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Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs

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Cancer Drug Resistance 2019年第4期2卷 994-1001页

作者： william h.Gmeiner Department of Cancer Biology Wake Forest School of MedicineWinston-SalemNC 27157USA

Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer *** the last 20 years,multiple studies have shown Top1 activity is modulated by non-native DNA structures and this can lead to trapping of Top1 cleavage complexes(Top1cc)and conversion to DNA double strand *** the perturbations to DNA structure that generate Top1cc are nucleoside analogs that are incorporated into genomic DNA during replication including cytarabine,gemcitabine,and 5-fluoro-2’-deoxyuridine(FdU).We review the literature summarizing the role of Top1cc in mediating the DNA damaging and cytotoxic activities of nucleoside *** also summarize studies demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs,particularly with regard to DNA ***,these studies demonstrate that,while Top1 is a common target for both Top1 poisons such as CPT and nucleoside analogs such as FdU,these agents are not *** recent years,studies have shown that Top1 poisons and nucleoside analogs together with other anti-cancer drugs such as cisplatin cause replication stress and the DNA repair pathways that modulate the cytotoxic activities of these compounds are being *** present an overview of this evolving literature,which has implications for how targeting of Top1 with nucleoside analogs can be used more effectively for cancer treatment.

关键词： DNA topoisomerase 1 cancer chemotherapy cytarabine gemcitabine fluoropyrimidine

The Synoptic Climatology of Monthly Mean Surface Temperature in Asia in Relation to the 700 hPa Circulation

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Advances in Atmospheric Sciences 1989年第2期6卷 227-238页

作者： Runhua Yang william h.Klein Department of Meteorology University of Maryland College ParkMD 20742Department of MeteorologyUniversity of Maryland College ParkMD 20742

The synoptic climatology of monthly mean surface air temperature anomaly (MMATA) at 47 surface stations in Asia is assessed by two types of maps. The first consists of simple linear correlation coefficients between the MMATA at a station and the monthly mean 700 hPa height anomaly (MMhA) at 134 grid points in the Northern hemisphere. In winter, these fields generally contain two equally important centers: a center of maximum positive correlation approximately 1300 km from the reference station and a negative center about 2800 km to its northwest. In summer, the positive center is located an average of 800 km from the reference station and strongly dominates the MMATA, while the negative center is no longer as important as in winter. The second kind of map is a special type of anomaly composite, constructed by multiplying the correlation coefficient at each grid point by the standard deviation of MMhA at the same point. This map shows the optimum distribution of height anomalies for abnormally warm (or cold) weather for winter and summer in each of several climatologically similar regions into which Asia is subdivided.

关键词：天气气候学月平均地表温度大气环流亚洲

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Unintended consequences of rangeland conservation structures

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International Soil and Water Conservation Research 2021年第1期9卷 158-165页

作者： Mary h.Nichols Jeremy R Shaw william K.Brandau Southwest Watershed Research Center USDA-ARS2000 E.Allen Rd.TucsonAZ85719USA Colorado State University Department of Forest&Rangeland Stewardship Fort CollinsCO80523-1472USA University of Arizona Cooperative Extension Service(retired) SaffordAZ85551USA

By the 1930's vast areas of the western US were severely degraded by overgrazing and *** response,Congress authorized conservation work including the construction of erosion control and water storage,distribution,and conveyance *** of structures such as check dams,water spreaders,and contour berms were built during the 1930s and 40s to control water and sediment in an attempt to restore degraded ***,across most of the western US,these soil and water conservation measures were implemented without the benefit of local hydrologic data or technical design *** of the established conservation practices had been developed for humid regions and were untested for use in semiarid areas that are characterized by highly variable rainfall and flash *** a result,many structures proved ineffective and were subsequently *** in cases where structures were effective,many never received maintenance after their initial *** structurally compromised,abandoned and unmaintained structures continue to alter surface runoff patterns and can greatly exacerbate *** sites in Arizona,USA were selected to charac-terize the multi-decadal impacts of conservation *** have formed in 100%of contour berms(n=67)while 96%of water spreader berms(n=26)were *** failures in these structures has created concentrated flow paths that reorganized routing of runoff and sediment thus transforming sheetflow regimes to concentrated flow *** study emphasizes the unin-tended legacy impacts of soil and water conservation structures and highlights their role as a potential constraint on contemporary resource management.

