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Oncology Research 2024年第5期32卷 799-805页

作者： SANDRA STICKLER BARBARA RATH gERHARD hamilton Institute of Pharmacology Medical University of ViennaViennaA-1090Austria

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient *** Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for ***,the most common KRAS mutations in PDAC are g12D(44%),g12V(34%)and g12R(20%)that are not amenable to treatment by KRAS g12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung *** g12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of ***,the KRAS g12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in *** other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(gEF)Son of Sevenless 1 that drives *** agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

关键词： Pancreatic cancer PDAC KRAS SOS1 PROTAC

Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： gERHARD hamilton MARIE-THERESE EggERSTORFER SANDRA STICKLER Institute of Pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS g12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the g12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

Colorful facial markings are associated with foraging rates and affiliative relationships in a wild group-living cichlid fish

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Current Zoology 2024年第1期70卷 70-78页

作者： Brett M.Culbert James B.Barnett Isaac Y.Ligocki Matthew g.Salena Marian Y.L.Wong Ian M.hamilton Sigal Balshine Department of Integrative Biology University of GuelphGuelphOntarioCanada Department of Psychology Neuroscience&BehaviourMcMaster UniversityHamiltonOntarioCanada Department of Evolution Ecologyand Organismal BiologyThe Ohio State UniversityColumbusOHUSA Department of Biology Millersville UniversityMillersvillePAUSA School of Earth Atmospheric and Life SciencesUniversity of WollongongWollongongNew South WalesAustralia Department of Mathematics The Ohio State UniversityColumbusOHUSA

Many animals use color to signal their quality and/or behavioral *** signals have been well studied in the contexts of competi-tion and mate choice;however,the role of these signals in nonsexual,affiliative relationships is not as well ***,we used wild social groups of the cichlid fish Neolamprologus pulcher to investigate whether the size of a brightly colored facial patch was related to 1)individual quality,2)social dominance,and/or 3)affiliative *** with larger patches spent more time foraging and tended to perform more aggressive acts against conspecific territory *** did not find any evidence that the size of these yellow patches was related to social rank or body size,but dominant males tended to have larger patches than dominant ***,patch size had a rank-specific relationship with the number of affiliative interactions that individuals engaged *** males with large patches received fewer affiliative acts from their groupmates compared to dominant males with small ***,subordinates with large patches tended to receive more affiliative acts from their groupmates while performing fewer affiliative acts *** together,our results suggest that patch size reflects interindividual variation in foraging effort in this cichlid fish and offer some of the first evidence that colorful signals may shape affiliative relationships withinwildsocialgroups.

关键词： affiliation foraging Lake Tanganyika Neolamprologus pulcher visual signals

How Agent Orange impacts prostate cancer risk, pathology, and treatment outcomes

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CURRENT UROLOgY 2024年第2期18卷 79-86页

作者： Paracha, Awais Siddiqui, Zohair Abid, Ali Deol, Ekamjit Waheed, Fatima hamilton, Zachary St Louis Univ Sch Med St Louis MO USA St Louis Univ St Louis MO USA 3507 Laclede Ave St Louis MO 63103 USA New York Inst Technol Coll Osteopath Med Old Westbury NY USA St Louis Univ Sch Med Dept Surg Div Urol St Louis MO USA 1402 S grand Blvd St Louis MO 63104 USA

Between 2.6 and 3.8 million veterans served in Vietnam while the US military dispersed Agent Orange (AO), although the exact number of exposed individuals is unknown. Agent Orange, an herbicide, is a known risk factor for various cancers, including sarcoma and leukemia, but less is known about its link with prostate cancer (PC). Prostate cancer is the most commonly diagnosed malignancy in men and the fifth most common cause of cancer-related death in men worldwide. In 2023, approximately 288,300 patients will be given a diagnosis of PC, and an estimated 34,700 fatalities will occur in the United States. However, whether the pathologic characteristics of PC among those exposed to AO differ from those in the general population remains unclear. Our review synthesizes the literature regarding the impact of AO exposure on PC incidence and disease course. A comprehensive PubMed literature search of articles published beginning in 1950 was performed using the primary search terms "Agent Orange," "TCDD," and "tetrachlorodibenzodioxin" and the secondary search terms "prostate cancer" or "prostate neoplasm." The search was limited to studies that focused on human participants and were published in English. Four authors thoroughly reviewed the retrieved articles for relevancy to the study aims: discussion of PC diagnosis, prognosis, or management among patients exposed to AO. Of 108 studies identified in our search, 13 were included in this systematic review. Findings within studies concerning AO exposure with relation to PC incidence, age at diagnosis or treatment initiation, and PC severity seemed to be mixed and generally conflicting. However, the literature seems to indicate that there are no significant differences in survivorship between exposed and unexposed veterans who are given a diagnosis of PC. given these heterogeneous outcomes, the evidence does not encourage a significantly different approach to the diagnosis and management of PC for veterans exposed to AO. Clin

