tbuckley/cabot-search huggingface dataset:
Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets
Authors: David C. Wedge, Gunes Gundem, Thomas Mitchell, Dan J. Woodcock, Inigo Martincorena, Mohammed Ghori, Jorge Zamora, Adam Butler, Hayley Whitaker, Zsofia Kote-Jarai, Ludmil B. Alexandrov, Peter Van Loo, Charlie E. Massie, Stefan Dentro, Anne Y. Warren, Clare Verrill, Dan M. Berney, Nening Dennis, Sue Merson, Steve Hawkins, William Howat, Yong-Jie Lu, Adam Lambert, Jonathan Kay, Barbara Kremeyer, Katalin Karaszi, Hayley Luxton, Niedzica Camacho, Luke Marsden, Sandra Edwards, Lucy Matthews, Valeria Bo, Daniel Leongamornlert, Stuart McLaren, Anthony Ng, Yongwei Yu, Hongwei Zhang, Tokhir Dadaev, Sarah Thomas, Douglas F. Easton, Mahbubl Ahmed, Elizabeth Bancroft, Cyril Fisher, Naomi Livni, David Nicol, Simon Tavaré, Pelvender Gill, Christopher Greenman, Vincent Khoo, Nicholas Van As, Pardeep Kumar, Christopher Ogden, Declan Cahill, Alan Thompson, Erik Mayer, Edward Rowe, Tim Dudderidge, Vincent Gnanapragasam, Nimish C. Shah, Keiran Raine, David Jones, Andrew Menzies, Lucy Stebbings, Jon Teague, Steven Hazell, Cathy Corbishley, Johann de Bono, Gerhardt Attard, William Isaacs, Tapio Visakorpi, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Paul Workman, Chris Sander, Freddie C. Hamdy, Andrew Futreal, Ultan McDermott, Bissan Al-Lazikani, Andrew G. Lynch, G. Steven Bova, Christopher S. Foster, Daniel S. Brewer, David E. Neal, Colin S. Cooper, Rosalind A. Eeles
Journal: Nature Genetics (2018)
The MFHR1 Fusion Protein Is a Novel Synthetic Multitarget Complement Inhibitor with Therapeutic Potential
Authors: Stefan Michelfelder, Friedericke Fischer, Astrid Wäldin, Kim V. Hörle, Martin Pohl, Juliana Parsons, Ralf Reski, Eva L. Decker, Peter F. Zipfel, Christine Skerka, Karsten Häffner
Journal: Journal of the American Society of Nephrology (2018)

The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1. In vitro , MFHR1 showed cofactor and decay acceleration activity and inhibited C5 convertase activation and C5b-9 assembly, which prevented C3b deposition and reduced C3a/C5a and C5b-9 generation. Furthermore, this fusion protein showed the ability to escape deregulation by FH-related proteins and form multimeric complexes with increased inhibitory activity. In addition to substantially inhibiting alternative and classic pathway activation, MFHR1 blocked hemolysis mediated by serum from a patient with aHUS expressing truncated FH. In FH−/− mice, MFHR1 administration augmented serum C3 levels, reduced abnormal glomerular C3 deposition, and ameliorated C3 glomerulopathy. Taking the unique design of MFHR1 into account, we suggest that the combination of proximal and terminal cascade inhibition together with the ability to form multimeric complexes explain the strong inhibitory capacity of MFHR1, which offers a novel basis for complement therapeutics.
Trends in Carotid Revascularization Procedures—Reply
Authors: Judith H. Lichtman, George Howard, Thomas G. Brott
Journal: JAMA (2018)

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
Strategies to target the Hedgehog signaling pathway for cancer therapy
Authors: Minhang Xin, Xinyue Ji, Ladie Kimberly De La Cruz, Suresh Thareja, Binghe Wang
Journal: Medicinal Research Reviews (2018)

Abstract Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first‐in‐class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.
Reduction of PTSD Symptoms With Pre-Reactivation Propranolol Therapy: A Randomized Controlled Trial
Authors: Alain Brunet, Daniel Saumier, Aihua Liu, David L. Streiner, Jacques Tremblay, Roger K. Pitman
Journal: American Journal of Psychiatry (2018)

