in hereditary PCa;they also provide evidence for revealingthe complicated biologic features of PCa and for exploring newdiagnostic and treatmentstrategies.The DD3PCA3encoding gene is located on chromosome9(9q2122).The gene includes four exons and three introns.InPCa,the most frequent mutation is the selective splicing of thesecond exon.At present,there is a vast body of ongoing studieson PCA3.Hopefully they can further confirm the role of PCA3inthe occurrence and the development of PCa and provide newtreatment targets for patients with PCa.Hessels . 11 suggestedthat using quantitative reverse transcriptase polymerase chainreaction(RTPCR)for the detection of urine DD3PCA3was avaluable molecular detection method in patients with PCa andcould help reduce unnecessary biopsies.In a multicenter studydesigned to examine the diagnostic capacity of urine PCA3detection,the AUC of urine PCA3detection was0.66,while theAUC of serum PCA3detection was merely0.57.The sensitivityand specificity of PCA3detection were65%and66%,respectively 12 .Recently,researchers have suggested that serumPSA level plus PCA3detection was the most promisingdiagnostic method for PCa 13 .All these studies show that PCA3isprobably an important urine marker for PCa.It also provides anew clue for developing noninvasive detection methods for PCa.Hence,PCA3may have considerable significance in multipletumormarker screening of patients for PCa in thefuture.TMPRSS2encodes an androgendependent transmembraneserine protease.The ETS transcription factor regulates thosegenes related to cancerous biologic processes(such as cellgrowth,differentiation,and transformation).Numerous publishedstudies have already revealed the fusion of the TMPRSS2gene(which is located on21q22.3)and the ETS transcription factorfamily(such as ERG[21q22.2],ETV1[7p21.2],ETV4[17q21],and ETV5[3q28])in PCa 14 .The TMPRSS2:ETS fusion geneenables the ETS gene to be activated by the promoter of theTMPRSS2gene,and thus launches the effects of the ETStranscription factor in cancerous biologic processes.The latestresearch also revealed that the TMPRSS2:ETS fusion gene is in50%or more of earlyor middlestage localized PCa andhormoneresistant metastatic PCa,while in highgrade prostaticintraepithelial neoplasia,such gene fusion was rarely seen 15 .Furusato . 16 used RTPCR and found the TMPRSS2:ETSgene fusion in at least one tumor site in30out of45patients.In80tumor sites,39patients presented such gene fusion.Moreimportantly,the sensitivity,specificity,negative predictive value,and positive predictive value of the detection of the TMPRSS2:ETS fusion gene in urine samples were37%,93%,36%,and94%,respectively 17 .This provides evidence for developing andoptimizing urine detection for PCa in the future.Gene fusion isone of the mechanisms that initiates tumor occurrence.It isnecessary to further study the potential value of the TMPRSS2: ETS fusion gene in the early detection,targeted treatment, response evaluation,and prognostic prediction ofPCa.GSTP1is an important multifunctional detoxicating enzyme in the glutathioneStransferase family.By catalyzing the binding of electrophilic carcinogens to glutathione,glutathioneStransferase deactivates the carcinogens.The GSTP1gene methylation can silence this gene and thus disable its expression.Available studies have demonstrated that GSTP1expression was rarely seen in most ing methylationspecific PCR,methylation of the deoxycytidine in the CpG island at the5'terminal of GSTP1could be identified in intraepithelial neoplasia and PCa and in the body fluids of patients with PCa(plasma,serum, semen,and urine),but such methylation was not found in benign prostate epithelial cells 18 .Subsequently,Thompson . 19 used genomic DNA chips to compare seminal vesicles(seminal vesicles share much homogeneity with the prostate,but seminal vesicle tumors are rare),normal prostate tissue,and PCa,and also reported significantly decreased expression of GSTP1in PCa.Recent studies also showed that hypermethylation of GSTP1had statistically significant sensitivity and specificity in distinguishing PCa and benign prostatic hyperplasia 20 .Apparently, GSTP1gene methylation has deprived normal cells of protection by GSTP1and thus made them susceptible to damage by oxidation and electrophilic substances and subsequent malignant transformation.Likewise,cancerous cells may also be susceptible to attack due to the lack of GSTP1protection.Since absent or decreased GSTP1in normal cells may be related to carcinogenesis,but may be also related to better prognosis in cancer cells,the role of GSTP1changes before and after cell carcinogenesis in cancers needs to beclarified.AMACR is an enzyme that is encoded by the P504S gene (which is located on5p13)and contains382amino acids.Its main roles are to participate in the β oxidation in branched chain fatty acids and in the transformation from Risomer to Lisomer in fatty acids.For common prostate adenocarcinoma,the sensitivity of immunohistochemical staining for P504S/AMACR is80% 100% 21 .Particularly when PSA falls within the range of410 ng/mL,increased concentrations of the antiAMACR antibody can become the clue to distinguishing patients with PCa from healthy individuals.Its diagnostic sensitivity and specificity were62%and 72%,respectively 22 .However,the main shortcoming of AMACR as a biomarker for early PCa detection is that AMACR 21,23 is also expressed both in other normal tissue and in malignant tumor tissue.As a result,the specificity of AMACR as a screening approach for PCa will certainly be impaired.It is possible that AMACR is a common molecular basis for cancer occurrence, therefore it may have an important role in revealing common cancerous molecular mechanisms and common anticancertargets.GOLPH2,also known as GOLM1or GP73,is a type II Golgimembrane protein.Studies have demonstrated elevated levels ofGOLPH2mRNA expression in PCa tissue 24 .Since proteins andlipids synthesized in the endoplasmic reticulum will be furtherprocessed,modified,and classified in the Golgi apparatus andthen partially excreted out of the cells and partially transferred intothe cytomembrane and the endosome,changes in the structureand function of the Golgi apparatus may impact the structures,functions,and characteristics of the cells.Wei . 25 usedrealtime RTPCR,Western blot,and tissue microarraytechniques and further confirmed that the expression level ofGOLPH2was elevated in PCa.It was also demonstrated by thesemiquantitative evaluation system for staining intensity that theexpression level of GOLPH2was higher in PCa than in normaltissue( <0.001).The GOLPH2expression level was upregulated in567out of614tumor tissue specimens;elevatedGOLPH2expression was seen in26out of31AMACRnegativePCa specimens 26 .These findings suggest that changes in thestructures and functions of subcellular structure(Golgi apparatus,nucleus,mitochondria,and so forth)may also have an importantrole in the occurrence ofcancer.EPCA is a nuclear matrix ingimmunohistochemical staining,the staining intensity of EPCA wassignificantly different between patients with PCa and controls( <0.001),with sensitivity and specificity of84%and85%,respectively.It was also found that men with negative results onpathology but positive results for antiEPCA antibody staining inbiopsy tissue would be diagnosed with PCa within or after5years 27 .Fundamental research showed that some nuclear matrix proteinscould be seen in all types of cells and physiologic status andothers are tissuespecific or vary with cell status.In various cells,different nuclear matrix proteins maintain diverse cell nuclearshape,function,and elements.Changes in nuclear matrixproteins may be an early event in tumor occurrence.Paul . 28used ELISA(with a prespecified absorbance threshold of1.7at540nm)to compare study subjects,including patients with PCa,other tumors,or spinal cord injury,and healthy individuals,andfound that only those with PCa had serum EPCA levels above thethreshold.The EPCA level was significantly different betweenpatients with PCa and other groups,particularly healthyindividuals( <0.001),patients with bladder cancer( <0.003),and patients with spinal cord injury( <0.001),with thesensitivity and specificity of EPCA detection for PCa at92%and94%,respectively.An recent study suggested that the sensitivityand specificity of serum EPCA2in recognizing PCa were94%and92%,respectively.Moreover,it could distinguish localizedand metastatic PCa(AUC=0.89,95%CI0.820.97; <0.001) 29 .EPCA probably precedes microscopic pathologic changes and isthus a potential tumor marker that can actually detect early signsof cancer.Hence,further investigation is needed to reveal its rolein disease development and thereby provide evidence fordesigning highly sensitive and specific PCa screening methods inthefuture.In2009,Sreekumar . 30 reported the value of sarcosine inPCa.In an independent subset containing89tissue specimens,the sarcosine level was significantly elevated in localized PCa as compared to adjacent benign prostate specimens.When compared to localized PCa,the sarcosine level in metastatic specimens was even higher.When compared to a control group with negative biopsy results,the sarcosine level was significantly higher in urine sediments and urine supernatants obtained from patients with positive biopsy.The sarcosine level was markedly increased in PCa cell lines as compared to benign cell lines. Since a large number of current studies are exploring changes in genetic and protein profiles of tumors,changes in the metabolic profiles of tumors is poorly understood.Highlighting the metabolic features of tumors may help us understand tumors in a more comprehensive way and discover new diagnostic strategies and treatment targets for tumors.Therefore,this study is valuable in that it provides new directions for futurestudies.Currently,studies regarding prostatespecific membrane antigen(PSMA)are mainly focusing on investigating the value of PSMA as a treatment target by using antiPSMA dendritic cells and antiPSMA antibodies carrying radioactive isotopes or toxins, while studies with prostate stem cell antigen(PSCA)are mainly concentrating on the correlations between PSCA and the risk factors,high Gleason scores,later stage,frequent metastasis, and treatment targets of PCa.Whether they can become diagnostic or treatment tools has yet to be explored.Other tumor markers of interest include kallikreinrelated peptidase2(KLK2), urokinase plasminogen activator and receptor(uPA and uPAR), Hepsin,Annexin A3(ANAXA3),insulinlike growth factors and binding proteins(IGFs and IGFBPs),transforming growth factor 茁 1(TGF茁 1),enhancer of zeste homolog2(EZH2),prostate secretory protein94(PSP94),and cysteinerich secretory protein 3(CRISP3) 31.Environmental factors,genetic factors,or the interactionbetween the two initiate the molecular mechanisms underlyingPCa occurrence and development.So far,numerous moleculesrelated to PCa have been found,,which might derive fromdifferent stages and different molecular pathways in PCaoccurrence and development.This explains why the combinationof multiple tumor markers may improve the accuracy of PCadiagnosis.Hessels . 17 demonstrated in their study that theconcomitant detection of urine TMPRSS2:ERG fusion gene andPCA3could improve the sensitivity in diagnosing bineddetections of GOLPH2,serine peptidase inhibitor,Kazal type1(SPINK1),PCA3,and TMPRSS2:ERG fusion gene transcript inurine sediments was also better at identifying PCa than detectingPSA or PCA3alone 32 .Vener . 33 used quantitative methylationspecific PCR to measure urine GSTP1,retinoic acid receptorbeta(RARB),and adenomatous polyposis coli(APC)as earlydetectors for PCa.They reported that the sensitivity,specificity,and AUC of the combined detections of these three markers inthe first group of121patients were55%,80%,and0.69,respectively,and in the second group of113patients,thesensitivity,specificity,and AU C were53%,76%,and0.65,respectively.Schostak . 34 also reported that PSA plus urineAnnexin A3(ANAXA3)detection was better than the detection ofeither parameter alone.AUC was0.82when tPSA fell within therange of26ng/mL and was0.83when tPSA was410ng/mL.For all patients,AUC was0.81.In addition,they also foundexcellent detection capacity for the combination in the subgroupsof patients with negative results on digital rectal exam(DRE)andlow tPSA levels.Apparently,the combination of multiple tumormarkers can significantly improve diagnostic accuracy,representing an important future direction in the screening ofpatients forPCa.The studies mentioned above explored the screening of PCaon different levels(metabolic pathway,genetic,transcriptional,protein,subcellular,and metabolic),but the clinical value of thetumor biomarkers selected in these studies has not been fullyconfirmed yet,so multicenter and largescale studies areneeded.With the progress in high throughput techniques includingPCR,gene microarray,protein microarray,and the combinationof chromatogram/mass spectrogram,our ability to detect tumorbiomarkers has been greatly improved.If we can achieve thedetection of multiple tumor markers in urine to screen patients forPCa in the future,we will enjoy the convenience in just one singlesample while both reducing detection costs and avoiding thedamage from invasive procedures for patients.Negative markers(those with absent or decreased expressionin tumor tissue)may improve the specificity of detection.Thecombination of positive(those with increased expression in tumortissue)and negative markers may help optimize the multipletumormarker screening of PCa in the future.However,theproblem with the combination of multiple tumor markers is that,with a parallel combination of multiple tumor markers,thesensitivity will definitely be impaired,and when they are combinedserially,the specificity will be decreased.Therefore,in futurestudies on tumor screening and early detection,it is veryimportant to optimize a group of tumor markers with highsensitivity and specificity and to establish a perfectly sensitiveand specific detection model that can effectively integrate(ratherthan simple parallel or serial combinations)selected tumormarkers.At present,a number of studies are still centering on thechanges in one gene or one protein.However,tumor occurrenceand development is a dynamic and interrelated process.It istherefore extremely significant to establish genomic,transcriptomic,proteomic,metabonomic,and subcellular(Golgiapparatus,mitochondria,nucleus,ribosome,and so forth)information that covers the dynamic transformation from normalto abnormal cells on genetic,transcriptional,protein,metabolic,and subcellular levels.Since those information take intoconsideration the relationships among the various componentsand the interactions between the various components and cellsand are capable of revealing relevant biologic networks and咱员暂咱圆暂咱猿暂咱源暂咱缘暂咱远暂咱苑暂咱愿暂咱怨暂咱员园暂咱员员暂咱员圆暂咱员 3暂 relationships between abnormal expression and abnormal function,they will definitely be helpful in fully understanding the complicated biologic features of PCa and in establishing and optimizing the multiple tumormarker screening models for PCa.So far,most studies have selected patients with highrisk PCa as rated by existing clinical standards.Therefore,the sensitivity and specificity of tumor markers for screening the general population may be impacted and those tumor markers that can actually recognize early signs of cancer are probably neglected. On the other hand,the gold standard for diagnosis of PCa in existing clinical settings is that cancerous cells have been detected in the tissue samples,which may lag behind the progress in tumor ing this criteria in future studies may thus decrease the sensitivity of some tumor markers. Hence,study methods need to be further optimized.Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostatecancer among men with a prostate鄄 specific antigen level < or =4.0 ng per milliliter [J]. N Engl J Med, 2004, 350(22):2239-2246.Stamey TA, Johnstone IM, McNeal JE, et al. Preoperative serum prostatespecific antigen levels between 2 and 22ng/mL correlate poorly with post鄄 radical prostatectomy cancer morphology: prostate specific antigen curerates appear constant between 2 and 9 ng/mL [J]. J Urol, 2002,167(1):103-111.Scattoni V, Zlotta A, Montironi R, et al. Extended and saturation prostaticbiopsy in the diagnosis and characterisation of prostate cancer: a criticalanalysis of the literature [J]. Eur Urol, 2007,52(5):1309-1322.Roddam AW, Duffy MJ, Hamdy FC, et al. Use of prostate鄄 specific antigen(PSA) isoforms for the detection of prostate cancer in men with a PSAlevel of 2-10 ng/mL: systematic review and meta鄄 analysis [J]. Eur Urol, 2005,48(3):386-399.Bratslavsky G, Fisher HA, Kaufman RP Jr, et al. PSA鄄 related markers inthe detection of prostate cancer and high鄄 grade disease in thecontemporary era with extended biopsy [J]. Urol Oncol, 2008,26(2):166- 170.Sokoll LJ, Wang Y, Feng Z, et al. [-2]proenzyme prostate specificantigen for prostate cancer detection: a national cancer institute early detection research network validation study [J]. J Urol, 2008,180(2):539-543.Fitzpatrick JM, Banu E, Oudard S. Prostate鄄 specific antigen kinetics inlocalized and advanced prostate cancer [J]. BJU Int, 2009,103(5):578-587.Carpten J, Nupponen N, Isaacs S, et al. Germline mutations in theribonuclease L gene in families showing linkage with HPC1 [J]. NatGenet, 2002,30(2):181-184.Rokman A, Ikonen T, Seppala EH, et al. Germline alterations of theRNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer [J]. Am J Hum Genet, 2002,70(5):1299-1304.Rennert H, Zeigler鄄 Johnson C, Mittal RD, et al. Analysis of the RNASEL/HPC1, and macrophage scavenger receptor 1 in Asian鄄 Indian advanced prostate cancer [J]. Urology, 2008,72(2):456-460.Hessels D, Gunnewiek JM, van Oort I, et al. DD3PCA3鄄 based molecularurine analysis for the diagnosis of prostate cancer [J]. Eur Urol, 2003,44 (1):8-15.van Gils MP, Hessels D, van Hooij O, et al. The time鄄resolved fluorescence鄄 based PCA3 test on urinary sediments after digital rectalexamination; a Dutch multicenter validation of the diagnostic performance [J]. Clin Cancer Res, 2007,13(3):939-943.Neves AF, Ara俨 jo TG, Biase WK, et al. Combined analysis of multiplemRNA markers by RT鄄 PCR assay for prostate cancer diagnosis [J]. ClinBiochem, 2008,41(14-15):1191-1198.Yoshimoto M, Joshua AM, Cunha IW, et al. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome [J]. Mod Pathol, 2008,21(12):1451-1460.Mehra R, Tomlins SA, Yu J, et al. Characterization of TMPRSS2鄄 ETS gene aberrations in androgen鄄 independent metastatic prostate cancer [J]. Cancer Res, 2008,68(10):3584-3590.Furusato B, Gao CL, Ravindranath L, et al. Mapping of TMPRSS2鄄 ERG fusions in the context of multi鄄 focal prostate cancer [J]. Mod Pathol, 2008,21(2):67-75.Hessels D, Smit FP, Verhaegh GW, et al. Detection of TMPRSS2鄄 ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer [J]. Clin Cancer Res, 2007,13(17): 5103-5108.Meiers I, Shanks JH,Bostwick DG. Glutathione S鄄 transferase pi (GSTP1) hypermethylation in prostate cancer: review 2007 [J]. Pathology, 2007,39 (3):299-304.Thompson M, Lapointe J, Choi YL, et al. Identification of candidate prostate cancer genes through comparative expression鄄 profiling of seminal vesicle [J]. Prostate, 2008,68(11):1248-1256.Ellinger J, Bastian PJ, Jurgan T, et al. CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer [J]. Urology, 2008,71(1):161-167.Luo J, Zha S, Gage WR, et al. Alpha鄄 methylacyl鄄 CoA racemase: a new molecular marker for prostate cancer [J]. Cancer Res, 2002,62(8):2220- 2226.Sreekumar A, Laxman B, Rhodes DR, et al. Humoral immune response to alpha鄄 methylacyl鄄 CoA racemase and prostate cancer [J]. J Natl Cancer Inst, 2004,96(11):834-843.Jiang Z, Fanger GR, Woda BA, et al. Expression of alpha methylacyl鄄 CoA racemase (P504S) in various malignant neoplasms and normal tissues: a study of 761 cases [J]. Hum Pathol, 2003, 34(8):792-796.Kristiansen G, Pilarsky C, Wissmann C, et al. Expression profiling of microdissected matched prostate cancer samples reveals CD166/MEMD and CD24 as new prognostic markers for patient survival [J]. J Pathol, 2005, 205(3): 359-376.Wei SZ, Dunn TA, Isaacs WB, et al. GOLPH2 and MYO6: putative prostate cancer markers localized to the Golgi apparatus [J]. Prostate, 2008, 68(13):1387-1395.Kristiansen G, Fritzsche FR, Wassermann K, et al. GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue鄄based diagnostics [J]. Br J Cancer, 2008, 99(6):939-948. Dhir R, Vietmeier B, Arlotti J, et al. Early identification of individuals with prostate cancer in negative biopsies [J]. J Urol, 2004,171(4):1419-1423. Paul B, Dhir R, Landsittel D, et al. Detection of prostate cancer with a blood鄄 based assay for early prostate cancer antigen [J]. Cancer Res, 2005,65(10):4097-4100.Leman ES, Cannon GW, Trock BJ, et al. EPCA鄄 2: A highly specific serum marker for prostate cancer [J]. Urology, 2007,69(4):714-720.Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression [J]. Nature, 2009, 457(7231): 910-914.Sardana G,Dowell B, Diamandis EP. Emerging biomarkers for the diagnosis and prognosis of prostate cancer [J]. Clin Chem, 2008, 54(12): 1951-1960.Laxman B, Morris DS, Yu J, et al. A first generation multiplex biomarker analysis of urine for the early detection of prostate cancer [J]. Cancer Res, 2008,68(3):645-649.Vener T, Derecho C, Baden J, et al. Development of a multiplexed urine assay for prostate cancer diagnosis [J]. Clin Chem, 2008,54(5):874-882. Schostak M, Schwall GP, Poznanovic S, et al. Annexin A3 in urine: a highly specific noninvasive marker for prostate cancer early detection [J]. J Urol, 2009,181(1):343-353.咱14暂咱15暂咱16暂咱17暂咱18暂咱19暂咱20暂咱21暂咱22暂咱23暂咱24暂咱25暂咱26暂咱27暂咱28暂咱29暂咱30暂咱31暂咱32暂咱33暂咱34暂。

