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Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes

Translational Neurodegeneration 2014年第1期3卷 89-97页

作者： Justin B Miller Sarah J Banks Gabriel C léger jeffrey l cummings Cleveland Clinic Lou Ruvo Center for Brain Health888 W.Bonneville AveLas VegasNevada 89106USA

Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia(FTD).Targets for intervention have been identified,therapies are being developed,and clinical trials are advancing.A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous *** neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction,language impairments and behavioral *** variant FTD is characterized by an initial presentation of changes in personality,behavior and/or emotion,which are often difficult to objectively capture using traditional neuropsychological *** two principal language variants of FTD are Progressive Nonfluent Aphasia(PNFA)with predominant agrammatic/non-fluent impairments and Semantic Dementia(SD)with semantic impairments and visual *** of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change,yet specific enough to isolate signal from noise,and acceptable to regulatory *** the anticipated potential for small effect sizes,measures must be able to identify small incremental changes over *** is also imperative that the measures provide adequate coverage of the constructs or behaviors of *** outcome measures should be suitable for repeat administration,yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor *** facilitate widespread adoption as an endpoint,measures should be readily *** provide several examples of potential global,composite,and individual cognitive measures,as well as behavioral measures promising for FTD *** and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.

关键词： Frontotemporal dementia Primary endpoints Secondary endpoints Randomized controlled trial Methods

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神经精神科问卷知情者版中文译本的信效度

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中国心理卫生杂志 2010年第5期24卷 338-342,361页

作者：马万欣王华丽 jeffrey l.cummings 于欣北京大学精神卫生研究所卫生部精神卫生学重点实验室(北京大学)北京100191 北京市朝阳区第三医院北京100121 美国加州大学洛杉矶分校美国加利福尼亚州90095

目的:评价神经精神科问卷知情者版(Neuropsychiatric Inventory-Questionnaire,NPI-Q)中文译本的信度与效度。方法:从北京大学精神卫生研究所记忆中心的病例库中,选取51例符合NINCDS-ADR-DA诊断标准的阿尔茨海默病(probable AD)患者,接... 详细信息

目的:评价神经精神科问卷知情者版(Neuropsychiatric Inventory-Questionnaire,NPI-Q)中文译本的信度与效度。方法:从北京大学精神卫生研究所记忆中心的病例库中,选取51例符合NINCDS-ADR-DA诊断标准的阿尔茨海默病(probable AD)患者,接受简明智能精神状况检查(Mini-mental Status Exami-nation,MMSE)、日常生活活动量表(Activities of Daily living,ADl)、阿尔茨海默病评定量表(Alzheimer'sdisease Assessment Scale-Cognitiveportion,ADAS-cog)、神经精神科问卷(Neuropsychiatric Inventory,NPI)评定,并由其知情者进行NPI-Q评分。其中16例在临床干预3个月后进行重测。结果:(1)NPI-Q克朗巴赫系数α=0.851,Guttman分半系数为0.825;NPI-Q总分重测信度为ICC=0.860(P0.05)。(2)NPI-Q各条目评分之间的相关系数为0.01～0.97,均与总分呈正相关(r=0.33～0.87,Pl、ADAS-cog、NPI总分、NPI苦恼程度评分均相关(r=0.47～0.82,均Pl、ADAS-cog、NPI总分、NPI苦恼程度相关(r=0.29～0.68,P<0.05)。因子分析提示NPI-Q含有精神病性、情感损害和额叶功能3个因子,总贡献率达62.23%。结论:神经精神科问卷知情者版中文译本具有较好的信度和效度,值得推广应用。

关键词：神经精神科问卷知情者版(NPI—Q) 阿尔茨海默病信度效度

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Debris Fan Produced by Failure of Canyon-Blocking Pyroclastic Flows

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Journal of Water Resource and Protection 2024年第5期16卷 328-360页

作者： Michael l. cummings Department of Geology Portland State University Portland Oregon USA

