tbuckley/cabot-search huggingface dataset:
Molecular characterization of neuroendocrine prostate cancer (NEPC) and identification of new drug targets.
Authors: H. Beltran, D. Rickman, K. Park, A. Sboner, T. Macdonald, S. T. Tagawa, M. B. Gerstein, F. Demichelis, D. M. Nanus, M. A. Rubin
Journal: Journal of Clinical Oncology (2011)

19 Background: NEPC is an aggressive variant of prostate cancer that can arise de novo or from existing prostate adenocarcinoma (PCA). We sought to better understand the molecular transformation of NEPC and identify new drug targets. Methods: We used Next Generation RNA sequencing and oligonucleotide arrays to profile 7 NEPC, 30 PCA, 5 benign prostate (BEN), and validated findings on tumors from a large cohort of patients (30 NEPC, 118 PCA, 30 BEN) using IHC and FISH. Functional studies were performed using NCI-H660 (NEPC), VCaP and LnCaP (PCA), RWPE (BEN). Results: ERG rearrangement was present in 47% of NEPC, but ERG protein expression was absent and corresponded directly with lack of AR expression. 936/25932 genes were differentially expressed in NEPC versus PCA (P&lt;0.001). Aurora kinases (AURKA, AURKB) and N-myc (MYCN) were overexpressed in NEPC (P&lt;0.001) and AURKA and MYCN amplified. Using IHC and FISH, we validated these findings on a large cohort and found majority (&gt;80%) of NEPC showed Aurora overexpression, 35% had AURKA and MYCN amplification. A small subset of PCA (5%) and no BEN were positive. Transfection of MYCN induced AURKA expression and kinase activity in vitro, and MYCN or AURKA could induce expression of neuroendocrine (NE) markers (SYP, NSE). After validating NCI-H660 as model of NEPC, we observed dramatic and enhanced in vitro and in vivo sensitivity to the Aurora kinase inhibitor PHA-739358 in NCI-H660 compared to minimal to no effect in LnCaP and VCaP. Phospho-H3 expression, a downstream marker of Aurora kinase activity, was inhibited in the treated NCI-H660 and not in PCA. Notably, NE marker expression was also suppressed in the treated NCI-H660 xenografts, again supporting a role of Aurora kinase in modulating the NE phenotype. Conclusions: There is likely clonal origin of NEPC from PCA (with ERG fusion positivity seen in both), but ERG expression is limited to PCA and driven by AR signaling. We discovered significant overexpression and gene amplification of Aurora kinases and N-myc in NEPC and a small subset of PCA, and evidence that that they cooperate and induce a NE phenotype in prostate cells. In vitro and in vivo data confirms that these are novel drug targets for NEPC. No significant financial relationships to disclose.
A neuropathological study of cerebrovascular abnormalities in a signal transducer and activator of transcription 3–deficient patient
Authors: Marie-Olivia Chandesris, Françoise Gray, Patrick Bruneval, Arshid Azarine, Nathalie Boddaert, Catherine Oppenheim, François Paraire, Emmanuel Touzé, Damien Bonnet, Olivier Hermine, Olivier Lortholary, Valérie Cormier-Daire, Pierre Boutouyrie, Ziad Mallat, Alain Fischer, Capucine Picard
Journal: Journal of Allergy and Clinical Immunology (2015)
<i>Christmas Night (The Blessing of the Oxen)</i>
Authors: Jeanette M. Smith
Journal: JAMA (2015)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Darbepoetin alfa for treating anemia in patients with low-risk myelodysplastic syndromes: Exploratory analysis of baseline predictors of response
Authors: J. Gabrilove, R. Paquette, R. Lyons, C. Mushtaq, M. Sekeres, H. Lam, L. Dreiling
Journal: Journal of Clinical Oncology (2006)

