tbuckley/cabot-search huggingface dataset:
Fine-Tuning of PGC1α Expression Regulates Cardiac Function and Longevity
Authors: Xudong Zhu, Weiyan Shen, Ke Yao, Hu Wang, Bo Liu, Tangliang Li, Lijuan Song, Daojun Diao, Genxiang Mao, Ping Huang, Chengtao Li, Hongbo Zhang, Yejun Zou, Yugang Qiu, Yuzheng Zhao, Wengong Wang, Yi Yang, Zeping Hu, Johan Auwerx, Joseph Loscalzo, Yong Zhou, Zhenyu Ju
Journal: Circulation Research (2019)

Rationale: PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy. Objective: To determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner. Methods and Results: Moderate cardiac-specific PGC1α overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc −/− (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1α OE ) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1α knock in in G3 (G3 PGC1α OE ) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1α OE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. Conclusions: Fine-tuning the expression of PGC1α is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.
The characteristics and clinical course of MALT lymphoma: A 10-year single center analysis
Authors: M. Raderer, M. Troch, S. Woehrer, B. Streubel, A. Puespoek, M. Formanek, K. Turetschek, U. Jaeger, J. Drach, A. Chott
Journal: Journal of Clinical Oncology (2007)

8099 Background: An evaluation of clinical characteristics and potential risk factors affecting outcome in patients with MALT lymphoma was performed at our institution. Patients and Methods: As of 1997, a total of 170 consecutive patients with histologically verified MALT lymphoma (99 female/71 male) underwent uniform staging and assessment of clinical characteristics including assessment of genetic changes, presence of autoimmune disease (AD), Helicobacter pylori (HP)-status, monoclonal immunoglobulins (MG) and plasmacytic differentiation (PD). All patients with follow-up at our institution were analysed, and influence of various parameters on dissemination and outcome were evaluated. Sixty-four patients (38%) had gastric MALT-lymphoma (GML) and 106 (62%) extragastric MALT-lymphoma (EGML). Results: 66/170 patients (39%) had multiorgan-involvement upon presentation, while only 3 patients had bone marrow involvement. Patients with EGML (49/106, 46%) were at significantly higher risk for multiorgan-disease than patients with GML (17/64, 27%, p = 0.013). 58 patients had genetic aberrations, with t(11;18) being more common in GML (p = 0.002) and trisomy 3 (p = 0.03) and trisomy 18 (p = 0.02) in EGML. Among GML, translocation t(11;18) was significantly associated with multiorgan-disease, as was trisomy18 in EGML (p = 0.038). After a median follow-up time of 40 months, 139 patients (86%) are alive. 58 patients (39%) have relapsed, with the median to relapse being 60 months. Overall, multifocality and extragastric origin (p &lt; 0.001) were significantly associcated with relapse, while patients with t(11;18) had a significantly longer time to relapse (131 vs 49 months). Survival and relapse were not affected by the form of therapy applied (i.e. local vs systemic). An underlying AD was found in 65 patients (38%), and was significantly associated with EGML (p = 0.007) and multifocality (p = 0.04), but did not influence relapse and survival. HP-positivity was significantly associated with GML (p = 0.001), and patients with EGML did not respond to HP-eradication. Conslusion: Our data suggest dissemination and (late) relapse to be relatively common in MALT-lymphoma. Based on our findings, however, an individualized staging approach and risk-assessment is possible. No significant financial relationships to disclose.
Selective inhibition of MMP-14 inhibits tumor growth, invasion, and angiogenesis
Authors: Laetitia Devy, Douglas Rank, Csaba Pazmany, Simone Nicholson, Laurent Naa, Arumugam Muruganandam, Chris Tenhoor, Paula Henderikx, Daniel Dransfield
Journal: Cancer Research (2008)

