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Expression of O<sup>6</sup>-Methylguanine-DNA Methyltransferase Examined by Alkyl-Transfer Assays, Methylation-Specific PCR and Western Blots in Tumors and Matched Normal Tissue

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j.urnal of Cancer Therapy 2013年第4期4卷 919-931页

作者： Kimiko Ishiguro Krishnamurthy Shyam Philip G. Penketh Raymond P. Baumann Alan C. Sartorelli thomas j. rutherford Elena S. Ratner Department of Pharmacology and Developmental Therapeutics Program Cancer Center Yale University School of Medicine New Haven USA Division of Gynecologic Oncology Department of Obstetrics and Gynecology Yale University School of Medicine New Haven USA

The tumor selectivity of alkylating agents that produce guanine O6-chloroethyl (laromustine and carmustine) and O6-methyl (temozolomide) lesions depends upon O6-methylguanine-DNA methyltransferase (MGMT) activity being lower in tumor than in host tissue. Despite the established role of MGMT as a tumor resistance factor, consensus on how to assess MGMT expression in clinical samples is unsettled. The aim of this study is to examine the relationship between the values derived from distinctive MGMT measurements in 13, 12, 6 and 2 pairs of human tumors and matched normal adj.cent tissue from the colon, kidney, lung and liver, respectively, and in human cell lines. The MGMT measurements included 1) alkyl-transfer assays using [benzene-3H]O6-benzylguanine as a substrate to assess functional MGMT activity, 2) methylation-specific PCR (MSP) to probe MGMT gene promoter CpG methylations as a measure of gene silencing, and 3) western immunoblots to analyze the MGMT protein. In human cell lines, a strict negative correlation existed between MGMT activity and the extent of promoter methylation. In tissue specimens, by contrast, the correlation between these two variables was low. Moreover, alkyl-transfer assays identified 3 pairs of tumors and normal tissue with tumor-selective reduction in MGMT activity in the absence of promoter methylation. Cell line MGMT migrated as a single band in western analyses, whereas tissue MGMT was heterogeneous around its molecular size and at much higher molecular masses, indicative of multi-layered post-translational modifications. Malignancy is occasionally associated with a mobility shift in MGMT. Contrary to the prevalent expectation that MGMT expression is governed at the level of gene silencing, these data suggest that other mechanisms that can lead to tumorselective reduction in MGMT activity exist in human tissue.

关键词： O6-Methylguanine-DNA Methyltransferase (MGMT O6-Alkylguanine-DNA Alkyltransferase AGT) [Benzene-3H]O6-Benzylguanine Methylation-Specific PCR (MSP) Laromustine (Onrigin Cloretazine VNP40101M 101M) Temozolomide

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j.urnal of Cancer Therapy 2011年第2期2卷 217-223页

作者： Sarah N. Cross Elena S. Ratner Dan A. Silasi Alessandro D. Santin Masoud Azodi thomas j. rutherford Peter E. Schwartz Department of Obstetrics Gynecology and Reproductive Sciences Yale University School of Medicine New Haven USA.

Background: Bevacizumab is increasingly being used in the treatment of gynecologic malignancies, but has significant side-effects including hypertension and reversible posterior leukoencephalopathy (RPLS), which must be recognized by the gynecologic oncologist. Methods: A 26-month institutional retrospective review of bevacizumab in the treatment of gynecologic malignancies. Patients were grouped according to whether they had bevacizumab-related hypertension (defined as at least a grade one hypertensive toxicity) or not. There were no differences in patient demographics between the groups. Risk factors for developing bevacizumab-related hypertension were assessed using t-tests, Wilcoxon rank sum test and Fisher’s exact test. Results: Our group has treated 45 patients with bevacizumab. Fifteen (33%) patients had a pre-existing diagnosis of hypertension, 12 (80%) of whom had at least one elevated blood pressure during treatment. The 30 (67%) patients who did not have a pre-existing diagnosis of hypertension still had a high incidence of bevacizumab-related elevated blood pressure (14, 47%). The maj.rity of patients (26, 58%) had at least one therapy cycle complicated by hypertension. Patients who experienced bevacizumab-related hypertension were significantly more likely than not to have a history of hypertension (odds ratio of 4.6, 95% CI 1.1-19.6). There was a 4.4% incidence of reversible posterior leukoencephalopathy. Patients with age equal to or greater than 75 years, stage IV disease, and creatinine elevations greater than or equal to 1.4 mg/dL were significantly more likely to develop bevacizumab-related hypertension. Other factors such as numbers of prior chemotherapies, cycles of bevacizumab, BMI, cancer site, and histology were not significantly associated with bevacizumab-related hypertension. Conclusions: Hypertension is a problem for patients on bevacizumab whether or not they have a pre-existing diagnosis. However, those with a history of hypertension we

