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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through mYC degradation

Signal Transduction and Targeted Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.mello metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel Colm morrsey Sanjoy mehta Jesse Barnes michael C.Haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia molina-Pinelo Sohrab Salehi Helena A.Yu Joseph m.Chan charles m.rudin Department of medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer Biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Graduate School of medical Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human Biology and Clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening Core Facility memorial Sloan Kettering Cancer Center New YorkNYUSA Department of Laboratory medicine and Pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell medical College New York NYUSA Present address:Swiss Institute for Experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the mYC Proto-Oncogen(mYC),implicated in stemness and histological *** overexpression of a degradation-resistant mYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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RABL-regulated pathways： a new tale in sperm function

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Asian Journal of Andrology 2013年第1期15卷 87-88页

作者： charles m Allan ANZAC Research Institute Concord Hospital Universityof Sydney Sydney NSW 2139 Australia

mammalian sperm have a specialized motile flagellum to provide the unidirectional propulsion required to achieve fertilisation of the egg. Defective flagella development and/or function is a significant cause of reduced sperm motility （asthenospermia） and male infertility. Over the past decade, a growing number of distinct proteins with crucial roles in sperm flagella have been identified by genetic loss-offunction approaches in mice, in which the deliberately engineered or spontaneous mutation of individual genes have lead to anomalies in sperm tail assembly,

关键词： X-ray crystallography G protein-coupled receptors

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Nanoscience and the nano-bioelectronics frontier

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Nano Research 2015年第1期8卷 1-22页

作者： Xiaojie Duan charles m. Lieber Department of Biomedical Engineering College of Engineering Peking University Beijing 100871 China Department of Chemistry and Chemical Biology Harvard University Cambridge MA 02138 USA School of Engineering and Applied Sciences Harvard University Cambridge MA 02138 USA

This review describes work presented in the 2014 inaugural Tsinghua University Press-Springer Nano Research Award lecture, as well as current and future opportunities for nanoscience research at the interface with brain science. First, we briefly summarize some of the considerations and the research journey that has led to our focus on bottom-up nanoscale science and technology. Second, we recapitulate the motivation for and our seminal contributions to nanowire- based nanoscience and technology, including the rational design and synthesis of increasingly complex nanowire structures, and the corresponding broad range of ＂applications＂ enabled by the capability to control structure, com- position and size from the atomic level upwards. Third, we describe in more detail nanowire-based electronic devices as revolutionary tools for brain science, including （i） motivation for nanoelectronics in brain science, （ii） demonstration of nanowire nanoelectronic arrays for high-spatial/high-temporal resolution extracellular recording, （iii） the development of fundamentally-new intracellular nanoelectronic devices that approach the sizes of single ion channels, （iv） the introduction and demonstration of a new paradigm for innervating cell networks with addressable nanoelectronic arrays in three-dimensions. Last, we conclude with a brief discussion of the exciting and potentially transformative advances expected to come from work at the nanoelectronics-brain interface.

关键词： one-dimensional materials two-dimensional materials nanowires carbon nanotubes bottom-up paradigm nanoelectronics nanoelectronic arrays neural probes electrophysiolog35neural circuits brain activity map chronic recording and stimulation brain-machine interfaces

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Effects of grid size on predictions of bed expansion in bubbling fluidized beds of Geldart B particles： A generalized rule for a grid-independent solution of TFm simulations

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Particuology 2017年第5期15卷 61-69页

作者： m. Helal Uddin charles J. Coronella Department of Chemical and materials Engineering University of Nevada Reno NV 89557 USA

Numerical simulations of gas-solid fluidized beds based on the kinetic theory of granular flow exhibit a significant dependence on domain discretization. Bubble formation, bubble size and shape all vary greatly with the discretization, and the use of an inappropriate scale resolution leads to inaccurate predictions of fluidization hydrodynamics. In this study, grid-independent solutions of the two fluid model were examined by comparing the bed expansions obtained from numerical simulations with experimental results and empirical predictions, based on bubbling fluidized beds of Geldart B particles. Grid indepen- dence was achieved with a grid resolution equal to 18 times the particle diameter. The simulation results were compared with previously published data for verification purposes. The results of this work should provide a guideline for choosing the appropriate grid size and thereby minimize the time and expense associated with large simulations.

