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What we have learned from randomized trials of prostate cancer screening

Asian Journal of Andrology 2011年第3期13卷 369-373,510页

作者： richard m hoffman Anthony Y Smith medicine Service New Mexico VA Health Care System Albuquerque NM 87108 USA Department of medicine University of New Mexico School of Medicine Albuquerque NM 87108 USA Department of Surgery University of New Mexico School of Medicine Albuquerque NM 87108 USA

The introduction of prostate-specific antigen （PSA） for prostate cancer screening in the late 1980s led to an epidemic of prostate cancer, particularly in developed countries. However, the first valid reports from randomized controlled trials on the efficacy of screening were not published until 2009. men in the screening group in the European Randomized Study of Screening for Prostate Cancer were 20% less likely than those in the control group to die from prostate cancer. The absolute difference was only 0.7/1000, implying that over 1400 men needed to be screened to prevent one prostate cancer death. Screening was also associated with a 70% increased risk for being diagnosed with prostate cancer. The American Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found no survival benefit for screening. Results were not conclusive because a substantial proportion of study subjects had previously undergone PSA testing, over half of the control group had PSA testing, follow-up was relatively short, and fewer than 100 subjects died from prostate cancer. Balancing the potential survival benefit from screening is the risk of overdiagnosis--finding cancers that would not otherwise cause clinical problems^and the risk of treatment complications, including urinary, sexual and bowel dysfunction. Prostate cancer screening efforts would benefit from improved biomarkers, which more readily identify clinically important cancers. Cancer control efforts might also need to include chemoprevention, though currently available agents are controversial. In the meantime, oatients need to be supoorted in achievine informed decisions on whether to be screened for orostate cancer.

关键词： cancer screening prostate-specific antigen prostatic neoplasms randomized controlled trials as topic

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前列腺癌筛查：调和初级保健和专科的视角矛盾

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中国全科医学 2013年第13期16卷 1451-1452页

作者： richard m.hoffman michael J.Barry richard G.Roberts Harold C.Sox 邵钧(翻译) New mexico大学医学院家庭医学和社区医学系美国新墨西哥州 Harvard医学院马萨诸塞州 Wisconsin大学医学和公共卫生学院家庭医学系威斯康辛州 Dartmouth医学院 Dartmouth研究所新罕布什尔州中国全科医学杂志社

当初级保健医生实施专科医生制定的筛查指南时,两者可能因视角不同而产生分歧。两则由专科机构最近发布的临床指南就足以说明这一问题。美国泌尿学会(AUA)指南小组和美国国家综合癌症网络(NCCN)建议,具有前列腺癌一般患病风险的男性在4... 详细信息

当初级保健医生实施专科医生制定的筛查指南时,两者可能因视角不同而产生分歧。两则由专科机构最近发布的临床指南就足以说明这一问题。美国泌尿学会(AUA)指南小组和美国国家综合癌症网络(NCCN)建议,具有前列腺癌一般患病风险的男性在40岁对前列腺特异性抗原筛查风险和好处进行咨询,而此前建议的年龄是50岁。不过,目前没有直接证据证明此建议对前列腺癌死亡率有具体影响。为了不妨碍初级保健医生为患者提供好处和价值已被证实的服务,专业机构在制定指南时应遵循适当的标准。初级保健协会和医疗系统也应该对现有证据进行评估,以判断临床建议实施的可行性和适用性。

关键词：前列腺特异性抗原癌症早期检测指南话题循证医学

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Biomarker and animal models for assessment of retinoid efficacy in cancer chemoprevention

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Acta Pharmacologica Sinica 2007年第9期28卷 1383-1391页

作者： richard m NILES Department of Biochemistry and microbiology Joan C Edwards School of MedicineMarshall UniversityHuntingtonWV 25701USA