关键词： Ovarian Cancer Bevacizumab Hypertension Posterior Reversible Leukoencephalopathy

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Theory and classification of mass extinction causation

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National Science Review 2024年第1期11卷 16-36页

作者： thomas j.Algeo j.n Shen State Key Laboratory of Biogeology and Environmental Geology China University of Geosciences—Wuhan State Key Laboratory of Geological Processes and Mineral Resources China University of Geosciences—Wuhan Department of Geosciences University of Cincinnati

Theory regarding the causation of mass extinctions is in need of systematization, which is the focus of this contribution. Every mass extinction has both an ultimate cause, i.e. the trigger that leads to various climato-environmental changes, and one or more proximate cause(s), i.e. the specific climato-environmental changes that result in elevated biotic mortality. With regard to ultimate causes, strong cases can be made that bolide(i.e. meteor) impacts, large igneous province(LIP) eruptions and bioevolutionary events have each triggered one or more of the Phanerozoic Big Five mass extinctions, and that tectono-oceanic changes have triggered some second-order extinction events. Apart from bolide impacts, other astronomical triggers(*** flares, gamma bursts and supernova explosions) remain entirely in the realm of speculation. With regard to proximate mechanisms, most extinctions are related to either carbon-release or carbon-burial processes, the former being associated with climatic warming, ocean acidification, reduced marine productivity and lower carbonate δ13C values, and the latter with climatic cooling, increased marine productivity and higher carbonate δ13C values. Environmental parameters such as marine redox conditions and terrestrial weathering intensity do not show consistent relationships with carbon-cycle *** this context, mass extinction causation can be usefully classified using a matrix of ultimate and proximate factors. Among the Big Five mass extinctions, the end-Cretaceous biocrisis is an example of a bolide-triggered carbon-release event, the end-Permian and end-Triassic biocrises are examples of LIP-triggered carbon-release events, and the Late Ordovician and Late Devonian biocrises are examples of bioevolution-triggered carbon-burial events. Whereas the bolide-impact and LIP-eruption mechanisms appear to invariably cause carbon release, bioevolutionary triggers can result in variable carbon-cycle changes, e.g. carbon burial durin

关键词： biocrisis ultimate cause proximate cause bolide large igneous province bioevolutionary event

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EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

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Signal Transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： Keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell j.n Okabe Ishant Khurana thomas Karagiannis j.lia j.Liang Lina Mariana thomas Loudovaris thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release *** type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-*** of these cells leads to a lifelong dependence on exogenous insulin administration for ***,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell *** and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation *** transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 *** the present study,we show that transient stimulation of exocrine cells,derived from j.venile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell *** transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin *** EZH2 is fundamental toβ-cell regenerative *** pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex *** pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

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Adeno-associated virus as a delivery vector for gene therapy of human diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： j.ang-Hui Wang Dominic j.Gessler Wei Zhan thomas L.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

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Examining the“revisability”benefit of hip resurfacing arthroplasty

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World j.urnal of Orthopedics 2024年第6期15卷 554-559页

作者： j.se George Adam j.Taylor thomas P Schmalzried Department of Orthopedics Harbor UCLA Medical CenterTorranceCA 90509United States

