tbuckley/cabot-search huggingface dataset:
Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity
Authors: Xiaojing Chen, Lucia Poncette, Thomas Blankenstein
Journal: The Journal of Experimental Medicine (2017)

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development
Authors: Hanako Kobayashi, Jiao Liu, Andres A. Urrutia, Mikhail Burmakin, Ken Ishii, Malini Rajan, Olena Davidoff, Zubaida Saifudeen, Volker H. Haase
Journal: Kidney International (2017)
Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia
Authors: Prakash Gangadaran, Ramya Lakshmi Rajendran, Ho Won Lee, Senthilkumar Kalimuthu, Chae Moon Hong, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Journal: Journal of Controlled Release (2017)
Microbial Lineages in Sarcoidosis. A Metagenomic Analysis Tailored for Low–Microbial Content Samples
Authors: Erik L. Clarke, Abigail P. Lauder, Casey E. Hofstaedter, Young Hwang, Ayannah S. Fitzgerald, Ize Imai, Wojciech Biernat, Bartłomiej Rękawiecki, Hanna Majewska, Anna Dubaniewicz, Leslie A. Litzky, Michael D. Feldman, Kyle Bittinger, Milton D. Rossman, Karen C. Patterson, Frederic D. Bushman, Ronald G. Collman
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: The etiology of sarcoidosis is unknown, but microbial agents are suspected as triggers.Objectives: We sought to identify bacterial, fungal, or viral lineages in specimens from patients with sarcoidosis enriched relative to control subjects using metagenomic DNA sequencing. Because DNA from environmental contamination contributes disproportionately to samples with low authentic microbial content, we developed improved methods for filtering environmental contamination.Methods: We analyzed specimens from subjects with sarcoidosis (n = 93), control subjects without sarcoidosis (n = 72), and various environmental controls (n = 150). Sarcoidosis specimens consisted of two independent sets of formalin-fixed, paraffin-embedded lymph node biopsies, BAL, Kveim reagent, and fresh granulomatous spleen from a patient with sarcoidosis. All specimens were analyzed by bacterial 16S and fungal internal transcribed spacer ribosomal RNA gene sequencing. In addition, BAL was analyzed by shotgun sequencing of fractions enriched for viral particles, and Kveim and spleen were subjected to whole-genome shotgun sequencing.Measurements and Main Results: In one tissue set, fungi in the Cladosporiaceae family were enriched in sarcoidosis compared with nonsarcoidosis tissues; in the other tissue set, we detected enrichment of several bacterial lineages in sarcoidosis but not Cladosporiaceae. BAL showed limited enrichment of Aspergillus fungi. Several microbial lineages were detected in Kveim and spleen, including Cladosporium. No microbial lineage was enriched in more than one sample type after correction for multiple comparisons.Conclusions: Metagenomic sequencing revealed enrichment of microbes in single types of sarcoidosis samples but limited concordance across sample types. Statistical analysis accounting for environmental contamination was essential to avoiding false positives.
Abstract 188: Sarcomere Protein Cardiac Myosin Binding Protein C Regulates Cardiomyocyte Proliferation
Authors: Jianming Jiang, Hiroko Wakimoto, Kenji Onoue, Gregory M Fomovsky, Richard T Lee, Jonathan G Seidman, Christine E Seidman
Journal: Circulation Research (2013)

