tbuckley/cabot-search huggingface dataset:
Dabigatran Compared With Rivaroxaban vs Warfarin
Authors: Ying Jiao Zhao, Wee Shiong Lim
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
Activation of FAK is not required during Akt-mediated anoikis resistance of human osteosarcoma SAOS-2 cells
Authors: Brian P. Eliceiri, Mai Nguyen, Richard Tritz, Bobbie Gomez, German G. Gomez, Susana B. Read, Geoffrey C. Owens, Ralph Mattern, Carol A. Kruse
Journal: Cancer Research (2005)

3768  Introduction. Anoikis is a form of apoptosis triggered by the lack of attachment to the extracellular matrix (ECM). Anoikis resistant transformed cells have increased survival times in the absence of attachment facilitating their migration and colonization of distant sites. Clonal lines derived from the human osteosarcoma cell line SAOS-2 were established and clones sensitive to anoikis were chosen. Culturing these clones under cycles of adhered and suspended conditions resulted in the induction of an anoikis resistant phenotype (SAOSar). The purpose of this study was to identify the signal transduction pathway involved during anoikis resistance of SAOSar cells. Methods. Anoikis was assayed after culture on poly-HEMA treated culture wells followed by propidium iodide staining and flow cytometry analyses. Src, PI-3K and Akt activity were pharmacologically inhibited using commercially available specific inhibitors. Activated states of FAK, Src, and Akt were determined by western immunoblot using phosphospecific antibodies Results. Akt is known as an important mediator that promotes cell survival. Therefore, its role during anoikis of SAOS cells was examined. Increased phosphorylation of Akt at Ser473 was found in SAOSar cells regardless of their culture conditions, suggesting a constitutively active state. Pharmacological inhibition of Akt or its upstream mediator, PI3-K, resulted in anoikis sensitivity. Since FAK, through the formation of focal adhesions, is central in coordinating the signals that arise from the ECM, it was expected that in anoikis resistant SAOSar cells FAK would remain phosphorylated despite suspended conditions, and thus maintaining the survival signals. No difference was found among the phosphorylation patterns of FAK between apoptotic (SAOSp) and non-apoptotic (SAOSar) cells after culture under anoikis-inducing conditions. These results indicate that the major component of the focal adhesion complex is functioning normally and is not aberrantly upregulated in anoikis resistant SAOSar cells. Moreover, this suggests that anoikis resistance in SAOSar cells is achieved through a mechanism independent of FAK. Since Src is known to be involved in anchorage-dependent survival, its role was then analyzed. Src activity was found to be upregulated in SAOSar cells. Moreover, pharmacological inhibition of Src activity correlated with a decrease in PKB/Akt activity and restored sensitivity to anoikis. Conclusions. The mechanism of anoikis resistance in SAOSar cells involves the activation of PKB/Akt by Src, independently of FAK tyrosine phosphorylation. In this way, Src activation in suspended anoikis resistant SAOSar cells is able to maintain survival by activating PKB/Akt, therefore circumventing the requirement for attachment-mediated integrin signaling.
Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study
Authors: G.V. Long, K.T. Flaherty, D. Stroyakovskiy, H. Gogas, E. Levchenko, F. de Braud, J. Larkin, C. Garbe, T. Jouary, A. Hauschild, V. Chiarion-Sileni, C. Lebbe, M. Mandalà, M. Millward, A. Arance, I. Bondarenko, J.B.A.G. Haanen, J. Hansson, J. Utikal, V. Ferraresi, P. Mohr, V. Probachai, D. Schadendorf, P. Nathan, C. Robert, A. Ribas, M.A. Davies, S.R. Lane, J.J. Legos, B. Mookerjee, J.-J. Grob
Journal: Annals of Oncology (2017)

Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
3,3′-Diindolylmethane stimulates exosomal Wnt11 autocrine signaling in human umbilical cord mesenchymal stem cells to enhance wound healing
Authors: Hui Shi, Xiao Xu, Bin Zhang, Jiahao Xu, Zhaoji Pan, Aihua Gong, Xu Zhang, Rong Li, Yaoxiang Sun, Yongmin Yan, Fei Mao, Hui Qian, Wenrong Xu
Journal: Theranostics (2017)

