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Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

Asian Journal of Urology 2016年第4期3卷 185-194页

作者： cameron m.Armstrong Allen C.Gao Department of Urology University of CaliforniaDavisSacramentoCAUSA Comprehensive Cancer Center University of CaliforniaDavisSacramentoCAUSA VA Northern California Health Care System SacramentoCAUSA

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and ***,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the *** the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been *** receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,member C3(AKR1C3)are among the many mechanisms associated with resistance to *** regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current *** instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone ***1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment *** review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

关键词： Prostate cancer Castration resistant prostate cancer Enzalutamide Abiraterone Docetaxel Drug resistance

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Ischemic cholangiopathy after livertransplantation

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Hepatobiliary & Pancreatic Diseases International 2005年第4期4卷 495-501页

作者： Andrew m. cameron Ronald W. Busuttil Division of Liver and Pancreas Transplantation Department of SurgeryDavid Geffen School of Medicine at UCLALos AngelesCalifornia 90095-7054USA

Orthotopic liver transplantation ( OLT) has evolved over the last forty years from an experimental endeavor to standard of care therapy for many patients with end stage hepatic disease. many technical advances have contributed to the current success of OLT, but surgical complications, especially involving the biliary reconstruction, remain a morbid problem. Biliary complications after OLT include leaks and strictures. Strictures may be anastoinotic or intrahepatic and diffuse, as seen in cases of hepatic artery thrombosis. Current efforts to expand the limited donor pool include the use of non-heart beating donors. The organ procurement process in these donors entails an increased period of warm ischemia and results with non-heart beating donor grafts have been mixed. It is now appreciated that there is an increased incidence of subsequent diffuse biliary stricturing or ' ischemic cholangiopathy' in recipients of these organs. Animal models of this phenomenon and potential therapeutic strategies targeted at ischemic cholangiopathy are being developed with potential applicability to non-heart beating donation and will be the focus of this review.

关键词： orthotopic liver transplantation biliary strictures non-anastoinotic strictures ischemic cholangiopathy non-heart beating donor

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Current strategies for targeting the activity of androgen receptor variants

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Asian Journal of Urology 2019年第1期6卷 42-49页

Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor ***,cancer cells are very adaptable and,over time,these cells develop mechanisms by which they can circumvent *** of the many mechanisms that have been discovered is the generation of AR *** variants are generated through alternative splicing of the full length AR and often lack the ligand binding *** leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of *** high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and *** these are the antihelminthic drug,niclosamide,which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and *** AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains,which are retained in most AR *** clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical *** this review,we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.

关键词： Prostate cancer Androgen receptor variants Drug resistance

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Duplicate publication bias weakens the validity of metaanalysis of immunosuppression after transplantation

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World Journal of Gastroenterology 2017年第39期23卷 7198-7200页

作者： cameron J Fairfield Ewen m Harrison Stephen J Wigmore Department of Clinical Surgery University of Edinburgh Royal Infirmary of Edinburgh

Duplicate publication can introduce significant bias into a meta-analysis if studies are inadvertently included more than once. many studies are published in more than one journal to maximize readership and impact of the study findings. Inclusion of multiple publications of the same study within a meta-analysis affords inappropriate weight to the duplicated data if reports of the same study are not linked together. As studies which have positive findings are more likely to be published in multiple journals this leads to a potential overestimate of the benefits of an intervention. Recent advances in immunosuppression strategies following liver transplantation have led to many studies investigating immunosuppressive regimes including immunosuppression monotherapy. In this letter we focus on a recently published meta-analysis by Lan et al investigating studies assessing immunosuppression monotherapy for liver transplantation. The authors claim to have identified fourteen separate randomised studies investigating immunosuppression monotherapy. Seven of the references appear to relate to only three studies which have been subject to duplicate publication. Several similarities can be identified in each of the duplicate publications including similar authorship, identical immunosuppression regimes, identical dates of enrolment and citation of the original publication in the subsequent manuscripts. We discuss the evidence of the duplicate publication inclusion in the meta-analysis.