BACKGROUND Hip resurfacing arthroplasty(HRA)is an alternative to total hip arthroplasty(THA)that is typically reserved for young active patients because it preserves ***,the benefits of HRA only hold true if conversion THA after failed HRA provides acceptable *** To compare patient reported outcomes for conversion THA after HRA failure to primary *** A retrospective review of 36 patients(37 hips)that underwent conversion THA for failed HRA between October 2006 and May 2019 by a single surgeon was *** reported outcomes[modified Harris Hip Score(mHHS),University of California Los Angeles(UCLA)activity score]were obtained via an email-based responder-anonymous *** were compared to normative data of a primary THA cohort with similar *** analysis was performed comparing outcomes of conversion THA for adverse local tissue reaction(ALTR)vs all other causes for *** The study group had a lower mHHS than the control group(81.7±13.8 vs 90.2±11.6,P<0.01);however,both groups had similar UCLA activity levels(7.5±2.3 vs 7.2±1.6,P=0.51).Patients that underwent conversion for non-ATLR causes had similar mHHS(85.2±11.5 vs 90.2±11.6,P=0.11)and higher UCLA activity levels(8.5±1.8 vs 7.2±1.6,P<0.01)compared to the control *** that underwent conversion for ATLR had worse mHHS(77.1±14.5 vs 90.2±11.6,P<0.01)and UCLA activity levels(6.1±2.3 vs 7.2±1.6,P=0.05)when compared to the control *** Patient outcomes equivalent to primary THA can be achieved following HRA conversion to ***,inferior outcomes were demonstrated for ALTR-related HRA *** selection and perhaps further studies examining alternative HRA bearing surfaces should be considered.

关键词： Total hip arthroplasty Hip resurfacing arthroplasty Conversion total hip arthroplasty Adverse local tissue reaction Patient reported outcome measures

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Influence of water evaporation on elastohydrodynamic lubrication with water-containing polyalkylene glycols

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Friction 2024年第10期12卷 2370-2388页

作者： Stefan HOFMANN thomas LOHNER Karsten STAHL Technical University of Munich School of Engineering and DesignDepartment of Mechanical EngineeringGear Research Center(FZG)Boltzmannstraße 1585748 Garching near MunichGermany

The reduction of frictional power losses in power transmitting gears takes a crucial role in the design of energy-and resource-efficient ***-containing lubricants like glycerol and polyalkylene glycols have shown great potential in achieving friction within the superlubricity regime with coefficients of friction lower than 0.01 under elastohydrodynamic ***,a bio-based production of the base stocks can lead to the development of green ***,one challenge associated with the application of water-containing lubricants to gearboxes is the evaporation of water and its impact on the lubricant *** this study,the influence of water evaporation on elastohydrodynamic friction and film thickness was investigated for three water-containing polyalkylene *** nominal water contents of 20 wt%and 40 wt%and two viscosities were *** results show that the friction increases continuously with higher evaporated water content,while the overall friction level remains low in nearly water-free states.A similar trend is observed for film thickness,where the strong increase in viscosity results in a notable increase in film ***,the sensitivity of friction and film thickness to water evaporation is low for small amounts of evaporated *** allows generous thresholds for permissible variations in water content.

关键词： friction superlubricity aqueous lubrication elastohydrodynamic lubrication(EHL) evaporation polyalkylene glycol

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Energy and blast performance of beryllium in a model thermobaric composition in comparison with aluminum and magnesium

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Defence Technology（防务技术） 2024年第6期36卷 13-19页

作者： thomas M.Klapotke Stanisław Cudziło Waldemar A.Trzcinski j.zef Paszula Energetic Materials Research Department of ChemistryUniversity of Munich(LMU)Butenandtstrasse 5-13(D)81377MunichGermany Military University of Technology Faculty of Advanced Technologies and ChemistrySylwester Kaliski Str.200-908WarsawPoland

