tbuckley/cabot-search huggingface dataset:
Abstract 224: Mitochondrial Complex I Deficiency Promotes Oxidative Stress During Ischemia Reperfusion Of Cardiac Myocytes
Authors: Guohua Gong, Georgios Karamanlidis, Chi Fung Lee, Rong Tian, Wang Wang
Journal: Circulation Research (2013)

Normal cardiac function relies on highly coordinated intracellular events, such as calcium cycling and contraction, with adequate mitochondrial energy metabolism. However, mitochondrial respiration unavoidably produces reactive oxygen species (ROS) as electrons leak from the electron transport chain (ETC). Complex I of the ETC is believed to be the major site for ROS generation in the mitochondria. However, suppression of Complex I activity by chemical inhibitors leads to oxidative cell damage. In this study, we used a genetic model of Complex I deficiency, in which a key component of Complex I, Ndufs4, was deleted in the heart, to determine the causal role of Complex I in ischemia-reperfusion-induced oxidative stress in adult cardiac myocytes. Germline deletion of Ndufs4 in the heart (Ndufs4H-/-) leads to a ~75% decline of Complex I activity in cardiac mitochondria without obvious disease phenotype in the mice. As predicted, the mitochondrial respiration-coupled superoxide production events, superoxide flashes, were significantly decreased at baseline in the Ndufs4H-/- myocytes. Respiration substrate (pyruvate, 20 mM) failed to stimulate mitochondrial superoxide flash production in Ndufs4H-/- myocytes. This is accompanied by the slightly decreased steady state intracellular and mitochondrial ROS levels determined by the targeted H2O2 indicator, Hyper. The intracellular redox homeostasis is also tilted toward more reduced state, since the NADH/NAD ratio increased 67%. Surprisingly, ischemia reperfusion mimetic treatment of the myocytes caused dramatic increase in mitochondrial ROS production in Ndufs4H-/- groups, which contributed to the elevated overall cellular oxidative status. Overexpression of catalase in the mitochondria prevented these effects. Mechanistically, increased reducing equivalent (NADH) contributed to the dramatic ROS production during ischemia and reperfusion in Ndufs4H-/- myocytes. In summary, mitochondrial Complex I plays a critical role in controlling mitochondrial and cytosolic ROS homeostasis under normal conditions, and compromised Complex I function leads to accumulation of electron donors that paradoxically promote ROS production during ischemia reperfusion.
CHAPTER VII: Pulmonary Angiography
Journal: Circulation (1973)

Of 160 patients entered in the Trial, 150 had interpretable preinfusion and postinfusion angiograms. The advantage of urokinase over heparin was apparent in the subjective evaluations of pre-and postinfusion angiograms and in the objective analysis of the angiograms, which was concerned [see figure in the PDF file] only with the quantifiable amount of emboli. Patients with massive pulmonary emboli showed somewhat greater improvement than those with submassive emboli. In the very small group of patients in shock, the treatment effect with urokinase was impressive.
DI-Leu16-IL2, an Anti-CD20-Interleukin-2 Immunocytokine, Is Safe and Active in Patients with Relapsed and Refractory B-Cell Lymphoma: A Report of Maximum Tolerated Dose, Optimal Biologic Dose, and Recommended Phase 2 Dose
Authors: Frederick Lansigan, Ryotaro Nakamura, Donald P. Quick, Daniel Vlock, Andrew Raubitschek, Stephen D. Gillies, Veronika Bachanova
Journal: Blood (2016)
Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial
Authors: Marc Tardieu, Michel Zérah, Marie-Lise Gougeon, Jérome Ausseil, Stéphanie de Bournonville, Béatrice Husson, Dimitrios Zafeiriou, Giancarlo Parenti, Philippe Bourget, Béatrice Poirier, Valérie Furlan, Cécile Artaud, Thomas Baugnon, Thomas Roujeau, Ronald G Crystal, Christian Meyer, Kumaran Deiva, Jean-Michel Heard
Journal: The Lancet Neurology (2017)
Consider the Monobrow
Authors: Helena Jenkinson
Journal: JAMA Dermatology (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 Dermatology 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 Dermatology journal
Potassium 2-(1-hydroxypentyl)-benzoate attenuates neuronal apoptosis in neuron–astrocyte co-culture system through neurotrophy and neuroinflammation pathway
Authors: Dongmei Liu, Man Zhang, Xianfang Rong, Jiang Li, Xiaoliang Wang
Journal: Acta Pharmaceutica Sinica B (2017)