关键词： mesh effectHydrodynamicsComputational fluid dynamicsEuler-Euler method mFIX

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The skeleton gets a （reproductive） life

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Asian Journal of Andrology 2011年第5期13卷 651-652页

作者： charles m Allan David l Handelsman ANZAC Research Institute Concord Hospital Universityof Sydney Sydney NSW 2139 Australia

To most well-informed scientists who do not work on bone, the idea that bones determine anything other than your posture and location for the miseries of arthritis would come as quite a surprise. It would be like imagining that the walls of our home played something more than a passive role in the complexities of the lives conducted within. Yet something precisely as radical as that is what Karsenty and his colleagues boldly imagined,1 and then provocatively established in a series of studies over the past decade.20steocalcin （OCN） is a vitamin K- dependent peptide hormone secreted by the bone-formine osteoblasts.

关键词： Transcription

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Husbandry practices and gut health outcomes in weaned piglets:A review

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Animal Nutrition 2017年第3期3卷 205-211页

作者： Balachandar Jayaraman charles m.Nyachoti Department of Animal Sciences University of Manitoba

The immediate post-weaning period is one of the most stressful phases in a pig's life, and during this period, piglets are usually exposed to environmental, social and psychological stressors which have direct or indirect effects on gut health and overall growth performance. In this review, the impact of husbandry practices on gut health outcomes and performance of piglets is discussed. Husbandry practices in the swine barn generally include nutrition and management practices, maintenance of hygienic standards and disease prevention protocols, and animal welfare considerations. Poor husbandry practices could result in reduced feed intake, stress and disease conditions, and consequently affect gut health and performance in weaned piglets. Reduced feed intake is a major risk factor for impaired gut structure and function and therefore a key goal is to maximize feed intake in newly weaned piglets. In weaned piglets, crowding stress could reduce pig performance, favor the proliferation of pathogenic bacteria resulting in diarrhea, stimulate immune responses and interfere with beneficial microbial activities in the gut. Sanitation conditions in the swine barn plays an important role for optimal piglet performance, because unclean conditions reduced growth performance, shifted nutrient requirements to support the immune system and negatively affected the gut morphology in weaned piglets. Appropriate biosecurity measures need to be designed to prevent disease entry and spread within a swine operation,which in turn helps to keep all pigs and piglets healthy. Collectively, husbandry practices relating to feeding and nutrition, animal welfare, biosecurity and disease prevention are important determinants of gut health and piglet performance. Thus, it is suggested that adopting high husbandry practices is a critical piece in strategies aimed at raising pigs without the use of in-feed antibiotics.

关键词： Gut health Husbandry practices Weaned piglets

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Application of resistant starch in swine and poultry diets with particular reference to gut health and function

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Animal Nutrition 2018年第3期4卷 305-310页

作者： Alemu Regassa charles m.Nyachoti Department of Animal Science University of Manitoba

The immediate post-weaning period poses a major challenge on the survival of piglets. Similarly, newly hatched chicks face life threatening challenges due to enteric infections. In the past several years, in-feed antibiotics have been used to reduce these production problems and improve growth. However, in-feed antibiotics have been banned in many jurisdictions and therefore the most effective alternatives to infeed antibiotics must be developed. To date, several studies have been conducted to develop alternatives to antibiotics. One of the potential candidates as alternatives to in-feed antibiotics is resistant starch(RS). Resistance starch is a type of starch that resists enzymatic digestion in the upper parts of the gastrointestinal tract and therefore passes to hindgut where it can be fermented by resident microorganisms. microbial fermentation of RS in the hindgut results in the production of short chain fatty acids(SCFA). Production of SCFA in turn results in growth and proliferation of colonic and cecal cells, increased expression of genes involved in gut development, and creation of an acidic environment. The acidic environment suppresses the growth of pathogenic microorganisms while selectively promoting the growth of beneficial microbes. Thus, RS has the potential to improve gut health and function by modifying and stabilising gut microbial community and by improving the immunological status of the host. In this review, we discussed the roles of RS in modifying and stabilising gut microbiota, gut health and function, carcass quality, and energy metabolism and growth performance in pigs and poultry.

