tbuckley/cabot-search huggingface dataset:
Inhibition of ID1–BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy
Authors: Xiong Jin, Xun Jin, Leo J.Y. Kim, Deobrat Dixit, Hee-Young Jeon, Eun-Jung Kim, Jun-Kyum Kim, Seon Yong Lee, Jinlong Yin, Jeremy N. Rich, Hyunggee Kim
Journal: Clinical Cancer Research (2017)

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear.Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice.Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice.Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383-94. ©2017 AACR.
Robust MR elastography stiffness quantification using a localized divergence free finite element reconstruction
Authors: Daniel Fovargue, Sebastian Kozerke, Ralph Sinkus, David Nordsletten
Journal: Medical Image Analysis (2017)

As disease often alters structural and functional properties in tissue, the noninvasive measurement of material stiffness in vivo is desirable. Magnetic resonance elastography provides an approach to in vivo tissue characterization, using images of wave motion in tissue and biomechanical principles to reconstruct and quantify stiffness. Successful clinical translation of this technology requires stiffness reconstruction algorithms that are robust, easy to manage, and fast. In this paper, a reconstruction method is presented which addresses these issues by using a local compact divergence-free reconstruction kernel coupled with non-physical constraint elimination and inverse residual weighting to reliably reconstruct stiffness. The proposed technique is compared with local curl reconstructions and global stiffness-pressure reconstructions across two ground-truth phantoms as well as in vivo data sets. Sensitivity analysis is also performed, assessing the variability of reconstruction results and robustness to noise. It is shown that the proposed method can be robustly applied across data sets, is less sensitive to noise, attains comparable (or improved) accuracy, provides better correlation to anatomical features, and can be completed in short timescales.
Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells
Authors: Li Li, Vivian Barry, Stephane Daffis, Congrong Niu, Erik Huntzicker, Dorothy M. French, Igor Mikaelian, Robert E. Lanford, William E. Delaney, Simon P. Fletcher
Journal: Journal of Hepatology (2017)
Abstract 18677: Disease Progression in Human Heart Failure is Associated With Leptin Deficiency and Ketosis
Authors: J. Eduardo Rame, Anne R Cappola, Benjamin C French, Kenneth C Bedi, Alan Wu, Kenneth B Margulies, Thomas P Cappola
Journal: Circulation (2015)

Introduction: Dysregulation of the adipocyte hormone leptin has been implicated in insulin resistance and metabolic syndromes of excess non-esterified free-fatty acids (NEFAs). We have recently identified a reliance on ketones in the human end-stage failing heart, and described a metabolic signature of decreased myocardial acylcarnitines, disrupted Krebs cycling, and increased circulating NEFAs. We hypothesize that the progression to end-stage heart failure is marked by loss of circulating leptin, as cachexia and increased lipolysis deplete the adipocyte mass sustaining the utilization of peripheral ketones by the heart. Methods: Leptin was measured for 1159 subjects in the Penn Heart Failure Study (R&amp;D Systems ELISA). Circulating β-hydroxybutyrate (β-HB) was assayed utilizing a commercially available colorimetric assay (Caymen) in 16 lean, non-diabetic patients with end-stage heart failure at the time of cardiac transplantation and 18 non-failing, non-diabetic donors as controls. Results: Over a median follow-up time of 4.2 years, there were 337 events: 218 deaths, 92 transplants, and 27 LVAD placements. The figure below presents Kaplan-Meier curves for survival free from transplant or LVAD implantation by leptin tertiles (Logrank p=0.0003). After adjustment for covariates including BMI lower leptin levels remained associated with worsening survival (third versus first tertile of leptin: HR 0.73, p=0.04). In the patients with end-stage heart failure we found a significant increase in circulating β-HB (mean 145 μM versus 19 μM in non-failing, p=0.02) and NEFAs (mean 1.03mM versus 0.56mM in non-failing, p=0.01) Conclusion: Decreased circulating leptin is associated with worsening survival in human heart failure, while serum β-hydroxybutyrate is increased in advanced heart disease. Future studies will explore the mechanistic link between ketogenesis and dysregulated leptin in the emerging metabolic syndrome of heart failure.
Vitamin D Supplementation and Upper Respiratory Tract Infections in Children—Reply
Authors: Mary Aglipay, Jonathon L. Maguire
Journal: JAMA (2017)

In Reply Drs Davidson and Alansari suggest that a difference between high-dose and standard-dose vitamin D supplementation may be found among children with lower baseline serum 25-hydroxyvitamin D concentration at a 90-day end point.
Search Images and Extrapolation Risk—Reply
Authors: Joshua A. Halpern, Bilal Chughtai, Hassan Ghomrawi
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma
Authors: A.K. Krug, D. Enderle, C. Karlovich, T. Priewasser, S. Bentink, A. Spiel, K. Brinkmann, J. Emenegger, D.G. Grimm, E. Castellanos-Rizaldos, J.W. Goldman, L.V. Sequist, J.-C. Soria, D.R. Camidge, S.M. Gadgeel, H.A. Wakelee, M. Raponi, M. Noerholm, J. Skog
Journal: Annals of Oncology (2017)