关键词： Liver transplantation Immunosuppression meta-analysis Duplicate publication Bias

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Divergence and constraint in the thermal sensitivity of aquatic insect swimming performance

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Current Zoology 2020年第5期66卷 555-564页

作者： Alisha A.SHAH Eva m.S.Bacmeister Juan G.Rubalcaba cameron K.Ghalambor Department of Biology Colorado State UniversityFort CollinsCO80526USA Division of Biological Sciences University of MontanaMissoulaMT59812USA Department of Biology McGill University1205 Docteur PenfieldMontrealQCCanada Department of Biology Centre for Biodiversity DynamicsNorwegian University of Science and Technology(NTNU)TrondheimNorway

Environmental temperature variation may play a significant role in the adaptive evolutionary divergence of ectotherm thermal performance curves(TPCs).However,divergence in TPCs may also be constrained due to various ***,we measured TPCs for swimming velocity of temperate and tropical mayflies(Family:Baetidae)and their stonefly predators(Family:Perlidae)from different *** predicted that differences in seasonal climatic regimes would drive divergence in TPCs between temperate and tropical *** tropical temperatures should favor the evolution of"specialists"that perform well across a narrow range of ***,variable temperatures in temperate zones,however,should favor"generalists"that perform well across a broad range of *** phylogenetically paired comparisons of mayflies and stoneflies,swimming speed was generally unaffected by experimental temperature and did not differ among populations between latitudes,suggesting a maintenance of performance breadth across elevation and *** exception was found between temperate and tropical mayflies at low elevation where climatic differences between latitudes are *** addition,TPCs did not differ between mayflies and their stonefly predators,except at tropical low *** results indicate that divergence in TPCs may be con strai ned in aquatic in sects except under the most differe nt ther・mal regimes,perhaps because of trade-offs that reduce thermal sensitivity and increase performance breadth.

关键词： aquatic insects climate variability elevation latitude predator-prey swimming performance thermal performance curve

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Summer monsoon and dust signals recorded in the Dasuopu firn core, central Himalayas

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Chinese Science Bulletin 1999年第21期44卷 2010-2015页

作者： cameron P.Wake Paul A.mayewski Climate Change Research Center Institute for the Study of EarthOcean and Space(EOS)University of New Hampshire DurhamNH 03824USAClimate Change Research CenterInstitute for the Study of EarthOcean and Space(EOS)University of New Hampshire DurhamNH 03824USA

In September 1997, a 15-m firn core was recovered from an elevation of 7 000 m a. s.l. from the Dasuopu Glacier in the central Himalayas. The analysis of δ18O values and major ion (Ca2+ , mg2+ , NH4+ , SO2- and NO3-) concentrations shows that average annual accumulation is 0.75 m (water equivalent) in the Dasuopu firn core. The seasonal variations of δ18O values and major ion concentrations in the core indicate that present summer monsoon and

关键词： firn core records of summer monsoon and dust signals central Himalayas.

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Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts

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Bone Research 2016年第3期4卷 164-173页

作者： Allahdad Zarei Alireza morovat Kassim Javaid cameron P Brown Botnar Research Centre Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science University of Oxford Oxford UK Clinical Biochemistry Oxford University Hospitals NHS Trust Oxford UK

The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor （VDR）, we examined their response to different concentrations of 25-hydroxy vitamin D3 [25（OH）D3] （100 or 500 nmol·L^-1） and 1,25-dihydroxy vitamin D3 [1,25（OH）2D3] （0.1 or 0.5 nmol·L^-1） metabolites in cell cultures. Specifically, CD14＋ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand （RANKL） and macrophage colony-stimulating factor （m-CSF）. Tartrate-resistant acid phosphatase （TRAP） histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue （ex vivo） by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR （qRT-PCR） was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L^-1 of 25（OH）D3 and 0.1-0.5 nmol·L^-1 of 1,25（OH）2D3, upregulating cytochrome P450 family 27 subfamily B member I （CYP27B1） and cytochrome P450 family 24 subfamily A member I （CYP24A1）. Osteoclast fusion transcripts transmembrane 7 subfamily member 4 （tm7sf4） and nuclear factor of activated T-cell cytoplasmic 1 （nfatcl） where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25（OH）D3 and 1,25（OH）2D3 reduced osteoclast size and number when co-treated with RANKL and m-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25（OH）2D3 on osteoclasts in vitro may therefore provide

关键词： Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts bone

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Effectiveness of exercise in hepatic fat mobilization in nonalcoholic fatty liver disease: Systematic review

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World Journal of Gastroenterology 2016年第27期22卷 6318-6327页

