tbuckley/cabot-search huggingface dataset:
JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment
Authors: Yun Zhang, Ruifang Liang, Chih-Wei Chen, Tatjana Mallano, Clara Dees, Alfiya Distler, Adam Reich, Christina Bergmann, Andreas Ramming, Kolja Gelse, Dirk Mielenz, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2017)

Janus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-β. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.The antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.The antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.Fibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.
Expert witnesses: stuck between the courts and the GMC
Authors: Michael J Powers
Journal: BMJ (2017)

Beware the majority opinion

Decisions about the reliability of all expert witnesses should be left to the courts, but the General Medical Council currently exercises an unacceptable level of control over medical expert witnesses. The problem was highlighted in the recent case of the paediatric neuropathologist Waney Squier.1 Shaken baby syndrome describes a hypothesis to explain a triad of thin layer subdural haematomata, retinal haemorrhages, and encephalopathy in babies whose carers are being investigated for possibly inflicting intentional injury. Most doctors prepared to give evidence on the syndrome believe in the hypothesis, although there is little or no scientific support for this belief.2 Whereas it is the scientist’s duty to attempt to prove even popular hypotheses wrong, danger awaits any doctor challenging majority opinion when it comes to shaken baby syndrome.

Squier was struck off the Medical Register for dishonestly giving evidence in cases of alleged shaken baby syndrome after she expressed doubt that the forces from shaking were sufficient to cause the syndrome. A panel of the Medical Practitioner Tribunal Service found she had dishonestly gone beyond her expertise. The High Court on appeal …
Recurrent Endometrioid Adenocarcinoma of Endometrium With Bone Metastases
Authors: Alex Cheen Hoe Khoo, Nisa Kamila Abdul Rashid
Journal: Clinical Nuclear Medicine (2017)

Endometrial cancer, a common cancer affecting women, has the tendency to metastasize to the lung and liver. Bone metastases in endometrial cancers are rare and accounts for less than 1% of the overall incidence of metastases. We report a case of a 30-year-old single nulliparous woman with metastatic recurrence of endometrioid adenocarcinoma of the endometrium involving the pelvic bone, and the role of bone scintigraphy in detection and staging of the disease.
In vivo evaluation of Bevacizumab as a single agent or in combination with standard agents in a panel of human tumor xenograft models
Authors: Jennifer Marty, Mario Sepulveda, Wesley Lowell, Lionel Gomez, Scott Kelley, Gretchann Koehler, Miachael J. Wick, Chris Takimoto
Journal: Cancer Research (2006)

254   Bevacizumab (Avastin) is a humanized monoclonal antibody which disrupts tumor vascularization by blocking signaling through the vascular endothelial growth factor (VEGF) receptor. Recent preclinical and clinical studies have demonstrated some treatment benefit by combining bevacizumab with standard chemotherapy. To further identify sensitive preclinical tumor models and potentially useful combination therapies, we examined activity of standard agents and bevacizumab alone or in combination in a panel of human tumor xenograft models representing non-small cell lung (MV 522, NCI:H460), colon (HT-29), glioma (U87), and pancreas (MIA PaCa-2, BxPC-3) cancers. Standard agents for these studies included docetaxel tested at 12.5 mg/kg in lung (QODx3), irinotecan at 100 mg/kg in colon (Q7Dx3), temozolomide at 137 mg/kg in glioma (QDx5), and gemcitabine at 40 mg/kg in pancreas (Q3Dx4); bevacizumab was dosed at a single concentration in each study ranging from 1-10 mg/kg once every three days until study completion (Q3D to end). Significant endpoints included tumor growth inhibition (TGI), tumor regression, and weight loss. Co-treatment with bevacizumab and docetaxel produced no antitumor benefit in MV 522; however, a significant additive effect (p
Obesity As a Risk Factor for Acute Promyelocytic Leukemia. Results from Population and Case-Control Studies Across Western Countries and Correlation with Gene Expression in the TCGA
Authors: Luca Mazzarella, Edoardo Botteri, Anthony Matthews, Davide Disalvatore, Vincenzo Bagnardi, Massimo Breccia, Pau Montesinos, Teresa Bernal, Cristina Gil, Timothy J. Ley, Miguel A. Sanz, Krishnan Bhaskaran, Francesco Lo Coco, Pier Giuseppe Pelicci
Journal: Blood (2016)
Sacubitril–Valsartan in Heart Failure
Authors: Kevin E. Vitting
Journal: Annals of Internal Medicine (2017)