关键词： Contour berm Erosion human altered landscape Restoration Semiarid Water spreader

Sodium-Glucose Cotransporter 2 Inhibitors in Adult and Pediatric Congenital heart Disease: Review of Emerging Data and Future Directions

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Congenital heart Disease 2024年第4期19卷 419-433页

作者： william h.Marshall V Lydia K.Wright Division of Cardiovascular Medicine Department of Internal MedicineThe Ohio State UniversityColumbusOH 43210USA The heart Center Nationwide Children’s HospitalColumbusOH 43205USA

heart failure(hF)is common in patients with congenital heart disease(ChD)and there are limited medical ***-glucose cotransporter 2 inhibitors(SGLT2i)are a proven medical therapy in patients with acquired hF,though data are limited in patients with *** aim of this review is to summarize the current evidence for use of SGLT2i in patients with ChD and identify future directions for *** available publica-tions,SGLT2i in patients with ChD seem to be well tolerated,with similar side effect proﬁle to patients with acquired *** in functional capacity and natriuretic peptides are mixed,though there is a signal for potential reduction in hF *** prospective study in patients with systemic right ventricles showed an improvement in systolic function for patients already on maximal hF medical *** lim-ited,there is emerging data on use of SGLT2i in pediatric patients with ChD and *** prospective studies are needed to evaluate for clinically meaningful endpoints,including hF hospitalization,as well as evaluate the hemodynamic impact in subtypes of ChD at high risk for hF.

关键词： Congenital heart disease heart failure sodium-glucose 2 cotransporter inhibitors systemic right ventricle Fontan

Meso-Scale VOC-Mixture Analyzer with Tunable Separation and Microsensor Array Detection

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稀有金属材料与工程 2006年第A3期35卷 61-64页

作者： Qiongyan Zhong william h. Steinecker Edward T. Zellers Department of Environmental health Sciences University of Michigan 109 S. Observatory St. Ann Arbor MI 48109-2029 USA Department of Chemistry University of Michigan 109 S. Observatory St. Ann Arbor MI 48109-2029 USA

A novel portable instrument developed for field determinations of complex mixtures of volatile organic compounds (VOCs) is *** key features of the instrument are a miniature multi-stage adsorbent preconcentrator/focuser,two series-coupled separation columns with pressure and temperature tunable retention control,and an integrated array of four chemiresistor (CR) sensors coated with Au-thiolate monolayer-protected nanoparticles (MPN).MPN-CR array response patterns are used with retention times to identify eluting *** is used as the carrier *** of 20 common indoor air contaminants gave LODs in the range of 0.05 ng/g～0.53 ng/g for a 1 L sample *** of preliminary analyses of characteristic VOCs generated from *** as well as vapor-phase markers of environmental tobacco smoke (ETS) at low-or sub-ng/g levels are presented.

关键词： microsensor gas chromatography nanoparticle sensor array portable ETS

Improved potency of F10 relative to 5-fluorouracil in colorectal cancer cells with p53 mutations

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Cancer Drug Resistance 2018年第1期1卷 48-58页

作者： Anthony Dominijanni william h.Gmeiner Department of Cancer Biology Wake Forest School of MedicineWinston-SalemNC 27157USA

Aim:Resistance to fluoropyrimidine drugs(FPs)is a major cause of mortality in colorectal cancer(CRC).We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil(5-FU)in four human CRC cell lines that differ only in TP53 mutational status to determine how p53 mutations affect drug response and whether F10 is likely to improve ***:hCT-116 human CRC cells(p53^(+/+))and three isogenic variants(p53^(-/-),R248W/+,R248W/-)were assessed for drug *** factors were derived from cell viability data and used to establish the relative potency advantage for *** studies with exogenous uridine/thymidine determined if cytotoxicity resulted from DNA-directed ***:Significant resistance to 5-FU resulted from p53-loss or from gain-of-function(GOF)mutation(R248W)and was greatest when GOF mutation was coupled with loss of wild-type p53.F10 is much more potent than 5-FU(137-314-fold depending on TP53 mutational status).F10 and 5-FU induce apoptosis by DNA-and RNA-directed mechanisms,respectively,and only F10 shows a modest enhancement in cytotoxicity upon co-treatment with ***:TP53 mutational status affects inherent sensitivity to FPs,with p53 GOF mutations most deleterious.F10 is much more effective than 5-FU regardless of TP53 mutations and has potential to be effective to CRC that is resistant to 5-FU due,in part,to TP53 mutations.

