tbuckley/cabot-search huggingface dataset:
Safety and Side Effects of Rifampin versus Isoniazid in Children
Authors: Thierno Diallo, Menonli Adjobimey, Rovina Ruslami, Anete Trajman, Oumou Sow, Joseph Obeng Baah, Guy B. Marks, Richard Long, Kevin Elwood, David Zielinski, Martin Gninafon, Diah A. Wulandari, Lika Apriani, Chantal Valiquette, Federica Fregonese, Karen Hornby, Pei-Zhi Li, Philip C. Hill, Kevin Schwartzman, Andrea Benedetti, Dick Menzies
Journal: New England Journal of Medicine (2018)

The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment — 9 months of isoniazid — has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid.
Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I
Authors: Zhichao Zhou, Ali Mahdi, Yahor Tratsiakovich, Szabolcs Zahorán, Oskar Kövamees, Filip Nordin, Arturo Eduardo Uribe Gonzalez, Michael Alvarsson, Claes-Göran Östenson, Daniel C Andersson, Ulf Hedin, Edit Hermesz, Jon O Lundberg, Jiangning Yang, John Pernow
Journal: Journal of the American College of Cardiology (2018)
<i>Lactobacillus plantarum</i> 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery Disease
Authors: Mobin Malik, Tisha M. Suboc, Sudhi Tyagi, Nita Salzman, Jingli Wang, Rong Ying, Michael J. Tanner, Mamatha Kakarla, John E. Baker, Michael E. Widlansky
Journal: Circulation Research (2018)

Rationale: A strong association has emerged between the gut microbiome and atherosclerotic disease. Our recent data suggest Lactobacillus plantarum 299v (Lp299v) supplementation reduces infarct size in male rats. Limited human data are available on the impact of Lp299v on the vasculature. Objective: To determine whether oral Lp299v supplementation improves vascular endothelial function and reduces systemic inflammation in humans with stable coronary artery disease (CAD). Methods and Results: Twenty men with stable CAD consumed a drink containing Lp299v (20 billion CFU) once daily for 6 weeks. After a 4-week washout, subjects were given an option of additionally participating in a 10-day study of oral liquid vancomycin (250 mg QID). Vascular endothelial function was measured by brachial artery flow-mediated dilation. Before and after Lp299v, plasma short-chain fatty acids, trimethylamine oxide, and adipokine levels were measured. Additional plasma samples underwent unbiased metabolomic analyses using liquid chromatography/mass spectroscopy. 16S rRNA sequencing was used to determine changes of the stool microbiome. Arterioles from patients with CAD were obtained, and endothelium-dependent vasodilation was measured by video microscopy after intraluminal incubation with plasma from Lp299v study subjects. Lp299v supplementation improved brachial flow-mediated dilation ( P =0.008) without significant changes in plasma cholesterol profiles, fasting glucose, or body mass index. Vancomycin did not impact flow-mediated dilation. Lp299v supplementation decreased circulating levels of IL (interleukin)-8 ( P =0.01), IL-12 ( P =0.02), and leptin ( P =0.0007) but did not significantly change plasma trimethylamine oxide concentrations ( P =0.27). Plasma propionate ( P =0.004) increased, whereas acetate levels decreased ( P =0.03). Post-Lp299v plasma improved endothelium-dependent vasodilation in resistance arteries from patients with CAD ( P =0.02).16S rRNA analysis showed the Lactobacillus genus was enriched in postprobiotic stool samples without other changes. Conclusions: Lp299v improved vascular endothelial function and decreased systemic inflammation in men with CAD, independent of changes in traditional risk factors and trimethylamine oxide. Circulating gut-derived metabolites likely account for these improvements and merit further study. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01952834.
Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival
Authors: Wu Zhang, Chen Zhao, Junmei Zhao, Yongmei Zhu, Xiangqin Weng, Qiusheng Chen, Huiping Sun, Jian-Qing Mi, Junmin Li, Jiang Zhu, Zhu Chen, Pier Paolo Pandolfi, Saijuan Chen, Xiaojing Yan, Jie Xu
Journal: Theranostics (2018)