BackgroundA major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients.Patients and methodsMatched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing.ResultsFor exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n= 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection.ConclusionsCombining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone.Clinical TrialsNCT01526928
Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms
Authors: Maria Kleppe, Richard Koche, Lihua Zou, Peter van Galen, Corinne E. Hill, Lauren Dong, Sofie De Groote, Efthymia Papalexi, Amritha V. Hanasoge Somasundara, Keith Cordner, Matthew Keller, Noushin Farnoud, Juan Medina, Erin McGovern, Jaime Reyes, Justin Roberts, Matthew Witkin, Franck Rapaport, Julie Teruya-Feldstein, Jun Qi, Raajit Rampal, Bradley E. Bernstein, James E. Bradner, Ross L. Levine
Journal: Cancer Cell (2017)
Length of Stay After Overlapping Surgery
Authors: Joseph A. Hyder, Elizabeth B. Habermann, Robert R. Cima
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A polymorphic MYC response element in KBTBD11 influences colorectal cancer risk, especially in interaction with an MYC-regulated SNP rs6983267
Authors: J. Gong, J. Tian, J. Lou, X. Wang, J. Ke, J. Li, Y. Yang, Y. Gong, Y. Zhu, D. Zou, X. Peng, N. Yang, S. Mei, R. Zhong, J. Chang, X. Miao
Journal: Annals of Oncology (2017)
A multicenter, randomized, phase Ib/II trial of the oral c-Met inhibitor MSC2156119J as monotherapy versus sorafenib in Asian patients with MET-positive (MET+) advanced hepatocellular carcinoma (HCC) and Child-Pugh Class A liver function.
Authors: Shukui Qin, Ann-Lii Cheng, Ho Yeong Lim, Lianzhe Xu, Friedhelm Bladt, Andreas Johne, Cindy Li, Hongxia Zheng, Giorgio Massimini
Journal: Journal of Clinical Oncology (2014)

TPS4151 Background: Patients (pts) with HCC have a poor prognosis. Effective treatments are limited, particularly in Asia, which carries about 80% of the HCC burden. In a Phase I trial (Falchook et al. J Clin Oncol 2013:31(Suppl):2506), the highly selective c-Met inhibitor MSC2156119J showed promising antitumor activity and a recommended Phase II dose was determined (RP2D; 500 mg/d). This Phase Ib/II, multicenter, open-label trial evaluates the efficacy of MSC2156119J monotherapy in first-line treatment vs sorafenib in pts with MET+ advanced HCC (NCT01988493). Methods: Primary objectives are to confirm the RP2D of 500 mg MSC2156119J in HCC pts (Phase Ib) and to assess efficacy of MSC2156119J monotherapy vs sorafenib, as determined by time to progression (TTP) per independent read (Phase II). Secondary objectives include pharmacokinetics, preliminary antitumor activity of MSC2156119J (Phase Ib), safety, tolerability, and antitumor activity of MSC2156119J vs sorafenib (Phase II: progression-free survival and TTP per investigator read, overall survival, time to symptomatic progression, objective response, and disease control). Adults with confirmed, advanced HCC of BCLC Stage C, Child-Pugh Class A liver function, life expectancy >3 mo, and ECOG status 0–2 (Phase II only: MET+, defined as moderate or strong protein overexpression determined by immunohistochemistry, eligible for sorafenib treatment, and measurable disease according to RECIST v1.1) are recruited in mainland China, South Korea, Taiwan, and other Asian countries. Key exclusion criteria: prior treatment with a c-Met/HGF pathway-targeting agent or systemic anticancer therapy (Phase II only), history of liver transplant or neoplasms other than HCC, impaired cardiac function, and chronic gastrointestinal disease. Up to 18 pts are planned for the Phase Ib part (3+3 design; 300 or 500 mg MSC2156119J p.o./d; 21-d cycle). In the Phase II part, 140 pts are planned to be randomized 1:1 to receive either MSC2156119J at the RP2D p.o./d or 400 mg sorafenib p.o./twice daily (21-d cycle). Enrollment began on Jan 9, 2014. Clinical trial information: NCT01988493.
Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients
Authors: William Hankey, Michael A. McIlhatton, Kenechi Ebede, Brian Kennedy, Baris Hancioglu, Jie Zhang, Guy N. Brock, Kun Huang, Joanna Groden
Journal: Cancer Research (2017)

APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding β-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Furthermore, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA (The Cancer Genome Atlas) data for colorectal cancer outcomes. Transcriptional patterns exhibited evidence of activated canonical Wnt signaling in both types of adenomas, with Apc-mutant adenomas also exhibiting unique changes in pathways related to proliferation, cytoskeletal organization, and apoptosis. Apc-mutant adenomas were characterized by increased expression of the glial nexin Serpine2, the human ortholog, which was increased in advanced human colorectal tumors. Our results support the hypothesis that APC-mutant colorectal tumors are transcriptionally distinct from APC-wild-type colorectal tumors with canonical WNT signaling activated by other mechanisms, with possible implications for stratification and prognosis.Significance: These findings suggest that colon adenomas driven by APC mutations are distinct from those driven by WNT gain-of-function mutations, with implications for identifying at-risk patients with advanced disease based on gene expression patterns. Cancer Res; 78(3); 617-30. ©2017 AACR.
A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors
Authors: Jeffrey S. Miller, Chihiro Morishima, Douglas G. McNeel, Manish R. Patel, Holbrook E.K. Kohrt, John A. Thompson, Paul M. Sondel, Heather A. Wakelee, Mary L. Disis, Judith C. Kaiser, Martin A. Cheever, Howard Streicher, Steven P. Creekmore, Thomas A. Waldmann, Kevin C. Conlon
Journal: Clinical Cancer Research (2017)

Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing.Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated.Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Clin Cancer Res; 24(7); 1525-35. ©2017 AACR.
3D TECA hydrogel reduces cellular senescence and enhances fibroblasts migration in wound healing
Authors: Luay Thanoon Younis, Mohamed Ibrahim Abu Hassan, Tara Bai Taiyeb Ali, Tommy Julianto Bustami
Journal: Asian Journal of Pharmaceutical Sciences (2017)

This study was designed to investigate the effect of 3D TECA hydrogel on the inflammatory-induced senescence marker, and to assess the influence of the gel on the periodontal ligament fibroblasts (PDLFs) migration in wound healing in vitro. PDLFs were cultured with 20 ng/ml TNF-α to induce inflammation in the presence and absence of 50 µM 3D TECA gel for 14 d. The gel effect on the senescence maker secretory associated-β-galactosidase (SA-β-gal) activity was measured by a histochemical staining. Chromatin condensation and DNA synthesis of the cells were assessed by 4',6-diamidino-2-phenylindole and 5-ethynyl-2'-deoxyuridine fluorescent staining respectively. For evaluating fibroblasts migration, scratch wound healing assay and Pro-Plus Imaging software were used. The activity of senescence marker, SA-β-gal, was positive in the samples with TNF-α-induced inflammation. SA-β-gal percentage is suppressed (>65%, P < 0.05) in the treated cells with TECA gel as compared to the non-treated cells. Chromatin foci were obvious in the non-treated samples. DNA synthesis was markedly recognized by the fluorescent staining in the treated compared to non-treated cultures. Scratch wound test indicated that the cells migration rate was significantly higher (14.9 µm2/h, P < 0.05) in the treated versus (11 µm2/h) for control PDLFs. The new formula of 3D TECA suppresses the inflammatory-mediated cellular senescence and enhanced fibroblasts proliferation and migration. Therefore, 3D TECA may be used as an adjunct to accelerate repair and healing of periodontal tissues.
MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy
Authors: Franziska Pankratz, Catherine Hohnloser, Xavier Bemtgen, Caterina Jaenich, Sheena Kreuzaler, Imo Hoefer, Gerard Pasterkamp, Justin Mastroianni, Robert Zeiser, Christian Smolka, Laura Schneider, Julien Martin, Maike Juschkat, Thomas Helbing, Martin Moser, Christoph Bode, Sebastian Grundmann
Journal: Circulation Research (2017)

The interaction of circulating cells within the vascular wall is a critical event in chronic inflammatory processes, such as atherosclerosis, but the control of the vascular inflammatory state is still largely unclear.This study was undertaken to characterize the function of the endothelial-enriched microRNA miR-100 during vascular inflammation and atherogenesis.Based on a transcriptome analysis of endothelial cells after miR-100 overexpression, we identified miR-100 as a potent suppressor of endothelial adhesion molecule expression, resulting in attenuated leukocyte-endothelial interaction in vitro and in vivo as shown by flow cytometry and intravital imaging. Mechanistically, miR-100 directly repressed several components of mammalian target of rapamycin complex 1-signaling, including mammalian target of rapamycin and raptor, which resulted in a stimulation of endothelial autophagy and attenuated nuclear factor κB signaling in vitro and in vivo. In a low-density lipoprotein receptor-deficient atherosclerotic mouse model, pharmacological inhibition of miR-100 resulted in enhanced plaque lesion formation and a higher macrophage content of the plaque, whereas a systemic miR-100 replacement therapy had protective effects and attenuated atherogenesis, resulting in a decrease of plaque area by 45%. Finally, analysis of miR-100 expression in >70 samples obtained during carotid endarterectomy revealed that local miR-100 expression was inversely correlated with inflammatory cell content in patients.In summary, we describe an anti-inflammatory function of miR-100 in the vascular response to injury and inflammation and identify an important novel modulator of mammalian target of rapamycin signaling and autophagy in the vascular system. Our findings of miR-100 as a potential protective anti-athero-miR suggest that the therapeutic replacement of this microRNA could be a potential strategy for the treatment of chronic inflammatory diseases, such as atherosclerosis, in the future.