脑卒中患者血清VILIP-1、PRDX1、Pannexin1表达水平及其与预后的关系

脑卒中患者血清VILIP-1、PRDX1、Pannexin1表达水平及其与预后的关系郝井志1，王瑞2，刘晓琳2延安大学咸阳医院脑血管病研究所1、检验科2，陕西咸阳721000【摘要】目的探讨脑卒中患者血清视锥蛋白样蛋白-1(VILIP -1)、过氧化还原蛋白1(PRDX1)、泛连接蛋白1(Pannexin1)的表达水平对预后的影响。

方法选取2020年1月至2022年3月延安大学咸阳医院脑血管病研究所诊治的110例脑卒中患者作为观察组，并选择同期我院120例身体健康的体检者作为对照组，比较观察组与对照组，观察组不同病情、不同预后患者的血清VILIP -1、PRDX1、Pannexin1水平，并采用多因素Logistic 回归分析影响脑卒中患者预后的危险因素。

结果观察组患者的VILIP -1、PRDX1、Pannexin1水平分别为(9.17±1.18)ng/mL 、(9.30±1.83)ng/mL 、(5.37±0.80)mg/mL ，明显高于对照组的(3.10±0.60)ng/mL 、(3.66±0.78)ng/mL 、(2.02±0.61)mg/mL ，差异均有统计学意义(P <0.05)；随着脑卒中患者病情的严重程度加重，血清VILIP -1、PRDX1、Pannexin1表达水平均逐渐升高，其中重度组明显高于中度和轻度组，中度组明显高于轻度组，差异均有统计学意义(P <0.05)；预后良好组患者的VILIP -1、PRDX1、Pannexin1水平分别为(4.69±0.81)ng/mL 、(7.46±1.68)ng/mL 、(4.95±1.13)mg/mL ，明显低于预后不良组的(7.98±1.25)ng/mL 、(12.01±1.93)ng/mL 、(6.14±1.29)mg/mL ，差异均有统计学意义(P <0.05)；预后良好组患者的高血压、糖尿病、冠心病、高同型半胱氨酸、高脂血症、吸烟、酗酒的发生率明显低于预后不良组，差异均有统计学意义(P <0.05)；经多因素Logistic 回归性分析结果显示，血清VILIP -1、PRDX1、Pannexin1均是影响脑卒中患者预后的危险因素(P <0.05)。