6579 Background: Patients (pts) with myelodysplastic syndromes (MDS) often develop anemia, resulting in fatigue and increased transfusions. The erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in low-risk MDS pts. Baseline (BL) endogenous erythropoietin (eEPO) levels, transfusion history, and FAB sub-type can be predictive factors of response to ESAs (Hellström-Lindberg et al., 2003). Methods: This is an ongoing, fully enrolled (n = 209), phase 2, single-arm, 52-week (wk) study of DA 500 mcg every three weeks (Q3W) for treating anemia (Hb ≤ 11 g/dL) in low- or intermediate-risk MDS pts. A planned interim analysis was done after 13 wks (n = 189). The primary endpoint is the proportion of pts with an erythroid response by 13 wks. Other endpoints include change in Hb levels and in FACT-F score from BL. Results are stratified by whether pts received an ESA before enrollment: ESA-naïve (ESA-N) pts vs ESA-treated (ESA-T) pts. Exploratory analyses of the percentage of pts with an erythroid response adjusted by BL eEPO or FAB category were done. Results: Of 130 ESA-N pts, 52% were women, 86% were white, 58% had refractory anemia (RA), 34% had RA with ringed sideroblasts (RARS), 8% had RA with excess blasts (RAEB), and the mean (SD) age was 74.8 (10.1) years. The 59 ESA-T pts had similar demographics. A majority of ESA-N pts had an erythroid response, achieved a target Hb of 11 g/dL, and had a clinically significant rise in FACT-F score; ESA-N pts with lower BL eEPO levels were more likely to have a major erythroid response ( Table ). A major erythroid response was seen in 50% of pts with RA (n = 111), in 30% of pts with RARS (n = 64), and in 23% of pts with RAEB (n = 13). Of all 189 pts, 78% had an adverse event (AE), 1 had a serious treatment-related AE (hypertension), and none had thrombotic events. Conclusions: These interim results suggest that FAB sub-type and BL eEPO may affect response. Final 13-wk data from all enrolled pts (n = 209) will be shown. [Table: see text] [Table: see text]
Global and Regional Patterns in Cardiovascular Mortality From 1990 to 2013
Authors: Gregory A. Roth, Mark D. Huffman, Andrew E. Moran, Valery Feigin, George A. Mensah, Mohsen Naghavi, Christopher J.L. Murray
Journal: Circulation (2015)

There is a global commitment to reduce premature cardiovascular diseases (CVDs) 25% by 2025. CVD mortality rates have declined dramatically over the past 2 decades, yet the number of life years lost to premature CVD deaths is increasing in low- and middle-income regions. Ischemic heart disease and stroke remain the leading causes of premature death in the world; however, there is wide regional variation in these patterns. Some regions, led by Central Asia, face particularly high rates of premature death from ischemic heart disease. Sub-Saharan Africa and Asia suffer disproportionately from death from stroke. The purpose of the present report is to (1) describe global trends and regional variation in premature mortality attributable to CVD, (2) review past and current approaches to the measurement of these trends, and (3) describe the limitations of existing models of epidemiological transitions for explaining the observed distribution and trends of CVD mortality. We describe extensive variation both between and within regions even while CVD remains a dominant cause of death. Policies and health interventions will need to be tailored and scaled for a broad range of local conditions to achieve global goals for the improvement of cardiovascular health.
Abstract 17315: Low Occurrence of Left Ventricular Reverse Remodeling and Poor Long-term Prognosis in Dilated Cardiomyopathy with Higher Immunohistological Expression of Myocardial Tenascin-C
Authors: Tetsuro Yokokawa, Yasuo Sugano, Takafumi Nakayama, Masao Takigami, Toshiyuki Nagai, Hideaki Kanzaki, Taka-aki Matsuyama, Keiko Ohta-Ogo, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Takeshi Nakatani, Hisao Ogawa, Satoshi Yasuda, Toshihisa Anzai
Journal: Circulation (2014)