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are suggested as a promising therapeutic tool in regenerative medicine, however, their efficacy requires improvement. Small molecules and drugs come up to be a convenient strategy in regulating stem cells fate and function. Here, we evaluated 3,3'-diindolylmethane (DIM), a natural small-molecule compound involved in the repairing effects of hucMSCs on a deep second-degree burn injury rat model. HucMSCs primed with 50 μM of DIM exhibited desirable repairing effects compared with untreated hucMSCs. DIM enhanced the stemness of hucMSCs, which was related to the activation of Wnt/β-catenin signaling. β-catenin inhibition impaired the healing effects of DIM-primed hucMSCs (DIM-hucMSCs)
The Pro-Tumorigenic Vascular Niche Sustains the T-Cell Acute Lymphoblastic Leukemia Phenotype and Fosters Resistance to Therapy
Authors: Filomena Di Giacomo, Xujun Wang, Danilo Fiore, Lorena Consolino, Jude Phillip, Marcello Gaudiano, Lydia Roman-Gonzalez, Ramona Crescenzo, Sabina Chiaretti, Valentina Gianfelici, Ginsberg Michael, Jose Gabriel Barcia Duran, Jesus Maria Gomez Salinero, Rohan Bareja, Olivier Elemento, Anna Guarini, Robin Foà, Leandro Cerchietti, Shahin Rafii, Giorgio Inghirami
Journal: Blood (2016)
Preliminary clinical pharmacokinetics and pharmacodynamics of Debio 1347 (CH5183284), a novel FGFR inhibitor.
Authors: Claudio Zanna, Anne Vaslin, Martin Henner Voss, Rebecca Suk Heist, Cinta Hierro, Jeffrey G Supko, Kiyohiko Nakai, Nobuya Ishii, Annick Menetrey, Marie-Claude Roubaudi-Fraschini, Julien Cordier, Jerome Douchain, Valerie Nicolas-Metral
Journal: Journal of Clinical Oncology (2015)

2540 Background: Deregulated fibroblast growth factor receptor (FGFR) signaling is associated with tumorigenesis. Debio 1347 is an orally-available ATP competitive inhibitor of FGFR 1, 2 and 3 with preclinical data showing high target-specificity and antitumor activity across models of FGFR amplified, mutated or translocated tumors for various human malignancies. Debio 1347 is currently investigated in selected patients harboring FGFR genetic alterations. Methods: The first-in-human, phase I dose-escalation study enrolls patients with advanced solid tumor malignancies harboring defined activating alterations of FGFR 1, 2, or 3. Patients receive Debio 1347 orally once daily. With a starting dose level of 10 mg the study follows a 3+3 dose-escalation scheme on a modified Fibonacci sequence (MH Voss et al, abstr TPS2629^, ASCO 2014). Debio 1347 plasma levels are measured after single and repeated dosing using a validated LC-MS/MS assay. The PD profile of Debio 1347 is also assessed by measuring plasma levels of several biomarkers including FGF23 and phosphate. PK/PD relationships are explored graphically. Results: Preliminary data from 22 patients treated with 10-40 mg/day during the dose escalation phase of the trial indicate that Debio 1347 is rapidly absorbed with a median tmax occurring at 3 hours post-dose. Apparent oral clearance (CL/F) and volume of distribution (Vz/F) are on average 8 L/hour and 130 L, respectively. Plasma levels generally decrease mono-exponentially with an average half-life of 11 hours. Debio 1347 plasma exposure is dose-proportional and accumulation after 28-day repeated dosing is in general insignificant. Plasma PD markers show time-dependent changes in several patients, particularly on higher dose levels enrolled to date, and appear correlated with Debio 1347 plasma levels. Hyperphosphatemia starts to be observed after 8 days of treatment in several patients and returns to normal values in few days in case of treatment withdrawal. Conclusions: The PK and PD properties of Debio 1347 suggest a once daily oral dosing regimen is appropriate and preliminary PD findings are indicative of Debio 1347 target engagement in patients with FGFR gene alterations.
Amylase, Lipase, and Acute Pancreatitis in People With Type 2 Diabetes Treated With Liraglutide: Results From the LEADER Randomized Trial
Authors: William M. Steinberg, John B. Buse, Marie Louise Muus Ghorbani, David D. Ørsted, Michael A. Nauck
Journal: Diabetes Care (2017)