前列腺癌相关生物标志物的研究进展

㊃综述㊃前列腺癌相关生物标志物的研究进展周朴帆1,6,沈瑞林2,熊烈1,6,盛涛3,宋保林3,王省白4,陆海娟5,黄涛3,史汉强1,6,邵欢3,赫艳梅3,王晓庭3,江大为3,石彦波1,6∗(浙江中医药大学附属嘉兴中医院:1分子医学研究中心中心实验室,3泌尿外科,4放射科,5超声科,浙江嘉兴314001;2嘉兴市第二医院泌尿外科,浙江嘉兴314001;6嘉兴市糖尿病血管病变研究重点实验室,浙江嘉兴314001)ʌ摘㊀要ɔ㊀前列腺癌作为男性最为常见的癌症之一,严重威胁着男性的健康安全㊂前列腺癌在预测㊁诊断㊁预后方面都面临着诸多挑战㊂虽然用于指导前列腺癌的各种生物标志物具有一定的临床意义,但在单独使用时仍然显现出各自的局限性㊂精确诊断㊁防止过度活检㊁生物标志物联合诊断体系构建等仍然是当今前列腺癌检测的研究热点㊂本文分析了前列腺癌在检测中所面临的问题,并就临床上常用的前列腺癌生物标志物及其相关检测体系的研究进展进行综述㊂ʌ关键词ɔ㊀前列腺癌;生物标志物;诊断ʌ中图分类号ɔ㊀R737.25㊀㊀㊀㊀ʌ文献标志码ɔ㊀A㊀㊀㊀㊀ʌDOI ɔ㊀10.11915/j.issn.1671-5403.2021.01.016收稿日期:2020-01-11;接受日期:2020-02-20基金项目:浙江省基础公益研究计划项目(LGF18H200004);嘉兴市科技计划项目(2017BY18041)通信作者:石彦波,E-mail:shiyanbocas@Research progress in biologic markers for prostate cancerZHOU Pu-Fan 1,6,SHEN Rui-Lin 2,XIONG Lie 1,6,SHENG Tao 3,SONG Bao-Lin 3,WANG Xing-Bai 4,LU Hai-Juan 5,HUANG Tao 3,SHI Han-Qiang 1,6,SHAO Huan 3,HE Yan-Mei 3,WANG Xiao-Ting 3,JIANG Da-Wei 3,SHI Yan-Bo 1,6∗(1Central Laboratory of Molecular Medicine Research Center,3Department of Urology Surgery,4Department of Radiology,5Department of Ultrasound,Jiaxing Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medicial University,Jiaxing 314001,Zhe-jiang Province,China;2Department of Urology Surgery,Jiaxing Second Hospital,Jiaxing 314001,Zhejiang Province,China;6Jiaxing Key Laboratory of Diabetic Angiopathy,Jiaxing 314001,Zhejiang Province,China)ʌAbstract ɔ㊀As one of the most common cancers in men,prostate cancer seriously threatens their health and safety.There are many challenges of prostate cancer in prediction,diagnosis and prognosis.Although biomarkers for the prostate cancer have shown certain clinic significance,they still have limitations when used alone.Accurate diagnosis,prevention of excessive biopsies,and construction of a diagnostic system of combined biomarkers are still trending research topics in the detection of prostate cancer.Here we analyze the cha-llenges in the detection of prostate cancer and review the research progress in biomarkers and related detection systems of prostate cancer.ʌKey words ɔ㊀prostate cancer;biomarker;diagnosisThis work was supported by Basic Public Welfare Research Project of Zhejiang Provincie (LGF18H200004)and Jiaxing Science and Technology Projects (2017BY18041).Corresponding author :SHI Yan-Bo ,E-mail :shiyanbocas@㊀㊀前列腺癌(prostate cancer,PCa)是男性最为常见的癌症之一,严重威胁男性的生命健康㊂美国癌症协会的统计数据显示,PCa 已经成为导致美国男性癌症死亡的第二大病因[1]㊂中国PCa 的发病率在近几年呈现出快速上升的趋势,2015年,中国PCa 发病率在中国男性恶性肿瘤中排第7位,死亡率排第10位[2]㊂中国PCa 的发病率逐年升高的主要原因在于对PCa 的诊断评价体系不断完善以及中国社会逐渐步入老龄化这两方面㊂国内外统计数据均显示中老年群体是PCa 的高发人群[3],不断上升的发病率使PCa 的研究越来越受到关注㊂PCa 若早期诊断治疗,Ⅰ期患者5年的生存率可达到90%以上,但转移性PCa 患者5年生存率仅为10%~15%㊂因此,进行高危人群筛查,做到早诊断早治疗对于提高患者生存率至关重要㊂目前对于PCa 的检测依赖于相关的生物标志物,血清前列腺特异性抗原(prostate specific antigen,PSA)的检测仍然是诊断和评估PCa最常用的指标,但血清PSA的敏感性和特异性在PCa的诊断㊁预后评估方面一直存在争议,临床上至今缺少准确的PSA 阈值来界定PCa与其他病变㊂在过去的10年中,寻找准确高效的生物标志物,一直是PCa的重要研究内容,目前临床上所用到的生物标志物几乎涵盖了PCa预测到预后所有阶段㊂这些标志物种类多样,包括DNA及表观遗传变化(DNA甲基化)㊁mRNA的变化以及单个或多个蛋白质水平的变化等[4],其来源也涵盖了前列腺组织㊁尿液㊁外周血液以及精液等多种样本㊂本文旨在总结PCa相关的经典生物标志物,为临床PCa的有效诊断和治疗提供理论依据㊂1㊀PSA㊀㊀PSA是由前列腺上皮细胞和前列腺腺泡所分泌的丝氨酸蛋白酶,是目前公认的最重要的PCa 标志物之一㊂当发生PCa或其他前列腺疾病时,基底层㊁内皮细胞以及基底膜构成的屏障遭到破坏,使得腺泡内容物外流,PSA水平升高[5]㊂PSA 高敏感性的特点能够使其满足PCa的早期筛查需求,但由于PSA具有前列腺组织特异性而非肿瘤组织特异性,因此前列腺炎㊁尿路感染甚至前列腺按摩等相关检测皆会导致PSA水平的升高㊂据报道,当单独使用4.0ng/ml的血清PSA作为检测标准时,PSA的特异性仅为12.8%,其假阳性率高,并会导致大量不必要的连续活检[6]㊂为了提高PSA标志物的准确性,临床上出现了游离PSA比值㊁PSA前列腺体积比值㊁移行带前列腺特异性抗原密度以及PSA速率等相关衍生指标,但这些方法仍然存在诸多局限性,临床诊断价值有限㊂为进一步弥补PSA及相关指标的上述缺点,临床上还会将PSA与其异构体㊁PCa相关的mRNA㊁DNA等其他生物标志物联合使用,这其中常用的诊断体系有前列腺健康指数(prostate health index,PHI)[7]㊁4Kscore[8]㊁密歇根前列腺评分(Michigan prostate score,MiPS)[9]等㊂这些体系都具有更大的受试者工作特征(receiver operating characteristic,ROC)曲线下面积(area under curve,AUC),表现出更高的鉴别能力㊂2㊀前列腺特异性抗原前体㊀㊀前列腺特异性抗原前体(precursor of prostate specific antigen,Pro-PSA)又称[-7]Pro-PSA,由N 端7个氨基的前导肽和237个氨基酸构成[10],其被人激肽酶家族及其他蛋白酶裂解后产生3种不同截断形式的PSA前体:[-5]㊁[-4]㊁[-2] Pro-PSA,其中[-5]和[-4]Pro-PSA不稳定,会被进一步裂解为有活性的PSA[10],而[-2]Pro-PSA 不会被进一步裂解并稳定存在于人体内,其可以作为一种更加特异性的标志物用于PCa的诊断㊂目前研究中常将[-2]Pro-PSA与fPSA的比值(%p2PSA),以及%p2PSA与tPSA平方根的乘积(PHI)作为p2PSA的衍生指标㊂Vukovic等[11]研究发现,在PSA 为2~10ng/ml的水平时,通过统计对照人群与PCa 人群的生物标志物后,PHI,%p2PSA的AUC均高于tPSA,分别为(0.680,0.723,0.563),当维持90%的敏感度时,其特异度分别为26.6%,34.4%,9.2%㊂而在统计Gleason<7和Gleasonȡ7人群后PHI,%p2PSA 的AUC也高于tPSA,分别为(0.645,0.673,0.538),当维持92%的敏感度时,其特异度分别为22.5%, 20%,10%,这些结果说明[-2]Pro PSA的相关指标相比于PSA不仅在筛查过程中具有更高的诊断意义,且能减少不必要的组织活检,在PCa分型过程中也有其临床价值,辅助医师判断癌症进展进程㊂3㊀前列腺癌抗原3㊀㊀前列腺癌抗原3(prostate cancer antigen3,PCA3),是PCa细胞过度表达的一段基因[12],该基因对PCa特异,在其他正常或癌症组织中低表达㊂该生物标志物来源于PCa细胞,因此可以通过尿液㊁精液㊁前列腺液甚至血液进行标本收集㊂目前临床上PCA3常用检测为直肠指诊后PCA3评分,即PCA3与PSA mRNA比值,PCA3评分在临床上能够辅助PSA检测,提高诊断准确性,减少不必要的穿刺活检,其被美国食品药品监督管理局批准用于既往活检呈阴性且无非典型小腺泡增生的疑似患者,帮助临床医师在25阈值条件下判断是否再次进行活检[13]㊂但是与大多数其他PCa检测指标一样,单独的PCA3评分仍然有其局限性,在Gittelman 等[14]对466例患者重复活检的研究中,25阈值的PCA3评分能够正确防止48%的疑似患者重复活检,但仍会导致8例高级别的癌症患者漏检㊂因此临床上还会采用包含PCa相关的联合诊断体系来提高效能,如血清中PSA蛋白含量和尿液中PCA3㊁TMPRSS2:ERG融合基因水平联合诊断的MiPS,以及尿液中ERG㊁PCA3㊁SPDEF基因联合诊断的ExoDx评价体系等㊂4㊀跨膜丝氨酸蛋白酶2基因:ETS相关基因㊀㊀2005年,Tomlins等[15]通过荧光原位杂交法发现跨膜丝氨酸蛋白酶2(transmembrane protease, serine2,TMPRSS2)基因与ETS相关基因(ETS releated gene,ERG)发生融合,并且这种融合在PCa过程中频繁发生㊂有多篇文献报道AR与TMPRSS2: ERG融合的发生密切相关,其通过核苷酸中CAG的重复多态促进了TMPRSS2与ERG的融合[16,17]㊂TMPRSS2:ERG指标对于PCa特异,在正常和其他癌症细胞均不表达[18],但是TMPRSS2:ERG发生率还受到人种影响,目前研究认为西方PCa患者中约50%表现出TMPRSS2:ERG融合,但在亚洲人群中,中国㊁日本和韩国则都表现出较低的发生率[19],孙颖浩课题组[20]通过meta分析进一步发现27%的亚洲患者TMPRSS2:ERG融合呈阳性,约为西方人群的一半,而亚洲印度雅利安血统人种融合阳性率为52%,这更加证明TMPRSS2:ERG融合具有种族差异性㊂有研究发现,TMPRSS2:ERG融合基因可以与PCa评分联合使用,从而提高诊断效能,Leyten等[21]发现在欧洲前列腺筛查的随机研究中加入TMPRSS2: ERG和PCa评分体系能够提高癌症预测的准确性, PCA3<25和TMPRSS2:ERG<10的联合阈值可以避免35%的错误活检㊂Tomlins等[22]又在此基础上加入了包含血清PSA指标的前列腺癌预防试验风险计算器(prostate cancer prevention trial risk calculator, PCPTrc),并将其命名为密歇根前列腺评分㊂MiPS 和PCPTrc在高水平PCa中的AUC分别为0.779和0.707,这说明MiPS在任何高水平PCa中都能表现出更高的预测准确性㊂5㊀早期前列腺癌抗原㊀㊀早期前列腺癌抗原(early prostate cancer anti-gen,EPCA)是一种与PCa密切相关的核基质蛋白,决定着细胞的形状和结构,在癌变过程中产生有别于正常前列腺细胞的一系列特征性差异㊂2005年, Paul等[23]用ELISA法对46例PCa患者的血清EP-CA进行了测定分析,并发现其水平远高于正常人㊂当设定阈值为1.7后,这种检测指标的灵敏度能够达到92%㊂在血清中还存在另一种核基质蛋白称为EPCA-2,根据表位不同可将其分为EPCA-2.22, EPCA-2.19,EPCA-2.2434㊂Wang等[24]对632例人员进行研究并比较了PSA和EPCA-2的诊断效能,当选择24.4ng/ml作为血清EPCA-2的阈值, 4ng/ml作为血清PSA的阈值时,其灵敏度分别为86.2%和81.9%,差异无统计学意义(P>0.05),特异度为58.3%和87.6%,差异有统计学意义(P< 0.01)[24]㊂这说明EPCA-2相较于PSA能够更精确地从人群中筛选出PCa患者,其作为一种PCa筛查用生物标志物具有一定的潜力㊂6㊀非编码RNA㊀㊀非编码RNAs(non-coding RNAs,ncRNAs)是一类无法编码翻译蛋白质的RNA,根据长度可分为长ncRNAs㊁小ncRNAs㊂有些ncRNAs的表达会在PCa 的发生发展过程中发生改变,这些ncRNAs与PCa 高度相关,使得其特异性能够满足临床诊断需要㊂而相较于mRNA,ncRNA的含量更多,使得其敏感性能够满足临床诊断的需求㊂6.1㊀长链非编码RNA㊀㊀通常将大于200个核苷酸的非编码RNA定义为长链非编码RNA(long non-coding RNA,lncRNA)㊂有研究发现,PCAT1作为一段lncRNA,在PCa组织中高度表达,其通过与cMYc蛋白结合促进PCa细胞增殖[25]㊂此外其通过抑制抑癌基因BCAR2的功能来阻碍DNA的修复[26]㊂PCAT1与PCA3同属于PCa相关的lncRNA,但是PCA3在几乎所有的原发PCa中高表达,而在去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC)和转移病灶中表达程度较低㊂PCAT1则在预后评价方面比PCA3更具有临床价值[27]㊂SChLAP1能够在25%的PCa中表达,其表达更多见于CRPC,且与癌症复发㊁临床进展㊁转移和PCa 特异性死亡的风险显著相关[28]㊂Wang等[29]发现lncRNA SChLAP1在PCa患者中的水平明显要高于良性前列腺增生患者㊂将SChLAP1作为侵袭性和进展性PCa的标志物用于识别CRPC进展风险较高的PCa的患者具有独特的优势㊂肺腺癌转移相关转录因子MALAT-1在PCa活检阳性尿液中的表达量显著高于活检阴性患者[30]㊂但其并非对PCa特异,其能够在乳腺癌㊁胰腺癌和结肠癌等多种癌症中高度表达[31],Wang等[30]使用最近发展起来的尿液MALAT1评分模型可以防止约1/3的不必要活检,并且不会遗漏任何高级别癌症㊂6.2㊀小非编码RNA㊀㊀microRNA是一类长度在21~24bp的单链非编码RNA,由于其在发育和疾病过程具有基因调控功能而被广泛研究㊂let-7会在PCa组织中表达下降[32],其不仅能作为预测PCa的生物标志物,也能作为治疗PCa的重要基因靶点㊂let-7家族中的let-7c在体内和体外都抑制了PCa的生长㊂过表达let-7c可抑制PCa细胞的锚定依赖生长和锚定无关生长,而使用慢病毒编码的let-7c在人PCa细胞异种移植中重新表达,可显著抑制肿瘤生长[33]㊂miR-25低表达于人类PCa干细胞,但在癌干细胞分化为腔上皮细胞表型的过程中,miR-25表达量稳步上升㊂进一步研究发现miR-25能够调控整合素的表达,从而减少PCa细胞的迁移,并强烈影响PCa细胞的形态[34],其作为生物标志物对于PCa的进展和分级具有一定的参考作用㊂miR-21在PCa的骨转移过程中起到一定的评估作用,有文献报道miR-15和miR-16的下调以及miR-21的上调能够共同促进PCa的骨转移[35]㊂miR-21能够作为PCa预测生物标志物,用于分子靶向制剂和骨转移治疗药物的疗效评估㊂非编码RNA作为一种与PCa高度相关的生物标志物对于疾病的发展和预后密切相关,单独RNA指标的临床价值仍然有限㊂目前常通过多个RNA指标的联合检测来揭示PCa的预后,如Oncotype Dx Genomic Prostate Score ㊁Prolaris ㊁Decipher 等㊂7㊀DNA甲基化㊀㊀DNA甲基化是指甲基基团结合CpG二核苷酸的胞嘧啶第5位碳原子上的过程,其常常导致抑癌㊁修复㊁细胞周期调控等基因表达沉默,是促进PCa发生的重要因素之一㊂启动子GSTP1是一种损伤修复基因,其在超过90%的PCa中均发生甲基化㊂Dumache等[36]将GSTP1甲基化指标用于判断PCa,其灵敏度和特异度分别达到了97%和89%,GSTP1的AUC则达到了0.936㊂其作为PCa的检测指标具有很高的临床应用价值㊂PCa相关的肿瘤抑制基因APC甲基化有助于临床诊断和预后的判断,有研究报道,APC的甲基化与PCa特异性死亡率的增加有关[37],当PCa患者基因中APC发生甲基化,其死亡率会高于未甲基化患者㊂RASSF1同样属于肿瘤抑制基因,其甲基化会使细胞恶性转化㊂该基因的甲基化并非对PCa特异,在乳腺㊁肺㊁膀胱等器官组织的癌症中均能看到RASSF1的甲基化㊂Daniunaite等[38]的研究中, RASSF1甲基化指标对于PCa的特异度为66.7%,但是45%的PCa尿液样本甲基化强度明显高于良性前列腺增生病例(P=0.018)㊂临床研究中常将GSTP1㊁APC㊁RASSF1等其他甲基化DNA指标联用,这种评价体系称为ConfirmMDx,其用于研究前列腺恶性肿瘤周围的病变表观遗传改变[39](及晕轮效应)㊂这种方法适用于首次前列腺组织活检阴性病例㊂由于较高的阴性预测值, ConfirmMDx可用于判断有无再次活检的必要㊂8㊀总结㊀㊀目前用于PCa的评估体系几乎涵盖了从预测到预后的所有阶段,但是这些评估方法都表现出了一定的局限性㊂具有相同组织学特征或生物标志物水平的患者,其临床表现㊁治疗结果也会表现出显著差异㊂临床上仍然需要一种更加可靠具体的生物标志物来区别不同的患者㊂而在前列腺的筛查过程中,找到一种或多种新的生物标志物,从而减少不必要的活检也是目前的研究热点之一㊂不同标志物之间的联合,从而互补各自之间的缺陷,提高PCa的鉴别能力也将是未来临床检验的主要发展方向㊂ʌ参考文献ɔ[1]㊀Siegel RL,Miller KD,Jemal A.Cancer statistics,2016[J].CACancer J Clin,2016,66(1):7-30.DOI:10.3322/caac.21332.[2]㊀Chen 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选择与坚持：跨期选择与延迟满足之比较