Introduction: Wildtype neonatal murine cardiomyocytes become bi-nucleated, hypertrophy and terminally differentiate, and concurrently develop well-organized striation patterns of sarcomeres of myofibrils. Neonatal mice lacking cardiac myosin binding protein C (Mybpc t/t ) have subtle abnormalities in myofibrillar structure and ventricular dilation, but remain healthy life-long. Hypothesis: Deficits in MybpC impacts formation of bi-nucleated and cell proliferation of cardiomyocytes. Methods: We studied the cardiac development in Mybpc t/t mice and hearts depleted of cMyBP-C by adeno-associated virus (AAV)-mediated RNAi. Results: Mybpc t/t hearts presented significant increase in mono-nucleated cardiomyocytes (18.28 ± 1.68%) and decrease in bi-nucleated cardiomyocytes (74.87 ± 87%), compared to wildtype hearts (mono-nucleated: 5.85% ± 1.14%, p&lt;0.001; bi-nucleated: 89.83 ± 2.04%, p&lt;0.001, n=4 in each genotype). Similar distribution of mono-nucleated (25.25 ± 3.15%) and bi-nucleated cardiomyocytes (73.55 ± 3.8%) was also observed in cardiomyocytes depleted of cMyBP-C by AAV-mediated RNAi (n=4). Significant increase in EdU incorporation was observed in Mybpc t/t cardiomyocytes (47.02 ± 2.5%) compared to wildtype cardiomyocytes (29.35 ± 3.06%, p&lt;0.005). Phosphorylated histone H3, a marker of mitosis, was approximately two-fold more positive in Mybpc t/t than wildtype cardiomyocytes at postnatal day 3, day 7 and day10 (p&lt;0.01). In addition, we observed a 15-fold increase of Aurora B expression within the cytoplasmic bridge between cardiomyocytes undergoing cytokinesis in Mybpc t/t hearts compared to wildtype hearts at postnatal day 7 (p&lt;0.001). The predicted consequence of protracted cardiomyocyte proliferation in neonatal Mybpc t/t mice, a significantly increased number of cardiomyocytes, was demonstrated. In comparison to wildtype, the number of cardiomyocytes in Mybpc t/t hearts was significantly increased by 40% (n=3 in each group, p&lt;0.01). Conclusions: Loss of cMyBP-C causes neonatal cardiomyocytes to undergo extra round of cytokinesis and continued progression of the cell cycles. Changes in cell number, rather than cell size, may be responsible for morphologic abnormalities of some cardiomyopathies.
Impact of insulin-like growth factor 1 receptor (<i>IGF1R</i>) and amphiregulin (<i>AREG</i>) expressions on survival in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Wataru Ichikawa, Masanori Terashima, Atsushi Ochiai, Koji Kitada, Issei Kurahashi, Shinichi Sakuramoto, Hitoshi Katai, Takeshi Sano, Hiroshi Imamura, Mitsuru Sasako
Journal: Journal of Clinical Oncology (2012)

4012 Background: Exploratory biomarker analysis was conducted to identify factors related to outcomes of patients enrolled in the ACTS-GC study, a randomized controlled trial comparing adjuvant S-1 administration with surgery alone in 1,059 patients with stage II/III gastric cancer. Methods: Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 829 patients (78.3%), and 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression levels were normalized to the geometric mean expressions of GAPDH, ACTB, and RPLP0, used as reference genes. The expression of each gene was categorized into low and high values at those median. The impacts of gene expression on survival were analyzed using the 5-year survival data of the ACTS-GC. The Benjamini and Hochberg procedure was used to control the false discovery rate (FDR). Results: Among 63 screened genes, IGF1R and AREG most strongly correlated with overall survival (OS), with FDR of 0.0048 and 0.018, respectively. OS was significantly worse in IGF1R high patients than in IGF1R low patients, but better in AREG high patients than in AREG low patients. The hazard ratio (HR) for death in the analysis of OS (S-1 vs. surgery alone) was lower in the high IGF1R group (HR, 0.55; 95%CI, 0.40-0.76) than in the low IGF1R group (HR, 0.72; 95%CI, 0.49-1.06). Likewise, the HR for death in the analysis of OS (S-1 vs. surgery alone) was much smaller in the low AREG group (HR, 0.57; 95%CI, 0.41-0.79) than in the high AREG group (HR, 0.74; 95%CI, 0.51-1.08). Interactions were not statistically significant. Conclusions: IGFR1 gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No interaction for survival was evident between S-1 and these gene expressions.
Antiangiogenic properties of the IMPDH inhibitor AVN944
Authors: Zoe Weaver, Jeffrey Strovel, Marion Chakiath, Pachai Natarajan, Tammy Lawrence, David Bol
Journal: Cancer Research (2007)