A direct comparison is made between the effectiveness of Al,Mg,and Be powders as additional fuels in model thermobaric compositions containing 20%fuel,20%ammonium perchlorate,and 60%RDX(1,3,5-Trinitro-1,3,5-triazacyclohexane)passivated with *** determined calorimetric measurements of the heat of detonation,along with the overpressure histories in an explosion chamber filled with nitrogen,were used to determine the quasi-static pressure(QSP)under anaerobic *** measurements were also performed in a semi-closed bunker,and all blast wave parameters generated after the detonation of 500 g charges of the tested explosives were *** calorimetry results,QSP values,and blast wave parameters(pressure amplitude,specific and total impulses)clearly indicate that Be is much more effective as an additional fuel than either Al or Mg in both anaerobic post-detonation reactions as well as the subsequent aerobic *** heat of detonation of the RDXwax/AP/Be explosive mixture is over 40%and 50%higher than that of the mixture containing aluminum and magnesium instead of beryllium,***,the TNT equivalent of the Be-containing composition due to the overpressure in the nitrogen-filled explosion chamber is 1.66,while the equivalent calculated using an air shock wave-specific impulse at a distance of 2.5 m is equal to *** high values of these parameters confirm the high reactivity of beryllium in both the anaerobic and aerobic stages of the thermobaric explosion.

关键词： Thermobaric explosives Beryllium Heat of detonation Quasi-static overpressure Blast wave parameters

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Dynamic convergent shock compression initiated by return current in high-intensity laser-solid interactions

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Matter and Radiation at Extremes 2024年第4期9卷 40-53页

作者： Long Yang Martin Rehwald thomas Kluge Alej.ndro LasoGarcia Toma Toncian Karl Zeil Ulrich Schramm thomas E.Cowan Lingen Huang Helmholtz-Zentrum Dresden-Rossendorf 01328 DresdenGermany Technische Universitat Dresden 01062 DresdenGermany

We investigate the dynamics of convergent shock compression in solid cylindrical targets irradiated by an ultrafast relativistic laser *** particle-in-cell simulations and coupled hydrodynamic simulations reveal that the compression process is initiated by both magnetic pressure and surface ablation associated with a strong transient surface return current with density of the order of 10^(17) A/m^(2) and lifetime of 100 *** results show that the dominant compression mechanism is governed by the plasma β,i.e.,the ratio of thermal pressure to magnetic *** targets with small radius and low atomic number Z,the magnetic pressure is the dominant shock compression *** to a scaling law,as the target radius and Z increase,the surface ablation pressure becomes the main mechanism generating convergent ***,an indirect experimental indication of shocked hydrogen compression is provided by optical shadowgraphy measurements of the evolution of the plasma expansion *** results presented here provide a novel basis for the generation of extremely high pressures exceeding Gbar(100 TPa)to enable the investigation of high-pressure physics using femtosecond j.level laser pulses,offering an alternative to nanosecond kj.laser pulse-driven and pulsed power Z-pinch compression methods.

关键词： shock convergent return

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Development of sustainable thermal insulation based on bio-polyester filled with date pits

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j.urnal of Bioresources and Bioproducts 2024年第1期9卷 74-89页

作者： Amal Mlhem thomas Teklebrhan Evenezer Bokuretsion Basim Abu-j.ayil Chemical&Petroleum Engineering Department United Arab Emirates UniversityPO Box 15551United Arab Emirates National Water and Energy Center United Arab Emirates UniversityPO Box 15551United Arab Emirates

Date palm pit(DPP)-filled poly(-hydroxybutyrate)(PHB)composites were prepared,evaluated,and characterized to determine their thermal insulation *** conductivity values ranged between 0.086 and 0.100 W/(m·K).At a maximum filler concentration(50%(w)),the specific heat capacity and thermal diffusivity were 1183 j.(kg·K)and 0.0689 mm^(2)/s,*** DPP increased the thermal stability,and the highest compressive strength obtained was 80 MPa at 30%filler *** PHB-DPP composites exhibited promising water absorption(less than 6%)and tensile strength(6-14 MPa).Date-pit-based PHB composites could be used in sustainable building engineering and cleaner production.

关键词： Green construction material Sustainable thermal insulator Date pit Polyhydroxybutyrate

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