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Accumulation of poly(adenosine diphosphate-ribose)by sustained supply of calcium inducing mitochondrial stress in pancreatic cancer cells

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World Journal of Gastroenterology 2022年第27期28卷 3422-3434页

作者： Keun-Yeong Jeong Jae Jun Sim Minhee Park Hwan Mook Kim Research and Development Metimedi PharmaceuticalsIncheon 22006South Korea

BACKGROUND The biochemical phenomenon defined as poly adenosine diphosphate(ADP)-ribosylation(PARylation)is essential for the progression of pancreatic ***,the excessive accumulation of poly ADP-ribose(PAR)induces apoptosis-inducing factor(AIF)release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer *** To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR *** Two pancreatic cancer cell lines,AsPC-1 and CFPAC-1 were used for the *** influx and mitochondrial reactive oxygen species(ROS)were observed by fluorescence *** in enzyme levels,as well as PAR accumulation and energy metabolism,were measured using assay ***-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium *** Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer ***,excess PAR accumulation,decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels,and energy deprivation were *** vitro and in vivo antitumor effects were confirmed to accompany elevated AIF *** This study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer,however elucidating a clear mode of action remains a challenge,and it should be accompanied by further studies to assess its potential for clinical application.

关键词： Pancreatic cancer Calcium Reactive oxygen species Poly adenosine diphosphate-ribose Poly adenosine diphosphate-ribosylation Poly adenosine diphosphate-ribose polymerase Apoptosis-inducing factor Nicotinamide adenine dinucleotide Anticancer effect

Single-arm phase II three-outcome designs with handling of over-running/under-running

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Statistical Theory and Related Fields 2023年第4期7卷 276-286页

作者： Wenchuan Guo Jianan Hui Bob Zhong Seagen Inc. BothellWAUSA Servier pharmaceuticals BostonMAUSA Regeneron pharmaceuticals TarrytownNYUSA

Phase II clinical trials are commonly conducted as pilot studies to evaluate the efficacy and safety of the investigational drug in the targeted patient population with the disease or condition to be treated or *** designing such a trial considering efficacy conclusions,people natu-rally think as follows:if efficacy evidence is very strong,a go decision should be made;if efficacy evidence is very weak,a no-go decision should be made;if the efficacy evidence is neither strong nor weak,no decision can be made(inconclusive).The designs presented in this paper match this natural thinking process with go/no-go/inconclusive *** two-/three-stage designs are developed with three ***,a general approach based on conditional error function is implemented such that new decision boundaries can be calculated to handle mid-course sample size change which results in either‘over-running’or‘under-running’and ensure the control of overall type I error.A free open-source R package tsdf that calculates the proposed two-/three-stage designs is available on CRAN.

关键词： Phase II trials two-stage and three-stage designs go/no-go/inconclusive outcomes asymmetric alpha alpha spending optimal designs over-running and under-running

Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment

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World Journal of Gastrointestinal Oncology 2021年第6期13卷 574-588页

作者： Keun-Yeong Jeong Minhee Park Research and Development Metimedi PharmaceuticalsIncheon 22006South Korea

The development of colorectal cancer(CRC)can result from changes in a variety of cellular systems within the tumor ***,it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC *** on this background,the potential to focus on poly[adenosine diphosphate(ADP)-ribose]polymerase(PARP)-1 and poly-ADP ribosylation(PARylation)as the main causes of malignant formation of CRC may be *** of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid(DNA)repair function,which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and ***-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin *** the high importance of these processes in CRC,it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC ***,this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles;furthermore,it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting *** understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC,which may present the potential to identify various research topics that can be challenged both nonclinically and clinically.

关键词： Colorectal cancer Poly adenosine diphosphate-ribose polymerase-1 Poly adenosine diphosphate-ribose Poly-adenosine diphosphate ribosylation

An Efficient Approach to 6, 7-Disubstituted-1H-quinoxalin-2-ones

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Chinese Chemical Letters 2004年第12期15卷 1400-1402页

作者： Xun LI Qing Ping HU Xue Gui CUI Dong Hua WANG College of Pharmacy, Shandong University, Jinan 250100 College of pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072 College of Pharmacy Shandong University College of pharmaceuticals and Biotechnology Tianjin University

A novel approach to the synthesis of 6, 7-disubstituted-1H-quinoxalin-2-ones is *** title compounds were regioselectively prepared by starting from substituted phenylamines andchloroacetyl chloride through the efficie... 详细信息

关键词： 6 7 -Disubstituted-1H-quinoxalin-2-ones regioselective substituted phenylamine.