3983  AVN944 is an orally bioavailable inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH). IMPDH2 is the rate limiting enzyme for the de novo production of guanine nucleotides, and is highly up-regulated in many malignancies, including hematologic cancers. AVN944 has been shown to be a potent inhibitor of cancer cell proliferation, and to elicit a specific set of cellular responses directly related to depletion of cellular GTP pools (Strovel et al., 2006). Recent reports (Chong et al., 2006) have suggested that IMPDH inhibition could provide added benefit as a cancer therapy through blockade of tumor angiogenesis. To investigate this hypothesis, we evaluated AVN944 in a series of angiogenesis assays to determine the potential utility of this drug as an antiangiogenic agent for cancer treatment. AVN944 was found to potently inhibit endothelial cell proliferation, with an IC50 of approximately 30nM, significantly more potent than the IMPDH inhibitor mycophenolic acid (MPA; 130nM). Other in vitro assessments of AVN944 activity in endothelial cells included a comprehensive analysis of global gene expression changes resulting from IMPDH inhibition in these cells. The pathways and genes affected by IMPDH inhibition in endothelial cells were compared to those affected by AVN944 treatment of cancer cells, in an attempt to distinguish the reported dependence of endothelial cells on IMPDH 1 versus 2. Even more specifically, a broad set of biomarkers, currently being used to monitor response in patient samples from a phase I clinical trial with AVN944, was analyzed to assess the similarity of the response of endothelial cells to GTP depletion, as compared to cancer cells and patient samples. In addition, AVN944 antiangiogenesis activity was analyzed in the in vivo matrigel plug assay and in a renal carcinoma xenograft model. These results, detailing the potent inhibition of endothelial cells in vitro combined with inhibition of angiogenesis in relevant in vivo models, could position this drug for rapid development as a novel antiangiogenic agent for cancer therapy.
心筋梗塞治療に対するアポトーシス遺伝子サイレンシングおよび血管新生遺伝子発現の同時調節:SHP‐1 siRNAおよびVEGF発現pDNAの単一キャリアーデリバリー
Authors: Kim Dongkyu, Ku Sook Hee, Kim Hyosuk, Jeong Ji Hoon, Lee Minhyung, Kwon Ick Chan, Choi Donghoon, Kim Sun Hwa
Journal: Journal of Controlled Release (2016)
ER phospholipid composition modulates lipogenesis during feeding and in obesity
Authors: Xin Rong, Bo Wang, Elisa N.D. Palladino, Thomas Q. de Aguiar Vallim, David A. Ford, Peter Tontonoz
Journal: Journal of Clinical Investigation (2017)

Sterol regulatory element-binding protein 1c (SREBP-1c) is a central regulator of lipogenesis whose activity is controlled by proteolytic cleavage. The metabolic factors that affect its processing are incompletely understood. Here, we show that dynamic changes in the acyl chain composition of ER phospholipids affect SREBP-1c maturation in physiology and disease. The abundance of polyunsaturated phosphatidylcholine in liver ER is selectively increased in response to feeding and in the setting of obesity-linked insulin resistance. Exogenous delivery of polyunsaturated phosphatidylcholine to ER accelerated SREBP-1c processing through a mechanism that required an intact SREBP cleavage-activating protein (SCAP) pathway. Furthermore, induction of the phospholipid-remodeling enzyme LPCAT3 in response to liver X receptor (LXR) activation promoted SREBP-1c processing by driving the incorporation of polyunsaturated fatty acids into ER. Conversely, LPCAT3 deficiency increased membrane saturation, reduced nuclear SREBP-1c abundance, and blunted the lipogenic response to feeding, LXR agonist treatment, or obesity-linked insulin resistance. Desaturation of the ER membrane may serve as an auxiliary signal of the fed state that promotes lipid synthesis in response to nutrient availability.
細菌死と創傷消毒のためのAu/g C_3N_4ハイブリッドnanozymeによる反応性酸素種の生物学的に関連した準位の活性化【Powered by NICT】
Authors: Wang Zhenzhen, Dong Kai, Liu Zhen, Zhang Yan, Chen Zhaowei, Sun Hanjun, Ren Jinsong, Qu Xiaogang
Journal: Biomaterials (2017)
A review of 565 phase II trial abstracts from ASCO 2005: Design characteristics of contemporary trials evaluating cytotoxic versus non-cytotoxic regimens
Authors: C. Elser, G. Pond, E. Chen, L. Siu
Journal: Journal of Clinical Oncology (2007)