OBJECTIVE To evaluate serum amylase and lipase levels and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5–5.0 years. RESEARCH DESIGN AND METHODS A total of 9,340 patients with type 2 diabetes were randomized to either liraglutide or placebo (median observation time 3.84 years). Fasting serum lipase and amylase were monitored. Acute pancreatitis was adjudicated in a blinded manner. RESULTS Compared with the placebo group, liraglutide-treated patients had increases in serum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 6 months and then remained stable. During the study, 18 (0.4% [1.1 events/1,000 patient-years of observation] [PYO]) liraglutide-treated and 23 (0.5% [1.7 events/1,000 PYO]) placebo patients had acute pancreatitis confirmed by adjudication. Most acute pancreatitis cases occurred ≥12 months after randomization. Liraglutide-treated patients with prior history of pancreatitis (n = 147) were not more likely to develop acute pancreatitis than similar patients in the placebo group (n = 120). Elevations of amylase and lipase levels did not predict future risk of acute pancreatitis (positive predictive value &amp;lt;1.0%) in patients treated with liraglutide. CONCLUSIONS In a population with type 2 diabetes at high cardiovascular risk, there were numerically fewer events of acute pancreatitis among liraglutide-treated patients (regardless of previous history of pancreatitis) compared with the placebo group. Liraglutide was associated with increases in serum lipase and amylase, which were not predictive of an event of subsequent acute pancreatitis.
The Failure of Solanezumab — How the FDA Saved Taxpayers Billions
Authors: Chana A Sacks, Jerry Avorn, Aaron S Kesselheim
Journal: New England Journal of Medicine (2017)

The failure of solanezumab offers a window into the U.S. drug regulatory system, particularly in the context of the 21st Century Cures Act and the national debate about the role of the FDA. The solanezumab story is an important case of a regulatory system that worked.
Outcome of elderly patients after failure to hypomethylating agents given as frontline therapy for acute myeloid leukemia: Single institution experience*
Authors: Rama Nanah, Kristen McCullough, William Hogan, Kebede Begna, Mrinal Patnaik, Michelle Elliott, Mark Litzow, Aref Al‐Kali
Journal: American Journal of Hematology (2017)

Outcomes of acute myeloid leukemia (AML) in elderly patients unfit for intensive chemotherapy is challenging. Hypomethylating agents (HMAs) can be effective in these patients but responses are usually short‐lived. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs. The data on 56 AML patients at Mayo Clinic, Rochester were reviewed. Patients were considered for our study if they received HMA as frontline therapy for their AML. Out of 56 patients, 15 (27%) patients received azacitidine (AZA) and 41 (73%) received decitabine. Complete remission was found in 10 (18%), with overall response of 28% and median response duration of 10 months. Thirteen (81%) out of 16 responders relapsed. Therefore 53 patients were included in the primary or secondary failure analysis with a median overall survival (OS) of 2 months after the date of failure. Out of 53 patients, 12 (23%) received subsequent treatments. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs. 2 months, P = .0009). Outcome for patients who have primary or secondary failure is very poor. Our study provides important historical data for future novel therapies, which are sorely needed for these patients.
Construction and Testing of Two Distinct Humanized CD19-Specific Chimeric Antigen Receptors (CARs) for the Treatment of B-Cell Malignancies
Authors: Ramakrishnan Gopalakrishnan, Hittu Matta, Sunju Choi, Xu Han, Rekha Prakash, Nell Narasappa, Songjie Gong, Saurabh Chitnis, Michael Kahn, Jennifer Sernas, Prottasha Khan, Preet Chaudhary
Journal: Blood (2016)
Multicenter phase II study of oral care program for head and neck cancer patients treated with chemoradiotherapy.
Authors: Tomoya Yokota, Tetsuhito Konishi, Hiroyuki Tachibana, Takashi Yurikusa, Satoshi Hamauchi, Kensuke Sakai, Masaya Nishikawa, Maho Sato, Masataka Taguri, Satoshi Morita, Toru Eguchi, Kaoru Kubota, Sadamoto Zenda
Journal: Journal of Clinical Oncology (2015)

