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Profiling of immune features to predict immunotherapy efficacy

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The Innovation 2022年第1期3卷 71-82页

作者： Youqiong Ye Yongchang Zhang Nong Yang Qian Gao Xinyu Ding Xinwei Kuang Rujuan bao Zhao Zhang Chaoyang Sun bingying Zhou Li Wang Qingsong Hu Chunru Lin Jianjun Gao Yanyan Lou Steven HLin Lixia Diao Hong Liu Xiang Chen gordon b.mills Leng Han Shanghai Institute of Immunology Department of Immunology and MicrobiologyShanghai Jiao Tong University School of MedicineShanghai 200025China Department of biochemistry and Molecular biology The University of Texas Health Science Center at Houston McGovern Medical SchoolHoustonTX 77030USA Department of Medical Oncology Lung Cancer and Gastrointestinal UnitHunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunan 410008China Department of Dermatology Xiangya HospitalCentral South UniversityChangshaHunan 410008China Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China State Key Laboratory of Cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Genitourinary Medical Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Division of Hematology and Oncology Mayo ClinicJacksonvilleFL 32224USA Department of Radiation Oncology Division of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of bioinformatics and Computational biology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Knight Cancer Institute Oregon Health and Science UniversityPortlandOR 97239USA Center for Epigenetics and Disease Prevention Institute of Biosciences and TechnologyTexas A&M UniversityHoustonTX 77030USA Department of Translational Medical Sciences College of MedicineTexas A&M UniversityHoustonTX 77030 USA

Immune checkpoint blockade(ICb)therapies exhibit substantial clinical benefit in different cancers,but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune ***,we reveal overall positive correlations among immune checkpoints and immune cell ***,patients benefiting from ICb exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy,suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune *** proof-of-concept,we demonstrated that the immune activation score(ISD)based on dynamic alteration of interleukins in patient plasma as early as two cycles(4-6 weeks)after starting immunotherapy can accurately predict immunotherapy *** results reveal a systematic landscape of associations among immune features and provide a noninvasive,cost-effective,and time-efficient approach based on dynamic profiling of pre-and on-treatment plasma to predict immunotherapy efficacy.

关键词： immunotherapy features mutual

Targeting proprotein convertase subtilisin/kexin type 9(PCSK9):from bench to bedside

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Signal Transduction and Targeted Therapy 2024年第2期9卷 509-557页

作者： Xuhui bao Yongjun Liang Hanman Chang Tianji Cai baijie Feng Konstantin gordon Yuekun Zhu Hailian Shi Yundong He Liyi Xie Institute of Therapeutic Cancer Vaccines Fudan University Pudong Medical CenterShanghaiChina Shanghai Key Laboratory of Regulatory biology School of Life SciencesEast China Normal UniversityShanghaiChina Department of Oncology Fudan University Pudong Medical CenterShanghaiChina Center for Clinical Research Fudan University Pudong Medical CenterShanghaiChina Clinical Research Center for Cell-based Immunotherapy Fudan UniversityShanghaiChina Department of Pathology Duke University Medical CenterDurhamNCUSA Center for Medical Research and Innovation Fudan University Pudong Medical CenterShanghaiChina Institute for Food Safety and Health Illinois Institute of TechnologyChicagoILUSA Department of Sociology University of MacaoTaipaMacaoChina Medical Institute Peoples’Friendship University of RussiaMoscowRussia A.Tsyb Medical Radiological Research Center ObninskRussia Department of Colorectal Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineZhangjiang Hi-tech ParkShanghaiChina Department of Radiation Oncology Fudan University Shanghai Cancer CenterShanghaiChina Department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina

Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,*** exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular *** also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient *** advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular *** therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular ***,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer *** review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer *** conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms acr

关键词： PCSK9 metabolism convert

Ovarian cancer recurrence:“is the definition of platinum resistance modified by PARP inhibitors and other intervening treatments?”

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Cancer Drug Resistance 2022年第2期5卷 451-458页

作者： Tanja Pejovic Katherine Fitch gordon mills Knight Cancer Institute Oregon Health&Science UniversityPortlandOR 97239USA. Department of Obstetrics&Gynecology Oregon Health&Science UniversityPortlandOR 97239USA.

PolyADP ribose polymerase inhibitors(PARPi)have transformed the treatment of ovarian *** in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),PARPi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to *** this review,we discuss the role of PARPi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and PARP inhibitors.