Acute myeloid leukemia (AML) with an NPM1 mutation (NPMc+) has a distinct gene expression signature and displays molecular abnormalities similar to mixed lineage leukemia (MLL), including aberrant expression of the PBX3 and HOXA gene cluster. However, it is unclear if the aberrant expression of PBX3 and HOXA is essential for the survival of NPM1-mutated leukemic cells. Methods: Using the gene expression profiling of TCGA and E-MTAB-3444 datasets, we screened for high co-expression of PBX3 and HOXA9 in NPMc+ leukemia patients. We performed NPMc+ depletion and overexpression experiments to examine aberrant H3K79 methylation through epigenetic regulation. Through RNA interference technology and small-molecule inhibitor treatment, we evaluated the effect of methyl-modified H3K79 on cell survival and explored the possible underlying mechanism. Results: We showed that NPMc+ increased the expression of PBX3 and HOXA9, which are both poor prognosis indicators in AML. High PBX3 and HOXA9 expression was accompanied by increased dimethylated and trimethylated H3K79 in transgenic murine Lin-Sca-1+c-Kit+ cells and human NPMc+ leukemia cells. Using chromatin immunoprecipitation sequencing (ChIP-seq) assays of NPMc+ cells, we determined that hypermethylated H3K79 was present at the expressed HOXA9 gene but not the PBX3 gene. PBX3 expression was positively regulated by HOXA9, and a reduction in either PBX3 or HOXA9 resulted in NPMc+ cell apoptosis. Importantly, an inhibitor of DOT1L, EPZ5676, effectively and selectively promoted NPMc+ human leukemic cell apoptosis by reducing HOXA9 and PBX3 expression. Conclusion: Our data indicate that NPMc+ leukemic cell survival requires upregulation of PBX3 and HOXA9, and this action can be largely attenuated by a DOT1L inhibitor.
Abstract 15497: Clinical Significance of the Overshoot Phenomena of Respiratory Gas Indices During Recovery After Maximal Exercise Testing in Cardiac Patients
Authors: Osamu Nagayama, Akira Koike, Yuta Takayanagi, Arisa Nagamine, Qin Ru Jie, Jo Kato, Tomoko Himi, Yuko Kato, Akira Sato, Takeshi Yamashita, Kazutaka Aonuma
Journal: Circulation (2016)

Background: Overshoot phenomena of the gas exchange ratio (R:VCO2/VO2), ventilatory equivalent for O2 (VE/VO2), and end-tidal O2 pressure (PETO2) are commonly observed during recovery from maximal ...
Accuracy of quick sequential organ failure assessment score to predict mortality in hospitalized patients with suspected infection in an HIV/AIDS reference centre in Rio de Janeiro, Brazil
Authors: J. Moreira, A. Paixão, J. Oliveira, W. Jaló, O. Manuel, R. Rodrigues, A. Oliveira, L. Tinoco, J. Lima, B. Grinsztejn, V.G. Veloso, A.M. Japiassú, C.C. Lamas
Journal: Clinical Microbiology and Infection (2018)

To compare the discriminatory capacity of the quick sequential organ failure assessment (qSOFA) vs. the systemic inflammatory response syndrome (SIRS) score for predicting 30-day mortality and intensive care unit (ICU) admission in patients with suspicion of infection at an HIV reference centre.We performed a prospective cohort study including consecutive adult patients who had suspected infection and who were subsequently admitted to the medical ward. Variables related to qSOFA and SIRS were measured at admission. The performance (area under the receiver operating curve, AUROC) of qSOFA (score ≥2) and SIRS (≥2 criteria) as a predictor of 30-day mortality and ICU admission was evaluated.One hundred seventy-three patients (mean ± standard deviation age, 42.6 ± 12.4 years) were included in the analysis; 107 (61.8%) were male, and 111 (64.2%) were HIV positive. Respiratory and gastrointestinal infections occurred in 49 (28.3%) and 23 (13.3%), respectively. The 30-day mortality rate was 9 (5.2%) of 173. The prognostic performance of qSOFA was similar compared to SIRS, with an AUROC of 0.68 (95% confidence interval, 0.55-0.81) and 0.69 (95% confidence interval, 0.53-0.86) (p 0.96). Twenty patients (11%) were admitted to the ICU; qSOFA and SIRS had a similar discriminatory capacity for ICU admission (AUROC 0.63 (95% confidence interval, 0.51-0.75) and 0.63 (95% confidence interval, 0.50-0.76)), respectively).We found a poor prognostic accuracy of the qSOFA to predict 30-day mortality in hospitalized patients suspected of infection in a setting with a high burden of HIV infection.
Patient‐Reported Outcomes and the Economic Effects of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: The Value Proposition
Authors: Zobair M. Younossi
Journal: Hepatology (2018)