关键词： Fluoropyrimidine colorectal cancer p53 drug resistance

Ionic and nonionic polymers can prevent surfactant inactivation

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Acta Pharmacologica Sinica 2003年第12期 159-161页

作者： Karen W LU,h william TAEUSCh Department of Pediatrics University of California San Francisco CA 94110 USA Department of Pediatrics University of California San Francisco CA 94110 USA

It is well known that treatment with exogenous surfactant works well in premature infants with lung surfactant deficiency. Effects of surfactant therapy are less dramatic when used to treat lung diseases associated with acute lung injury(ALI)and adult respiratory distress syndrome(ARDS). This less successful clinical response may be due in part to surfactant inactivation by leakage of plasma and inflammatory products into the alveoli. It is therefore important to find a way of preventing or reversing inactivation of surfac-

关键词： ARDS were PEG of with in for that

Free vibration and transient response of double curved beams connected by intermediate straight beams

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Applied Mathematics and Mechanics(English Edition) 2025年第1期46卷 37-62页

作者： R.A.JAFARI-TALOOKOLAEI h.GhANDVAR E.JUMAEV S.KhATIR T.CUONG-LE School of Mechanical Engineering Babol Noshirvani University of Technology Department of Mechanical Engineering Faculty of Engineering New Uzbekistan University University of Business and Science Center for Engineering Application and Technology Solutions Ho Chi Minh City Open University

This paper investigates the free vibration and transient response of interconnected structures including double curved beams and intermediate straight beams,which are all constructed from functionally graded porous(FGP) materials. The strain potential and kinetic energies of each beam along with the work done by the external force are calculated. Additionally, a higher-order beam element is introduced to derive stiffness and mass matrices, along with the force vector. The curved and straight beams are discretized, and their assembled stiffness, mass matrices, and force vectors, are *** conditions at the joints are used to derive the total matrices of the entire structure. Subsequently, the natural frequencies and transient response of the system are determined. The accuracy of the mathematical model and the self-developed computer program is validated through the comparison of the obtained results with those of the existing literature and commercial software ANSYS, demonstrating excellent ***, a comprehensive study is conducted to investigate the effects of various parameters on the free vibration and transient response of the considered structure.

关键词： Kinetic energy

Review of 5-FU resistance mechanisms in colorectal cancer:clinical significance of attenuated on-target effects

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Cancer Drug Resistance 2023年第2期6卷 257-272页

作者： william h.Gmeiner Charles Chidi Okechukwu Department of Cancer Biology and Comprehensive Cancer Center Wake Forest University School of MedicineWinston-SalemNC 27157USA Integrative Physiology and Pharmacology Graduate Program InstitutionWake Forest University School of MedicineWinston-SalemNC 27157USA

The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based(5-FU-based)regimens is an important factor in the mortality of metastatic CRC(mCRC).The causes of 5-FU resistance are multifactorial,and besides DNA mismatch repair deficiency(MMR-D),there are no widely accepted criteria for determining which CRC patients are not likely to be responsive to 5-FU-based ***,there is a need to systematically understand the mechanistic basis for 5-FU treatment failure and an urgent need to develop new approaches for circumventing the major causes of 5-FU *** this manuscript,we review mechanisms of 5-FU resistance with an emphasis on:(1)altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate(5-Fluoro-2'-deoxyuridine-5'-O-monophosphate;FdUMP);(2)elevated expression or activity of the primary enzymatic target thymidylate synthase(TS);and(3)dysregulated programmed cell death as important causes of 5-FU ***,these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine(FP)polymers(e.g.,CF10)that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.

关键词： Fluoropyrimidine 5-FU resistance colorectal cancer chemotherapy precision medicine thymidylate synthase