Real-world treatment patterns of gastrointestinal neuroendocrine tumors: A claims database analysis

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World Journal of Gastroenterology 2017年第33期23卷 6128-6136页

作者： Al B Benson III Michael S Broder Beilei Cai Eunice Chang Maureen P Neary Elya Papoyan Northwestern University Partnership for Health Analytic Research Novartis pharmaceuticals

AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques. Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF) and combinations. We identified patients at least 18 years of age,with ≥ 1 inpatient or ≥ 2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14. A 6 mo clean period prior to first treatment ensured patients were newly treated. Patients were followed until end of enrollment or the study end date,whichever was *** We identified 2258 newly treated GI NET patients: mean(SD) age was 55.6 years(SD = 9.7),47.2% of the patients were between 55 and 64 years,and 48.8% were female. All regions of the United States were represented. 59.6% started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3% CC,3.6% TT,and 0.5% IF. The remainder received combinations. Mean follow up was 576 d. Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT). 58.9% of patients had no pharmacological treatment beyond first line. The most common secondline was combination therapy with SSA. In graphical pattern analysis,there was no clear pattern visible after first line *** In this study,60% of patients initiated treatment with SSA alone or in combination. The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.

关键词： Gastrointestinal neuroendocrine tumors Treatment patterns Insurance claims Somatostatin analogue Targeted therapy Chemotherapy

Studies on Enzyme Kinetics by Microchip and Related Techniques

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高等学校化学学报 2004年第Z1期25卷 165-166页

作者： James J. Bao WANG Huai-Feng ZHOU Da-Wei Ken R. Wehmeyer College of pharmaceuticals Tianjin University Tianjin 300072 China College of Pharmaceuticals Tianjin University Tianjin 300072 China College of Pharmaceuticals Tianjin University Tianjin 300072 China Procter & Gamble Pharmaceuticals 8700 Mason-Montgomery Road Mason OH 45040 USA

Both conventional and microchip-based capillary electrophoresis(CE) technologies have been used for the analysis of enzymes. Practical procedures of using CE to determine the Km and Vmax values of an enzyme have been developed. By studying the inhibition to the enzyme, it is possible to select a suitable drug candidate. When compared with the conventional CE method, single lane microchip-based method can improve the speed for the assay three times. By using multiple lane-based microchip, the speed can be further increased.

关键词： Enzyme Enzyme kinetics Inhibition Enzyme activity

Amination of electron deficient aryl chlorides promoted by nano sized Mg(OH)_2 under transition metals free condition

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Chinese Chemical Letters 2012年第2期23卷 137-140页

作者： Zhi Hao Cui Zi Hui Meng Yan Qing Mi Peng Wang Qi Wang Lin Man Zhao Ke Jian Cui Fang Yu Zhi Bin Xu Department of Applied Chemistry and pharmaceuticals Beijing Institute of TechnologyBeijing 100081China

This paper presents the amination reactions of electron deficient aryl chlorides promoted by Mg（OH）_2 without transition metals. Only using stoichiometric amount of nano sized Mg（OH）_2,good to moderate isolated yi... 详细信息

关键词： Anination Electron deficient aryl chloride Cyclic secondary amines Nano sized Magnesium hydroxide

A Facile Synthesis of N-alkyl-4'-methyl-1,1'-biphenyl-2-sulfona-mide via Linking DoM Reaction with Suzuki Reaction

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Journal of Beijing Institute of Technology 2009年第3期18卷 327-332页

作者：章军周智明薛为哲李志怀 Research and Development Center for pharmaceuticals School of Chemical Engineering and EnvironmentBeijing Institute of Technology

Six N-alkyl-4＇-methyl-1,1＇-biphenyl-2-sulfonamides were synthesized facilely and efficiently from low cost and readily available benzenesulfonyl chloride and C1-C4 fatty amines via linking DoM reaction with Suzuki *** structures of the new compounds synthesized were confirmed by elemental analysis,IR,1H NMR and *** new method makes a feature of low cost and readily available starting material,fewer steps,mild condition,easiness to operate and higher yield.

关键词： Do M reaction Suzuki cross-coupling reaction N-alkyl-4'-methyl- 1, l'-biphenyl-2-sulfonamide synthesis

TREM2 as an evolving therapeutic target in Alzheimer's disease

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Neural Regeneration Research 2023年第12期18卷 2680-2681页

作者： Jacob George Cognyxx pharmaceuticals Tel Aviv Israel and Kaplan Heart CenterRehovotIsrael

Triggering receptor expressed on myeloid cells 2(TREM2) is type I transmembrane protein receptor found in osteoclasts, dendritic cells, macrophages, and microglia(Ulland and Colonna, 2018). In the central nervous system, TREM2 expression is confined exclusively to microglia. TREM2 comprises an extracellular V-type immunoglobulin(Ig) ectodomain, a connecting stalk followed by a transmembrane region and a short C-terminal tail.

关键词： Alzheimer therapeutic Colon