The authors assessed the efficacy of trauma memory reactivation performed under the influence of propranolol, a noradrenergic beta-receptor blocker, as a putative reconsolidation blocker, in reducing symptoms of posttraumatic stress disorder (PTSD).This was a 6-week, double-blind, placebo-controlled, randomized clinical trial in 60 adults diagnosed with long-standing PTSD. Propranolol or placebo was administered 90 minutes before a brief memory reactivation session, once a week for 6 consecutive weeks. The hypothesis predicted a significant treatment effect of trauma reactivation with propranolol compared with trauma reactivation with placebo in reducing PTSD symptoms on both the Clinician-Administered PTSD Scale (CAPS) and the patient-rated PTSD Checklist-Specific (PCL-S) in an intention-to-treat analysis.The estimated group difference in posttreatment CAPS score, adjusted for pretreatment values (analysis of covariance), was a statistically significant 11.50. The within-group pre- to posttreatment effect sizes (Cohen's d) were 1.76 for propranolol and 1.25 for placebo. For the PCL-S, the mixed linear model's estimated time-by-group interaction yielded an average decrease of 2.43 points per week, for a total significant difference of 14.58 points above that of placebo. The pre- to posttreatment effect sizes were 2.74 for propranolol and 0.55 for placebo. Per protocol analyses for both outcomes yielded similar significant results.Pre-reactivation propranolol, a treatment protocol suggested by reconsolidation theory, appears to be a novel and efficacious treatment for PTSD. Replication studies using a long-term follow-up in various trauma populations are required.
No expression of FasL molecule by human monocyte derived dendritic cells with cytostatic and cytotoxic activity against hematopoietic tumor cells in vitro
Authors: F. M. Ayres, M. Narita, M. Takahashi, T. Yano, N. Sato, T. Furukawa, K. Toba, Y. Aizawa
Journal: Blood (2003)
Metabolic Syndrome, Its Components, and Knee Osteoarthritis: The Framingham Osteoarthritis Study
Authors: Jingbo Niu, Margaret Clancy, Piran Aliabadi, Ramachandran Vasan, David T. Felson
Journal: Arthritis & Rheumatology (2017)

Previous studies have suggested that metabolic syndrome is associated with osteoarthritis (OA). However, analyses have often not included adjustment for body mass index (BMI) and have not addressed whether levels of individual metabolic syndrome components are related to OA. This study was undertaken to examine the relationship of metabolic syndrome and its components with radiographic and symptomatic knee OA.Framingham Study subjects were assessed for OA in 1992-1995 and again in 2002-2005. Near the baseline visit, subjects had components of metabolic syndrome assessed. We defined incident radiographic OA as present when a knee without radiographic OA at baseline had a Kellgren/Lawrence grade of ≥2 at follow-up, and defined incident symptomatic OA as present when a knee developed the new combination of radiographic OA and knee pain. After excluding knees with prevalent OA at baseline, we tested the relationship of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria and its components with the risk of incident radiographic OA and symptomatic OA before and after adjusting for BMI using the risk ratio from a binary regression with generalized estimating equations.A total of 991 subjects (55.1% women) with a mean age of 54.2 years were studied, and 26.7% of men and 22.9% of women had metabolic syndrome. Metabolic syndrome and many of its components were associated with both incident radiographic OA and symptomatic OA, but after adjustment for BMI, almost all of these associations became weak and nonsignificant. An association of high blood pressure, especially diastolic pressure, with OA outcomes persisted in both men and women.After adjustment for BMI, neither metabolic syndrome nor its components were associated with incident OA. There may be an association between OA and high blood pressure that needs further study.
<i>In Silico</i> Evaluation of Pharmacokinetic Optimization for Antimitogram-Based Clinical Trials
Authors: Skerdi Haviari, Benoît You, Michel Tod
Journal: Cancer Research (2018)