Background: Tenascin-C (TN-C) is an extracellular matrix protein, and may regulate matrix organization during tissue remodeling. Although serum TN-C is reported as a prognostic biomarker in patients with dilated cardiomyopathy (DCM), the clinical significance of myocardial expression of TN-C remains undetermined. The objective of this study is to clarify the significance of myocardial TN-C expression on left ventricular (LV) remodeling and long-term prognosis in patients with DCM. Methods: Eighty consecutive patients in 2005 and 2006, who were diagnosed with DCM by excluding ischemic cardiomyopathy and secondary cardiomyopathy by coronary angiography and right ventricular endomyocardial biopsy, were analyzed. Those patients were followed up to 73±34 months, and their clinical data were obtained. Immunohistochemistry for TN-C was performed on stored biopsy specimens to examine the association of TN-C deposition with the occurrence of LV reverse remodeling as well as long-term mortality. Immunostained area of myocardial TN-C was measured densitometrically and calculated in percent by the fraction of TN-C stained area to the whole myocardium (TN-C area). LV reverse remodeling was defined as LV end-diastolic dimension ≤55 mm and fractional shortening ≥25% by 60 months after diagnosis. Results: TN-C area was 1.2±1.6% on average. Twenty-two patients (28%) underwent LV reverse remodeling. Patients with LV reverse remodeling showed less TN-C area at diagnosis than those without (TN-C area; 0.6±0.5 vs. 1.5±1.8%, p=0.021). Patients were divided into two groups according to the extent of TN-C area; high TN-C group (TN-C area≥1.5%, n=19) and low TN-C group (TN-C area&lt;1.5%, n=61). LV reverse remodeling occurred less frequently in high TN-C group compared with low TN-C group (5% vs 33%, p=0.01). Eleven patients (14%) died during the observation period. Kaplan-Meier analysis revealed high TN-C group had worse prognosis than low TN-C group (p=0.009). Conclusions: Patients with higher immunohistological expression of myocardial TN-C in DCM were characterized with lower occurrence of later LV reverse remodeling and poorer long-term prognosis. Myocardial TN-C may have some crucial role in LV remodeling process in patients with DCM.
A pretty rash
Authors: Noha Elshimy
Journal: BMJ (2015)

A 24 year old woman presented with a five day history of an itchy raised rash on her left shoulder. Two weeks earlier a temporary tattoo of a flower had been drawn in the exact distribution of the rash⇓. What is the diagnosis?



Allergic contact dermatitis in response to a black henna tattoo. 

### Discussion

Allergic contact …
Outbreak of Clostridium Welchii Food-poisoning
Authors: W. H. Parry
Journal: BMJ (1963)

The roles played in the spread of hepatitis in the Bristol outbreak by housing type, population density, sanitary pro- vision, social class, play situation, locality itself, and the possible roles of dental shedding and virus transfer to water reservoirs by migrating wildfowl have been referred to elsewhere (Bothwell (1963a(Bothwell ( , 1963b)). SummaryAn outbreak of 2,395 cases of infectious hepatitis in Bristol is recorded, and investigations of the 2,107 cases in 1960 and 1961 are described.The outbreak reached its maximum between October, 1960, and January, 1961, and had subsided by the end of 1962.It appeared to be part of a world-wide increase in the incidence of the infection.The age and sex incidence was similar to that in previous British studies-that is, predominance in 5-10-year-oldsbut differed from that reported from Canada.The incubation period was usually about a month, so that the out- break can be attributed to virus A. The spread of cases from central wards to peripheral wards may simply be an indication of concentration of susceptible sections of the population in these areas.Definite or strong presumptive contact history was avail- able in 76% and 87% respectively of two groups checked.There was no distinct evidence that poor hygiene was a factor in the spread of the disease.School meals and water supplies were not incriminated as spreading infection, nor were prophylactic injections.The implications of such an outbreak for blood-transfusion departments are considerable.Three patients died, but it appears that permanent liver damage is seldom a sequel in survivors, so far as current follow-up studies extend.Supplies of gamma-globulin would have to be more extensive than at present to cope with this type of outbreak.Statutory notification for Britain as a whole would help in the detection of early cases and would enhance the chances of control by gamma-globulin.We are glad to acknowledge the assistance of senior admini- strative education, medical, and nursing colleagues, district health visitors, head teachers, and school welfare officers.Among hospital staff, who readily gave us access to records, we are particularly grateful to Dr. J. Macrae and Dr. A. E. Read.The success of the inquiry was made possible by the co-operation
FTY720, a fungus metabolite, inhibits invasion ability of androgen independent prostate cancer cells through inactivation of RhoA-GTPase
Authors: Rita C. Zhou, Ming-Tat Ling, Terence Kin-Wah Lee, Kwan Man, Xianghong Wang, Yong-Chuan Wong
Journal: Cancer Research (2005)