关键词： Resistant starch Swine Poultry Gut health and function Growth performance

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Advances in the management of infertility in men with spinal cord injury

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Asian Journal of Andrology 2016年第3期18卷 382-390,I0007,I0008页

作者： Emad Ibrahim Nancy L Brackett charles m Lynne The miami Project to Cure Paralysis University of Miami Miller School of Medicine Miami FL USA Department of Urology University of Miami Miller School of Medicine Miami FL USA.

Couples with a spinal cord injured male partner require assisted ejaculation techniques to collect semen that can then be further used in various assisted reproductive technology methods to achieve a pregnancy. The majority of men sustaining a spinal cord injury regardless of the cause or the level of injury cannot ejaculate during sexual intercourse. Only a small minority can ejaculate by masturbation. Penile vibratory stimulation and electroejaculation are the two most common methods used to retrieve sperm. Other techniques such as prostatic massage and the adjunct application of other medications can be used, but the results are inconsistent. Surgical sperm retrieval should be considered as a last resort if all other methods fail. Special attention must be paid to patients with T6 and rostral levels of injury due to the risk of autonomic dysreflexia resulting from stimulation below the level of injury. Bladder preparation should be performed before stimulation if retrograde ejaculation is anticipated. Erectile dysfunction is ubiquitous in the spinal cord injured population but is usually easily managed and does not pose a barrier to semen retrieval in these men. Semen analysis parameters of men with spinal cord injury are unique for this population regardless of the method of retrieval, generally presenting as normal sperm concentration but abnormally low sperm motility and viability. When sperm retrieval is desired in this population, emphasis should be placed on initially trying the simple methods of penile vibratory stimulation or electroejaculation before resorting to more advanced and invasive surgical procedures.

关键词： assisted reproductive technology ejaculation electroejaculation male infertility paraplegia penile vibratory stimulation semen sperm spinal cord injury surgical sperm retrieval

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Carbon star CGCS 673 identified as a semi-regular variable star

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Research in Astronomy and Astrophysics 2020年第11期20卷 235-238页

作者： Stephen m.Brincat charles Galdies Kevin Hills Flarestar Observatory(mPC 171) Fl.5/BGeorge Tayar StreetSan GwannSGN 3160Malta Institute of Earth Systems University of MaltaMsidaMSD 2080Malta Tacande Observatory(La Palma Spain)c/o 4 Grange DriveHartfordCheshire CW83AEUK

This study reports that the carbon star CGCS 673 is a semi-regular(SR)variable star with a period of 135 d and an amplitude of 0.18mag in the *** light curve obtained by this study correlates well with the SR classification as the photometric data obtained show noticeable periodicity in the light changes of CGCS 673 that is occasionally interrupted by a period of irregular *** derived period and colour index obtained from our data and those from professional databases indicate that the attributes of this star fall within the parameters of the SR class of variable *** our notification of the discovery that this star is a variable source,CGCS 673 has received the AAVSO Unique Identifier of(AAVSO UID)000-BmZ-492.

关键词： techniques photometric stars variables semi-regular variable stars individual CGCS

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Computation of Two-Phase Biomembranes with Phase Dependent material Parameters Using Surface Finite Elements

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Communications in Computational Physics 2013年第2期13卷 325-360页

作者： charles m.Elliott Björn Stinner mathematics Institute and Centre for Scientific Computing University of WarwickCoventry CV47ALUnited Kingdom

The shapes of vesicles formed by lipid bilayers with phase separation are governed by a bending energy with phase dependent material parameters together with a line energy associatedwith the phase *** present a numericalmethod to approximate solutions to the Euler-Lagrange equations featuring triangulated surfaces,isoparametric quadratic surface finite elements and the phase field approach for the phase ***,the method involves an iterative solution scheme that is based on a relaxation dynamics coupling a geometric evolution equation for the membrane surface with a surface Allen-Cahn *** and grid adaptivity are discussed,and in various simulations the influence of several physical parameters is investigated.

关键词： Biomembrane surface finite elements relaxation dynamics

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