1148  MMP-14 is a membrane-bound zinc-endopeptidase that drives the pericellular proteolysis that leads to tumor cell invasion. It does this directly by degrading ECM components and activating zymogens such as proMMP-2. DX-2400 is a potent and selective antibody inhibitor of MMP-14 that we have used to examine the contribution of this protease to tumor growth. This antibody displays potent anti-invasive and anti-angiogenic activity in vitro and inhibits the proliferation and angiogenesis of human tumors in preclinical models, decreasing their metastatic spread. Our studies have pharmacologically validated the role of MMP-14 in tumor growth and demonstrate the potential of a selective MMP-14 inhibitor for the treatment of solid tumors.
Epimorphin stimulates side-branching and alveolar development in the mouse mammary gland and is regulated by the endocrine hormones 17 β -estradiol and progesterone
Authors: Jamie Bascom, Hidetoshi Mori, Jimmie Fata, Mina Bissell
Journal: Cancer Research (2007)

3053  Epimorphin/syntaxin-2 (EPM) is a stromally derived mammary morphogen that stimulates branching and lumen formation of mammary epithelial cells in 3-dimensional collagen-1 gel assays. Transgenic mice that overexpress EPM under whey acidic protein promoter have been shown to have enlarged mammary ducts in midpregnancy, and they are prone to develop mammary tumors as they age (Bascom et al, Cancer Research 2005). To determine whether EPM plays a role in normal mouse mammary gland development, we studied EPM expression and localization during mammary gland ontogeny, whether EPM is under regulation by the mammogenic hormones, 17β-estradiol and progesterone, and whether developmental defects occur as a result of EPM overproduction in the mammary gland.  We show that EPM overexpression in WAP-EPM transgenic mice or exogenous EPM treatment by intramammary injection of recombinant protein, leads to precocious sidebranching and alveolar bud formation in the virgin mouse mammary gland and delays postlactional involution. In wildtype mice, EPM expression is highest in virgin mice at the time that the primary ductal structure branches into the stromal fatpad. EPM level also increases during late pregnancy and lactation. We show that EPM is negatively regulated by the endocrine hormones 17β-estradiol and progesterone, in the mouse mammary gland. Interestingly, it is the fibroblasts and not epithelial cells that show downregulation of EPM when treated with progesterone.  Our results suggest that EPM plays a role in primary ductal branching and the development and maintenance of alveolar structures in midpregnant and lactating mice and that EPM is under negative regulation by 17β-estradiol and progesterone. The later finding suggests that another mammogenic factor stimulates EPM production during branching morphogenesis. (Funded by the DOE and the NCI)
Determinants of secondary alterations in <i>WWTR1-CAMTA1</i> fusion epithelioid hemangioendothelioma.
Authors: Nathan David Seligson, Achal Awasthi, Sherri Z. Millis, David A. Liebner, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2019)

11045 Background: Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma characterized by the WWTR1- CAMTA1 fusion ( WC-F) in a majority of cases. EHE demonstrates a biphasic clinical course; remaining indolent for many years before suddenly demonstrating aggressive progression. Cell cycle mutations have been previously noted to account for some secondary alterations; however, little is known regarding the chronicity of these secondary alterations or their clinical implications. Here we present the largest assessment of secondary genomic variants and their clinical import. Methods: Comprehensive genomic profiling from 45 WC-F positive EHE patients (pts) were provided by Foundation Medicine (FMI). 8 of these 45 pts were treated at The Ohio State University (OSU) and were evaluated retrospectively through chart review. Known deleterious alterations, variants of unknown significance (VUS), and genomic copy quantification for the WC-F was included in our analysis. Targetable gene variants were defined by OncoKB. Chi-square and student’s t-tests were used as appropriate. Results: Genomic copy number of the WC-F best fit a log-normal distribution (range: 13-2,131 copies). 20 pts (44%) did not exhibit any secondary genomic variants. The most commonly altered genes included: CDKN2A/B (7 variants), RB1 (3 variants), and ATRX (3 variants). Commonly identified pathways included: cell cycle (9 pts, 20.0%), epigenetic modulators (7 pts, 15.6%), and DNA damage repair (7 pts, 15.6%). Eight pts exhibited targetable gene variants (18%) as defined by OncoKB. Subjects ≥50 years of age exhibited a greater proportion of clinically targetable variants (27.6% vs 0%; p = 0.02). Pts with a secondary genomic variant exhibited elevated WC-F copy numbers (p &lt; 0.001). OSU pts with aggressive EHE were more likely to have a second genomic variant (80% vs 0%; p = 0.03) when compared to indolent EHE, with trends toward higher WC-F copy numbers (809±315 vs 207±147; p = 0.2) and older age at diagnosis (59.5±5.5 vs 36.7±8.8; p = 0.1). Conclusions: In this study, secondary genomic variants in WC-F driven EHE are more common in older patients ( &gt; 50 yo). Further, the presence of secondary genomic variants is associated with an aggressive phenotype and may drive poor prognosis. Prospective research is needed to confirm these findings.
Human fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatment
Authors: Casey M. Theriot, Joshua R. Fletcher
Journal: Journal of Clinical Investigation (2019)

