tbuckley/cabot-search huggingface dataset:
A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity
Authors: Jiye Liu, Tianyu Song, Wenrong Zhou, Lijie Xing, Su Wang, Matthew Ho, Zhengang Peng, Yu-Tzu Tai, Teru Hideshima, Kenneth C. Anderson, Yong Cang
Journal: Leukemia (2018)
Competing and conflicting interests in the care of critically ill patients
Authors: Alison E. Turnbull, Sarina K. Sahetya, E. Lee Daugherty Biddison, Christiane S. Hartog, Gordon D. Rubenfeld, Dominique D. Benoit, Bertrand Guidet, Rik T. Gerritsen, Mark R. Tonelli, J. Randall Curtis
Journal: Intensive Care Medicine (2018)
Case 39-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Timothy E. Guiney, John T. Fallon
Journal: New England Journal of Medicine (1993)

Presentation of CaseAn 83-year-old woman was admitted to the hospital because of severe upper-back pain, hypertension, and anuria.There was a history of hypertension that dated back 34 years and was treated in recent years with propranolol, atenolol, and hydrochlorothiazide-triamterene at various times. She had smoked half a pack of cigarettes daily for unknown years. Ten years before admission the patient began to have transient cerebral ischemic attacks that were characterized by weakness and numbness of the left hand and arm. Two years thereafter a right cerebrovascular accident was treated at another hospital, with a satisfactory recovery.Three months . . .
Protein‐protein interactions as antibiotic targets: A medicinal chemistry perspective
Authors: Peter J. Cossar, Peter J. Lewis, Adam McCluskey
Journal: Medicinal Research Reviews (2018)

Abstract There are 27 small molecule protein‐protein interaction (PPI) modulators in Phase I, II, and III clinical trials targeting cancer, viruses, autoimmune disorders, and as immune suppression agents. Targeting PPIs as an antibiotic drug discovery strategy remains in relative infancy by comparison. However, a number of molecules are in development which target PPI within the replisome, divisome, transcriptome, and translatome are showing significant promise at the medicinal chemistry stage of drug development. Hence, the success of future PPI agents as antibiotics will build upon the techniques and design strategies of these molecules.
Review: In uncontrolled, persistent asthma, adding LAMAs to inhaled corticosteroids reduce exacerbations
Authors: Professor Francis Thien
Journal: Annals of Internal Medicine (2018)

Source Citation Sobieraj DM, Baker WL, Nguyen E, et al. Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and meta-analysis. JAMA. 2018;319:1473-84. 29554174
Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming
Authors: Rajeev Mishra, Subhash Haldar, Veronica Placencio, Anisha Madhav, Krizia Rohena-Rivera, Priyanka Agarwal, Frank Duong, Bryan Angara, Manisha Tripathi, Zhenqiu Liu, Roberta A. Gottlieb, Shawn Wagner, Edwin M. Posadas, Neil A. Bhowmick
Journal: Journal of Clinical Investigation (2018)

Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified a Ras inhibitor, RASAL3, as epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In an orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.
Reflectance Confocal Microscopic and En Face Histopathologic Correlation of the Dermoscopic “Circle Within a Circle” in Lentigo Maligna
Authors: Cristian Navarrete-Dechent, Konstantinos Liopyris, Miguel Cordova, Klaus J. Busam, Ashfaq A. Marghoob, Chih-Shan Jason Chen
Journal: JAMA Dermatology (2018)