Vitamin A is essential for normal growth and *** andlaboratory studies suggest that decreased vitamin A levels and defective metabo-lism/action may contribute to the genesis of certain *** on thisinformation,natural and synthetic derivatives of vitamin A (retinoids) have beenused for chemoprevention of *** have had some success in thechemoprevention of leukoplakia and in the decreased incidence of second prima-ries in head and neck *** is little information on biomarkers that can beused to assess the efficacy of the chemopreventive activity of *** of retinoids to induce RARb has been consistently shown to correlate withthe response of cells and tissues to retinoic acid,but few other biomarkers havebeen certified as indicators of retinoid *** light of the failure of the ATBCand CARET clinical intervention trials for chemoprevention of lung cancer,greateruse of animal models for chemoprevention studies is *** potentialcombination of phytochemicals that inhibit DNA methyltransferase activity withretinoids holds promise for more effective chemoprevention of retinoid-unrespon-sive premalignant lesions.

关键词： vitamin A retinoic acid chemoprevention biomarkers animal models transgenic animals

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Hereditary pancreatitis

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World Journal of Gastroenterology 2003年第1期9卷 1-4页

作者： richard m Charnley Consultant Surgeon Freeman HospitalNewcastle upon TyneNE7 7DNUK

Hereditary pancreatitis is an autosomal dominant condition,which results in recurrent attacks of acute pancreatitis,progressing to chronic pancreatitis often at a young *** majority of patients with hereditary pancreatitis expressone of two mutations (R122H or N29I) in the cationictrypsinogen gene (PRSS1 gene). It has been hypothesisedthat one of these mutations, the R122H mutation causespancreatitis by altering a trypsin recognition site sopreventing deactivation of trypsin within the pancreas andprolonging its action, resulting in autodigestion. Families withthese two mutations have been identified in many countriesand there are also other rarer mutations, which have alsobeen linked to hereditary *** with hereditary pancreatitis present in the sameway as those with sporadic pancreatitis but at an earlierage. It is common for patients to remain undiagnosed formany years, particularly ifthey present with non-specificsymptoms. Hereditary pancreatitis should always beconsidered in patients who present with recurrent pancreatitiswith a family history of pancreatic disease. If patients withthe 2 common mutations are compared, those with theR122H mutation are more likely to present at a younger ageand are more likely to require surgical intervention than thosewith N29I. Hereditary pancreatitis carries a 40 % lifetimerisk of pancreatic cancer with those patients aged between50 to 70 being most at risk in whom screening tests maybecome important.

关键词： Trypsin Genetic Counseling Genetic Screening Humans Pancreatitis Point mutation Risk Factors Trypsinogen

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Application of lung microphysiological systems to COVID-19 modeling and drug discovery:a review

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Bio-Design and manufacturing 2021年第4期4卷 757-775页

作者： Argus m.Sun Tyler hoffman Bao Q.Luu Nureddin Ashammakhi Song Li Department of Bioengineering Samueli School of EngineeringUniversity of California-Los Angeles420 Westwood Plaza 5121 Engineering V University of CaliforniaLos AngelesCA 90095-1600USA UC San Diego Healthcare UCSDLa JollaCA 92037USA Pulmonary Diseases and Critical Care Scripps Green HospitalScripps HealthLa JollaCA 92037USA Department of Biomedical Engineering College of EngineeringMichigan State UniversityEast LansingMI 48824USA Department of medicine David Geffen School of MedicineUCLALos AngelesCA 90095USA

There is a pressing need for effective therapeutics for coronavirus disease 2019(COVID-19),the respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)*** process of drug development is a costly and meticulously paced process,where progress is often hindered by the failure of initially promising *** aid this chal-lenge,in vitro human microphysiological systems need to be refined and adapted for mechanistic studies and drug screening,thereby saving valuable time and resources during a pandemic *** SARS-CoV-2 virus attacks the lung,an organ where the unique three-dimensional(3D)structure of its functional units is critical for proper respiratory *** in vitro lung models essentially recapitulate the distinct tissue structure and the dynamic mechanical and biological interactions between different cell *** model systems include Transwell,organoid and organ-on-a-chip or microphysiological systems(mPSs).We review models that have direct relevance toward modeling the pathology of COVID-19,including the processes of inflammation,edema,coagulation,as well as lung immune *** also consider the practical issues that may influence the design and fabrication of *** role of lung mPS is addressed in the context of multi-organ models,and it is discussed how high-throughput screening and artificial intelligence can be integrated with lung mPS to accelerate drug development for COVID-19 and other infectious diseases.