关键词： Agent Orange 2,3,7,8-Tetrachlorodibenzo-p-dioxin Prostate cancer Veterans AIR-FORCE VETERANS VIETNAM VETERANS EXPOSURE DIOXIN RECURRENCE ACID

Spatial analysis of the osteoarthritis microenvironment: techniques, insights, and applications

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Bone Research 2024年第1期12卷 1-19页

作者： Xiwei Fan Antonia Rujia Sun Reuben S.E.Young Isaac O.Afara Brett R.hamilton Louis Jun Ye Ong Ross Crawford Indira Prasadam Centre for Biomedical Technologies Queensland University of TechnologyBrisbaneQLDAustralia School of Mechanical Medical&Process EngineeringQueensland University of TechnologyBrisbaneQLDAustralia Central Analytical Research Facility Queensland University of TechnologyBrisbaneQLDAustralia Molecular Horizons University of WollongongWollongongNSWAustralia Department of Technical Physics University of Eastern FinlandKuopioFinland School of Electrical Engineering and Computer Science Faculty of EngineeringArchitecture and Information TechnologyUniversity of QueenslandBrisbaneQLDAustralia Centre for Microscopy and Microanalysis University of QueenslandBrisbaneQLDAustralia The Prince Charles Hospital BrisbaneQLDAustralia

Osteoarthritis(OA)is a debilitating degenerative disease affecting multiple joint tissues,including cartilage,bone,synovium,and adipose *** presents diverse clinical phenotypes and distinct molecular endotypes,including inflammatory,metabolic,mechanical,genetic,and synovial ***,innovative technologies are needed to support the development of effective diagnostic and precision therapeutic *** analysis of bulk OA tissue extracts has limitations due to technical constraints,causing challenges in the differentiation between various physiological and pathological phenotypes in joint *** issue has led to standardization difficulties and hindered the success of clinical *** insights into the spatial variations of the cellular and molecular structures in OA tissues,encompassing DNA,RNA,metabolites,and proteins,as well as their chemical properties,elemental composition,and mechanical attributes,can contribute to a more comprehensive understanding of the disease *** resolved biology enables biologists to investigate cells within the context of their tissue microenvironment,providing a more holistic view of cellular *** advances in innovative spatial biology techniques now allow intact tissue sections to be examined using various-omics lenses,such as genomics,transcriptomics,proteomics,and metabolomics,with spatial *** fusion of approaches provides researchers with critical insights into the molecular composition and functions of the cells and tissues at precise spatial ***,advanced imaging techniques,including high-resolution microscopy,hyperspectral imaging,and mass spectrometry imaging,enable the visualization and analysis of the spatial distribution of biomolecules,cells,and *** these molecular imaging outputs to conventional tissue histology can facilitate a more comprehensive characterization of disease *** review summarizes the rec

关键词： insight Spatial enable

Leptomeningeal metastases in prostate cancer:A review of the current literature

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Current Urology 2024年第3期18卷 159-166页

作者： Umar Durrani Kasem Rifai Maha Arshad Awais Paracha Ekamjit Deol Maria Paracha Fatima Waheed Zohair Siddiqui Ali Abid Esed Mustafic Wilson Rodriguez Zachary hamilton Saint Louis University School of Medicine Saint LouisMOUSA University of Missouri School of Medicine ColumbiaMOUSA University of Virginia CharlottesvilleVAUSA New York Institute of Technology College of Osteopathic Medicine Old WestburyNYUSA Saint Louis University Saint LouisMOUSA Department of Neurology Saint Louis University School of MedicineSaint LouisMOUSA Division of Urology Department of SurgerySaint Louis University School of MedicineSaint LouisMOUSA

Leptomeningeal metastasis/leptomeningeal carcinomatosis(LMC;terms used interchangeably)is an inflammatory complication of primary tumors that involves the spread of the disease to the meninges(specifically the arachnoid and pia maters)and spinal *** the United States,approximately 110,000 new cases are diagnosed each year,and the prognosis is usually *** of LMC include cognitive impairment,cranial nerve dysfunction,ischemic stroke,and *** survival times of untreated and treated LMC are approximately 4–6 weeks and 2–4 months,*** carcinomatoses are usually metastatic cancers that spread to the central nervous *** lung and breast cancers have a clearly defined relationship with LMC,it remains unclear whether prostate cancer(PC)is also directly associated with *** determine whether such association exists,we conducted a PubMed review of the literature on patients with PC with coexisting *** search yielded 23 case reports of patients with preexisting PC who developed *** addition,2 retrospective cohort studies were *** findings were identified in the revised cases and *** first 3 findings were related to the progression of the disease:patients presenting with neurological disease symptoms were in remission from PC for 7 years on average,LMCs tended to occur after other cancer diagnoses,and the disease had already rapidly progressed by the time the symptoms were *** diagnosis,the major finding was that most LMCs were detected by magnetic resonance imaging(which does not detect early dissemination),and it was suggested that single-photon emission computed tomography or positron emission tomography imaging could be used for earlier ***,in terms of treatment,the main finding was that treatment was palliative rather than curative and that prognosis remained poor despite *** the basis of these results,we recommend for individuals with risk facto