关键词： PARP inhibitors olaparib niraparib ovarian cancer maintenance therapy

TREMble before TREM2:The Mighty Microglial Receptor Conferring Neuroprotective Properties in TDP-43 Mediated Neurodegeneration

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Neuroscience bulletin 2023年第1期39卷 163-166页

作者： William A.mills III Ukpong b.Eyo brain Immunology and Glia Center University of VirginiaCharlottesvilleVA22903USA Department of Neuroscience University of VirginiaCharlottesvilleVA22903USA Robert M.berne Cardiovascular Research Center University of VirginiaCharlottesvilleVA22903USA

Microglia were long hailed as solely infammatory cells,and though they are responsible for the brain's immuneresponse,they perform a variety of neuroprotective func-tions including the clearance of cellular and toxic debris^([1]).One toxic molecule known to be cleared by microglia isthe protein aggregate found in Alzheimer's Disease(AD),amyloid-b.

关键词： protective degeneration Alzheimer

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国际海道测量标准

海洋测绘 1999年第3期20卷 59-61,54页

作者： Gerald b.mills 朱津

一、背景国际海道测量局(IHb)成立于1921年,与此同时国际海道测量组织(IHO)也应运而生,主要致力于海道测量数据采集与海图出版的规范化工作。1970年9月,当时的成员国代表正式投票通过决议,开始采用国际海道测量组织这一名称。

关键词：海道测量局国际海道测量组织测深数据随机误差置信度定位精度测线间距侧扫声纳潮汐观测系统误差

Histological changes of the testis and epididymis in adult rats as a result of Leydig cell destruction after ethane dimethane sulfonate treatment:a morphometric study

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Asian Journal of Andrology 2006年第3期8卷 289-299,386页

作者： Nathaniel mills Department of biology Texas Woman's UniversityDentonTexas 76204USA

Aim:To quantitatively study the histological changes of the testis and epididymis as a result of a drastic reduction of testosterone ***:Fourteen adult Sprague-Dawley rats were injected intraperitoneally with ethane dimethane sulfonate(EDS,75 mg/kg)and the same number of animals were injected with normal saline as a control. At days 7 and 12(after treatment),respectively,half of the animals from each group were *** testes and epididymides were removed and tissue blocks embedded in methacrylate *** cell number per testis was esti- mated using the stereological optical disector and some other parameters were obtained using other morphometric ***:The EDS treatment resulted in an almost complete elimination of Leydig cells but had no effect on the numbers of Sertoli cells per *** day 7 after EDS treatment,many elongated spermatids were retained in the seminiferous epithelium and many round spermatids could be seen in the epididymal *** day 12,a looser arrangement of spermatids and spermatocytes became evident,with apparent narrow empty spaces being formed between germ cells in an approximately radial direction towards the tubule lumen;the numbers(per testis)of non- type b spermatogonia and spermatocytes were similar to controls,whereas that of type b spermatogonia increased by 59%,and that of early round,elongating and late elongated spermatids decreased by 37%,72% and 52%,respectively. Conclusion:The primary spermatogenic lesions following EDS administration were(i)spermiation failure and(ii) detachment of spermatids and spermatocytes associated with impairment in spermiogenesis and meiosis.

关键词： epididymis ethane dimethane sulfonate Leydig cells morphometry spermatogenesis stereology testis testosterone

Unlearning Descartes:Sentient AI is a Political Problem

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Journal of Social Computing 2023年第3期4卷 193-204页

作者： gordon Hull the School of Data Science UNC CharlotteCharlotteNC 28223USA

The emergence of Large Language Models(LLMs)has renewed debate about whether Artificial Intelligence(AI)can be conscious or *** paper identifies two approaches to the topic and argues:(1)A“Cartesian”approach treats consciousness,sentience,and personhood as very similar terms,and treats language use as evidence that an entity is *** approach,which has been dominant in AI research,is primarily interested in what consciousness is,and whether an entity possesses it.(2)An alternative“Hobbesian”approach treats consciousness as a sociopolitical issue and is concerned with what the implications are for labeling something sentient or *** both enables a political disambiguation of language,consciousness,and personhood and allows regulation to proceed in the face of intractable problems in deciding if something“really is”sentient.(3)AI systems should not be treated as conscious,for at least two reasons:(a)treating the system as an origin point tends to mask competing interests in creating it,at the expense of the most vulnerable people involved;and(b)it will tend to hinder efforts at holding someone accountable for the behavior of the systems.A major objective of this paper is accordingly to encourage a shift in *** place of the Cartesian question-is AI sentient?-I propose that we confront the more Hobbesian one:Does it make sense to regulate developments in which AI systems behave as if they were sentient?