第2期
任天虹等 : 选择与坚持：跨期选择与延迟满足之比较
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会通过预实验选择一对较为恰当的 SS 与 LL, 以保证 SS 与 LL 之间的差异既要大到足以使被试愿意选择后者 , 又要小到使 SS 对儿童有足够的诱惑 , 从而避免等待时间的天花板效应与地板效应 (Mischel & Underwood, 1974)。动物实验在跨期选择与延迟满足的研究中都有所涉及 , 这些动物研究的实验范式直观易懂 , 对儿童被试的研究也颇有启示意义。随着研究内容的扩展与研究范式的改进 , 跨期选择与延迟满足在研究对象上有融合的趋势。 3.2 研究内容跨期选择关注被试的时间折扣 (time discounting), 而延迟满足则更关注被试在等待时间上的个体差异、自我控制策略及其有效性 (Ainslie, 1975; Mischel et al., 1989)。如果说跨期选择的研究者将其研究重点放在了计算、分析、推理、权衡等较为高级的认知过程上 , 那么延迟满足的研究者则将其重点放在了情绪、意志力、动机强度等更为基础的本能反应上。时间折扣是跨期选择研究的基本假设 , 也是其研究的重要内容 , 它是指在跨期选择中 , 个体首先会对延迟结果的价值根据其延迟的时间进行一定的折扣, 然后再对两个结果进行比较(Frederick et al., 2002; Scholten & Read, 2010)。经济学家力图找到某一通用的公式来描述折扣程度与结果及延迟时间之间的关系 , 表现为数理模型的优化 ; 心理学家则更关注外界因素对个体时间折扣程度的影响 , 表现为认知神经机制的揭示。延迟满足的研究者并不关注折扣程度 , 他们更加关注等待时间上的个体差异 , 并在实验中细致地检验被试自我控制策略的选择与使用状况 , 这些研究者热衷于以追踪研究揭示儿童在实验中的表现与其个性及行为特征之间的关系 (Mischel et al., 1989)。 3.3 研究范式跨期选择的研究关注被试的选择过程 , 它要求被试做出一系列选择 ; 延迟满足则更关注被试的坚持过程 , 要求被试坚持完成选择后的等待过程。尽管在跨期选择的部分任务中也涉及到等待过程 , 但是它与延迟满足有本质的区别。被试在延迟满足任务中能够自主选择中止等待 , 而在跨期选择任务中则只能消极等待延时结束 (Evans & Beran, 2007)。