作者： Pegah Golabi cameron T Locklear Patrick Austin Sophie Afdhal melinda Byrns Lynn Gerber Zobair m Younossi Betty and Guy Beatty Center for Integrated Research Inova Health System Department of medicine Center for Liver Disease Inova Fairfax Hospital Health Sciences Library Inova Fairfax Hospital

AIm: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease(NAFLD) ***: Ovid-medline, Pub med, EmBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: "NASH", "NAFLD", "nonalcoholic steatohepatitis", "non-alcoholic fatty liver disease", "fat", "steatosis", "diet", "exercise", "mR spectroscopy" and "liver biopsy". NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy(H-mRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria(6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-mRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared thetwo interventions. The beneficial effects of exercise on intrahepatic triglyceride(IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid ***: Prescribed exercise in subjects with NAFLD red

关键词： Non-alcoholic fatty liver disease Exercise Diet Fat mobilization Lifestyle modification

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Outrunning the Red Queen： bystander activation as a means of outpacing innate immune subversion by intracellular pathogens

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Cellular & molecular Immunology 2017年第1期14卷 14-21页

作者： Alicia m Holmgren cameron A mcConkey Sunny Shin Depatment of microbiology Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104-6060 USA Immunology Graduate Group Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104-6060 USA

Originally described by the late evolutionary biologist Leigh Van Valen, the Red Queen hypothesis posits that the evolutionary arms race between hosts and their pathogens selects for discrete, genetically encoded events that lead to competitive advantages over the other species. Examples of immune evasion strategies are seen throughout the co-evolution of the mammalian immune system and pathogens, such as the enzymatic inactivation of nuclear factor-KB signaling or host translation by pathogen-encoded virulence factors. Such immunoevasive maneuvers would be expected to select for the evolution of innate immune counterstrategies. Recent advances in our understanding of host immunity and microbial pathogenesis have provided insight into a particular innate immune adaptation, termed bystander activation. Bystander activation occurs as a consequence of infected cells alerting and instructing neighboring uninfected cells to produce inflammatory mediators, either through direct cell contact or paracrine signals. Thus, bystander activation can allow the immune system to overcome the ability of pathogens to disarm immune signaling in directly infected cells. This review presents an overview of the general hallmarks of bystander activation and their emerging role in innate immunity to intraceUular pathogens, as well as examples of recent mechanistic discoveries relating to the bystander activation during infection with specific pathogens relevant to human health and disease.

关键词： cell-cell communication cGAS exosomes gap junctions inflammasomes innate immunity

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Atomically dispersed dual-metal-site PGm-free electrocatalysts for oxygen reduction reaction:Opportunities and challenges

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Susmat 2022年第5期2卷 569-590页

作者： Xiaoxuan Yang cameron Priest Yang Hou Gang Wu College of Chemical and Biological Engineering Zhejiang UniversityHangzhouChina Department of Chemical and Biological Engineering University at BuffaloThe State University of New YorkBuffaloNew YorkUSA Institute of Zhejiang University-Quzhou QuzhouChina School of Biological and Chemical Engineering NingboTech UniversityNingboChina

Atomically dispersed and nitrogen coordinated single metal site(mNx,m=Fe,Co,or mn)moieties embedded in partially graphitized carbon(denoted as m–N–C)are recognized as the most promising platinum group metal-free catalysts for the oxygen reduction reaction(ORR)in proton exchange membrane fuel ***,simply regulating their coordination environments and local structures of single metal sites cannot fundamentally change active site structure,which leads to insufficient activity and stability.A second transition metal can be incorporated to design dual-metal sites,offering a new opportunity to modulate the electronic and geometric structures of m–N–C ***,exploring optimal atomically dispersed dual-metal-site is essential to designing new active sites with enhanced ORR activity,and stability,especially breaking the activity-stability *** review provides a comprehensive analysis of the advances in developing atomically dispersed dual-metal site catalysts for the ORR,including innovative synthesis methods,primary structural configurations,and the mechanisms to promote catalytic *** aim to elucidate the crucial structure–property correlation,emphasizing the inherent electronic and geometric effects of dual metal ***,we discuss the current challenges of dual-metal site catalysts concerning rational design,precise synthesis,and high-fidelity structural characterization.

关键词： dual metal sites electrocatalysis fuel cells oxygen reduction PGm-free catalyst

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