Clostridioides difficile is a significant public health threat, and diagnosis of this infection is challenging due to a lack of sensitivity in current diagnostic testing. In this issue of the JCI, Robinson et al. use a logistic regression model based on the fecal metabolome that is able to distinguish between patients with non–C. difficile diarrhea and C. difficile infection, and to some degree, patients who are asymptomatically colonized with C. difficile. The authors construct a metabolic definition of human C. difficile infection, which could improve diagnostic accuracy and aid in the development of targeted therapeutics against this pathogen.
Abstract 17121: Predictors of Death and Major Adverse Cardiovascular Events in the ACCORD Trial Identified by Random Survival Forest Based Machine-Learning
Authors: Md Shamsuzzaman, Eileen Navarro Almario, Tejas Patel, Gyorgy Csako, Colin O Wu, Xin Tian, Bereket Tesfaldet, Jerome Fleg, Anna Kettermann, Charu Gandotra, George Sopko, Helena Sviglin, Lawton Cooper, Sean Coady, Avantika Banerjee, Nashwan Farooque, Gauri Dandi, Laboni Hoque, Carlos Cure, Ruth Kirby, Lijuan Liu, Jue Chen, Ye Yan, Iffat Chowdhury, Keith Burkhart, Karim Calis, Eric Leifer, Ana Szarfman, Michael Domanski, Frank Pucino, Yves Rosenberg, Ahmed A Hasan
Journal: Circulation (2018)

Background: Patients with type 2 diabetes (T2D) are at high risk of cardiovascular (CV) morbidity/mortality. The ACCORD trial (NCT00000620) tested intensive glycemic, lipid and blood pressure interventions on major CV events in 10,251 T2D patients with baseline HbA1c concentration &gt;7.5%. Despite its landmark findings, a data-driven systematic evaluation of predictors for major cardiovascular events among hundreds of ACCORD variables has not been conducted. Methods: Random Survival Forest (RSF), a machine-learning method for survival analysis, identified important predictors for total mortality (TM), CV death (CVd), hospitalization/death due to heart failure (hdHF), fatal/non-fatal stroke (CVA), non-fatal myocardial infarction (MI) and MACE (composite of CVd, MI and CVA). Among 378 risk factors, including some highly correlated features, the top-ranked predictors (collected at baseline or derived from repeated measures prior to events) were selected, resulting in a hierarchy of predictive variables. Effects of RSF-selected predictors were then evaluated by multivariate Cox Proportional Hazards Models. Results: Table 1 presented the top ten predictors for six major events. Variables associated with changes in renal function predicted TM, CVd, and hdHF with ~90% accuracy. Insulin use was an important predictor along with predefined composite renal microvascular events for MI, CVA and MACE (74-79% accuracy). The Cox regression models based on RSF variable selection yielded similar findings for these important predictors of events. Conclusions: RSF approach revealed that insulin use and overt renal microvascular events were predictors for the occurrence of MI, stroke, and MACE in T2D patients. Moreover, dynamic changes in urinary renal function biomarkers had additional predictive values for fatal events. These results provide important clinical insights for reducing CV events in Type 2 diabetes patients.
Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model
Authors: Chuanshan Zhang, Renyong Lin, Zhide Li, Shuting Yang, Xiaojuan Bi, Hui Wang, Abudusalamu Aini, Ning Zhang, Abuduaini Abulizi, Cheng Sun, Liang Li, Zhibin Zhao, Rongde Qin, Xiaohong Li, Liang Li, Tuerganaili Aji, Yingmei Shao, Dominique A. Vuitton, Zhigang Tian, Hao Wen
Journal: Hepatology (2019)