Potassium 2-(1-hydroxypentyl)-benzoate (d,l-PHPB), a new drug candidate for ischemic stroke at the phase II clinic trial, has been shown to protect neurons by inhibiting oxidative injury and reducing neuron apoptosis in previous studies. But the mechanisms of d,l-PHPB remain to be studied. In this study, a neuron-astrocytes co-culture system was used to elucidate the roles of astrocytes in neuroprotection of d,l-PHPB under oxygen-glucose deprivation/reoxygenation (OGD/R) condition. Our data showed that d,l-PHPB reduced neuronal apoptosis in mono-culture system and this effect was enhanced in neuron-astrocyte co-culture system under the OGD/R condition. Meanwhile, d,l-PHPB obviously increased the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which were mainly secreted from astrocytes, in the co-culture system after OGD/R. The PI3K/AKT and ERK signaling pathways as well as the p-TRKA/B receptors were involved in the process. In addition, the levels of TNF-α and IL-1β secreted from astrocytes after OGD/R were markedly reduced after d,l-PHPB treatment, which was mainly due to the suppression of phosphorylated p38. In conclusion, the present study demonstrates that the neuroprotective effects of d,l-PHPB were improved by astrocytes, mainly mediated by increasing the release of BDNF/NGF and attenuating inflammatory cytokines.
Abstract 013: Role for β-Arrestins in Stem/Precursor Cell Function and Cardiac Regeneration
Authors: Anna M Gumpert, Mai Chen, Henriette Brinks, Jang-Whan Bae, Karsten Peppel, Erhe Gao, Walter J Koch
Journal: Circulation Research (2013)

Chronic heart failure after myocardial injury (MI) is characterized by an extensive loss of myocytes due to considerable cell death. Bone marrow derived stem cells (BMSCs) can transdifferentiate and show potential for regenerating the myocardium after MI. Stem cell mobilization, egress from the bone marrow and recruitment to the site of injury can be regulated by signals through G protein coupled receptors (GPCRs). βArrestins have signalling and scaffolding functions and act as downstream regulators of GPCR desensitization and endocytosis. We explored the potential role for βArrestins in cardiac precursor cell function, concentrating on BMSCs. Using knockout (KO) mice, we investigated the role βArrestin1 (βArr1) and βArrestin2 (βArr2), their modulation of regenerative competence of BMSCs and their contribution to cardiac repair after ischemic injury. in vitro, we observed that BM derived cells devoid of either βArr1 or βArr2 are slower to proliferate, colonize and migrate, compared to wild type (WT) BM cells. We also observed elevated cell death in βArr2 deficient cells following oxidative stress. Additionally, the number of cKit+ stem cells, thought to be potential cardiac precursor cells, was significantly lower in the BM and blood of βArr KO vs WT. Similarly, BM and blood of the chimeras contained fewer and less viable cardiac stem/precursor cells pre and post MI, compared to WT transplanted controls. In our in vivo study, we carried out BM transplants to determine whether the βArrs may be involved in cardiac repair. WT mice were irradiated and received BM transplants from WT, βArr1 KO or βArr2 KO mice. Following BM reconstitution, mice underwent MI and their recovery was monitored. Interestingly, chimeric mice with βArr1 and βArr2 KO BM had significantly inferior outcomes, including significantly decreased post MI survival with βArr2 KO BM and both βArr chimeras had significantly lower cardiac function post MI than mice receiving WT BM. Histology revealed that both chimeras developed larger infarcts and hypertrophy at an faster rate. We conclude that βArrs play a novel role downstream of GPCR desensitization in cardiac progenitor cells in BM and appear to be critically involved in the heart’s response to ischemic injury via cardiac repair and regeneration.
Treatment sequencing and duration among HR+/HER2- advanced breast cancer patients in community-based oncology practices.
Authors: Yanni Hao, James E. Signorovitch, Alexander R. Macalalad, Eric Qiong Wu, Peggy L. Lin, Zhou Zhou, Jinlin Song, Erika Ohashi, Caroline Kelley, Suleiman Alfred Massarweh
Journal: Journal of Clinical Oncology (2014)