关键词： artificial intelligence Large Language Model consciousness sentience personhood Descartes Hobbes

Transient thermal analysis as measurement method for IC package structural integrity

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Chinese Physics b 2015年第6期24卷 47-64页

作者： Alexander Han Maximilian Schmid E Liu gordon Elger Technische Hochschule Ingolstadt

Practices of IC package reliability testing are reviewed briefly, and the application of transient thermal analysis is examined in great depth. For the design of light sources based on light emitting diode （LED） efficient and accurate reliability testing is required to realize the potential lifetimes of 105 h. Transient thermal analysis is a standard method to determine the transient thermal impedance of semiconductor devices, e.g. power electronics and LEDs. The temperature of the semiconductor junctions is assessed by time-resolved measurement of their forward voltage （Vf）. The thermal path in the IC package is resolved by the transient technique in the time domain. This enables analyzing the structural integrity of the semiconductor package. However, to evaluate thermal resistance, one must also measure the dissipated energy of the device （i.e., the thermal load） and the k-factor. This is time consuming, and measurement errors reduce the accuracy. To overcome these limitations, an innovative approach, the relative thermal resistance method, was developed to reduce the measurement effort, increase accuracy and enable automatic data evaluation. This new way of evaluating data simplifies the thermal transient analysis by eliminating measurement of the k-factor and thermal load, i.e. measurement of the lumen flux for LEDs, by normalizing the transient Vf data. This is especially advantageous for reliability testing where changes in the thermal path, like cracks and delaminations, can be determined without measuring the k-factor and thermal load. Different failure modes can be separated in the time domain. The sensitivity of the method is demonstrated by its application to high- power white InGaN LEDs. For detailed analysis and identification of the failure mode of the LED packages, the transient signals are simulated by time-resolved finite element （FE） simulations. Using the new approach, the transient thermal analysis is enhanced to a powerful tool for reliability

关键词： transient thermal analysis thermal resistance reliability light emitting diode

Human hematopoietic cells express two forms of thecytokine receptor common γ-chain (γc)

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Cell Research 1997年第2期7卷 195-205页

作者： SHI YU FANG MARY HILL ANTON NOVAK ZHIQING CHEN RUO XIANG WANG CHOONGCHIN LIEW gordon b. mills (Oncology Research, The Toronto Hospital, 200 ElizabcthSt., Toronto, Ontario, Canada MSG 2C4Department of Immunology, Holland Laboratoryof American Red Cr Oncology Research The Toronto Hospital Toronto Canada Department of Immunology Holland Laboratory of American Red Cross Rockville USA Department of Genetics Research Institute The Hospital for Sick Children Toronto Canada Department of Clinical biochemistry University of Toronto Toronto Canada Department of Molecular Oncology MD Anderson Cancer Center University of Texas Houston

Recent studies have revealed that the γ-chain of theIL-2 receptor is shared by the receptors for IL-4, IL7, IL-9, IL-13, and IL-15, and it is therefore also referred toas the common γ-chain (γc). Mutations of γc result inX-linked severe combined immunodeficiency syndrome inhumans, indicating that rye is essential for normal development and function of the immune system. We demonstratethat human hematopoietic cells express two γc transcriptsdiffering in their carboxyl terminal coding region. Onetranscript is the previously reported sequence (γc-long),whereas the newly identified sequence exhibits a deletion of72 nucleotides close to the 3'-end of the open reading frame(γc-short). This alteration predicts a loss of 24 amino acidsincluding a conserved tyrosine residue which is shared byseveral members of the cytokine receptor family. Thepresence of these two distinct forms of rye transcripts wasdemonstrated by sequencing of reversely transcribed andpolymerase chain reaction (RT-PCR) amplified mRNA, restriction digestion of the RT-PCR products, RNAse protection, and Northern blotting from human cell lines andhuman peripheral blood lymphocytes. Furthermore, thetwo variants were present in peripheral blood lymphocytesfrom both female and male donors, which rules out allelicvariants since rye is a single copy gene located on the Xchromosome. A truncation mutant at a site near the observed changes in γc-short has been reported by othersto alter biochemical events activated by cytokines. Thiscombined with the loss of a potential SH2 "docking" sitein γc-short suggests that γc-long and γc-short may link todifferent signaling pathways and may play an importantrole in determining the cellular response to IL-2, IL-4, IL-7, IL-9, IL-13, IL-15.

关键词： IL-2 receptor γ-chain cytokine receptor common γ-chain IL-2 receptor cytokine receptors RNA splicing