The cestode Echinococcus multilocularis infection, a serious health problem worldwide, causes alveolar echinococcosis (AE), a tumor-like disease predominantly located in the liver and able to spread to any organs. Until now, there have been few studies that explore how T-cell exhaustion contributes to the parasite's escape from immune attack and how it might be reversed.In this study, we found that liver T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was significantly enhanced and positively correlated with lesion activity in AE patients. High TIGIT expression in both liver-infiltrating and blood T cells was associated with their functional exhaustion, and its ligand CD155 was highly expressed by hepatocytes surrounding the infiltrating lymphocytes. In co-culture experiments using human blood T cells and hepatic cell line HL-7702, CD155 induced functional impairment of TIGIT+ T cells, and in vitro blockade with TIGIT antibody restored the function of AE patients' T cells. Similar TIGIT-related functional exhaustion of hepatic T cells and an abundant CD155 expression on hepatocytes were observed in E. multilocularis-infected mice. Importantly, in vivo blocking TIGIT prevented T-cell exhaustion and inhibited disease progression in E. multilocularis-infected mice. Mechanistically, CD4+ T cells were totally and CD8+ T cells partially required for anti-TIGIT-induced regression of parasite growth in mice.This study demonstrates that E. multilocularis can induce T-cell exhaustion through inhibitory receptor TIGIT, and that blocking this checkpoint may reverse the functional impairment of T cells and represent a possible approach to immunotherapy against AE.
The MEK1/2 inhibitor AZD6244 (ARRY-142886) interacts synergistically with the novel Chk1 inhibitor AZD7762 to induce apoptosis in human multiple myeloma cells
Authors: Xin-Yan Pei, Yun Dai, Shuang Chen, Wesley Bodie, Lora Kramer, Paul Dent, Steven Grant
Journal: Cancer Research (2008)

LB-103  Chk1 represents a key component in the DNA damage checkpoint machinery triggered by endogenous or environmental genotoxic insults. This has prompted the development of Chk1 inhibitors to improve the anti-cancer efficacy of DNA-damaging agents or radiation. An alternative strategy is based on the notion that tumor cells are ill-equipped to survive simultaneous interruption of both pro-survival Ras/MEK/ERK signaling and checkpoint pathways. To determine whether such a strategy is operative in the case of newer generation agents targeting these pathways, interactions between inhibitors of MEK1/2 (AZD6244) and Chk1 (AZD7762; both from Astra Zeneca and currently undergoing clinical evaluation) were examined in human multiple myeloma (MM) cells. Exposure of H929 cells to minimally toxic concentrations of AZD7762 resulted in increased phosphorylation/activation of Raf-1, MEK1/2 and ERK1/2. Co-administration of nontoxic concentrations of either AZD6244 or PD184352 largely blocked AZD7762-mediated ERK1/2 phosphorylation, accompanied by markedly enhanced cdc2 activation and gammaH2A.X expression, as well as apoptosis. AZD6244/AZD7762 also dramatically diminished clonogenicity in H929 cells. Moreover, exposure of H929 cells to AZD7762 also led to an increase in Bim phosphorylation and subsequent degradation. This event was diminished in cells co-exposed to AZD6244, resulting in marked accumulation of Bim accompanied by Bax translocation and mitochondrial injury. Isobologram analysis revealed Combination Index values
Analysis of Vibrio cholerae genomes identifies new type VI secretion system gene clusters
Authors: Cristian V. Crisan, Aroon T. Chande, Kenneth Williams, Vishnu Raghuram, Lavanya Rishishwar, Gabi Steinbach, Samit S. Watve, Peter Yunker, I. King Jordan, Brian K. Hammer
Journal: Genome biology (2019)