生物信息学主要英文术语及释义（续完）

⽣物信息学主要英⽂术语及释义（续完）These substitutions may be found in an amino acid substitution matrix such as the Dayhoff PAM and Henikoff BLOSUM matrices. Columns in the alignment that include gaps are not scored in the calculation. Perceptron（感知器，模拟⼈类视神经控制系统的图形识别机) A neural network in which input and output states are directly connected without intervening hidden layers. PHRED （⼀种⼴泛应⽤的原始序列分析程序，可以对序列的各个碱基进⾏识别和质量评价） A widely used computer program that analyses raw sequence to produce a 'base call' with an associated 'quality score' for each position in the sequence. A PHRED quality score of X corresponds to an error probability of approximately 10-X/10. Thus, a PHRED quality score of30 corresponds to 99.9% accuracy for the base call in the raw read. PHRAP （⼀种⼴泛应⽤的原始序列组装程序） A widely used computer program that assembles raw sequence into sequence contigs and assigns to each position in the sequence an associated 'quality score', on the basis of the PHRED scores of the raw sequence reads. A PHRAP quality score of X corresponds to an error probability of approximately 10-X/10. Thus, a PHRAP quality score of 30 corresponds to 99.9% accuracy for a base in the assembled sequence. Phylogenetic studies（系统发育研究） PIR （主要蛋⽩质序列数据库之⼀，翻译⾃GenBank） A database of translated GenBank nucleotide sequences. PIR is a redundant (see Redundancy) protein sequence database. The database is divided into four categories: PIR1 - Classified and annotated. PIR2 - Annotated. PIR3 -Unverified. PIR4 - Unencoded or untranslated. Poisson distribution（帕松分布） Used to predict the occurrence of infrequent events over a long period of time 143or when there are a large number of trials. In sequence analysis, it is used to calculate the chance that one pair of a large number of pairs of unrelated sequences may give a high local alignment score. Position-specific scoring matrix (PSSM)（特定位点记分矩阵，PSI-BLAST等搜索程序使⽤） The PSSM gives the log-odds score for finding a particular matching amino acid in a target sequence. Represents the variation found in the columns of an alignment of a set of related sequences. Each subsequent matrix column corresponds to the next column in the alignment and each row corresponds to a particular sequence character (one of four bases in DNA sequences or 20 amino acids in protein sequences). Matrix values are log odds scores obtained by dividing the counts of the residue in the alignment, dividing by the expected number of counts based on sequence composition, and converting the ratio to a log score. The matrix is moved along sequences to find similar regions by adding the matching log odds scores and looking for high values. There is no allowance for gaps. Also called a weight matrix or scoring matrix. Posterior (Bayesian analysis) A conditional probability based on prior knowledge and newly uated relationships among variables using Bayes rule. See also Bayes rule. Prior (Bayesian analysis) The expected distribution of a variable based on previous data. Profile（分布型） A matrix representation of a conserved region in a multiple sequence alignment that allows for gaps in the alignment. The rows include scores for matching sequential columns of the alignment to a test sequence. The columns include substitution scores for amino acids and gap penalties. See also PSSM. Profile hidden Markov model（分布型隐马尔可夫模型） A hidden Markov model of a conserved region in a multiple sequence alignment that includes gaps and may be used to search new sequences for similarity to the aligned sequences. Proteome（蛋⽩质组） The entire collection of proteins that are encoded by the genome of an organism. Initially the proteome is estimated by gene prediction and annotation methods but eventually will be revised as more information on the sequence of the expressed genes is obtained. Proteomics （蛋⽩质组学） Systematic analysis of protein expression_r of normal and diseased tissues that involves the separation, identification and characterization of all of the proteins in an organism. Pseudocounts Small number of counts that is added to the columns of a scoring matrix to increase the variability either to avoid zero counts or to add more variation than was found in the sequences used to produce the matrix. 144PSI-BLAST （BLAST系列程序之⼀） Position-Specific Iterative BLAST. An iterative search using the BLAST algorithm. A profile is built after the initial search, which is then used in subsequent searches. The process may be repeated, if desired with new sequences found in each cycle used to refine the profile. Details can be found in this discussion of PSI-BLAST. (Altschul et al.) PSSM （特定位点记分矩阵） See position-specific scoring matrix and profile. Public sequence databases （公共序列数据库，指GenBank、EMBL和DDBJ） The three coordinated international sequence databases: GenBank, the EMBL data library and DDBJ. Q20 (Quality score 20) A quality score of > or = 20 indicates that there is less than a 1 in 100 chance that the base call is incorrect. These are consequently high-quality bases. Specifically, the quality value "q" assigned to a basecall is defined as: q = -10 x log10(p) where p is the estimated error probability for that basecall. Note that high quality values correspond to low error probabilities, and conversely. Quality trimming This is an algorithm which uses a sliding window of 50 bases and trims from the 5' end of the read followed by the 3' end. With each window, the number of low quality (10 or less) bases is determined. If more than 5 bases are below the threshold quality, the window is incremented by one base and the process is repeated. When the low quality test fails, the position where it stopped is recorded. The parameters for window length low quality threshold and number of low quality bases tolerated are fixed. The positions of the 5' and 3' boundaries of the quality region are noted in the plot of quality values presented in the" Chromatogram Details" report. Query （待查序列/搜索序列） The input sequence (or other type of search term) with which all of the entries in a database are to be compared. Radiation hybrid (RH) map （辐射杂交图谱） A genome map in which STSs are positioned relative to one another on the basis of the frequency with which they are separated by radiation-induced breaks. The frequency is assayed by analysing a panel of human–hamster hybrid cell lines, each produced by lethally irradiating human cells and fusing them with recipient hamster cells such that each carries a collection of human chromosomal fragments. The unit of distance is centirays (cR), denoting a 1% chanceof a break occuring between two loci Raw Score （初值，指最初得到的联配值S） The score of an alignment, S, calculated as the sum of substitution and gap scores. Substitution scores are given by a look-up table (see PAM, BLOSUM). Gap scores are typically calculated as the sum of G, the gap opening penalty 145and L, the gap extension penalty. For a gap of length n, the gap cost would be G+Ln. The choice of gap costs, G and L is empirical, but it is customary to choose a high value for G (10-15)and a low value for L (1-2). Raw sequence （原始序列/读胶序列） Individual unassembled sequence reads, produced by sequencing of clones containing DNA inserts. Receiver operator characteristic The receiver operator characteristic (ROC) curve describes the probability that a test will correctly declare the condition present against the probability that the test will declare the condition present when actually absent. This is shown through a graph of the tesls sensitivity against one minus the test specificity for different possible threshold values. Redundancy （冗余） The presence of more than one identical item represents redundancy. In bioinformatics, the term is used with reference to the sequences in a sequence database. If a database is described as being redundant, more than one identical (redundant) sequence may be found. If the database is said to be non-redundant (nr), the database managers have attempted to reduce the redundancy. The term is ambiguous with reference to genetics, and as such, the degree of non-redundancy varies according to the database manager's interpretation of the term. One can argue whether or not two alleles of a locus defines the limit of redundancy, or whether the same locus in different, closely related organisms constitutes redundency. Non-redundant databases are, in some ways, superior, but are less complete. These factors should be taken into consideration when selecting a database to search. Regular expression_rs This computational tool provides a method for expressing the variations found in a set of related sequences including a range of choices at one position, insertions, repeats, and so on. For example, these expression_rs are used to characterize variations found in protein domains in the PROSITE catalog. Regularization A set of techniques for reducing data overfitting when training a model. See also Overfitting. Relational database（关系数据库）Organizes information into tables where each column represents the fields of informa-tion that can be stored in a single record. Each row in the table corresponds to a single record. A single database can have many tables and a query language is used to access the data. See also Object-oriented database. Scaffold （⽀架，由序列重叠群拼接⽽成） The result of connecting contigs by linking information from paired-end reads from plasmids, paired-end reads from BACs, known messenger RNAs or other sources. The contigs in a scaffold are ordered and oriented with respect to one another. 146 Scoring matrix（记分矩阵） See Position-specific scoring matrix. SEG （⼀种蛋⽩质程序低复杂性区段过滤程序） A program for filtering low complexity regions in amino acid sequences. Residues that have been masked are represented as "X" in an alignment. SEG filtering is performed by default in the blastp subroutine of BLAST 2.0. (Wootton and Federhen) Selectivity (in database similarity searches)（数据库相似性搜索的选择准确性） The ability of a search method to locate members of a protein family without making a false-positive classification of members of other families. Sensitivity (in database similarity searches)（数据库相似性搜索的灵敏性） The ability of a search method to locate as many members of a protein family as possi-ble, including distant members of limited sequence similarity. Sequence Tagged Site （序列标签位点） Short cDNA sequences of regions that have been physically mapped. STSs provide unique landmarks, or identifiers, throughout the genome. Useful as a framework for further sequencing. Significance（显著⽔平） A significant result is one that has not simply occurred by chance, and therefore is prob-ably true. Significance levels show how likely a result is due to chance, expressed as a probability. In sequence analysis, the significance of an alignment score may be calcu-lated as the chance that such a score would be found between random or unrelated sequences. See Expect value. Similarity score (sequence alignment) （相似性值） Similarity means the extent to which nucleotide or protein sequences are related. The extent of similarity between two sequences can be based on percent sequence identity and/or conservation. In BLAST similarity refers to a positive matrix score. The sum of the number of identical matches and conservative (high scoring) substitu-tions in a sequence alignment divided by the total number of aligned sequence charac-ters. Gaps are usually ignored. Simulated annealing A search algorithm that attempts to solve the problem of finding global extrema. The algorithm was inspired by the physical cooling process of metals and the freezing process in liquids where atoms slow down in movement and line up to form a crystal. The algorithm traverses the energy levels of a function, always accepting energy levels that are smaller than previous ones, but sometimes accepting energy levels that are greater, according to the Boltzmann probability distribution. Single-linkage cluster analysis An analysis of a group of related objects, e.g., similar proteins in different genomes to identify both close and more distant relationships, represented on a tree or dendogram. The method joins the most closely related pairs by the neighbor-joining algorithm by representing these pairs as outer branches on 147the tree. More distant objects are then pro-gressively added to lower tree branches. The method is also used to predict phylogenet-ic relationships by distance methods. See also Hierarchical clustering, Neighbor-joining method. Smith-Waterman algorithm（Smith-Waterman算法） Uses dynamic programming to find local alignments between sequences. The key fea-ture is that all negative scores calculated in the dynamic programming matrix are changed to zero in order to avoid extending poorly scoring alignments and to assist in identifying local alignments starting and stopping anywhere with the matrix. SNP （单核苷酸多态性） Single nucleotide polymorphism, or a single nucleotide position in the genome sequence for which two or more alternative alleles are present at appreciable frequency (traditionally, at least 1%) in the human population. Space or time complexity（时间或空间复杂性） An algorithms complexity is the maximum amount of computer memory or time required for the number of algorithmic steps to solve a problem. Specificity (in database similarity searches)（数据库相似性搜索的特异性） The ability of a search method to locate members of one protein family, including dis-tantly related members. SSR （简单序列重复） Simple sequence repeat, a sequence consisting largely of a tandem repeat of a specific k-mer (such as (CA)15). Many SSRs are polymorphic and have been widely used in genetic mapping. Stochastic context-free grammar A formal representation of groups of symbols in different parts of a sequence; i.e., not in the same context. An example is complementary regions in RNA that will form sec-ondary structures. The stochastic feature introduces variability into such regions. Stringency Refers to the minimum number of matches required within a window. See also Filtering. STS （序列标签位点的缩写） See Sequence Tagged Site Substitution （替换） The presence of a non-identical amino acid at a given position in an alignment. If the aligned residues have similar physico-chemical properties the substitution is said to be "conservative". Substitution Matrix （替换矩阵） A substitution matrix containing values proportional to the probability that amino acid i mutates into amino acid j for all pairs of amino acids. such matrices are constructed by assembling a large and diverse sample of verified pairwise alignments of amino acids. If the sample is large enough to be statistically significant, the resulting matrices should reflect the true probabilities of mutations occuring through a period of evolution. 148Sum of pairs method Sums the substitution scores of all possible pair-wise combinations of sequence charac-ters in one column of a multiple sequence alignment. SWISS-PROT （主要蛋⽩质序列数据库之⼀） A non-redundant (See Redundancy) protein sequence database. Thoroughly annotated and cross referenced. A subdivision is TrEMBL. Synteny The presence of a set of homologous genes in the same order on two genomes. Threading In protein structure prediction, the aligning of the sequence of a protein of unknown structure with a known three-dimensional structure to determine whether the amino acid sequence is spatially and chemically compatible with that structure. TrEMBL （蛋⽩质数据库之⼀，翻译⾃EMBL） A protein sequence database of Translated EMBL nucleotide sequences. Uncertainty（不确定性） From information theory, a logarithmic measure of the average number of choices that must be made for identification purposes. See also Information content. Unified Modeling Language (UML) A standard sanctioned by the Object Management Group that provides a formal nota-tion for describing object-oriented design. UniGene （⼈类基因数据库之⼀） Database of unique human genes, at NCBI. Entries are selected by near identical presence in GenBank and dbEST databases. The clusters of sequences produced are considered to represent a single gene. Unitary Matrix （⼀元矩阵） Also known as Identity Matrix.A scoring system in which only identical characters receive a positive score. URL（统⼀资源定位符） Uniform resource locator. Viterbi algorithm Calculates the optimal path of a sequence through a hidden Markov model of sequences using a dynamic programming algorithm. Weight matrix See Position-specifc scoring matrix.。

前列腺癌新辅助化疗进展

前列腺癌新辅助化疗进展发布时间：2021-09-07T05:44:11.471Z 来源：《科学与技术》2021年5月第13期作者：梁鹏陈飞飞田志崇胡俊超[导读] 根治性前列腺切除术（RP）是前列腺癌患者的重要治疗手段，梁鹏陈飞飞田志崇胡俊超华北理工大学附属医院河北省唐山市 063000摘要：根治性前列腺切除术（RP）是前列腺癌患者的重要治疗手段，但是前列腺患者术前分期困难重重，为了使得更多病人能在RP中获益，新辅助治疗的地位也在越来越高。

其中，以多西他赛为基础的新辅助化疗手段值得我们关注。

关键词：前列腺癌；根治性前列腺切除术（RP）；新辅助治疗；新辅助化疗；多西他赛前列腺癌是最常被诊断出的癌症之一，由于与发达国家相比，我国早期发现和筛查相关的诊断活动较差，故前列腺癌并不是我们诊断最常见的癌症类型，但可能包括逐步实施前列腺特异性抗原筛查和改进的活检技术又或日益西化的生活方式的影响，前列腺癌在我国的发病率及病死率正逐步上升【1】。

总体而言，高危和局部进展期的前列腺癌是威胁患者生命的主要原因，这部分患者在初诊时比例可达20%-30%【2】。

前列腺癌根治性切除术是低危局限性前列腺癌患者的最佳治疗方式，随着近些年来的研究，指南逐渐将手术适应症放宽到中-低危前列腺癌，甚至于已有研究者在转移性前列腺癌中实施包括手术在内的综合性治疗。

但随之而来的，是手术失败、放疗失败、生化复发率高等问题【3，4】，故许多学者开始对前列腺癌的新辅助治疗进行了探索。

前列腺癌新辅助包括辅助内分泌治疗（neoad-juvanthormonaltherapy，NHT）、新辅助化疗（neoadjuvantchemotherapy，NCT）以及两者的结合，其中NHT研究占了大多数。

然而，目前欧洲泌尿外科学会的指南不推荐在根治性切除术前进行新辅助内分泌治疗(证据等级别strong)，美国国家综合癌症网络也不建议患者接受除临床试验以外的新辅助内分泌治疗。

PSA

·64·ቤተ መጻሕፍቲ ባይዱ
中华临床医师杂志(电子版)2014 年 1 月第 8 卷第 1 期 Chin J Clinicians(Electronic Edition),January 1,2014,Vol.8,No.1
·临床论著·
健康男性前列腺特异性抗原指标的年龄相关性及其曲线分布特征
孙伟桂胡晓武李之珍武萍郑奇传
aged from 11 to 94 years, were simultaneously detected tPSA,fPSA and %fPSA levels in their sera. A few data of 17 men(7.15%) who had higher tPSA levels (above 4 ng/ml) were beforehand ruled out in case of owning possible prostate cancer. The mean levels and 95% confidence intervals were classified with every 10 years old into 8 groups, and these data were analyzed by SPSS 19.0 statistics software. The relationships between PSA and age were mainly studied on the features of age-related three distribution curves. Results With age increasing, the levels of tPSA and fPSA were both elevated in positive proportion (P＜ 0.001), however, %fPSA had no direct proportional with age (P＞0.05). Before 70 years old, there had two rapidly rising segments in tPSA curve, located in 0-19 years old (tPSA from 0 to 0.9 ng/ml with annual growth rate of 0.045 ng/ml) and 60-69 years old (tPSA from 1.13 to 1.39 ng/ml with annual growth rate of 0.02 ng/ml). Between ranges 20-59 for 40 years long, tPSA only got a very slow annual growth speed of

游离前列腺特异性抗原联合癌胚抗原对前列腺癌的早期诊断价值

第30卷第20期中国现代医学杂志 Vol. 30 No.20 2020年10月 China Journal of Modern Medicine Oct. 2020收稿日期：2020-04-22DOI: 10.3969/j.issn.1005-8982.2020.20.017文章编号： 1005-8982（2020）20-0082-05游离前列腺特异性抗原联合癌胚抗原对前列腺癌的早期诊断价值陈妹，陈玲，曹明杰（滁州市第一人民医院检验科，安徽滁州 239000）摘要：目的分析游离前列腺特异性抗原（fPSA）联合癌胚抗原（CEA）对前列腺癌的早期诊断价值。