e11549 Background: Multiple endocrine and chemotherapies are used for hormone receptor-positive (HR+), human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (aBC). Clinical guidelines suggest using three consecutive lines of endocrine therapy before transition to chemotherapy. This study describes treatment sequencing and durations for aBC in real-world practice. Methods: Medical records were reviewed for women withHR+/HER2- aBC who received care in a US network of community-based oncology practices. Patients were required to have a first progression (index progression) between 1/1/2004 and 9/30/2010 following either 1) initiation of adjuvant therapy (recurrent aBC), or 2) initiation of 1st-line treatment for aBC (de novo aBC). The study was approved by the jurisdictional Institutional Review Board. Information was collected on patient characteristics and treatment patterns for aBC. Kaplan-Meier analysis was used to estimate median treatment durations. Results: We studied 211 HR+/HER2- aBC patients (mean age 59.8 years). Of those, 99 patients had recurrent disease and received a median of 3 lines of aBC therapy, including 1 line of endocrine therapy and 2 lines of chemotherapy. The median duration of treatment for recurrent aBC patients was 3.0 years following initiation of first aBC treatment. The 112 patients with de novo aBC received a median of 4 lines of aBC therapy, including 2 lines with endocrine therapy and 2 lines with chemotherapy. The median duration of aBC treatment for de novo aBC patients was 2.8 years following initiation of first aBC treatment. About 11% of all patients received 3 consecutive lines of endocrine therapy for aBC. Median treatment duration decreased for each subsequent line: 7.4 months for 1st-line, 4.2 for 2nd-line and 3.1 for 3rd-line. Conclusions: The majority of HR+/HER2- aBC patients in clinical practice received fewer than 3 consecutive lines of endocrine therapy before transition to chemotherapy. De novo aBC patients were more likely to receive multiple lines of endocrine therapy than patients with recurrent aBC in this sample. The median overall duration of treatment for aBC was approximately 3 years for both groups.
Brief Report: Clinical and Molecular Phenotypes of Low‐Penetrance Variants of <i><scp>NLRP</scp>3</i>: Diagnostic and Therapeutic Challenges
Authors: J. B. Kuemmerle‐Deschner, D. Verma, T. Endres, L. Broderick, A. A. de Jesus, F. Hofer, N. Blank, K. Krause, C. Rietschel, G. Horneff, I. Aksentijevich, P. Lohse, R. Goldbach‐Mansky, H. M. Hoffman, S. M. Benseler
Journal: Arthritis & Rheumatology (2017)

Objective Cryopyrin‐associated periodic syndromes ( CAPS ) result from gain‐of‐function mutations in the NLRP 3 gene, which causes excessive release of interleukin‐1β ( IL ‐1β) and systemic inflammation. While pathogenetic NLRP 3 variant phenotypes are well‐characterized, low‐penetrance NLRP 3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti– IL ‐1 treatment in patients with low‐penetrance NLRP 3 variants. Methods A multicenter study of consecutive symptomatic patients with low‐penetrance NLRP 3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP 3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF ‐κB release, cell death, and IL ‐1β release, were performed. Treatment effects of IL ‐1 were determined. Comparisons between low‐penetrance and pathogenetic NLRP 3 variants were performed. Results The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP 3 low‐penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP 3 variants. Patients with low‐penetrance NLRP 3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low‐penetrance NLRP 3 variants as compared to wild‐type and pathogenetic NLRP 3 variants. All treated patients responded to IL ‐1 inhibition, with complete response documented in 50% of patients. Conclusion Patients with low‐penetrance NLRP 3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL ‐1β and non– IL ‐1β–mediated inflammatory pathway activation.
One in four women who had abortion in 2016 used hormonal or long acting contraception, show figures
Authors: Susan Mayor
Journal: BMJ (2017)