关键词： Bioengineering microfluidics COVID-19 Organ-on-a-chip Lung microvascular networks Drug development

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Fluorescence-guided hepatobiliary surgery with long and short wavelength fluorophores

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Hepatobiliary Surgery and Nutrition 2020年第5期9卷 615-639页

作者： Thinzar m.Lwin Robert m.hoffman michael Bouvet Department of Surgery University of California San DiegoSan DiegoCAUSA AntiCancer Inc.San DiegoCAUSA VA San Diego Healthcare System San DiegoCAUSA

Importance:Fluorescence-guided surgery(FGS)is a potentially powerful tool for hepatobiliary(HPB)*** high sensitivity of fluorescence navigation is especially useful in settings where tactile feedback is ***:The present narrative review evaluates literature on the use of FDA-approved fluorophores such as methylene blue(mB),5-aminolevulinic acid(5-ALA),and indocyanine green(ICG)for clinical intra-operative image-guidance during HPB *** Review:Approaches such as dosing,timing,imaging devices and comparative endpoints are *** feasibility and safety of fluorophores in visualizing the biliary tree,identify biliary leaks,outline anatomic hepatic segments,identify tumors,and evaluate perfusion and graft function in liver transplants are ***:Tumor-specific probes are a promising advancement in FGS with a greater degree of *** current status of tumor-specific probes being evaluated in clinical trials are *** and Relevance for Reviews:Relevant discussion of promising tumor-specific probes in pre-clinical development are ***-guidance in HPB surgery is relatively new,but current literature shows that the dyes are reliably able to outline desired structures with a variety of dosing,timing,and imaging devices to provide real-time intra-operative anatomic information to *** of tumor-specific probes will further advance the field of HPB surgery especially during oncologic resections.

关键词： Fluorescence-guided surgery(FGS) methylene blue(mB) 5-aminolevulinic acid(5-ALA) indocyanine green(ICG) hepatobiliary surgery(HPB surgery) tumor-specific probes near-infrared fluorescence(NIR fluorescence)

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Orientation of larval and juvenile horseshoe crabs Limulus polyphemus to visual cues: Effects of chemical odors

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Current Zoology 2010年第5期56卷 618-633页

作者： Julie m.mEDINA richard A.TANKERSLEY Department of Biological Sciences Florida Institute of Technology

Adult horseshoe crabs Limulus polyphemus have long served as models for the study of vision in marine arthropods. Yet, little is known about the ability of early life history stages to detect and respond to visual cues. We examined the visually directed movements of larvae and first stage juveniles to horizons containing dark visual targets of different sizes. The study tested the hypotheses that （1） larval and juvenile crabs can detect and respond to visual targets and （2） the direction of orientation varies with the presence of chemical cues associated with settlement habitats. Orientation of larval and juvenile crabs to rectangles subtending angles from 30--330~ was tested in a circular arena containing water that either lacked estuarine chemical cues （offshore water） or contained odors from aquatic vegetation or known predators. In the absence of chemical odors, larvae oriented toward and juveniles moved away from dark horizons subtending angles 〉 60~. When placed in water containing chemical odors from potential nursery habitats, including the seagrasses Halodule wrightii and Syringodium filiforme, crabs reversed their direction of orientation relative to their responses in offshore water. Odors from two known predators, the mummichug Fundulus grandis and blue crab Callinectes sapidus, had no affect on the orientation of larvae. Yet, juveniles responded to both odors by moving toward the visual target. Results support the hypothesis that the visual orientation of larval and juvenile horseshoe crabs changes upon exposure to habitat and predator cues and that the direction of the response undergoes an ontogenetic shift following metamorphosis

关键词： Orientation Visual cues Chemical odors

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Understanding Science Through the Computational Lens

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Journal of Computer Science & Technology 2011年第4期26卷 569-577页

作者： richard m.Karp Department of Electrical Engineering and Computer Sciences University of California

This article explores the changing nature of the interaction between computer science and the natural and social sciences. After briefly tracing the history of scientific computation, the article presents the concept of computational lens, a metaphor for a new relationship that is emerging between the world of computation and the world of the sciences. Our main thesis is that, in many scientific fields, the processes being studied can be viewed as computational in nature, in the sense that the processes perform dynamic transformations on information represented as digital data. Viewing natural or engineered systems through the lens of their computational requirements or capabilities provides new insights and ways of thinking. A number of examples are discussed in support of this thesis. The examples are from various fields, including quantum computing, statistical physics, the World Wide Web and the Internet, mathematics, and computational molecular biology.