e17003 Background: Oral mucositis (OM) is problematic adverse events induced by chemoradiotherapy (CRT) in patients with head and neck cancers (HNC). However, systematic management of OM has not been established yet. This study was designed to assess the clinical benefit of multidisciplinary oral care program in reducing the incidence of grade ≥ 3 OM induced by CRT. Methods: This is a multi-institutional phase II trial for HNC patients who were to receive definitive or postoperative CRT with over 50 Gy of irradiation for oral space and platinum-based chemotherapy. The oral care program includes routine oral screening by dentists, and instruction regarding oral care, nutrition, and lifestyle by referring the leaflet. Oral hygiene and oral care was continuously evaluated during and after the course of CRT. Opioid-based pain control and nutritional support by percutaneous endoscopic gastrostomy were recommended. The primary end point was the incidence of grade ≥ 3 OM assessed by the certified medical staff according to the CTCAE version 3.0. Results: From April 2012 to December 2013, 120 HNC patients with median age of 62 (range 26-75) years old were enrolled. Median radiation dose was 70 Gy (range 60-70) and the major combination chemotherapy regimen was cisplatin alone (116/120, 96.7%). 64 patients (53.3%) developed grade ≥ 3 OM (functional/symptomatic). The incidence of grade ≤ 1 OM (functional/symptomatic) was 34.2% at 2 weeks and 67.6% at 4 weeks after completion of RT, respectively. Clinical examination revealed that 51 patients (42.5%) developed grade ≥ 3 OM during CRT. The incidence of grade ≤ 1 OM (clinical exam) was 54.7% at 2 weeks and 89.2% at 4 weeks after completion of RT, respectively. Planned RT was completed in 99.2% (119/120) and unplanned break in RT was 6.7% (8/101). Conclusions: A systematic oral care program alone was insufficient for decreasing the severe OM for HNC patients during CRT. Additional management of nutrition and development of gurgle agents would be needed to prevent severe OM induced by CRT. Clinical trial information: UMIN000006660.
PS01.56: IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients
Authors: Roy S. Herbst, Filippo De Marinis, Jacek Jassem, Sivuonthanh Lam, Simonetta Mocci, Alan Sandler, Ariel Lopez-Chavez, Yu Deng, Giuseppe Giaccone, David R. Spigel
Journal: Journal of Thoracic Oncology (2016)
Stem Cell Mobilization with High-Dose VP-16 Is Not Associated with an Increased Risk of Secondary MDS/AML after Autologous Transplant Against Malignant Lymphoma
Authors: Chiaki Naito, Hiroaki Shimizu, Yuri Miyazawa, Kohtaro Toyama, Takeki Mitsui, Hiromi Koiso, Hidemi Ogura, Morio Matsumoto, Akihiko Yokohama, Norifumi Tsukamoto, Yoshihisa Nojima, Hiroshi Handa
Journal: Blood (2016)
Eplerenone treatment alleviates the development of joint lesions in a new rat model of spontaneous metabolic-associated osteoarthritis
Authors: Chaohua Deng, Arnaud Bianchi, Nathalie Presle, David Moulin, Meriem Koufany, Cécile Guillaume, Hervé Kempf, Anne Pizard
Journal: Annals of the Rheumatic Diseases (2017)