Antimitograms are prototype in vitro tests for evaluating chemotherapeutic efficacy using patient-derived primary cancer cells. These tests might help optimize treatment from a pharmacodynamic standpoint by guiding treatment selection. However, they are technically challenging and require refinements and trials to demonstrate benefit to be widely used. In this study, we performed simulations aimed at exploring how to validate antimitograms and how to complement them by pharmacokinetic optimization. A generic model of advanced cancer, including pharmacokinetic-pharmacodynamic monitoring, was used to link dosing schedules with progression-free survival (PFS), as built from previously validated modules. This model was used to explore different possible situations in terms of pharmacokinetic variability, pharmacodynamic variability, and antimitogram performance. The model recapitulated tumor dynamics and standalone therapeutic drug monitoring efficacy consistent with published clinical results. Simulations showed that combining pharmacokinetic and pharmacodynamic optimization should increase PFS in a synergistic fashion. Simulated data were then used to compute required clinical trial sizes, which were 30% to 90% smaller when pharmacokinetic optimization was added to pharmacodynamic optimization. This improvement was observed even when pharmacokinetic optimization alone exhibited only modest benefit. Overall, our work illustrates the synergy derived from combining antimitograms with therapeutic drug monitoring, permitting a disproportionate reduction of the trial size required to prove a benefit on PFS. Accordingly, we suggest that strategies with benefits too small for standalone clinical trials could be validated in combination in a similar manner.Significance: This work offers a method to reduce the number of patients needed for a clinical trial to prove the hypothesized benefit of a drug to progression-free survival, possibly easing opportunities to evaluate combinations. Cancer Res; 78(7); 1873-82. ©2018 AACR.
ELTGOL airway clearance in bronchiectasis: laying the bricks of evidence
Authors: Conroy Wong, Cameron Sullivan, Lata Jayaram
Journal: European Respiratory Journal (2018)

The thought that flickers almost as a reflex when we think about airway clearance techniques in bronchiectasis is "where is the evidence?" A solid foundation for the efficacy of treatments should be based on randomised controlled trials. Currently, the evidence base is sparse but fortunately the field has not been abandoned. ELTGOL therapy is one of the best evidence-based airway clearance techniques for bronchiectasis <http://ow.ly/vXmU30gZUSR>
Low-Dose Second Generation TKI Is an Effective Approach to Reduce TKI Related Side Effects and Toxicity While Preserving Molecular Response in CML Patients with TKI Intolerance
Authors: Varun Mehra, Titilola Oyebamiji, Stefanie Widya, Robin M. Ireland, Austin G. Kulasekararaj, Kavita Raj, Donal McLornan, Judith Marsh, Victoria Potter, Joanna Large, Isabel Duggins, Aytug Kizilors, Nicholas Lea, Antonio Pagliuca, Ghulam Mufti, Hugues De Lavallade
Journal: Blood (2017)
Demethylation-Induced Overexpression of Shc3 Drives c-Raf–Independent Activation of MEK/ERK in HCC
Authors: Yun Liu, Xinran Zhang, Baicai Yang, Hao Zhuang, Hua Guo, Wen Wei, Yuan Li, Ruibing Chen, Yongmei Li, Ning Zhang
Journal: Cancer Research (2018)