669  The failure of controlling androgen-independent and metastatic prostate cancer growth is the main cause of death in prostate cancer patients. In this study, we have demonstrated a novel anticancer agent, FTY720, a fungus metabolite, in the suppression of metastatic ability of androgen independent prostate cancer cells. First, using colony forming assay, we found that FTY720 treatment led to decreased colony forming ability of androgen-independent prostate cancer cell lines DU145 and PC3, indicating its negative role on cancer cell survival. In addition, treatment with relatively low dose of FTY720 (i.e. Inhibitory Concentration of 50% cell survival) resulted in suppression of prostate cancer cell migration and invasion abilities demonstrated by Wound closure assay, 3-D collagen gel invasion assays and stress fiber staining. Furthermore, we found that the inhibitory effect of FTY720 on prostate cancer invasion was associated with down-regulation of GTP-bound active form of RhoA. Transfection of a dominant-active RhoA vector in DU145 and PC3 cells conferred resistance to FTY720-induced suppression of cell motility. These results indicate that FTY720 may be a potential effective agent against androgen independent prostate cancer. Since activation of RhoA-GTPase is associated with metastasis in many types of malignancies, our results not only suggest a new agent for the treatment of advanced prostate cancer, but also implicate a possible novel anti-cancer drug especially against metastatic cancers.
Macrophage recruitment by fibrocystin‐defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis
Authors: Luigi Locatelli, Massimiliano Cadamuro, Carlo Spirlì, Romina Fiorotto, Silvia Lecchi, Carola Maria Morell, Yury Popov, Roberto Scirpo, Maria De Matteis, Mariangela Amenduni, Andrea Pietrobattista, Giuliano Torre, Detlef Schuppan, Luca Fabris, Mario Strazzabosco
Journal: Hepatology (2015)

Congenital hepatic fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure; however, the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1 , a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin‐defective ( Pkhd1 del4/del4 ) mouse, which is orthologous of CHF, we show that Pkhd1 del4/del4 cholangiocytes are characterized by a β‐catenin‐dependent secretion of a range of chemokines, including chemokine (C‐X‐C motif) ligands 1, 10, and 12, which stimulate bone marrow‐derived macrophage recruitment. We also show that Pkhd1 del4/del4 cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up‐regulating αvβ6 integrin, an activator of latent local transforming growth factor‐β1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate‐induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. Conclusion: Fibrosis can be initiated by an epithelial cell dysfunction, leading to low‐grade inflammation, macrophage recruitment, and collagen deposition; these findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis, and macrophage polarization over time. (H epatology 2016;63:965–982)
Substrate Reduction Therapy With Miglustat In Type 1 Gaucher Disease In Spain. Nine Years Outcomes Update On ZAGAL Study
Authors: Pilar Giraldo, Marcio M Andrade, Blanca Medrano, Pilar Alfonso, Pilar Irún, Koldo Atutxa, Angeles Fernandez-Galan, Abelardo Barez, Rafael Franco, Inmaculada Roig, Vicente Giner, Lucia Villalon, Elisa Martinez-Estefano, Elisa Luño, Ines Loyola, Olga Salamero, Javier de la Serna, Miguel Pocovi
Journal: Blood (2013)
Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus
Authors: A. Vanessa Stempel, Alexander Stumpf, Hai-Ying Zhang, Tuğba Özdoğan, Ulrike Pannasch, Anne-Kathrin Theis, David-Marian Otte, Alexandra Wojtalla, Ildikó Rácz, Alexey Ponomarenko, Zheng-Xiong Xi, Andreas Zimmer, Dietmar Schmitz
Journal: Neuron (2016)
A1C Combined With Glycated Albumin Improves Detection of Prediabetes in Africans: The Africans in America Study
Authors: Anne E. Sumner, Michelle T. Duong, Paola C. Aldana, Madia Ricks, Marshall K. Tulloch-Reid, Jay N. Lozier, Stephanie T. Chung, David B. Sacks
Journal: Diabetes Care (2015)