This case report describes a process by which the dermoscopic “circle within a circle” feature can be correlated with findings of reflectance confocal microscopic (RCM) and en face histopathologic findings from a lentigo maligna lesion.
Reforming Payment for Primary Care—It’s Not Just the Money, It’s the Payment System
Authors: Allan H. Goroll
Journal: JAMA Internal Medicine (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 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
Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults
Authors: Issaka Sagara, Sara A Healy, Mahamadoun H Assadou, Erin E Gabriel, Mamady Kone, Kourane Sissoko, Intimbeye Tembine, Merepen A Guindo, M'Bouye Doucoure, Karamoko Niaré, Amagana Dolo, Kelly M Rausch, David L Narum, David L Jones, Nicholas J MacDonald, Daming Zhu, Rathy Mohan, Olga Muratova, Ibrahima Baber, Mamadou B Coulibaly, Michael P Fay, Charles Anderson, Yimin Wu, Sekou F Traore, Ogobara K Doumbo, Patrick E Duffy
Journal: The Lancet Infectious Diseases (2018)
Review: In type 2 diabetes, SGLT-2 inhibitors or GLP-1 agonists reduce mortality vs control or DPP-4 inhibitors
Authors: Aoife M. Egan, Victor M. Montori
Journal: Annals of Internal Medicine (2018)

Source Citation Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association between use of sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA. 2018;319:1580-91. 29677303
Non-breast solid malignancies among breast cancer survivors.
Authors: Kadri Altundag, Ibrahim Petekkaya, Ugur Sahin, Mustafa Solak, Yavuz Ozisik
Journal: Journal of Clinical Oncology (2012)

e11092 Background: Due to advances in treatment modalities and palliative care patients with breast cancer live longer compared to the past and thus encounter an increased risk for secondary cancers. This study aims at finding the frequency of other solid cancers in a retrospective cohort. Methods: A search for the history of a non-breast solid tumor (NBST) among 1914 women admitted to our institute with stage I to IV breast cancer between 2006 – 2012 was conducted. Frequency of NBST according to temporal relation with breast cancer diagnosis was calculated Results: Overall 79 NBST and 75 patients (3.9 %) with another solid tumor were discovered. Of the patients 4 had more than one tumor. For these patients the median age at diagnosis was 55 (28 – 93), median follow-up time for breast cancer was 32 months (1 – 132). Post-menopausality was 60.8 %. The most common breast cancer histology was infiltrative ductal carcinoma (70.9 %). Of the 79 NBST, 34 (43.0 %) were diagnosed after breast cancer; 30 (38.0 %) before; and 15 (19.0 %) synchronously. Median time of diagnosis for NBST after breast cancer was 21 months (7 – 296). The most common malignancies were cancers of the ovary, thyroid and uterus (17.7, 15.2 and 11.4 %, respectively). Conclusions: The frequency of gynecological cancers and thyroid cancer along the course of breast cancer is high. Common environmental and genetic factors and may be involved. These patients should be followed closely
Natural history of apical left ventricular to aortic conduits in pediatric patients.
Authors: Frommelt Pc, Rocchini Ap, Bove El
Journal: Circulation (1991)

To determine the long-term efficacy of apical left ventricular to aortic conduits in palliating complex left ventricular outflow obstruction, we reviewed our entire experience of 20 pediatric patients who underwent placement of a composite porcine valve-bearing conduit from the left ventricular apex to the aorta from November 1977 to April 1987. There were two early postoperative deaths, both in infants less than 2 months of age at the time of surgery. The remaining 18 patients had successful conduit placement with significant relief of the left ventricular outflow obstruction. Conduits have remained functional from 3 to greater than 9 years after initial placement. Long-term maintenance of a well-functioning conduit was limited by conduit heterograft valve dysfunction secondary to degeneration and calcification, with a 3-year conduit survival of 80 +/- 9% and a 7-year survival of 52 +/- 11%. Clinical identification of conduit valve insufficiency was found to be a useful early indicator of impending conduit failure, frequently preceding other signs and symptoms of conduit valve dysfunction. Eight patients required reoperation for conduit failure, and there were two late deaths associated with conduit valve dysfunction. Other long-term complications were rare. No thromboembolic events occurred despite avoidance of anticoagulant therapy, and there were no documented episodes of bacterial endocarditis. Thus, apical aortic conduit placement is an effective surgical technique for intermediate palliation of complex left ventricular outflow obstruction and may be useful in selected pediatric patients as a staging procedure before left ventricular outflow reconstruction.
Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial
Authors: Michael Friedlander, Val Gebski, Emma Gibbs, Lucy Davies, Ralph Bloomfield, Felix Hilpert, Lari B Wenzel, Daniel Eek, Manuel Rodrigues, Andrew Clamp, Richard T Penson, Diane Provencher, Jacob Korach, Tomasz Huzarski, Laura Vidal, Vanda Salutari, Clare Scott, Maria Ornella Nicoletto, Kenji Tamura, David Espinoza, Florence Joly, Eric Pujade-Lauraine
Journal: The Lancet Oncology (2018)
Circulating 27-Hydroxycholesterol and Breast Cancer Risk: Results From the EPIC-Heidelberg Cohort
Authors: Da-Lin Lu, Charlotte Le Cornet, Disorn Sookthai, Theron S Johnson, Rudolf Kaaks, Renée T Fortner
Journal: JNCI Journal of the National Cancer Institute (2018)