方法选取2017年1月—2019年12月在滁州市第一人民医院就诊的256例疑似前列腺癌患者作为研究对象。

血清总前列腺特异抗原（tPSA）水平介于4.0～20.0μg/L，根据血清tPSA 水平分为tPSA 4.0～10.0μg/L 组180例和tPSA 10.1～20.0μg/L 组76例。

比较两组前列腺癌与非前列腺癌患者血清fPSA、CEA、游离与总前列腺特异性抗原比值（f/tPSA）、前列腺健康指数（PHI）。

进行Pearson 相关性分析和线性回归性分析，使用受试者工作特征曲线下面积（AUC）评价fPSA 联合CEA 对前列腺癌的诊断效能。

结果 tPSA 4.0～ 10.0μg/L 组前列腺癌与非前列腺癌患者血清fPSA、CEA 水平比较，差异有统计学意义（P <0.05）；而年龄、血清tPSA 水平、f/t PSA 及PHI 比较，差异无统计学意义（P >0.05）。

tPSA 10.1～20.0μg/L 组前列腺癌与非前列腺癌患者血清fPSA、CEA 及PHI 比较，差异有统计学意义（P <0.05）；而年龄、血清tPSA 水平及 f/t PSA 比较，差异无统计学意义（P >0.05）。

Pearson 相关性分析显示，前列腺癌患者血清fPSA、CEA 水平与PHI 呈正相关（r =0.348和0.392，P <0.05）。

血清PSA在前列腺癌筛查中的意义探讨

血清PSA在前列腺癌筛查中的意义探讨前列腺癌是一种常见的泌尿生殖系统肿瘤，并且近年来发病呈上升趋势。

近年来，随着前列腺特异性抗原（PSA）筛查的广泛开展，前列腺癌的检出率较过去明显增加。

本文就PSA在前列腺癌筛查中的意义作一综述。

标签：前列腺癌；前列腺特异性抗原前列腺癌因具有发病部位局限并且发展缓慢的特点，因此，早期诊断对于前列腺癌的根治具有重要的意义。

事实上，前列腺肿瘤死亡率从1997年到2007年10年间降低了将近35%[1]，这与PSA大范围筛查是分不开的。

在本文中，我们回顾目前不同国家前列腺癌筛查的文献，评价PSA对于前列腺癌筛查的意义。

1是否存在统一的前列腺癌筛查标准？1.1美国前列腺癌筛查指南1.1.1美国癌症学会（ACS）ACS认为前列腺癌的筛查应建立在年龄大于50岁、预期生存时间大于10年的男性，或是年龄45岁的高风险男性，或是年龄40岁的超高风险男性（多个直系血亲诊断前列腺癌）中进行。

在讨论之后，对于需要筛查的人进行血清PSA检查，伴或不伴直肠指诊[2]。

1.1.2美国国立综合癌症网络（NCCN）NCCN推荐在前列腺癌筛查前进行全面的系统回顾、体格检查以发现受检者健康状况、并发症、家族史、种族、社会史和早先前列腺癌检测和治疗史。

以便决定前列腺癌筛查个体化方案[3]。

1.2国际前列腺癌筛查指南1.2.1欧洲泌尿外科学会（EAU）EAU认为早期前列腺癌筛查可能出现过度诊断和随后治疗的并发症将会大于获益情况。

缺少筛查的依据是因为现有筛查标准的不统一和筛查标准不能够选择出高风险和侵袭性前列腺癌。

因此，前列腺癌筛查应根据具体情况而定。

2前列腺癌筛查是否可以降低前列腺癌特异性死亡率？上述各国前列腺癌筛查指南都是得到许多大型随机试验验证的，这些试验使用PSA和直肠指诊进行前列腺癌筛查。

各大随机试验包括欧洲前列腺癌筛查试验（ERSPC），哥德堡瑞典筛查试验等。

2.1欧洲前列腺癌筛查试验（ERSPC）ERSPC是于1990年开始在欧洲多国家进行的试验，该试验对18.2万受试者进行了为期平均9年的研究，发现在死亡率上相对危险度下降了20%，且低风险疾病的比例也增高了[4]。

新高考模拟小练(二)

考题狂练新咼考模拟小练（Week Two Part I★★★★☆阅读下列短文，从每题所给的A、B、C、D四个选项中选出最佳选项。

The cancer death rate in the U.S.fell by the most on record1as advances in treatments for lung tumors（月中瘤）like video-assisted surgery helped prolong the lives of patients.The death rate from cancer has been gradually declining for26years,thanks in large part to fewer people smoking cigarettes.But from2016to2017,the most recent period available, it dropped by2.2%,the most ever in a single year,according to a report released Wednesday by the American Cancer Society.That compares with an average1.5%yearly decline over the decade.The drop translates to roughly2.9million fewer cancer deaths than would have occurred had death rates remained at their peak.For lung cancer specifically,the death rate declined4.3% annually from2013to2017."It is really lung cancer that is driving this,”said Rebecca Siegel,scientific director of surveillance research at the American Cancer Society,and lead author on the new study.“We found increases in survival for lung cancer at every stage in diagnosis.",She Attributed the lower deaths g2improvements in treatments,including video-assisted surgery that enables more patients with early lung tumors to become eligible（符合条件的）for operations;more precise radiati o n treatment;and better scanning tech n ology that allows doctors to better assess the stage of tumor,so the patient gets the best treatment right away.At later stages of illness,new,targeted drugs that gm^f3specific disease-causing genes are helping patients whose tumors have those genetic flaws（缺陷）.Overall,lung cancer death rates have dropped by51%for men since their peak in1990,and by26%for women since their peak in2002.There's the potential for more progress in future reports.Thafs because the latest death-rate statistics go only through2017,and likely don't in e lude the potential impact in lung cancer death from immune-therapy drugs.They became widely used in lung cancer only in the past few years.The report,based on ernment data,isrft all good news.Prostate（前歹!］腺）cancer death rates have leveled off recently after a period of decline.That may be because many doctors pulled back on°using the controversial prostate-specific antigen test,or PSA,which can spot the disease but can lead to over-treatment of men who may never have died from their tumors.“Though it was definitely causing harm,it was also contributing to5declines in death,"Siegel said.WhaVs needed now is better screening tests to detect only the prostate cancers that will goon to cause harm.Population death rates are considered one of the most reliable ways of measuring progress in cancer treatment and prevention.By contrast6cancer survival rates can sometimes be in f lue n eed by improveme n ts in diag no s ing tiny,early stage tumors that would n't n e cessarily be deadly.（选自2020年6月北京人大附中高三模拟考试）1.According to Paragraph2,___________.A.cancer death rate reached its peak in2017B.death rate has been decreasing over the past2decadesC.2.9million people die of cancer in America every yearD.most of the cancer patients in America suffer from lung cancer2. What can we learn from the passage?A.Female death rate of lung cancer drops more than that of male.B.Targeted drugs have led to rapid in crease in cancer death rates.C. Better scanning technology will lead to improvement in treating genetic flaws.D.Improper use of prostate-specific antigen test can lead to over-treatment of patients.3. What does the underlined phrase“level off H in Paragraph5most probably mean?A.Remain unchanged.B.Show up.C.Take off.D.Become sharp.4.What can be the best title of the passage?A. Medical progress prolonging patients'livesB.Cancer death rates dropping at the fastest paceC.Significant improvement in treating lung cancerD.Advanced technologies applied in cancer treatmentPart II★★★★☆_________________________阅读下面短文，从短文后的选项中选出可以填入空白处的最佳选项。