Invasion and intrahepatic metastasis are major factors of poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we show that increased Src homolog and collagen homolog 3 (Shc3) expression in malignant HCC cell lines associate with HCC invasion and metastasis. Shc3 (N-Shc) was significantly upregulated in tumors of 33 HCC patient samples as compared with adjacent normal tissues. Further analysis of 52 HCC patient samples showed that Shc3 expression correlated with microvascular invasion, cancer staging, and poor prognosis. Shc3 interacted with major vault protein, resulting in activation of MEK1/2 and ERK1/2 independently of Shc1 and c-Raf; this interaction consequently induced epithelial-mesenchymal transition and promoted HCC cell proliferation and metastasis. The observed increase in Shc3 levels was due to demethylation of its upstream promoter, which allowed c-Jun binding. In turn, Shc3 expression promoted c-Jun phosphorylation in a positive feedback loop. Analysis of metastasis using a tumor xenograft mouse model further confirmed the role of Shc3 in vivo Taken together, our results indicate the importance of Shc3 in HCC progression and identify Shc3 as a novel biomarker and potential therapeutic target in HCC.Significance: Ectopic expression of Shc3 forms a complex with MVP/MEK/ERK to potentiate ERK activation and plays an important role in sorafinib resistance in HCC. Cancer Res; 78(9); 2219-32. ©2018 AACR.
Single Cell Approaches to Define the Pathogenic Immune Cells that Mediate Drug Hypersensitivity
Authors: Katie D. White, Katherine C. Konvinse, Mark A. Pilkinton, Alec Redwood, Jason A. Trubiano, Jonathan Grant Peter, Rannakoe Lehloenya, Wen-Hung Chung, Shuen-Iu Hung, Ren-You Pan, Abha Chopra, Louise Barnett, Rama Gangula, Simon A. Mallal, Elizabeth J. Phillips
Journal: Journal of Allergy and Clinical Immunology (2018)
Efficacy of Once-Daily Tiotropium Respimat ® on Lung Function and Asthma Control in Adults with Asthma at GINA Steps 2–5
Authors: Roland Buhl, J. Mark FitzGerald, Eli O. Meltzer, Alberto de la Hoz, Ralf Sigmund, Huib A.M. Kerstjens, Eugene R. Bleecker
Journal: Journal of Allergy and Clinical Immunology (2018)
Association of National Institute of Child Health and Human Development Career Development Awards With Subsequent Research Project Grant Funding
Authors: Dennis A. Twombly, Sarah L. Glavin, Jennifer Guimond, Susan Taymans, Catherine Y. Spong, Diana W. Bianchi
Journal: JAMA Pediatrics (2018)

Investing in the next generation of researchers is essential, as recently highlighted in the 21st Century Cures Act. From its inception, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has supported training and career development to ensure a robust pipeline of investigators who are prepared to lead their respective fields of inquiry. In recent years, the NICHD has emphasized institutional over individual training awards to a greater degree than many other National Institutes of Health institutes of similar size.To evaluate the success of individuals supported by NICHD career development and training awards, as measured by subsequent application and receipt of independent National Institutes of Health research project grant funding.This retrospective cohort study identified 417 physician-scholars who were supported by NICHD career development awards between October 1, 1999, and September 30, 2001. This period was selected to allow adequate follow-up of research project grant applications and funding. Among these physician-scholars, 355 met inclusion criteria.The primary outcomes were the numbers of research project grant applications submitted and, of these, the numbers that were successfully funded.Among 355 physician-scientists, scholars who had an MD degree only and received a K award or both an individual K award and institutional K12 support were more likely than those who received only K12 support (individual K only vs institutional K12 only: odds ratio [OR], 4.86; 95% CI, 1.83-13.62; both K and K12 vs K12 only: OR, 3.19; 95% CI, 1.46-7.10) to apply for subsequent project grant funding (88.0% vs 82.8% vs 60.1%, respectively; P < .001) and to receive it (60.0% vs 60.9% vs 32.9%, respectively; P < .001). For physicians with both MD and PhD degrees, neither application nor funding rates were statistically significantly different whether their career development was supported by individual or institutional awards.Physician-scholars are more likely to apply for and receive a National Institutes of Health research grant if they are trained on an individual career development award, with or without an institutional training award. Based on the data, the NICHD intends to provide a greater proportion of its career development fund allocation to individual awards. The NICHD recognizes the importance of institutional awards and will continue to support them. The NICHD remains committed to training and intends to maintain its investment in training and career development awards going forward.
Development of a personalized cellular ex vivo CBL-b silencing cancer immune therapy.
Authors: Marc Oliver Salzberg, Guenther Lametschwandtner, Manfred Schuster, Hans Loibner, Monika Sachet, Hubert Hayden, Michaela Hassler, Joesph Friedl, Pierre Triozzi
Journal: Journal of Clinical Oncology (2014)