OBJECTIVE Slowing the diabetes epidemic in Africa requires improved detection of prediabetes. A1C, a form of glycated hemoglobin A, is recommended for diagnosing prediabetes. The glycated proteins, fructosamine and glycated albumin (GA), are hemoglobin-independent alternatives to A1C, but their efficacy in Africans is unknown. Our goals were to determine the ability of A1C, fructosamine, and GA to detect prediabetes in U.S.-based Africans and the value of combining A1C with either fructosamine or GA. RESEARCH DESIGN AND METHODS Oral glucose tolerance tests (OGTT) were performed in 217 self-identified healthy African immigrants (69% male, age 39 ± 10 years [mean ± SD], BMI 27.6 ± 4.5 kg/m2). A1C, fructosamine, and GA were measured. Prediabetes was diagnosed by American Diabetes Association criteria for glucose obtained from a 2-h OGTT. The thresholds to diagnose prediabetes by A1C, fructosamine, and GA were the cutoff at the upper tertile for each variable: ≥5.7% (39 mmol/mol) (range 4.2–6.6% [22.4–48.6 mmol/mol]), ≥230 µmol/L (range 161–269 µmol/L), and ≥13.35% (range 10.20–16.07%), respectively. RESULTS Prediabetes occurred in 34% (74 of 217). The diagnostic sensitivities of A1C, fructosamine, and GA were 50%, 41%, and 42%, respectively. The P values for comparison with A1C were both &amp;gt;0.3. Combining A1C with either fructosamine or GA increased sensitivities. However, the sensitivity of A1C combined with fructosamine was not better than for A1C alone (72% vs. 50%, P = 0.172). In contrast, the sensitivity of A1C combined with GA was higher than for A1C alone (78% vs. 50%, P &amp;lt; 0.001). CONCLUSIONS As individual tests, A1C, fructosamine, and GA detected ≤50% of Africans with prediabetes. However, combining A1C with GA made it possible to identify nearly 80% of Africans with prediabetes.
Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease
Authors: S Kugathasan, L J Saubermann, L Smith, D Kou, J Itoh, D G Binion, A D Levine, R S Blumberg, C Fiocchi
Journal: Gut (2007)

<h3>Background and aims:</h3> Crohn’s disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn’s disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn’s disease. <h3>Methods:</h3> Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn’s disease, children with long-standing Crohn’s disease, infectious colitis, and children without gut inflammation. <h3>Results:</h3> As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn’s disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-γ production and IL12Rβ2 chain expression. Th1 polarisation was not induced in clones from late Crohn’s disease. Mucosal levels of IL12p40 and IL12Rβ2 messenger RNA were significantly higher in children with early than late Crohn’s disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn’s disease. <h3>Conclusions:</h3> At the onset of Crohn’s disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn’s disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.
Scotland is to scrap QOF, health minister announces
Authors: Abi Rimmer
Journal: BMJ (2015)

Scotland will scrap the Quality and Outcomes Framework (QOF) in 2017, the Scottish cabinet secretary for health, wellbeing, and sport has said.

Speaking at the Royal College of General Practitioners’ conference in Glasgow on Thursday 1 October, Shona Robison announced that a new contract for GPs in Scotland would be introduced in 2017.

“We have been working with the BMA Scottish General Practitioners Committee to redesign the GP contract, and we will have the first version in …