Letters2 May 2017Sacubitril–Valsartan in Heart FailureKevin E. Vitting, MDKevin E. Vitting, MDFrom Suburban Nephrology Group, Wayne, New Jersey.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0049 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I agree with Packer and colleagues (1) that Entresto (Novartis) is a life-saving drug that improves quality of life for patients with advanced heart failure. However, as a busy nephrologist, I contend that it is not simply inertia that prevents more physicians from prescribing it. Entresto may be cost-effective, but the starting dose still costs more than $400 per month. Most commercial drug plans require prescribers to go through an onerous preauthorization process before they will cover it, often with a high copayment. This medication is just 1 more essential drug that nephrologists now use that requires ...Reference1. Packer M, Armstrong WM, Rothstein JM, Emmett M. Sacubitril–valsartan in heart failure: why are more physicians not prescribing it?. Ann Intern Med. 2016;165:735-6. [PMID: 27571568]. doi:10.7326/M16-1932 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Suburban Nephrology Group, Wayne, New Jersey.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0049. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoSacubitril–Valsartan in Heart Failure: Why Are More Physicians Not Prescribing It? Milton Packer , W. Mark Armstrong , Joseph M. Rothstein , and Michael Emmett Sacubitril–Valsartan in Heart Failure Brad Spellberg Sacubitril–Valsartan in Heart Failure Bennett E. Werner Sacubitril–Valsartan in Heart Failure Milton Packer , W. Mark Armstrong , Joseph M. Rothstein , and Michael Emmett Metrics 2 May 2017Volume 166, Issue 9Page: 680KeywordsConflicts of interestDisclosureDrugsHealth careHeart failurePhosphatesQuality of life ePublished: 2 May 2017 Issue Published: 2 May 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Measurement and correlation study of silymarin solubility in supercritical carbon dioxide with and without a cosolvent using semi-empirical models and back-propagation artificial neural networks
Authors: Gang Yang, Zhe Li, Qun Shao, Nianping Feng
Journal: Asian Journal of Pharmaceutical Sciences (2017)

The solubility data of compounds in supercritical fluids and the correlation between the experimental solubility data and predicted solubility data are crucial to the development of supercritical technologies. In the present work, the solubility data of silymarin (SM) in both pure supercritical carbon dioxide (SCCO2) and SCCO2 with added cosolvent was measured at temperatures ranging from 308 to 338 K and pressures from 8 to 22 MPa. The experimental data were fit with three semi-empirical density-based models (Chrastil, Bartle and Mendez-Santiago and Teja models) and a back-propagation artificial neural networks (BPANN) model. Interaction parameters for the models were obtained and the percentage of average absolute relative deviation (AARD%) in each calculation was determined. The correlation results were in good agreement with the experimental data. A comparison among the four models revealed that the experimental solubility data were more fit with the BPANN model with AARDs ranging from 1.14% to 2.15% for silymarin in pure SCCO2 and with added cosolvent. The results provide fundamental data for designing the extraction of SM or the preparation of its particle using SCCO2 techniques.
Chemotherapy and Post-traumatic Stress in the Causation of Cognitive Dysfunction in Breast Cancer Patients
Authors: Kerstin Hermelink, Markus Bühner, Philipp Sckopke, Franziska Neufeld, Judith Kaste, Varinka Voigt, Karin Münzel, Rachel Wuerstlein, Nina Ditsch, Karin Hellerhoff, Dorothea Rjosk-Dendorfer, Michael Braun, Franz Edler von Koch, Kristin Härtl, Stephan Hasmüller, Ingo Bauerfeind, Gerlinde Debus, Peter Herschbach, Sven Mahner, Nadia Harbeck
Journal: JNCI Journal of the National Cancer Institute (2017)

Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naïve patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress.Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function. Analysis of variance was used to compare three groups of participants-patients who did or did not receive chemotherapy and healthy control subjects-on age- and education-corrected cognitive performance and cognitive change. Differences that were statistically significant after correction for false discovery rate were investigated with linear mixed-effects models and mediation models. All statistical tests were two-sided.Of 226 participants (166 patients and 60 control subjects), 206 completed all assessment sessions (attrition: 8.8%). Patients demonstrated overall cognitive decline (group*time effect on composite z -score: -0.13, P = .04) and scored consistently worse on Go/Nogo errors. The latter effect was mediated by PTSD symptoms (mediation effect: B = 0.15, 95% confidence interval = 0.02 to 0.38). Only chemotherapy patients showed declined reaction time on a computerized alertness test. Overall cognitive performance correlated with self-reported cognitive problems at one year ( T = -0.11, P = .02).Largely irrespective of chemotherapy, breast cancer patients may encounter very subtle cognitive dysfunction, part of which is mediated by cancer-related post-traumatic stress. Further factors other than treatment side effects remain to be investigated.
Diurnal oscillation of CSF Aβ and other AD biomarkers
Authors: Brendan P. Lucey, Anne M. Fagan, David M. Holtzman, John C. Morris, Randall J. Bateman
Journal: Molecular Neurodegeneration (2017)

To assess stages of Alzheimer's disease (AD) pathogenesis and the efficacy of drugs during clinical trials, there has been immense interest in the field to establish baseline cerebrospinal fluid (CSF) concentrations for potential AD biomarkers such as amyloid-β (Aβ) and tau. Significant within-person variations in CSF Aβ concentrations over time found that this variation followed the sleep-wake cycle. A recent paper in Molecular Neurodegeneration reported the absence of diurnal variations in multiple classical and candidate AD biomarkers, such as soluble APP, Aβ, tau, p-tau, YKL-40, VILIP-1, or apolipoprotein E. This commentary addresses these apparently discordant results regarding the diurnal variability of APP and Aβ compared with the literature. Despite our concerns, we appreciate the authors' interest in this important topic and contribution to improve our knowledge about the factors influencing Aβ diurnal variation.
Abstract 19079: Major Room for Intensification of Statin Therapy in Patients With Severe Familial Hypercholesterolemia or Cardiovascular Disease Before Initiation of PCSK9 Inhibitors
Authors: David Nanchen, Pedro Marques-Vidal, Arnold von Eckardstein, Jacques Cornuz, Gerard Waeber, Vincent Mooser, Peter Vollenweider
Journal: Circulation (2016)

Introduction: PCSK9 inhibitors are indicated for patients with severe familial hypercholesterolemia (FH) or cardiovascular disease (CVD) not reaching ideal LDL-cholesterol levels despite maximum do...
Improving Mental Health: Four Secrets in Plain Sightby Lloyd I. Sederer, M.D. Washington, D.C., American Psychiatric Association Publishing, 2017, 129 pp., $29.00 (hardcover).
Authors: Noa Heiman
Journal: American Journal of Psychiatry (2017)

heightened by a continuous barrage of media images and stories in which females are powerless victims, as well as directly experienced micro-aggressive behavior.I suspect that the cumulative effect, perhaps at deep and unconscious levels, may be that many women find it inherently quite aversive to engage with men in the kinds of verbal and interpersonal sparring and self-promoting behaviors that are part of leadership roles.Can this change?Dr. Frangou would argue that it can, that it is changing already, and that it is well within our power to develop the skills that will allow us and our ideas as academic psychiatrists to thrive.It is only a matter of the four Ps: practice, persistence, and putting ourselves forward in the pursuit of happiness.
Association of BW with Thromboembolic and Bleeding Outcomes in Phase III Randomized Controlled Trials of Direct Oral Anticoagulants: Systematic Review and Meta-Analysis
Authors: Kochawan Boonyawat, Francois Caron, Ang Li, Chatree Chai-Adisaksopha, Wendy Lim, Iorio Alfonso, Renato Delascio Lopes, David A Garcia, Mark Crowther
Journal: Blood (2016)
Disclosing the Conflicts of Interest of US Food and Drug Administration Advisory Committee Members
Authors: Robert Steinbrook
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
Non-driver mutations in myeloproliferative neoplasm-associated myelofibrosis
Authors: Bing Li, Robert Peter Gale, Zefeng Xu, Tiejun Qin, Zhen Song, Peihong Zhang, Jie Bai, Lei Zhang, Yue Zhang, Jinqin Liu, Gang Huang, Zhijian Xiao
Journal: Journal of Hematology & Oncology (2017)