6569 Background: New phase II trial designs have been proposed to accommodate the non-cytotoxic nature of molecularly targeted agents. In particular, the use of alternative endpoints and controls has been suggested. The objectives of this survey are to review the designs of contemporary phase II trials, to compare trials of cytotoxic versus non-cytotoxic regimens, and to identify predictors of acceptance for presentation. Methods: Abstracts of phase II trials of systemic anticancer therapy published in the 2005 ASCO Proceedings were hand searched. The trial context, type of intervention, trial design, endpoints, and completeness of reporting were assessed. Results: Our search yielded 565 abstracts: 72% were multi-center, 44% North American, 25% clearly identified as industry-sponsored, the median number of patients was 44 (range 8–346). Only 83% explicitly reported the study phase, 29% the primary endpoint, 11% the number of stages, and 5% the statistical design. For design properties, 16% used multiple arms and 6% used enrichment. Of trials reporting the primary endpoint, 48% used radiological or marker response and 22% time-to-event endpoints. The median number of endpoints was 4 (range 1–8). Non- cytotoxic regimens, which included targeted agents, hormone- or immunotherapy, constituted 22% of the trials reviewed, purely cytotoxic regimens 60%, the remaining 18% contained combinations of both. Trials of non-cytotoxic and combination regimens were more likely to report the primary endpoint (p=0.02), use time-to-event endpoints (p=0.006), have multiple arms, use enrichment, be conducted in North America, be industry-sponsored, and be accepted for oral or poster presentation (all p&lt;0.001). Other predictors of publication type in multivariate analysis were multi-centricity, higher number of patients, industry involvement, and being conducted in North America (all p&lt;0.05). Conclusions: Design properties of contemporary phase II trials of non-cytotoxic agents differ from trials of cytotoxic chemotherapy, and are more likely to be accepted for presentation at ASCO. Proposed new trial designs start to be more widely adopted. Most abstracts incompletely report design properties. No significant financial relationships to disclose.
Abstract 18208: Intraindividual Variation of Tissue Doppler Velocities as Predictors of Cardiac Events in the General Population
Authors: Joanna N Wang, Tor Biering-Sørensen, Peter G Jørgensen, Jan S Jensen, Rasmus Møgelvang
Journal: Circulation (2015)

Introduction: Despite of Tissue Doppler imaging (TDI) being an important diagnostic tool for early detection of reduced myocardial function, there is still not a clear consensus on the site of measurement. It is complicated by the fact that the velocities vary between sites even within healthy individuals. Objectives: The aim of this study was to evaluate the predictive value of each mitral site along with the predictive value of the intraindividual variation between sites with respect to cardiac events. Methods: Cardiac function was evaluated by TDI in 2,064 participants within a large community-based population study. Peak systolic (s’), early diastolic (e’) and late diastolic (a’) velocities were obtained from 6 mitral annular sites. To assess global variation, two parameters were calculated using all 6 sites. One as their standard deviation divided by their mean, the other as their range divided by their median. To assess the variation within each apical projection, the difference between its two sites was divided by their mean. The end point was combined of admission with acute myocardial infarction, heart failure or cardiac death. Results: During a median follow-up of 10.9 years the endpoint occurred in 277 participants. In multivariable Cox proportional hazards regression adjusted for age and sex we found that a decrease in s’, e’ or a’ from any mitral site was associated with a significantly increased risk of the combined end point. However, neither the global variation nor the variation within each apical projection retained significant associations with the end point (Table). Conclusions: In the general population, systolic and diastolic TDI velocities at all mitral annular sites are important predictors of cardiac events. Along with the lack of association between intraindividual TDI variations and these events, it suggests that for the evaluation of cardiac prognosis the choice of site is of less importance.
MER-1001, a novel polymeric prodrug of camptothecin, is a potent inhibitor of LS174 and A2780 human tumor xenografts in a mouse model
Authors: Alex Yurkovetskiy, Mikhail Papisov, Alan Fischman, Alex Hiller, Mao Yin, James Rolke, S Harrison, Robin Ball, K Sheridan, Beth Hollister, Cheryl Napier, Ullrich Schwertschlag, Peter Leone, Julie Olson, Russell Petter
Journal: Cancer Research (2007)