27-hydroxycholesterol (27HC) was the first identified endogenous selective estrogen receptor modulator (SERM); 27HC promoted growth and metastasis in experimental models of estrogen receptor–positive mammary cancer. There are no data on prediagnosis circulating 27HC and breast cancer risk in women. We conducted a nested case–control study in the well-characterized Heidelberg, Germany, cohort of the European Investigation into Cancer and Nutrition (EPIC) including 530 incident invasive breast cancer cases, each matched to up to two control participants (n = 1036). Serum 27HC was analyzed by liquid chromatography–mass spectrometry (LC-MS) in blood samples collected at study recruitment. Multivariable conditional logistic regression models were used to quantify the association between circulating 27HC and breast cancer risk overall, by tumor hormone receptor status (ie estrogen and progesterone receptors), and by menopausal status at blood collection. All statistical tests were two-sided. 27HC was not associated with breast cancer risk overall (relative risk [RR]Quartile4vsQuartile1 [Q4vsQ1] = 0.90, 95% confidence interval [CI] = 0.66 to 1.22). The association between 27HC and breast cancer risk differed by menopausal status at blood collection (Phet = .02), but not by age at diagnosis (Phet = .78). Among women who were postmenopausal at blood collection, higher serum 27HC levels were associated with lower breast cancer risk (RRQ4vsQ1 = 0.56, 95% CI = 0.36 to 0.87). We observed no association between 27HC and breast cancer risk (RRQ4vsQ1 = 1.33, 95% CI = 0.75 to 2.38) among women who were premenopausal at blood collection. In this first prospective study, higher circulating 27HC was associated with lower risk of breast cancer in postmenopausal women. Identification of the first endogenous SERM associated with reduced risk of invasive breast cancer in postmenopausal women may offer novel avenues for breast cancer prevention strategies.
Canine Ventricular KCNE2 Expression Resides Predominantly in Purkinje Fibers
Authors: MarcPourrier, StephenZicha, JoachimEhrlich, WeiHan, StanleyNattel
Journal: Circulation Research (2003)

Mutations in minK-related peptide 1 (MiRP1), the product of the KCNE2 gene, have been associated with malignant ventricular arrhythmia syndromes related to impaired repolarization. MiRP1 interacts with a variety of ion-channel α-subunits, dysfunction of which could account for arrhythmia syndromes; however, the observation of very low-level expression of MiRP1 in ventricular tissue has led to doubts about its relevance. The specialized His-Purkinje system plays a key role in cardiac electrophysiology and is an important contributor to ventricular arrhythmias related to abnormal repolarization. We examined the relative abundance of MiRP1 in canine Purkinje versus ventricular tissue and found much greater expression at both mRNA and protein levels in Purkinje tissue. Thus, the cardiac Purkinje system is a strong candidate to play a role in arrhythmic syndromes due to MiRP1 abnormalities.
Long-acting hydrogel/microsphere composite sequentially releases dexmedetomidine and bupivacaine for prolonged synergistic analgesia
Authors: Wenjing Zhang, Weiguo Xu, Cong Ning, Mingqiang Li, Guoqing Zhao, Weiqian Jiang, Jianxun Ding, Xuesi Chen
Journal: Biomaterials (2018)
CRISPR–Cas13 Precision Transcriptome Engineering in Cancer
Authors: Javier T. Granados-Riveron, Guillermo Aquino-Jarquin
Journal: Cancer Research (2018)