Like many bacteria, Vibrio cholerae deploys a harpoon-like type VI secretion system (T6SS) to compete against other microbes in environmental and host settings. The T6SS punctures adjacent cells and delivers toxic effector proteins that are harmless to bacteria carrying cognate immunity factors. Only four effector/immunity pairs encoded on one large and three auxiliary gene clusters have been characterized from largely clonal, patient-derived strains of V. cholerae.We sequence two dozen V. cholerae strain genomes from diverse sources and develop a novel and adaptable bioinformatics tool based on hidden Markov models. We identify two new T6SS auxiliary gene clusters and describe Aux 5 here. Four Aux 5 loci are present in the host strain, each with an atypical effector/immunity gene organization. Structural prediction of the putative effector indicates it is a lipase, which we name TleV1 (type VI lipase effector Vibrio). Ectopic TleV1 expression induces toxicity in Escherichia coli, which is rescued by co-expression of the TliV1a immunity factor. A clinical V. cholerae reference strain expressing the Aux 5 cluster uses TleV1 to lyse its parental strain upon contact via its T6SS but is unable to kill parental cells expressing the TliV1a immunity factor.We develop a novel bioinformatics method and identify new T6SS gene clusters in V. cholerae. We also show the TleV1 toxin is delivered in a T6SS manner by V. cholerae and can lyse other bacterial cells. Our web-based tool can be modified to identify additional novel T6SS genomic loci in diverse bacterial species.
MAP2K3 and p38 are drivers of in vitro glioma invasion.
Authors: Tim Demuth, Jessica L. Rennert, Dominique B. Hoelzinger, Linsey B. Reavie, Christian Beaudry, Luigi Mariani, Michael E. Berens
Journal: Cancer Research (2005)

290  The early and pervasive tendency of glioma cells to invade into peritumoral normal brain underlies the poor prognosis for patients with glial tumors. This malignant diffusion of glioma prevents complete surgical resection, positions tumor cells behind an intact blood-brain barrier, and sequesters tumor cells outside the fields of focal radiation; each of these leads to heightened (almost certain) tumor recurrence. A three dimensional spheroid invasion assay was employed to determine the transcriptome of invasive glioma cells (U87WT and U87ΔEGFR) compared to their non-invading counterparts from the spheroid center. Cells from invasive rim and spheroid core were collected from three biological replicates representing each cell line by laser capture microdissection. Oligonucleotide microarray analysis resulted in the identification of 90 genes significantly differentially regulated with in vitro invasion, which were further categorized according to molecular function. Mitogen activated protein kinase kinase 3 (MAP2K3), a member of the MAP-kinase family was identified to be significantly up-regulated in invasive cells. MAP2K3 is involved in stress signaling, tumor cell invasion apoptosis resistance and activates p38 by phosphorylation. Immunofluoresence on paraffin embedded invasion assays revealed increased levels of MAP2K3 and phosphorylated p38 in invasive cells. Inhibition of these genes by siRNA and small molecules decreased invasiveness of spheroids in vitro while sensitizing them to apoptosis induction confirming significance of this pathway for glioma invasion. Invasion glioma tissue microarray revealed strong staining intensity for MAP2K3 and phosphorylated p38 in 100% of invasive glioma cells while only few cells from the core exhibited weak staining; non-cancerous brain revealed no staining for MAP2K3. This data demonstrates that this model system can be used as a tool for discovery of candidates such as MAP2K3 and p38 that are potential targets for anti-invasive therapies in combination with cytotoxic agents.
Neural Tissue Engineering: Human Neural Tissues from Neural Stem Cells Using Conductive Biogel and Printed Polymer Microelectrode Arrays for 3D Electrical Stimulation (Adv. Healthcare Mater. 15/2019)
Authors: Eva Tomaskovic‐Crook, Peikai Zhang, Annika Ahtiainen, Heidi Kaisvuo, Chong‐Yong Lee, Stephen Beirne, Zaid Aqrawe, Darren Svirskis, Jari Hyttinen, Gordon G. Wallace, Jadranka Travas‐Sejdic, Jeremy M. Crook
Journal: Advanced Healthcare Materials (2019)

In article number 1900425 Jadranka Travas-Sejdic, Jeremy M. Crook, and co-workers, describe development and maturation of human neural tissues with enhanced function and increased response to drug-induced disinhibition by 3D electrical stimulation using printed pillar microelectrode arrays interfaced with an electrically conductive human neural stem cell-laden biogel. The cover artwork portrays the work in the brave-new-world of neural tissue engineering, brain modelling, and electroceuticals.
Oprozomib in patients with newly diagnosed multiple myeloma
Authors: Parameswaran Hari, Jeffrey V. Matous, Peter M. Voorhees, Kenneth H. Shain, Mihaela Obreja, John Frye, Hisaki Fujii, Andrzej J. Jakubowiak, Davide Rossi, Pieter Sonneveld
Journal: Blood Cancer Journal (2019)