Abstract Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) can progress to cirrhosis, hepatocellular carcinoma (HCC), death, or liver transplantation. NASH has also been associated with impaired health‐related quality of life and poses a significant economic burden. Due to the negative clinical and patient‐reported outcomes and economic burden of NAFLD, it is necessary to review this disease through the lens of value‐based care, in which value is proportional to clinical and quality outcomes and inversely proportional to the costs of delivering these outcomes. I review the components of outcomes measured for patients with NAFLD and NASH and relate them to the value proposition, with the aim to deliver optimal patient‐centered care.
Abstract P115: Selective Vasoconstriction of the Ductus Arteriosus in the Rat by Stimulation of Thromboxane A2 Receptor
Authors: TomohiroYokota, TakashiAida, UtakoYokoyama, SusumuMinamisawa
Journal: Circulation Research (2011)

Objective: Patent ductus arteriosus (PDA) is a common life-threatening complication of premature infants. Cyclooxygenase inhibitors are frequently used for pharmacologic therapy of PDA to inhibit the synthesis of prostaglandin E2 (PGE2) that is the most potent vasodilator in the DA. However, they often cause severe side-effects. Thromboxane A2 (TXA2), a vasoconstrictive lipid mediator, induces vascular contraction via TXA2 receptor (TP). TXA2 is also known to counteract prostacycline, a vasodilative lipid mediator. Therefore, we hypothesized that TXA2-TP stimulation can be an alternative strategy to induce DA closure by counteracting PGE2. Methods and Results: Quantitative RT-PCR analysis revealed that the expression of TP mRNA was higher in the DA than in the aorta during fetal periods. When the selective TP agonist U46619 was intraperitoneally injected into Wister rat fetuses at embryonic day 19th (e19) and e21, we found that U46619 selectively constricted the fetal DA in a dose-dependent manner even th...
Abstract 510: MicroRNA-8073 as a tumor suppressor and a potential diagnostic and therapeutic target
Authors: Atsuko Mizoguchi, Aiko Takayama, Taiga Arai, Yuho Kida, Junpei Kawauchi, Hiroko Sudo
Journal: Cancer Research (2018)

Abstract MicroRNAs (miRNAs) generated inside cells are also present in peripheral blood. MiR-8073 has been studied in various disease model, but its molecular function had been unknown. In this study, we demonstrated that miR-8073 regulates target genes that participate in cell survival and works as a tumor suppressor controlling only cancer cells. First, we observed that miR-8073 expression was evidently decreased in multiple types of cancer cells compared to normal cells, but was increased in cancer exosome secreted into cultured supernatant. We then transfected synthetic miR-8073 mimic into various cancer cell lines and found dramatic reduction in cell proliferation, which was not detected in normal cells. Additionally, in tumor xenograft mice model, three-time subcutaneous injections of miR-8073 mimic at 2nM suppressed 57% growth of colorectal tumor weight. Through mRNA expression analysis and in silico sequence analysis, we further identified five potential miR-8073 targets that plays critical roles in regulation of cell proliferation, cycle and apoptosis, and demonstrated that miR-8073 indeed bound with the 3'-UTR of these target mRNAs and reduced both mRNA and protein expression. These results suggest that miR-8073 is a potential tumor suppressor, possibly discarded from cancer cells for their survival out to extracellular space, and circulates in bloodstream in the form of exosome. Our findings promise miR-8073 as a novel cancer diagnostic and therapeutic target. Citation Format: Atsuko Mizoguchi, Aiko Takayama, Taiga Arai, Yuho Kida, Junpei Kawauchi, Hiroko Sudo. MicroRNA-8073 as a tumor suppressor and a potential diagnostic and therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 510.
Abstract 768: Identification of signal transduction pathways specific for mutant KRas-dependent tumors
Authors: Oorvashi Roy Puli, Hua Yang, Bin Fang, Hong Yuan (Rays) Jiang, John Koomen, Said M. Sebti
Journal: Cancer Research (2018)