Ash-rich pyroclastic flows from the cataclysmic eruption of Mount Mazama (~7700 yr. B. P.), Cascade volcanic arc, Oregon, entered and blocked the narrow, bedrock-lined canyon of the Williamson River approximately 35 to 44 km from the source volcano. The blockage impounded a body of water which then released producing four stratigraphic units in the downstream debris fan. The four stratigraphic units are a boulder core comprised of locally sourced bedrock boulders and three sand-rich units including a fine-grained sand unit, a sandy pumice gravel (±basalt/hydrovolcanic tuff) unit, and a pumice pebble-bearing, crystal-rich sand unit. Hand-drilled auger holes up to ~1.6 m deep were used to obtain samples of the sand-rich units. Units were delimited using surface and down-hole observations, composition and texture, estimated density, statistical parameters of grain size, and vertical and lateral distribution of properties. Overtopping followed by rapid incision into the ash-rich pyroclastic flows progressively cleared the canyon, but a bedrock knickpoint near the head of the canyon limited the volume of debris available for transport to about 0.04 km3 to 0.08 km3. Co-deposition of bedrock boulders and lithic-rich sand was followed by rapid deposition with minimal reworking of remobilized pyroclastics. Continued draining of the impounded lake sent hyperconcentrated flows onto the debris fan depositing pumice-rich gravels that graded upward to crystal-rich sands.

关键词： Outburst Flood Mount Mazama Debris Fan Canyon Blockage Pyroclastic Flows

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Promoting the production of challenging proteins via induced expression in CHO cells and modified cell-free lysates harboring T7 RNA polymerase and mutant eIF2α

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Synthetic and Systems Biotechnology 2024年第3期9卷 416-424页

作者： jeffrey l.Schloßhauer lena Tholen Alexander Korner Stefan Kubick Sofia Chatzopoulou Anja Honow Anne Zemella Fraunhofer Project Group PZ-Syn of the Fraunhofer Institute for Cell Therapy and Immunology-IZI Branch Bioanalytics and Bioprocesses-IZI-BBAm MühlenbergPotsdamGermany Fraunhofer Institute for Cell Therapy and Immunology-IZI Branch Bioanalytics and Bioprocesses-IZI-BBAm MühlenbergPotsdamGermany Faculty of Health Sciences Joint Faculty of the Brandenburg University of Technology Cottbus-SenftenbergThe Brandenburg Medical School Theodor FontaneUniversity of PotsdamPotsdamGermany Institute for Chemistry and Biochemistry Laboratory of Protein BiochemistryFreie Universitat BerlinThielallee 6314195BerlinGermany Institute of Biotechnology Technische Universit¨at BerlinStraße des 17.Juni 13510623BerlinGermany New/era/mabs GmbH August-Bebel-Str.8914482PotsdamGermany

Chinese hamster ovary(CHO)cells are crucial in biopharmaceutical production due to their scalability and capacity for human-like post-translational ***,toxic proteins and membrane proteins are often difficult-to-express in living ***,cell-free protein synthesis can be *** study explores innovative strategies for enhancing the production of challenging proteins through the modification of CHO cells by investigating both,cell-based and cell-free approaches.A major result in our study involves the integration of a mutant eIF2 translation initiation factor and T7 RNA polymerase into CHO cell lysates for cell-free protein *** resulted in elevated yields,while eliminating the necessity for exogenous additions during cell-free production,thereby substantially enhancing ***,we explore the potential of the Rosa26 genomic site for the integration of T7 RNA polymerase and cell-based tetracycline-controlled protein *** findings provide promising advancements in bioproduction technologies,offering flexibility to switch between cell-free and cell-based protein production as needed.

关键词： Inducible expression CHO cells Cell-free protein synthesis CRISPR T7 RNA polymerase eIF2 Rosa26

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In vivo measurement of NADH fluorescence lifetime in skeletal muscle via -ber-coupled time-correlated single photon counting

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Journal of Innovative Optical Health Sciences 2024年第1期17卷 121-134页

作者： Kathryn M.Priest Jacob V.Schluns Nathania Nischal Colton l.Gattis jeffrey C.Wolchok Timothy J.Muldoon Department of Biomedical Engineering University of Arkansas FayettevilleARUSA

Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living ***-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue *** study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in *** muscle loss(VMl)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley *** lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of *** injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has *** data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.