TRANSPERINEALBIOPSYOFTHEPROSTATE

The British Association of Urological Surgeons 35-43 Lincoln’s Inn FieldsLondon WC2A 3PETel. 020 7869 6950TRANSPERINEAL BIOPSY OF THE PROSTATEProcedure Specific InformationWhat is the evidence base for this information?This publication includes advice from consensus panels, the British Association of Urological Surgeons, the Department of Health and evidence-based sources. It is, therefore, a reflection of best urological practice in the UK. It is intended to supplement any advice you may already have been given by your GP or other healthcare professionals. Alternative treatments are outlined below and can be discussed in more detail with your Urologist or Specialist Nurse.What does the procedure involve?This procedure involves using an ultrasound probe, inserted via the back passage, to scan the prostate. Biopsies are taken through the skin behind the testicles (the perineum) using a special grid shown below. The sampling is targeted and the number of samples taken depends on the size of the prostate, usually ranging from 30 to 50 samples.The reason this approach is adopted is because you have already undergone a number of biopsies previously (via the rectum) which havenot identified the cause of your elevated PSA. Transrectal biopsies, as you have had done before, carry a greater risk if performed in this number.What are the alternatives to this procedure?Observation with repeat blood tests but without biopsiesWhat should I expect before the procedure?You will usually be admitted on the day of your surgery. You will normally receive an appointment for pre-assessment to assess your general fitness, to screen for the carriage of MRSA and to perform some baseline investigations. After admission, you will be seen by members of the medical team which may include the Consultant, Specialist Registrar, House Officer and your named nurse.If you are taking Warfarin, you must inform the clinic staff at your pre-assessment visit so that you are advised when to stop your Warfarin prior to the procedure. Usually you are asked to withold Warfarin for 3 days. A blood test, INR, will be performed prior to your biopsy. If you are taking Aspirin, you do not need to stop these. If you are taking Clopidogrel, you must inform the medical staff because the biopsy may need to be postponed or alternative arrangements made.After checking for alllergies, you will normally be given an intravenous injection of antibiotic at the time of your anaesthetic.Please be sure to inform your surgeon in advance of your surgery if you have any of the following:∙an artificial heart valve∙ a coronary artery stent∙ a heart pacemaker or defibrillator∙an artificial joint∙an artificial blood vessel graft∙ a neurosurgical shunt∙any other implanted foreign body∙ a regular prescription for Warfarin, Aspirin or Clopidogrel (Plavix®)∙ a previous or current MRSA infection∙ a high risk of variant-CJD (if you have received a corneal transplant, a neurosurgical dural transplant or previous injections of human-derivedgrowth hormone)At some stage during the admission process, you will be asked to sign the second part of the consent form giving permission for your operation to take place, showing you understand what is to be done and confirming that you wish to proceed. Make sure that you are given the opportunity to discuss any concerns and to ask any questions you may still have before signing the form.Fact File 1 • The NHS ConstitutionSame-Sex AccommodationAs a result of the new NHS constitution, the NHS is committed to providing same-sex accommodation in hospitals by April 2010. This is because feedback from patients has shown that being in mixed-sex accommodation can compromise their privacy. The NHS pledges that:∙sleeping and washing areas for men and women will be provided∙the facilities will be easy to get to and not too far from patients’ beds To help accomplish this, the Department of Health has announced specific measures designe d to “all but eliminate mixed-sex accommodation” by 2010.These include:∙more money for improvements in hospital accommodation∙providing help and information to hospital staff, patients and the public∙sending improvement teams to hospitals that need extra support∙introducing measures so that the Department can see how hospitals are progressingWhat happens during the procedure?After the general or spinal anaesthetic has been given, a catheter will be placed in the water pipe (urethra). Your legs will be placed in special supports so that the surgeon can gain access to the skin behind the testicles and insert the ultrasound probe into the rectum. The doctor will examine the prostate through the back passage (anus) before inserting the ultrasound probe. This probe is as wide as a man’s thumb and approximately 4 inches long.In order to take samples (biopsies) of the prostate, a special grid is used so that all areas of the prostate can be covered. The biopsy needs are inserted into the prostate through the skin of the perineum, guided by the ultrasound probe. After the sampling has been completed, a dressing will be applied to the perineum and held in place with a pair of disposable pants.What happens immediately after the procedure?In general terms, you should expect to be told how the procedure went and you should:∙ask if what was planned to be done was achieved∙let the medical staff know if you are in any discomfort∙ask what you can and cannot do∙feel free to ask any questions or discuss any concerns with the ward staff and members of the surgical team∙ensure that you are clear about what has been done and what is the next moveThe catheter will be removed the day after surgery unless you have a fever or a lot of blood in the urine. You will normally be able to go home later the same day after check have been made to ensure that you are passing urine normally.Following this type of biopsy, blood in the urine is common for 2-3 days, with the occasional blood clot, but this should clear quickly if you increase your fluid intake. You may expect to see blood in the semen for up to 6 weeks.You will be given antibiotics to take home for a 3-day period .The average hospital stay is 1 day.Are there any side-effects?Most procedures have a potential for side-effects. You should be reassured that, although all these complications are well-recognised, the majority of patients do not suffer any problems after a urological procedure.Common (greater than 1 in 10)∙Blood in the urine for up to 10 days∙Blood in the semen – this may last for up to 6 weeks but is perfectlyharmless and poses no problem for you or your sexual partner∙Bruising in the perineal area∙ Urinary infection (10% risk)∙Sensation of discomfort from the prostate due to bruising∙Haemorrhage (bleeding) causing an inability to pass urine (2% risk)Occasional (between 1 in 10 and 1 in 50)∙Blood infection (septicaemia) requiring hospitalisation (2% risk)∙Haemorrhage (bleeding) requiring hospitalisation (1% risk)∙Failure to detect a significant cancer of the prostate∙The procedure may need to be repeated If the biopsies are inconclusive or your PSA level rises further at a later stage∙Inability to pass urine (retention of urine)Rare (less than 1 in 50)∙NoneHospital-acquired infection∙Colonisation with MRSA (0.9% - 1 in 110)∙Clostridium difficile bowel infection (0.2% - 1 in 500)∙MRSA bloodstream infection (0.08% - 1 in 1250)The rates for hospital-acquired infection may be greater in high-risk patients e.g. with long-term drainage tubes, after removal of the bladder for cancer, after previous infections, after prolonged hospitalisation or after multiple admissions.What should I expect when I get home?By the time of your discharge from hospital, you should:∙be given advice about your recovery at home∙ask when to resume normal activities such as work, exercise, driving, housework and sexual intimacy∙ask for a contact number if you have any concerns once you return home∙ask when your follow-up will be and who will do this (the hospital or your GP)∙ensure that you know when you will be told the results of any tests done on tissues or organs which have been removedWhen you leave hospital, you w ill be given a “draft” discharge summaryof your admission. This holds important information about your inpatientstay and your operation. If you need to call your GP for any reason or toattend another hospital, please take this summary with you to allow thedoctors to see details of your treatment. This is particularly important ifyou need to consult another doctor within a few days of your discharge.After the procedure, it is important that you:∙sit quietly at home for the first 48 hours after the biopsies∙drink twice as much fluid as you would normally for the first 48 hours after the biopsies∙maintain regular bowel function∙avoid physically-demanding activities∙complete your 3-day course of antibioticsAny discomfort can usually be relieved by simple painkillers.What else should I look out for?If you experience a fever, shivering or develop symptoms of cystitis (frequency and burning on passing urine), you should contact your GP. If there is a lot of bleeding in the urine, especially with clots of blood, you should contact the Urology Department.If you develop a fever outside surgery opening hours, you must telephone the emergency number at your GP surgery so that a doctor can assess your condition.Are there any other important points?You will receive an appointment for discussion of the biopsy results at the time of your examination.It will be at approximately 14 days before the pathology results on the tissue removed are available. It is normal practice for the results of all biopsies to be discussed in detail at a multi-disciplinary meeting before any further treatment decisions are made. You and your GP will be informed of the results after this discussion. We sometimes need to order additional tests as a result of the discussion at this meeting and, as a result, you may receive appointments for a bone scintigram, CT scan or MRI scan before you are seen again in outpatients.Driving after surgeryIt is your responsibility to ensure that you are fit to drive following your surgery. You do not normally need to notify the DVLA unless you have a medical condition that will last for longer than 3 months after your surgery and may affect your ability to drive. You should, however, check with your insurance company before returning to driving. Your doctors will be happy to provide you with advice on request.Is there any research being carried out in this area?Before your operation, your surgeon or Specialist Nurse will inform youabout any relevant research studies taking place, and, in particular, ifany surgically-removed tissue may be stored for future study. If this isthe case, you will be asked if you wish to participate and, if you agree,to sign a special form to consent to this.All surgical procedures, even those not currently the subject of active research, are subjected to rigorous clinical audit so that we can analyse our results and compare them with those of other surgeons. In this way, we can learn how to improve our techniques and our results; this means that our patients will get the best treatment available.Who can I contact for more help or information?For further information on the internet, here are some useful sites to explore: /patient_information/internet_sources (for information about anaesthetics).PILsWhat should I do with this information?Thank you for taking the trouble to read this publication. If you wish to sign it and retain a copy for your own records, please do so below.If you would like a copy of this publication to be filed in your hospital records for future reference, please let your Urologist or Specialist Nurse know. However, if you do agree to proceed with the scheduled procedure, you will be asked to sign a separate consent form which will be filed in your hospital record. You will, if you wish, be provided with a copy of this consent form.I have read this publication and I accept the information it provides. Signature............................................................... Date...........................................How can I get information in alternative formats?Please ask your local NHS Trust or PALS network if you require this information in other languages, large print, Braille or audio format.DisclaimerWhile every effort has been made to ensure the accuracy of the information contained in this publication, no guarantee can be given that all errors and omissions have been excluded. No responsibility for loss occasioned by any person acting or refraining from action as a result of the material in this publication can be accepted by the BritishAssociation of Urological Surgeons Limited.Fact File 2 • The NHS ConstitutionPatients’ Rights & ResponsibilitiesThe constitution, as a result of extensive discussions with staff and the public, sets out new rights for patients which will help improve their experience within the NHS.These new rights include:∙ a right to choice and a right to information that will help them make that choice∙ a right to drugs and treatments approved by NICE when it is considered clinically appropriate∙ a right to certain services such as an NHS dentist and access to recommended vaccinations∙the right that any official complaint will be properly and efficiently investigated, and that they be told the outcome of the investigations ∙the right to compensation and an apology if they have been harmed by poor treatmentThe constitution also lists patient responsibilities, including:∙providing accurate information about their health∙taking positive action to keep themselves and their family healthy∙trying to keep appointments∙treating NHS staff and other patients with respect∙following the course of treatment that they are given∙giving feedback, both positive and negative, after treatment。

前胃泌素释放肽ProGRP生物信息学分析及抗原决定簇预测

前胃泌素释放肽ProGRP生物信息学分析及抗原决定簇预测①郭玉凤张婷张超薛振伟孔晓娜周小林（中国辐射防护研究院，太原030006）中图分类号R392.11Q811.4Q518.1文献标志码A文章编号1000-484X（2021）23-2827-05［摘要］目的：分析预测前胃泌素释放肽（ProGRP）蛋白结构及其抗原决定簇，为抗ProGRP单克隆抗体的筛选及其相应的抗原结合位点的确定提供可靠依据。

方法：从NCBI网站获取ProGRP不同亚型的氨基酸序列进行比对分析（Clustalw），运用不同生物信息学软件分析蛋白理化性质（Protparam），跨膜区（TMHMM），二级结构、亲水性、表面可及性、柔韧性和抗原指数（DNAstar Protean），三级结构（Swiss Model）以及抗原决定簇（BepiPred-2.0及ABCpred）。

结果：ProGRP具有3个同型异构体，属于亲水性蛋白，半衰期为30h，无跨膜区；ProGRP氨基酸序列中含丰富的二级结构，包括α螺旋、β折叠、β转角和无规则卷曲；ProGRP具有5个潜在的抗原决定簇。

结论：该研究筛选的抗原决定簇具有较高的准确性，为鉴定ProGRP单克隆抗体结合位点以及小细胞肺癌（SCLC）的诊治奠定了良好的基础。

［关键词］ProGRP；生物信息学分析；理化性质；结构；抗原决定簇Bioinformatics analysis and epitope prediction of pro-gastrin-releasing peptide （ProGRP）GUO Yu-Feng，ZHANG Ting，ZHANG Chao，XUE Zhen-Wei，KONG Xiao-Na，ZHOU Xiao-Lin.China Institute for Radiation Protection，Taiyuan030006，China［Abstract］Objective：To analyze and predict the structure of pro-gastrin-releasing peptide（ProGRP）and its epitope，and provide a reliable basis for the screening of anti-ProGRP monoclonal antibodies and the determination of their corresponding antigen binding sites.Methods：Amino acid sequences of different subtypes of ProGRP were obtained from NCBI website for alignment analy‐sis（Clustalw）.The physicochemical properties were analyzed by Protparam，the transmembrane helix by TMHMM，the secondary structure，hydrophilicity，surface accessibility，flexibility regions and antigen index by DNAstar Protean，the tertiary structure by Swiss Model，the epitopes by BepiPred-2.0and ABCpred.Results：ProGRP had three isoforms，which were hydrophilic proteins with a half-life of30hours and no transmembrane region.There were abundant secondary structures in the amino acid sequence of ProGRP，includingα-helix，β-fold，β-turn and random curl.ProGRP had5potential epitopes.Conclusion：The antigenic determinants screened in this study have high accuracy，which lays a good foundation for identifying the binding site of ProGRP monoclonal anti‐body and the diagnosis and treatment of small cell lung cancer（SCLC）.［Key words］ProGRP；Bioinformatics analysis；Physicochemical properties；Structure；Epitope肺癌是发病率和病死率都极高的恶性肿瘤，其中小细胞肺癌（small cell lung cancer，SCLC）约占15%~20%［1］。