3070 Background: The E3 ubiquitin ligase cbl-b has been identified as an important gatekeeper limiting T cell activation. Concordantly, the immune system of cbl-b deficient mice can effectively fight tumors, thereby validating cbl-b as an excellent target to enhance anti-tumor immune activity. We have recently shown in proof-of-concept experiments that transfer of transiently cbl-b silenced murine T cells had efficacy to enhance the anti-tumor immune response in mouse models. Methods: A design algorithm was used to screen for siRNAs that are highly effective to silence cbl-b, and the optimized siRNA was produced at a GMP manufacturer. PBMCs were isolated from healthy donors or cancer patients, transfected with siRNA by electroporation and immune cell phenotype and activation was determined by FACS and ELISA. For enhancement of DC vaccination responses, PBMCs were ex vivo silenced, and co-administrated with the DC preparations intranodally to the cancer patient. Results: We have established a highly efficient transfection protocol using a commercial electroporation device enabling us to simultaneously transfect T, B, NK cells and monocytes with minimal cell damage. Using this protocol, we have identified a siRNA that was able to shut down cbl-b expression for more than 7 days in stimulated human T cells, resulting in strong enhancement of T cell activation, cytokine production and proliferation. Moreover, simultaneous silencing of cbl-b in all immune cells of the PBMCs yielded additional advantages, most notably enhancing NK cell reactivity against tumor cell and IL-2 stimulation. Silencing of cancer patient PBMCs yielded similar results ex vivo and intranodal transfer of autologous cbl-b silenced cells together with activated DCs to patients with advanced cancers was feasible and well tolerated. Conclusions: To enable the clinical implementation of a cbl-b ex vivo silencing treatment, we have established and tested a protocol that can be easily performed on any clinical unit that applies adoptive cell therapies to patients. Based on these results, a Phase I trial for the systemic administration of cbl-b silenced PBMCs to patients with advanced cancers will be initiated.
Fibroblast-Specific β-Catenin Signaling Dictates the Outcome of AKI
Authors: Dong Zhou, Haiyan Fu, Liangxiang Xiao, Hongyan Mo, Hui Zhuo, Xiaojun Tian, Lin Lin, Jianhua Xing, Youhua Liu
Journal: Journal of the American Society of Nephrology (2018)

AKI is a devastating condition with high morbidity and mortality. The pathologic features of AKI are characterized by tubular injury, inflammation, and vascular impairment. Whether fibroblasts in the renal interstitium have a role in the pathogenesis of AKI is unknown. In this study, we investigated the role of fibroblast-specific β -catenin signaling in dictating the outcome of AKI, using conditional knockout mice in which β -catenin was specifically ablated in fibroblasts (Gli1- β -cat−/−). After ischemia-reperfusion injury (IRI), Gli1- β -cat−/− mice had lower serum creatinine levels and less morphologic injury than Gli1- β -cat+/+ littermate controls. Moreover, we detected fewer apoptotic cells, as well as decreased cytochrome C release; reduced expression of Bax, FasL, and p53; and increased phosphorylation of Akt, in the Gli1- β -cat−/− kidneys. Gli1- β -cat−/− kidneys also exhibited upregulated expression of proliferating cell nuclear antigen and Ki-67, which are markers of cell proliferation. Furthermore, Gli1- β -cat−/− kidneys displayed suppressed NF-κB signaling and cytokine expression and reduced infiltration of inflammatory cells. Notably, loss of β -catenin in fibroblasts induced renal expression of hepatocyte growth factor (HGF) and augmented the tyrosine phosphorylation of c-met receptor after IRI. In vitro , treatment with Wnt ligands or ectopic expression of active β -catenin inhibited HGF mRNA and protein expression and repressed HGF promoter activity. Collectively, these results suggest that fibroblast-specific β -catenin signaling can control tubular injury and repair in AKI by modulating HGF expression. Our studies uncover a previously unrecognized role for interstitial fibroblasts in the pathogenesis of AKI.
Clinical features and allergen analysis in five children with macadamia nut allergy
Authors: Koichi Yoshida, Shoichiro Shirane, Kazue Kinoshita, Mayumi Furukawa, Yo Omura, Emi Kawaguchi, Shoko Matsushita, Masako Toda, Haruyo Nakajima-Adachi, Akira Akasawa
Journal: Journal of Allergy and Clinical Immunology (2018)