关键词： Glycolysis oxidative phosphorylation energy metabolism volumetric muscle loss

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Disease modification and Neuroprotection in neurodegenerative disorders

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Translational Neurodegeneration 2017年第1期6卷 232-238页

作者： jeffrey cummings Cleveland Clinic lou Ruvo Center for Brain Health 888 W Bonneville AveLas VegasNV 89106USA

Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and *** advances in understanding the neurobiology of NDD,there are no approved ***:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease *** modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the ***,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial *** multiple biomarkers is necessary to support a comprehensive view of disease ***:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell *** data are collected in clinical *** defining a DMT will assist in NDD drug development programs.

关键词： Alzheimer’s disease Frontotemporal dementia Progressive supranuclear palsy Corticobasal degeneration Amyotropic lateral sclerosis Multiple system atrophy Disease modification Disease modifying therapy

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Supplementation of vitamin E or a botanical extract as antioxidants to improve growth performance and health of growing pigs housed under thermoneutral or heat-stressed conditions

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Journal of Animal Science and Biotechnology 2024年第3期15卷 1101-1118页

作者： Ysenia V.Silva‑Guillen Consuelo Arellano jeffrey Wiegert R.Dean Boyd Gabriela E.Martinez Eric van Heugten Department of Animal Science North Carolina State UniversityRaleighNC 27695USA Department of Statistics North Carolina State UniversityRaleighNC 27695USA Department of Animal Science Texas A&M UniversityCollege StationTX 77843USA Animal Nutrition Research LLCAlvatonKY 42122USA.

Background Heat stress has severe negative consequences on performance and health of pigs,leading to significant economic *** objective of this study was to investigate the effects of supplemental vitamin E and a botanical extract in feed or drinking water on growth performance,intestinal health,and oxidative and immune status in grow-ing pigs housed under heat stress *** Duplicate experiments were conducted,each using 64 crossbred pigs with an initial body weight of 50.7±3.8 and 43.9±3.6 kg and age of 13-week and 12-week,***(n=128)were housed individually and assigned within weight blocks and sex to a 2×4 factorial arrangement consisting of 2 environments(thermo-neutral(21.2℃)or heat-stressed(30.9℃))and 4 supplementation treatments(control diet;control+100 IU/l of D-α-tocopherol in water;control+200 IU/kg of Dl-α-tocopheryl-acetate in feed;or control+400 mg/kg of a botanical extract in feed).Results Heat stress for 28 d reduced(P≤0.001)final body weight,average daily gain,and average daily feed intake(-7.4 kg,-26.7%,and-25.4%,respectively)but no effects of supplementation were detected(P>0.05).Serum vitamin E increased(Plementation in water and in feed(1.64 vs.3.59 and 1.64 vs.3.24),but not for the botanical extract(1.64 vs.1.67 mg/kg)and was greater when supplemented in water ***(P=0.002).liver vitamin E increased(Plementations in water(3.9 vs.31.8)and feed(3.9 vs.18.0),but not with the botanical extract(3.9 vs.4.9 mg/kg).Serum malondialdehyde was reduced with heat stress on d 2,but increased on d 28(interaction,Plementation compared to *** proliferation was reduced(P=0.037)in the jejunum under heat stress,but increased in the ileum when vitamin E was supplemented in feed and water under heat stress(interaction,P=0.04).Tumor necrosis factor-αin jejunum and ileum mucosa decreased by heat stress(P<0.05)and was re

关键词： Botanical extract Growing pigs Heat stress Immune status Oxidative status Tocopherol Water

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Remodeling Tumor Immune Microenvironment by Using Polymer-lipid-Manganese Dioxide Nanoparticles with Radiation Therapy to Boost Immune Response of Castration-Resistant Prostate Cancer

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Research 2024年第3期2023卷 83-96页

作者： Abdulmottaleb E.Zetrini HoYin lip Azhar Z.Abbasi Ibrahim Alradwan Taksim Ahmed Chunsheng He jeffrey T.Henderson Andrew M.Rauth Xiao Yu Wu Advanced Pharmaceutics and Drug Delivery laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoM5S 3M2TorontoONCanada. Departments of Medical Biophysics and Radiation Oncology University of TorontoM5G 1L7TorontoONCanada.

Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment. Herein, we exploited the bioreactivity of novel polymer–lipid manganese dioxide nanoparticles (PlMDs) to remodel the tumor immune microenvironment (TIME) by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death. This study demonstrated that PlMD treatment sensitized hypoxic human and murine CRPC cells to radiation, significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death, which enhanced the secretion of damage-associated molecular patterns, attributable to the induction of autophagy and endoplasmic reticulum stress. Reoxygenation via PlMDs also polarized hypoxic murine RAW264.7 macrophages toward the M1 phenotype, enhancing tumor necrosis factor alpha release, and thus reducing the viability of murine CRPC TRAMP-C2 cells. In a syngeneic TRAMP-C2 tumor model, intravenous injection of PlMDs suppressed, while radiation alone enhanced recruitment of regulatory T cells and myeloid-derived suppressor cells. Pretreatment with PlMDs followed by radiation down-regulated programmed death-ligand 1 and promoted the infiltration of antitumor CD8+ T cells and M1 macrophages to tumor sites. Taken together, TIME modulation by PlMDs plus radiation profoundly delayed tumor growth and prolonged median survival compared with radiation alone. These results suggest that PlMDs plus radiation is a promising treatment modality for improving therapeutic efficacy in radioresistant and immunosuppressive solid tumors.

关键词： RAW264.7 alone treatment

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

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Genes & Diseases 2024年第1期11卷 103-134页

作者： Kevin Qin Michael Yu Jiaming Fan Hongwei Wang Piao Zhao Guozhi Zhaoo Wei Zeng Connie Chen Yonghui Wang Annie Wang Zander Schwartz jeffrey Hong lily Song William Wagstaff Rex C.Haydon Hue H.luu Sherwin H.Ho Jason Strelzow Russell R.Reid Tong-Chuan He lewis l.Shi Chicago Medical School Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Clinical laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA laboratory of Craniofacial Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Wnt signaling plays a major role in regulating cell proliferation and *** Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and lRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical *** of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling *** crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ ***-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic *** complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic ***,both stimulatory and inhibitory treatments come with potential risks that need to be *** review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt *** thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+*** description involved each of its components and their involvement in other cellular ***,this review explained the various other pathways and processes that crosstalk with Wnt signaling.

关键词： β-catenin Canonical Wnt Noncanonical Wnt Signal transduction Signaling crosstalk

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Reflections on COPD comorbidities

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Chinese Medical Journal 2024年第12期137卷 1504-1506页

作者： Zhenming He Yue Wang lin Shan Yan Mou Yunhuan liu Guanhua Ma Yanxu Wu Huili Zhu jeffrey l.Curtis Shilei Cui Haiyan Ge Department of Pulmonary and Critical Care Medicine Huadong HospitalFudan UniversityShanghai 200040China Medical Service VA Ann Arbor Healthcare SystemAnn ArborMI 48105USA Pulmonary&Critical Care Medicine Division Department of Internal MedicineUniversity of MichiganAnn ArborMI 48109USA Graduate Program in Immunology University of MichiganAnn ArborMI 48109USA

To the Editor:Chronic obstructive pulmonary disease(COPD)is a common disease among the elderly,affecting over one-third of the elderly population *** progressive decline in lung function characteristic of COPD significantly impacts the quality of life and employability of affected individuals,resulting in a substantial direct and indirect socioeconomic *** frequently has comorbidities involving other organ *** all elderly COPD patients present with one or more comorbid conditions,collectively exacerbating health and economic *** viral and bacterial infections remain the most common triggers for COPD exacerbations(ECOPD).

关键词： morbid lung collective

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