关键词： Leptomeningeal carcinomatosis Prostate cancer Prostate cancer metastasis

Hardening Effects in Superhard Transition-Metal Borides

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Accounts of Materials Research 2022年第1期3卷 100-109页

作者： Lisa E.Pangilinan Shanlin Hu Spencer g.hamilton Sarah H.Tolbert Richard B.Kaner Department of Chemistry and Biochemistry University of CaliforniaLos Angeles(UCLA)Los AngelesCalifornia 90095United States Department of Chemistry and Biochemistry Department of Materials Science and Engineeringand California NanoSystems Institute(CNSI)University of CaliforniaLos Angeles(UCLA)Los AngelesCalifornia 90095United States

CONSPECTUS:Mechanical hardness is a physical property used to gauge the applications of materials in the manufacturing and machining *** of their high hardness and wear resistance,superhard materials(Vickers hardness,Hv≥40 gPa)are commonly used as cutting tools and *** diamond is the hardest known material used for industrial applications,its synthesis requires both high pressure and high *** in the field of superhard materials research has led to the search for alternatives with high hardness and thermal stability at low *** discovery of novel ultraincompressible,superhard materials has largely developed through trial and error along two *** one approach,researchers combine light elements,such as boron,carbon,nitrogen,and oxygen,often at high pressure,to replicate the highly directional,dense,covalent bonds of *** the second approach,these light elements(B,C,N,and O)are combined with highly incompressible,electron-rich transition metals to form dense covalently bonded networks at ambient pressure.

关键词： Transition boron gauge

文献快报(5):社交媒体使用消极体验而非使用时长增加青少年自杀意念

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中国学校卫生 2024年第5期45卷 614-614页

作者： hamilton J LDALACK M BOYD S I 李琪(编译) Department of Psychology Rutgers University Piscataway NJ USA. Department of Psychology George Washington University Washington DC USA. Department of Psychiatry University of Pittsburgh Pittsburgh PA USA.

社交媒体使用与青少年自杀风险的关联受到广泛关注。匹兹堡大学David教授领衔的团队在美国各地招募了60名青少年进行了为期8周的监测,通过每日3次生态瞬时评估询问青少年社交媒体使用相关的消极体验(如感到焦虑)、积极体验(如受到鼓励)... 详细信息

社交媒体使用与青少年自杀风险的关联受到广泛关注。匹兹堡大学David教授领衔的团队在美国各地招募了60名青少年进行了为期8周的监测,通过每日3次生态瞬时评估询问青少年社交媒体使用相关的消极体验(如感到焦虑)、积极体验(如受到鼓励)及自杀意念,首次通过密集监测设计探讨青少年社交媒体体验与自杀意念间的关联,结果显示,频繁经历消极的社交媒体体验的青少年更可能报告自杀意念,而积极的社交媒体体验与自杀意念报告率降低有关。此外,未发现社交媒体的使用时间(视屏时间)与自杀意念间的显著关联。研究提示社交媒体经历可能是青少年自杀可修饰的风险因素,未来的研究应将增强青少年社交媒体的积极体验感作为改善青少年心理健康和预防自杀的目标,而不仅仅是限制视屏时间。

关键词：社交媒体匹兹堡大学自杀意念青少年自杀积极体验青少年心理健康监测设计消极体验

SERVICE VALUE NETWORKS:INTO PRACTICE

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Journal of Systems Science and Systems Engineering 2007年第4期16卷 414-423页

作者： John hamilton Director of E-Business James Cook UniversityCairns4870Australia

Modeling a business to match its customer perceived （and customer desired） outcomes, remains an on-going task. This paper considers shows how a service value networks （SVNs） approach may be engaged to model, and deliver, understanding of the front-end business and its direct engagement with its immediate （or front-end） customers. These front-end customers may be either：（1） its off-line, in-store customers - engaging directly with the business sales staff （or representative）, or-（2） its on-line, virtual customers - engaging with the business via internet or remote access. In this situation, both the business, and the customer draw upon their respective viewpoints, and both sides influence the interaction. External to these business and customer influences are additional factors that capture the immediate and broader global effects - termed environmental effects. These three business-customer engagement areas of influence are captured by a SVN SEM approach. Without a business-customer encounter of some kind the likelihood of a services business, and a prospecting customer, successfully engaging in an exchange process is reduced. This exchange may be a physical, and/or services exchange, and/or an information and/or ideas exchange. To the business, this encounter is, in effect, a trade, and as a result, the business targets acquiring an economic exchange that will ultimately deliver a net positive economic outcome. To the customer, external and internal information feeds, servicing, perceived value, and satisfaction, are key encounter drivers. SVNs offers a new way to understand the business-customer encounter, and to then utilize this acquired knowledge to either：（1） build a strategic management model, or （2） reengineer its business networks, and to then create a re-positioned, more customer-aligned business operation - one that is capable of delivering win - win, competitive business-customer solutions.

关键词： Service value networks alignment structural equation modeling