Abstract Targeting KRas directly has proven difficult. Therefore, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach to target mutant KRas-driven tumors. Towards this goal, we used phosphoproteomics to dissect key differences in signaling pathways between mutant KRas-dependent and mutant KRas-independent human cancer cells. Mass spectrometry analysis led to the identification of 25 proteins with significantly higher (up to 410 fold) phosphorylation levels in mutant KRas-dependent cells. Among these, 25 proteins- 8, 8 and 3 were tyrosine (Y), Serine (S) and Threonine (T) phosphorylated, and 6 were phosphorylated on both S and T. Presently, CRISPR-Cas9 knockout and siRNA depletion studies are ongoing to identify which of these 25 hits are required for the survival of mutant KRas-dependent human cancer cells. These studies can lead to identifying signaling circuits that can be targeted to treat mutant KRas-driven cancers. Citation Format: Oorvashi Roy Puli, Hua Yang, Bin Fang, Hong Yuan (Rays) Jiang, John Koomen, Said M. Sebti. Identification of signal transduction pathways specific for mutant KRas-dependent tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 768.
Unusual Presentation of Hurthle Cell Carcinoma With TENIS Syndrome as Left Atrial Thrombus on 18F-FDG PET/CT
Authors: Apurva Sood, Ashwin Singh Parihar, Ashwani Sood, Rajender Kumar, Gaurav Prakash, Manphool Singhal, Ajay Gulati, Bhagwant Rai Mittal, Ajay Bahl, Shashank Singh
Journal: Clinical Nuclear Medicine (2018)

Differentiated thyroid cancer (DTC) with thyroglobulin elevation and negative I scintigraphy (TENIS) syndrome is a diagnostic and therapeutic dilemma. Treatment of differentiated thyroid cancer has an excellent outcome, but treatment options in TENIS are limited with the exception of surgically amenable disease. We present a case of TENIS syndrome with incidental detection of tumor thrombus in right pulmonary vein extending to the left atrium on F-FDG PET/CT and subsequently complicating as an occipital bleed. The timely detection of the thrombus facilitated early initiation of anticoagulant therapy. However, the intracranial bleed precluded the continuation of anticoagulant therapy.
Targeted Therapy With Anaplastic Lymphoma Kinase Inhibitor (Alectinib) in Adolescent Metastatic Non–Small Cell Lung Carcinoma
Authors: Sharjeel Usmani, Fahad Marafi, Rashid Rasheed, Muneera Al Maraghy, Fareeda al Kandari
Journal: Clinical Nuclear Medicine (2018)

Primary lung adenocarcinoma is extremely rare in the pediatric age group. We report an 18-year-old man with non-small cell lung carcinoma stage IV with brain and bone metastatic. Lung biopsy showed expression of PDL1 along with rearrangement of ALK gene at chromosome 2p23. However, neither mutation of ROS1 nor epidermal growth factor receptor overexpression was seen. Second-generation anaplastic lymphoma kinase (ALK) inhibitor (alectinib) is initiated as first line of treatment. After 8 months of treatment with alectinib, F-NaF PET/CT demonstrated resolution of bone lesions. The present case show rapid and good response to alectinib in metastatic ALK-positive non-small cell lung carcinoma.
Abstract 50: Elucidating the role of MUC5AC-MET axis in breast cancer brain metastasis
Authors: Mohd W. Nasser, Shailendra K. Gautam, Ranjana Kanchan, Pranita Atri, Jawed Siddiqui, Rakesh Bhatia, Joseph Carmicheal, Dario Ghersi, Sukhwinder Kaur, Siddharth Mahapatra, Maneesh Jain, Surinder K. Batra
Journal: Cancer Research (2018)