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated genes (Cas) system has been rapidly harnessed to perform various genomic engineering tasks. Recently, it has been demonstrated that a novel RNA-targeting CRISPR effector protein, called Cas13, binds and cleaves RNA rather than DNA substrates analogously to the eukaryotic RNA interference system. The known Cas13a-Cas13d effectors are able to efficiently cleave complementary target single-stranded RNAs, which represent a potentially safer alternative to deoxyribonuclease Cas9, because it induces loss-of-function phenotypes without genomic loss of the targeted gene. Furthermore, through the improvement in Cas13 effector functionalities, a system called REPAIR has been developed to edit full-length transcripts containing pathogenic mutations, thus providing a promising opportunity for precise base editing. Moreover, advanced engineering of this CRISPR effector also permits nucleic acid detection, allowing the identification of mutations in cell-free tumor DNA through a platform termed Specific High Sensitivity Enzymatic Reporter Unlocking. All of these properties give us a glimpse about the potential of the CRISPR toolkit for precise transcriptome engineering, possibly leading to an expansion of CRISPR technologies for cancer therapeutics and diagnostics. Here, we examine previously unaddressed aspects of the CRISPR-based RNA-targeting approach as a feasible strategy for globally interrogating gene function in cancer in a programmable manner. Cancer Res; 78(15); 4107-13. ©2018 AACR.
Association Between the Growth of Accountable Care Organizations and Physician Work Hours and Self-employment
Authors: Anwita Mahajan, Lucy Skinner, David I. Auerbach, Peter I. Buerhaus, Douglas O. Staiger
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The share of the population covered by accountable care organizations (ACOs) is growing, but the association between this increase and physician employment is unknown. <h3>Objective</h3> To investigate the association between the growth of ACOs and changes in physician work hours, probability of being self-employed, and probability of working in a hospital. <h3>Design, Setting, and Participants</h3> A fixed-effects design was used in this cross-sectional study to compare changes in physician employment in hospital referral regions with high vs low ACO growth. A nationally representative 1% sample of all working US physicians obtained annually from 2011 through 2015 from the American Community Survey (N = 49 582) was included. Data analysis was conducted from March 28, 2017, to April 10, 2018. <h3>Main Outcomes and Measures</h3> Physician hours worked per week, probability of being self-employed, and probability of working in a hospital. <h3>Results</h3> Of the 49 582 physicians included in the study, 63.5% were men; the mean (SD) age of sampled physicians was 46.01 (11.59) years. In 2011, sampled physicians worked a mean (SD) of 52.2 (16.1) hours per week, 24.43% were self-employed, and 42.03% worked in a hospital. A 10–percentage point increase in ACO enrollment in a hospital referral region was associated with a statistically significant reduction of 0.82 (95% CI, −1.52 to −0.13;<i>P</i> = .02) work hours in men and a decrease of 2% (95% CI, −3.8% to −0.1%;<i>P</i> = .04) in the probability of all physicians being self-employed. The association with self-employment was strongest (−5.0%; 95% CI, −8.7% to −1.4%;<i>P</i> = .006) in physicians aged 50 to 69 years, who were also more likely (4.0%; 95% CI, 1.0% to 6.9%;<i>P</i> = .009) to work in a hospital. <h3>Conclusions and Relevance</h3> The growth of ACOs within hospital referral regions appears to be associated with a reduction in hours of work and self-employment among physicians. These results suggest that ACOs may affect physician employment patterns.
Response to: ‘Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) induced by immune checkpoint inhibitors’ by Delyon <i>et al</i>
Authors: Marie Kostine, Thierry Schaeverbeke
Journal: Annals of the Rheumatic Diseases (2018)