We studied non-driver mutations in 62 subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis upon diagnosis, including 45 subjects with primary myelofibrosis (PMF) and 17 with post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF). Fifty-eight subjects had ≥1 non-driver mutation upon diagnosis. Mutations in mRNA splicing genes, especially in U2AF1, were significantly more frequent in PMF than in post-PV/ET MF (33 vs. 6%; P = 0.015). There were also striking differences in clonal architecture. These data indicate different genomic spectrums between PMF and post-PV/ET MF.
Interest of tumor to liver ratio 18F-FDG uptake in positron emission tomography for detection of neurofibrosarcoma in neurofibromatosis 1 patients.
Authors: Patrick Combemale, Thomas Mognetti, Laurence Allanore, Benoit Bensaid, Fransesco Giammarile, Stephane Pinson, Alain Drouet, Pierre Wolkeinstein, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2012)

10049 Background: Malignant peripheral nerve sheath tumors (MPNSTs) are difficult to detect in neurofibromatosis 1 (NF1) individuals. The 18F FDG positron emission tomoscintigraphy (FDG PET) is a useful tool. The Standard Uptake Value (SUV) is the gold standard but it is subject to individual variation among patients and medical centers. So we assessed the interest of FDG PET based on a specific tumor to liver uptake ratio (T/L) instead of SUV to find a reproducible and constant cut-off for detecting malignant tumors. Methods: From 2000 to 2010, we conduct a multi centric study: all patients with NF1 and presenting clinical signs of MPNST suspicion (increased tumor size, induration or pain) underwent a FDG PET. Preliminary study estimated a T/L ratio of 1.5 as cut-off for malignity. Based on semi-quantitative analysis of FDG PET images, patients were compared with this cut-off value. Results: 98 patients with 125 tumors were included. FDG PET evaluation identified 42/125 suspected lesions with T/L &gt; 1.5; among these 30 MPNST and 12 benign lesions were found. 83/125 tumors were classified as non-suspicious and 82 were actually benign according to histology or long term follow up. The 1.5 T/L cut off corresponds to 99 % Negative Predictive Value (NPV) and 71% Positive (PPV). The positive likelihood ratio (LR) was thus equal to 7, 69 and the Negative LR to 0, with 97% sensitivity and 87% specificity. When T/L ratio is &lt; 1.5, MPNST is eliminated with 99% NPV, thus avoiding useless surgery. When T/L ratio is above 1.5, there is a strong suspicion of malignancy. But there is a risk of false positivity, which requires discussion before any therapeutic decision. On the over hand we found no significant correlation between SUV max and malignancy. Conclusions: This study confirms the FDG PET in the detection of NF1-associated MPNST. The tumor/liver ratio with a cut off 1.5 has a very sensitive and specific value to sort out malignant from benign tumors and thus provides adequate surgery. More this semi-quantitative analysis method is just as easy as SUV, more sensitive and more reproducible.
ETV2/ER71 regulates hematopoietic regeneration by promoting hematopoietic stem cell proliferation
Authors: Can-Xin Xu, Tae-Jin Lee, Nagisa Sakurai, Karen Krchma, Fang Liu, Daofeng Li, Ting Wang, Kyunghee Choi
Journal: The Journal of Experimental Medicine (2017)

Recent studies have established that hematopoietic stem cells (HSCs) are quiescent in homeostatic conditions but undergo extensive cell cycle and expansion upon bone marrow (BM) transplantation or hematopoietic injury. The molecular basis for HSC activation and expansion is not completely understood. In this study, we found that key developmentally critical genes controlling hematopoietic stem and progenitor cell (HSPC) generation were up-regulated in HSPCs upon hematopoietic injury. In particular, we found that the ETS transcription factor Ets variant 2 (Etv2; also known as Er71) was up-regulated by reactive oxygen species in HSPCs and was necessary in a cell-autonomous manner for HSPC expansion and regeneration after BM transplantation and hematopoietic injury. We found c-Kit to be downstream of ETV2. As such, lentiviral c-Kit expression rescued Etv2-deficient HSPC proliferation defects in vitro and in short-term BM transplantation in vivo. These findings demonstrate that Etv2 is an important regulator of hematopoietic regeneration.