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Cardiovascular Risk and Known Coronary Artery Disease Are Associated With Colorectal Adenoma and Advanced Neoplasia
Authors: David Niederseer, Andreas Stadlmayr, Ursula Huber-Schönauer, Martin Plöderl, Christian Schmied, Dieter Lederer, Wolfgang Patsch, Elmar Aigner, Christian Datz
Journal: Journal of the American College of Cardiology (2017)
Gene Expression Signature to predict early development of brain metastasis in lung adenocarcinoma.
Authors: Oscar Arrieta, Alette Ortega, Claudia Rangel, Camilo Molina, Jorge Negueb MartÃÂnez, David Saavedra, Eleazar Omar Macedo, Alfredo Hidalgo, Gabriela Mercado, Rogelio Hernandez
Journal: Journal of Clinical Oncology (2015)

e19064 Background: Advances in systemic treatment have substantially improved the overall survival of advanced lung adenocarcinoma patients, and risk of brain metastases(BM) is higher. The survival of patients with symptomatic BM is poor. The identification of NSCLC patients with a high risk of developing BM would enable pre-emptive intervention to improve the outcome. Methods: A total of 53 biopsies of primary lung tumor adenocarcinoma stage IV treatment-naïve were analyzed for gene expression profiling using Affymetrix HuGene 1.0 ST and were processed in R using Bioconductor libraries. All patients were evaluated with brain MRI at diagnosis with a 3-month follow-up for BM development. Patients were classified into two groups: early-BM( < 6 months) and late-BM( > 6 months). A second independent cohort of 55 patients was analyzed to validate the gene expression signature (ClinicalTrials.gov: NCT00862173). Results: Samples were classified as early-BM(17) and late-BM(6), the remainder 30 never developed BM. Significant changes in gene expression of about100 genes were found. Eleven highly significant genes (B-stat > 12) were associated with process of cell-migrationCNN3(down-reg.) and adhesionCDH10(up-reg); anti-apoptosisBAG1(up-reg); immunological evasionSSX2(up-reg) and RAET1E(up-reg); signaling pathways related to RAS gene RAB9A(up-reg) and RAPGEF5(down-reg); mRNA-tRNA translocationDUS2L(up-reg); methylation controlNOC2L(up-reg); and members of the EGFR family EPGN(up-reg) and IGFR, IGF2BP1(up-reg). Conclusions: We describe an 11-gene signature that may predict the risk of BM which has the potential to classify patients and evaluate screening strategies that would facilitate pre-emptive interventional trials such as prophylactic cranial irradiation. Clinical trial information: NCT00862173.
Early Clinical Predictors of 5-Year Outcome After Concussive Blast Traumatic Brain Injury
Authors: Christine L. Mac Donald, Jason Barber, Mary Jordan, Ann M. Johnson, Sureyya Dikmen, Jesse R. Fann, Nancy Temkin
Journal: JAMA Neurology (2017)

The long-term clinical effects of wartime traumatic brain injuries (TBIs), most of which are mild, remain incompletely described. Current medical disability cost estimates from world conflicts continually surpass projections. Additional information regarding long-term functional trajectory is needed to reduce this extensive public health burden.
Reducing blood splatter in dermatological surgery: reply from the authors
Authors: S. Aguilar-Duran, A. Panthagani, L. Naysmith, S.A. Holme
Journal: British Journal of Dermatology (2017)

We thank Owen et al for their comment on our study about the incidence and risk factors of surgical blood splatter. They recommend the use of cotton gauze swabs over the tips of the bipolar forceps to minimize the risk of blood splatter. This is an interesting and novel approach. We wonder however, if this technique could result in loss of precise visualization of the surgical field, risking inadvertent cautery of adjacent structures and more difficult haemostasis.

This article is protected by copyright. All rights reserved.
“To define is to limit”: perspectives on asthma–COPD overlap syndrome and personalised medicine
Authors: Vanessa M. McDonald, Peter G. Gibson
Journal: European Respiratory Journal (2017)

Asthma and chronic obstructive pulmonary disease (COPD) are both common and usually distinct airway diseases. However, it is now well recognised that many patients, particularly those aged over 55 years, have features of both asthma and COPD [1–5]. This may occur in up to 20% of patients [3]. In recent years there has been intense interest in the coexistence of asthma and COPD, as evidenced by the proliferation of reviews and editorial space dedicated to the topic [1, 3, 6–9]. It has even been given a new name: asthma–COPD overlap syndrome, or ACOS. A precise definition of asthma–COPD overlap syndrome is lacking; personalised medicine is recommended <http://ow.ly/sobH30aroWK>