Response to: 'Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) induced by immune checkpoint inhibitors' by Delyon et alWe thank Delyon et al for their interest in our original paper 1 and for reporting on a patient with immune checkpoint inhibitors (ICI)-induced eosinophilic granulomatosis with polyangiitis (EGPA). 2 Since the first description in 2014 of giant cell arthritis (GCA) following treatment with ipilimumab (anti-CTLA-4 agent) in two patients with melanoma, 3 several vasculitis cases have been reported, as recently highlighted by Daxini et al in a systematic literature review. 4Overall, they compiled 20 cases of confirmed ICI-induced vasculitis, which were classified using the revised International Chapel Hill Consensus Conference nomenclature.The most commonly reported types of vasculitis were large vessel vasculitis and vasculitis of the nervous system, with a median exposure time to ICI of 3 months.The majority of patients received oral or intravenous corticosteroids and ICI was discontinued.Of note, a granulomatosis with polyangiitis occurred 1 week following anti-programmed cell death 1 (PD-1) agent for advanced melanoma, requiring methylprednisolone and oral daily cyclophosphamide. 5Unfortunately, data on cancer and vasculitis outcomes are often missing.By adding the first case report of EGPA, Delyon et al complete the unique and expanding list of ICI-related adverse events (irAEs).Interestingly, antineutrophil cytoplasmic antibodies were negative, similar with findings in other rheumatic irAEs such as myositis and inflammatory arthritis where autoantibodies are often negative, which should not exclude the diagnosis.Therefore, rheumatologists as well as other organ specialists involved in the diagnosis and management of irAEs have to consider vasculitis when evaluating patients receiving ICI.Notably, since polymyalgia rheumatica-like syndrome is frequently reported with anti-PD-(L)1 therapies, 6 we should pay particular attention to GCA symptoms.On the other hand, Zhang et al reported an insufficient negative signalling by the immune checkpoint PD-1/PD-L1 in the pathogenesis of GCA. 7 Indeed, they demonstrated low expression of PD-L1 in GCA dendritic cells compared with healthy arteries, unleashing PD-1 high T cells to infiltrate and damage the walls of large arteries.These data shed light on the association between vasculitis and the downregulation of PD-1/PD-L1 pathway, either spontaneous or induced by ICI, and may suggest future therapeutic immunomodulatory approaches in our classical vasculitis.
Chronic sun exposure is associated with histone acetylation changes
Authors: S. Ding, J. Chen, Q. Zeng, J. Lu, L. Tan, A. Guo, J. Kang, S. Yang, Y. Xiang, C. Zuo, J. Huang
Journal: British Journal of Dermatology (2018)

Photoaging is premature aging of the skin caused by sunlight or artificial UV exposure (e.g. tanning beds). It affects almost everyone in the world. Histones are proteins which are positively charged, allowing them to associate with DNA, which is negatively charged. Some histones are like spools for the thread‐like DNA to wrap around. This study, from China, aimed to analyse patterns of changes (modification) to histones, which can regulate gene expression in sun‐exposed and non‐exposed skin, and identify photoaging‐related genes modified by abnormal histones. We tested the histone modification profile in sun‐exposed and non‐exposed skin samples with ELISA (a test that uses antibodies and color change to identify a substance), and found that the level of histone H3 acetylation (a kind of histone modification) increased significantly in sun‐exposed skin samples compared with non‐exposed ones. The increased P300 and decreased HDAC1 and SIRT1 expression in sun‐exposed skin might be the main cause (P300, HDAC1 and SIRT1 are enzymes related to histone modification). Further, tests were performed to screen the genes whose histone H3 acetylation changed in sun‐exposed skin samples and non‐exposed ones. We found that 227 genes displayed significant hyperacetylation (simply put, over‐modification) of histone H3, and 81 genes displayed significant hypoacetylation (under‐modification) of histone H3 in sun‐exposed skin samples compared with non‐exposed ones. In summary, histone H3 hyperacetylation caused by chronic sun exposure may play a critical role in the development of skin photoaging.