781    Background and Rationale:   MER-1001 is a polymeric prodrug derivative of camptothecin (CPT) in which CPT is chemically tethered to a hydrophilic, bio-degradable 60-70-kDa polymer, Fleximer (poly[1-hydroxymethylene hydroxymethyl formal], PHF). When administered intravenously, MER-1001 releases camptothecin-20-( N -succinimido-glycinate) (CPT-SI), CPT, and camptothecin-20-( N -succinamidoyl-glycinate) (CPT-SA) over an extended time period.  Due to the biologically inert nature of Fleximer, MER-1001 distributes throughout the vascular space and slowly releases the prodrug CPT-SI, and to a lesser extent, CPT, over time. Initial PK measurements in animals confirm the release-limited PK of CPT and CPT-SI. Thus, in contrast to the known PK profile of CPT alone, MER-1001 (CPT+linker+PHF) releases CPT slowly and is not expected to be excreted at potentially toxic levels into the gall bladder, intestine, and urinary bladder. In addition, the dual-phase release mechanism affords a more sustained exposure to the active lactone form of CPT as the lactone ring is stabilized in prodrug CPT-SI. Both distribution and extended release are hypothesized to improve safety and efficacy over existing drugs of the same class.   Experimental procedures:   Nude mice bearing established tumor xenografts of human colon cancer (LS174T) were treated with MER-1001 at 56 mg/kg (of CPT equivalents) i.v. q7dx3, a molar equivalent dose of irinotecan at 94 mg/kg i.p. q7dx3, and camptothecin at 7.5 mg/kg i.v. q7dx3. In a second study, established human ovarian cancer tumors (A2780) at 70, 300, and 1100 mm 3  in nude mice were treated chronically with MER-1001 (20 mg/kg of CPT equivalents i.v., q4dx15). In both studies tumor size and time to endpoint (death or euthanasia) were measured over the course of 60 days.   Summary of Data:   Treatment of human colon cancer LS174T xenografts with MER-1001 as above led to tumor growth delay of 27 days (180%) and concomitant extension of time to endpoint (vs. no-treatment control) from 15 days to 42 days 13% weight loss. MER-1001 is more efficacious than comparable doses of irinotecan and camptothecin, with tumor growth delays of 104% and 49%, respectively, and median times to endpoint of 31 and 22 days, respectively. Chronic treatment of established human ovarian A2780 cancer tumors in nude mice with MER-1001 as above led to sustained inhibition of tumor growth regardless of baseline tumor size.   Conclusions:   MER-1001 is a potent and efficacious agent against LS174 and A2780 human tumor xenografts in nude mice.
Declines in the Incidence of Diabetes in the U.S.—Real Progress or Artifact?
Authors: Elizabeth Selvin, Mohammed K. Ali
Journal: Diabetes Care (2017)

National surveillance data show a sustained decline in the incidence rate of diagnosed diabetes, which has been heralded as a success in the battle against diabetes in the U.S. In this Perspective, we take a closer look at these data and provide additional insights to help interpret these trends. We examine multiple sources of data on the prevalence and incidence of diabetes in the U.S. as well as data on trends in diabetes risk factors to provide context for these national surveillance findings. Although some of the incidence decline may represent real progress against diabetes, it is likely that there are also nonbiological factors at play, especially changes in diagnostic criteria for diabetes. We present and discuss data that suggest improved detection and changes in screening and diagnostic practices may have resulted in the depletion of the “susceptible population.” Providing this context for the recent declines in new diabetes diagnoses observed in national data is critical to help avoid misinterpretation. We argue that it is premature to declare victory against the epidemic of diabetes in the U.S. and discuss how we might better focus current public health efforts, including a specific emphasis to address prediabetes.
In Vivo Recordings: A Ferroelectric Ceramic/Polymer Composite‐Based Capacitive Electrode Array for In Vivo Recordings (Adv. Healthcare Mater. 16/2017)
Authors: Changyong Chen, Miaomiao Xue, Yige Wen, Guang Yao, Yan Cui, Feiyi Liao, Zhuocheng Yan, Long Huang, Saeed Ahmed Khan, Min Gao, Taisong Pan, Hulin Zhang, Wei Jing, Daqing Guo, Sanfeng Zhang, Hailiang Yao, Xiong Zhou, Qiang Li, Yang Xia, Yuan Lin
Journal: Advanced Healthcare Materials (2017)

A new implantable capacitive electrocorticography electrode array is developed by Yuan Lin and co-workers in article number 1700305. The high permittivity barium titanate/polyimide nanocomposite acts as the ultrathin dielectric layer, endowing the electrode array with electrical safety and high conformability with the biological tissue. This work shows the potentials of capacitive electrode array in the field of brain/computer interfaces.
Genomic data can illuminate the architecture and evolution of cognitive abilities
Authors: James J. Lee, Christopher F. Chabris
Journal: Behavioral and Brain Sciences (2017)

Abstract Does general intelligence exist across species, and has it been a target of natural selection? These questions can be addressed with genomic data, which can rule out artifacts by demonstrating that distinct cognitive abilities are genetically correlated and thus share a biological substrate. This work has begun with data from humans and can be extended to other species; it should focus not only on general intelligence but also specific capacities like language and spatial ability.