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ORIGINAL ARTICLEThe new insight of prostate-speciﬁc antigen reduction during ﬁnasteride therapy in aging menDing Xu 1•Jie Ding 1•Yunkai Zhu 2•Xiaoqiang Qian 1•Liujian Duan 1•Jun Qi 1Received:24November 2015/Accepted:26November 2015ÓSpringer International Publishing Switzerland 2016AbstractObjective To evaluate the effect of ﬁnasteride on pros-tate-speciﬁc antigen (PSA)in Chinese population.Materials and methods From Feb 2011to Jan 2012,83benign prostatic hyperplasia (BPH)patients with prostate volume (PV)[30mL were enrolled in our study.All the patients were older than 50years and all of them received combined therapy (ﬁnasteride ?doxazosin).All the patients were required for 1-year follow-up.PSA level and PV was measured at the start,6and 12months,respectively.Results 79patients completed the follow up.PSA level reduced by approximately 40%during ﬁnasteride therapy.We deﬁned baseline PSA as PSA1,PSA at 6months as PSA2,PSA at 12months as PSA3.PSA1was signiﬁcantly correlated with PSA2/PSA1and PSA3/PSA1.However,prostate volume was not correlated with PSA1.We divided the patients into three groups according to PSA level.Groups 1,2,3represented the patients with PSA less than 2ng/mL,between 2and 4ng/mL and greater than 4ng/mL,respectively.Both the PSA2/PSA1and the PSA3/PSA1had signiﬁcant difference among three groups.Fur-thermore,group 1and group 2both showed the fairly large data variance.Conclusions When baseline PSA level was greater than 4ng/mL,the doubling rule could be used for screening.When baseline PSA level was less than 4ng/Ml,the dou-bling rule might not be an accurate predictor.We can use the PSA rise from nadir or proPSA to predict prostate cancer.Keywords Benign prostatic hyperplasia ÁProstate-speciﬁc antigen ÁFinasterideIntroductionBenign prostate hyperplasia (BPH),manifesting with lower urinary tract symptoms (LUTS),such as frequency,urgency,nocturia and dysuria,is one of the most common urological diseases among elderly men.The incidence of BPH increases from 50%in 60-year-old men to almost 100%in 80-year-old men [1].And the cost of BPH treatment ranges from $5824to $50,000per quality adjusted life year (QALY)[2].Furthermore,BPH can also be progressive,with a risk of urinary retention,bladder infection,hematuria,bladder stone,hydronephrosis and renal failure [3–5].Finasteride,a selective inhibitor of 5a -reductase,acts chemically by blocking dihydrotestosterone production and shrinking prostate volume [6,7]which ﬁrstly identiﬁed in 1984by Rasmusson et al.[8],is one of the ﬁrst medication used in treatment of BPH.From PLESS study,after 4-year follow-up,the prostate volume of ﬁnasteride group shrinked by 18%.On the contrary,the prostate volume of placebo group enlarged by 14%[9].Nowadays ﬁnasteride remains one of the most important drugs in BPH treatment.Prostate-speciﬁc antigen (PSA)testing,which was introduced into clinical use as a biochemical marker ofD.Xu and J.Ding contributed equally to this article.&Jun Qilisterdingzai@;jasonqi@1Department of Urology,XinHua Hospital Afﬁliate to Shanghai Jiao Tong University School of Medicine,1665Kongjiang Rd,Shanghai 200092,China2Department of Ultrasound,XinHua Hospital Afﬁliate to Shanghai Jiao Tong University School of Medicine,Shanghai,ChinaAging Clin Exp ResDOI 10.1007/s40520-015-0512-3recurrence in the mid-1980s,has become one of the stan-dard diagnostic and followup tools for prostate cancer[10]. In countries where the use of PSA for screening is wide-spread,it has contributed to an increased rate of prostate cancer diagnosis in the last decade[11],especially for early detection of this disease[12].Sinceﬁnasteride was widely used in the world,doctors found that PSA level could be suppressed duringﬁnasteride therapy.PCPT and other articles reported that PSA were reduced by approximately50%after several months of treatment[10,13].To keep the initial sensitivity and speciﬁcity of PSA test,Gormley et al.have proposed that the‘‘true’’PSA level inﬁnasteride treated men can be obtained by multiplying the observed level by a factor of2 [14].Thus,by doubling the PSA level,PSA could still be useful theoretically as a screening test for prostate cancer in men undergoingﬁnasteride treatment for BPH[15].However,most of the studies were carried out in developed countries,such as America and Europe.While several studies in other areas reached different conclusions.A study from Korea found that PSA decreased by only about36%after1-yearﬁnasteride taking[16].The aim of our study was to evaluate the effect ofﬁnasteride on PSA in aging men.Patients and methodsFrom Feb2011to Jan2012,83BPH patients older than 50years old,who visited our BPH outpatient department with prostate volume(PV)[30mL,were enrolled in our study.All the patients were diagnosed BPH on the basis of history,symptoms,physicalﬁndings and ultrasound.All the enrolled patients were evaluated by the digital rectal examination(DRE),height(cm),weight(kg),Body mass index(BMI),serum tPSA level(ng/mL)and PV(mL) when they initially visited our department.All of them signed their consents on a written form of information with guarantees of conﬁdentiality and received combined ther-apy[ﬁnasteride(Proscar,provided by MSD)5mg qd po?doxazosin(Cardura,provided by Pﬁzer)4mg qn po] for1year,for doxazosin had no impact on PSA[17].If PSA was greater than4ng/mL of abnormal DRE was found,a prostate biopsy is required to conﬁrm whether it was benign or not.Criteria for inclusion were age C50years,BPH which were conﬁrmed by the ultrasound or prostate biopsy.Cri-teria for exclusion were age\50years,previous bladder, prostate or urethral operation,previous treatment for BPH, prostate or bladder malignant tumor,urethral stricture, bladder stone,neurogenic bladder dysfunction,chronic urinary tract infection,chronic renal insufﬁciency and diabetes mellitus.All the patients were required for1-year follow-up.PSA level was measured at the start,6and12months,respec-tively.And we also measured PV at the start,6and 12months.After the follow-up,all the patients need to receive the prostate biopsy.The blood sample was drawn in the clinical laboratory in our hospital before any prostatic manipulations that might cause a transient increase of tPSA.The sample was preserved in4°refrigerator and then sent for analysis in 4h,using Hybritech calibrated Access tPSA assays.The ultrasound machine made by Siemens sequoia512(Linear array probe15L8W,frequency3–8MHz)was used to estimate prostate volume(mL).The parameters of prostate volume were measured by transrectal ultrasound(TRUS), which were all done by one experienced radiologist(Yun-kai Zhu).Images were obtained with the patient in the left decubitus position.PV were calculated using the formula of volume estimation of an ellipsoid:vol-ume=0.529transverse diameter(mm)9anteroposte-rior diameter(mm)9superoinferior diameter(mm).The 10-cores prostate biopsy was taken by two experienced radiologist guided by the TRUS.Specimens were pro-cessed and evaluated by a single experienced genitourinary pathologist.Statistical package for social science(SPSS),version 19.0was used for our statistic analysis.The data were presented as the mean±SD.Bivariate correlation was used toﬁnd the correlation between PSA and the other parameters.One-way ANOVA test was used to compare the delining rate of PSA among groups with different baseline PSA levels.For all statistic tests,a P value\0.05 was considered to be statistically signiﬁcant.ResultsFinally,79patients completed the follow up.Four patients withdrew from study,two patients lost the contact and two patients refused to continue the combined therapy and follow up.All the patients had negative DRE result and no patient was conﬁrmed prostate cancer according to the prostate biopsy.Characteristics of enrolled patients are shown in Table1.We deﬁned baseline PSA as PSA1,PSA at6months as PSA2,PSA at12months as PSA3.Accordingly,we also deﬁned PV1,PV2,PV3.Figure1showed the change of PSA and PV.PSA level reduced by approximately40%duringﬁnasteride therapy. PV shrinked by about13%after1year,which seemed a little weaker than that in PLESS study.Table2showed that PSA1was signiﬁcantly correlated with PSA2/PSA1and PSA3/PSA1.The higher the PSA1, the lower PSA2/PSA1and PSA3/PSA1,which means theAging Clin Exp Resgreater the declining rate.However,PSA1was not corre-lated with PV,height,weight and BMI.Similarly,PSA2/PSA1and PSA3/PSA1were both not correlated with PV2/PV1,PV3/PV1,height,weight and BMI.We divided the patients into three groups according to PSA level.Groups 1,2,3represented the patients with PSA less than 2ng/mL,between 2and 4ng/mL and greater than 4ng/mL,respectively.Table 3indicates that both the PSA2/PSA1and the PSA3/PSA1had signiﬁcant difference among three groups.Furthermore,group 1and group 2from Table 3both showed the fairly large data variance.DiscussionAs a result,our study suggested that PSA decreased 36.71%after 1year of ﬁnasteride taking,which was similar with the result of the study from Korea [16].After dividing the patients into three groups according to the baseline PSA,it is found that PSA decreased approxi-mately 50%during ﬁnasteride therapy when baseline PSA was greater than 4ng/mL and only about 30%when baseline PSA was less than 2ng/mL,indicating that the widely used doubled PSA rule may not always beappropriate for prostate cancer screening in men received ﬁnasteride treatment in Chinese population,especially in the group of men with baseline PSA was less than 2ng/mL.Serum PSA is a product of prostate epithelial cells that receives direct stimulation from intracellular dihy-drotestosterone [18]via inhibition of 5a-reductase,ﬁnas-teride blocks the conversion of testosterone to dihydrotestosterone in these cells and,thus,reduces the level of dihydrotestosterone.In other words,ﬁnasteride deprives prostate epithelial cells of a major trophic stim-ulus [19].As a result,PSA secretion by prostate epithelialTable 1The characteristics of enrolled patients (n =79)Mean SD Age 70.708.287Height (cm)174.89 5.294Weight (kg)70.7810.94BMI 23.03 2.54PSA (ng/mL) 3.40 2.33PV (mL)45.8015.34BMI body mass index,PSA prostate-speciﬁc antigen,PV prostatevolumeFig.1The change of PSA level and prostate volume during ﬁnasteride therapy.PSA level reduced by 39.33±14.86%after 6months and 35.91±25.13%after 12months.Prostate volume shrinked by 13.58%after 1yearTable 2Correlation among PSA and other parameters Parameter 1Parameter 2r value P value PSA1PSA2/PSA1-0.541\0.001*PSA1PSA3/PSA1-0.492\0.001*PSA1PV10.1580.164PSA1PV2/PV10.0710.537PSA1PV3/PV10.0610.591PSA1Height -0.0270.812PSA1Weight -0.0800.483PSA1BMI -0.0190.867PSA2/PSA1PV2/PV1-0.1060.351PSA2/PSA1Height 0.1710.131PSA2/PSA1Weight 0.0680.552PSA2/PSA1BMI 0.0270.813PSA3/PSA1PV3/PV10.0420.714PSA3/PSA1Height 0.1990.079PSA3/PSA1Weight 0.1460.198PSA3/PSA1BMI0.1850.102PSA1baseline PSA,PSA2PSA at 6months,PSA3PSA at 12months PV1baseline PV,PV2PV at 6months,PV3PV at 12months *P \0.01Aging Clin Exp Rescells is reduced and serum PSA levels fall in men treated withﬁnasteride[20].How these drug induced changes affect the value of PSA as a screening test for prostate cancer is still unknown.Low level of dihydrotestosterone causes the elevation of stromal-to-epithelial ratio.Based on histological examina-tion of prostate tissue from men with BPH before and after 6months ofﬁnasteride treatment,Montironi et al. demonstrated that the percent epithelium in the transitional zone was reduced from13.5to6%,the stromal-to-ep-ithelial ratio increased from4.4to10.3%and the total prostate volume decreased by more than25%in ten of26 treated men[21].After6months of treatment withﬁnas-teride overall prostate tissue composition in the peripheral zone,however,was not signiﬁcantly changed[22].In another study on prostate of hamster Mesocricetus auratus,after90days ofﬁnasteride taking,it is found a remarkable decrease in the acinous area as well as the area of the acinous epithelium occurred in the animals that receivedﬁnasteride.AgNORs were less expressed in ﬁnasteride treated animals and apoptosis was more intense in the experimental group.However,there was no statis-tical difference in the cellularity between both groups, maybe suggested that90days of treatment was not long enough to reduce the number of cells in the acinous of these animals[23].Why the declining rate of PSA in our study is different from other studies?Maybe the effect ofﬁnasteride on prostate is not the same among different races.In PLESS study,prostate volume shrinked by18%after1year of ﬁnasteride treatment.However,in our study,prostate vol-ume shrinked only by about13%.Genetic polymorphisms on type II5a-reductase genes may affect enzyme activity and,thus,lead to individual variability in drug efﬁcacy. Previous studies demonstrated that several mutations on the SRD5A2gene changed the type II5a-reductase expression level[24].A comprehensive association study of SNPs on the SRD5A2gene in a Chinese population showed that rs523349and rs612224on SRD5A2were signiﬁcantly associated with the change in IPSS and PSA afterﬁnasteride treatment[25].The SNP rs523349is also known as V89L(the89th amino acid changes from valine to leucine),which is a missense(or nonsynonymous) variant located in exon1of the SRD5A2gene[26].A pooled analysis of SRD5A2genotype frequencies in control populations demonstrated variation among racial/ ethnic groups[27].Frequency of the L allele at codon89 was highest among Asians(54.8%),followed by whites (30.4%)and African Americans(23.1%);Africans were least likely to carry this variant(18.8%)[28].This may explain why the declining rate of PSA and the effect of ﬁnasteride are both different in different races.Further-more,rs523349and rs612224were both not correlated with the change of PV[24],which was consistent with the result in our study.In our study,PSA level in the patients with PSA level less than4ng/ml showed the fairly large data variance, maybe due to the individual variability in drug efﬁcacy. Leonard et al.propose that a PSA increase from nadir of 0.3ng/mL or greater should be used as an additional biopsy trigger in men receiving a5ARI for BPH[10].The PSA increase from nadir appears to be a more accurate harbinger of cancer than a doubling rule in some patients, but it still should be conﬁrmed by further data from large clinical trials.Our study also had some limitations.The current study has fairly low sample volume and has no data of the blood dihydrotestosterone level and the information of SNPs. What’s more,the study lacks long-time follow-up to fur-ther conﬁrm ourﬁnding.Therefore,in the further study,we will expand our sample volume and extend the time of follow-up.Meanwhile,we will study the declining con-sistence between PSA and dihydrotestosterone in order to increase the diagnostic accuracy of prostate cancer.We could also further study the correlation between SNPs and PSA declining rate in different baseline PSA group.In addition,we will study the effect ofﬁnasteride on proPSA to evaluate the diagnostic accurary of prostate cancer in the patients receivedﬁnasteride treatment.ConclusionTo make a brief conclusion of ourﬁnding,when baseline PSA level was greater than4ng/mL,PSA level decreased by approximately50%,as reported by earlier documents. In such cases,the doubling rule could be used for screening in China.While,when baseline PSA level was less than 4ng/mL,PSA delinced by less than50%,the doubling rule might not be an accurate predictor.On the other hand,greatTable3The effect ofﬁnasteride on PSA in different PSA levelGroup1(n=28)(%)Group2(n=26)(%)Group3(n=25)(%)P valuePSA2/PSA10.7100±18.990.5596±13.410.5368±6.76\0.001* PSA3/PSA10.7633±33.380.5658±15.750.5137±8.71\0.001* PSA1baseline PSA,PSA2PSA at6months,PSA3PSA at12months*P\0.01Aging Clin Exp Resvariance in data might also affect the accuracy of predic-tion.Our study result is beneﬁt for us to use the doubling rule to predict prostate cancer.Acknowledgments The authors wish to thank all patients for their ongoing participation in this study.The authors also wish to thank Wen-bin Guan for his contribution of specimen procession and evaluation to this article.Funding This study was funded by a grant from Science and Technology Commission of Shanghai Municipality(CN)(No. 134119a0600and14430720800).Compliance with ethical standardsConﬂict of interest The authors declare that they have no conﬂict of interest.Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Xinhua Hospital Afﬁliated to Shanghai University School of Medicine and with the1964Helsinki declaration and its later amendments or comparable ethical standards. 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