关键词： computational process computer science and other sciences computational lens

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microRNAs and Alu elements in the p53-mdm2-mdm4 regulatory network

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Journal of molecular Cell Biology 2014年第3期8卷 192-197页

作者： Yonit hoffman Yitzhak Pilpel moshe Oren Department of molecular Genetics Weizmann Institute of Science Rehovot 76100 Israel Department of molecular Cell Biology Weizmann Institute of Science Rehovot 76100 Israel

p53 is a transcription factor that governs numerous stress response pathways within the ceil. maintaining the right levels of p53 is crucial for ceil survival and proper cellular homeostasis, The tight regulation of p53 involves many cellular components, most notably its major negative regulators mdm2 and mdm4, which maintain p53 protein amount and activity in tight check, microRNAs （miRNAs） are small non-coding RNAs that target specific mRNAs to translational arrest and degradation, miRNAs are also key compo- nents of the normal p53 pathway, joining forces with mdm2 and mdm4 to maintain proper p53 activity. Here we review the current knowledge of miRNAs targeting mdm2 and mdm4, and their importance in different tissues and in pathological states such as cancer. In addition, we address the role of Alu sequences-highly abundant retroelements spread throughout the human genome, and their impact on gene regulation via the miRNA machinery. Aius occupy a significant portion of genes＇ 31UTR, and as such they have the potential to impact mRNA regulation. Since Alus are primate-specific, they introduce a new regulatory layer into primate genomes. Atus can influence and alter gene regulation, creating primate-specific cancer-preventive regulatory mechanisms to sustain the transition to longer life span in primates. We review the possible influence of Alu sequences on miRNA functionality in general and specifically within the p53 network.

关键词： microRNA p53 mdm2 mdm4 Alu

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metamorphic consequences of secular changes in oceanic crust composition and implications for uniformitarianism in the geological record

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Geoscience Frontiers 2018年第4期9卷 1009-1019页

作者： richard m.Palin Brendan Dyck Department of Geology and Geological Engineering Colorado School of Mines Department of Earth Sciences Simon Fraser University

Cooling of the Earth＇s mantle since the meso-Archean is predicted by thermal and petrological models to have induced a secular change in the composition of primary mantle-derived magmas-and thus bulk oceanic crust; in particular, suggesting a decrease in maficity over time. This hypothesis underpins several recent studies that have addressed key geological questions concerning evolving plate tectonic styles, the rates and timing of continental crust formation, comparative planetology, and the emergence of complex life on Earth. major, minor, and trace element geochemical analyses of（meta）mafic rocks preserved in the geological record allows exploration of this theory, although no consensus currently exists about the magnitude of this change and what compositions-if anything-constitute representative examples of Paleo-, meso-, or Neo-Archean primitive oceanic crust. In this work, we review the current state of understanding of this issue, and use phase equilibria to examine the different mineral assemblages and rock types that would form during metamorphism of basalt of varying maficity in subduction zone environments. The presence（or absence） of such metamorphic products in the geological record is often used as evidence for（or against） the operation of modern-day subductiondriven plate tectonics on Earth at particular time periods; however, the control that secular changes in composition have on the stability of mineral assemblages diagnostic of subduction-zone metamorphism weakens such uniformitarianistic approaches. Geodynamic interpretations of the Archean metamorphic rock record must therefore employ a different set of petrological criteria for determining tectonothermal histories than those applied to Proterozoic or Phanerozoic equivalents.

关键词： Archean mantle cooling Oceanic crust Basalt metamorphism Uniformitarianism

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