Abstract Metastasis of breast cancer (BC) is the leading cause of mortality in American women. In particular, brain metastasis is a significant clinical problem present in 30-40% of triple receptor negative (TN) and epidermal growth factor receptor 2 (HER2) positive BC patients. These patients also have the worst prognosis of all breast cancers in women. Due to advances in clinical management at both the diagnostic and therapeutic levels, the lifespan or overall survival of these patients has increased, but the manifestation of brain metastasis at later stages of the disease remains an unfortunate burden for these patients. In addition, the blood-brain barrier (BBB) poses an additional hurdle for treatment of BC brain metastases, because the majority of chemotherapeutic drugs fail to cross the BBB. Furthermore, there is no single targeted therapy available for TNBC patients with brain metastasis, and thus there is an urgent requirement to discover novel biomarkers and therapeutics to address BC brain metastasis. In this regard, using a bioinformatics approach, we observed that several mucins, including MUC5AC, are significantly up-regulated in brain metastases of BC compared to primary tumors. However, we found the secretory mucin MUC5AC protein to be substantially high in brain-seeking BC (BSBC) cell lines and metastatic brain tissues. We also observed that knockdown of MUC5AC reduced proliferation and metastatic potential in these cell lines. Furthermore, we observed that MUC5AC colocalizes with activated MET receptor. MUC5AC knockdown in BSBC cell lines reduced MET activation and its downstream targets FAK and paxillin. Interestingly, MET and FAK inhibition using pharmacological inhibitors led to substantial decrease in MUC5AC expression. Overall, these studies suggest that MUC5AC-MET axis may regulate breast cancer brain metastasis. Understanding the MUC5AC-MET axis could be a novel approach for the development of better prognosis and prevention of life-threatening and treatment-resistant breast cancer brain metastasis. Citation Format: Mohd W. Nasser, Shailendra K. Gautam, Ranjana Kanchan, Pranita Atri, Jawed Siddiqui, Rakesh Bhatia, Joseph Carmicheal, Dario Ghersi, Sukhwinder Kaur, Siddharth Mahapatra, Maneesh Jain, Surinder K. Batra. Elucidating the role of MUC5AC-MET axis in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 50.
Adverse Childhood Experiences and the Risk of Diabetes: Examining the Roles of Depressive Symptoms and Cardiometabolic Dysregulations in the Whitehall II Cohort Study
Authors: Sonya S. Deschênes, Eva Graham, Mika Kivimäki, Norbert Schmitz
Journal: Diabetes Care (2018)

Adverse childhood experiences (ACEs) are associated with an increased risk of diabetes in adulthood. However, the potential mediating roles of depression and cardiometabolic dysregulations in this association are not clear.Prospective data were from the Whitehall II cohort study, with the phase 5 assessment (1997-1999) serving as baseline (n = 5,093, age range = 44-68 years, 27.3% female). ACEs were retrospectively reported at phase 5. Depressive symptoms (Center for Epidemiologic Studies Depression Scale) and cardiometabolic dysregulations (inflammation, central obesity, HDL cholesterol, triglycerides, impaired fasting glucose, and hypertension) were examined at phase 7 (2002-2004). Incident diabetes was examined at phases 8-11 (2006-2013) via self-report and blood samples. Participants reporting diabetes prior to phase 8 were excluded. Statistical mediation was examined with path analysis using structural equation modeling. ACEs were modeled as an observed continuous variable, whereas depressive symptoms and cardiometabolic dysregulations were modeled as latent variables. Unstandardized probit regression coefficients with 95% CI are reported for mediation analysis.ACEs were associated with an increased likelihood of diabetes, with every addition of ACE associated with an ∼11% increase in odds of diabetes (odds ratio 1.11 [95% CI 1.00, 1.24], P = 0.048). In mediation analysis, ACEs were indirectly associated with diabetes via depressive symptoms (indirect effect 0.03 [95% CI 0.02, 0.04], P < 0.001) and cardiometabolic dysregulations (indirect effect 0.03 [95% CI 0.01, 0.05], P = 0.03).This study provides further evidence of the detrimental psychological and physiological effects of ACEs and suggests that depression and cardiometabolic dysregulations may be pathways linking ACEs with diabetes in adulthood.