A quarter of the women who had an abortion at British Pregnancy Advisory Service clinics in 2016 were using hormonal or long acting, reversible contraception when they sought treatment, the service’s latest figures show.

The data for 60 592 women who had an abortion at any …
An Ocular Commensal Protects against Corneal Infection by Driving an Interleukin-17 Response from Mucosal γδ T Cells
Authors: Anthony J. St. Leger, Jigar V. Desai, Rebecca A. Drummond, Abirami Kugadas, Fatimah Almaghrabi, Phyllis Silver, Kumarkrishna Raychaudhuri, Mihaela Gadjeva, Yoichiro Iwakura, Michail S. Lionakis, Rachel R. Caspi
Journal: Immunity (2017)
INJURY SURVEILLANCE OF AN ENGLISH PREMIER LEAGUE FOOTBALL CLUB ACADEMY BETWEEN 2012–2014
Authors: Christopher Bacon, Carl Petersen
Journal: British Journal of Sports Medicine (2017)

Background Published research into injury surveillance at English Premier League club (EPL) academies is scarce. Objective To investigate the injury incidence rate (IIR) across two EPL U21 seasons. Design Retrospective observational epidemiological cohort study. Setting An EPL academy. Participants Forty-one male professional football players (Age 17.8±1.1 y; Mass 73.7±5.9 kg; Height 178.3±5.3 cm). Risk factor assessment Over two seasons, 2012–2014, injuries were diagnosed by a qualified physiotherapist. Each season consisted of 42-weeks, with ∼6×1-hour training sessions plus 1-fixture per week, with an accumulated squad total of 8054 hours on-legs exposure. Injury variables included; site, type, contact/non-contact, activity at onset and severity classification (days lost; £7, 3 8£14, 3 15). Main Outcome Measurements IIR was defined as the number of injuries per 1000 hours of training and matches. Inter-season comparisons were completed through X 2 analysis. Results Eighty-three injuries occurred across two seasons; 2012–13 n=27 and 2013–14 n=56 (10.3 IIR). The ankle (n=26, 3.2 IIR) was the highest recorded injury site. Muscular overuse and sprains both had equivalent IIR (n=16, 2.0 IIR). Over half (57%) of all injuries were sustain in matches (n=47, 5.8 IIR). High severity injuries (n=28) had 7 and 12 times the total days lost of Medium (n=22) and Low (n=33) severity injuries, respectively. Injuries classed as non-contact occurred 8% more often than those involving contact (54% vs. 46%). Statistically significant differences resulted between seasons only for muscle strains (1 vs. 11, P=0.02), training (7 vs. 23, P=0.01) and low severity injuries (10 vs. 23, P=0.01). Conclusions We recommend cost effective targeted injury prevention programs for ankles, muscular overuse, muscular sprains and high severity injuries.
Abstract 119: Targeting Cardiac Hypertrophy with Small Molecule Inhibitors of JMJD2A
Authors: Qing-jun Zhang, Ganesha Rai, Ajit Jadhav, Anton Simeonov, David Maloney, Zhi-Ping Liu
Journal: Circulation Research (2012)

One of the major challenges in managing and treating heart failure patients is to develop disease-modifying drugs that can prevent, reverse, or slow down the disease progression. Upon pathological insults, the heart undergoes remodeling processes, including left ventricular hypertrophy and reprogramming of gene expression. Understanding the mechanisms involved could provide a key to develop interventional therapeutics. Epigenetic modification of chromatin, including histone methylation, regulates gene transcription in response to environmental signals. JMJD2A is a trimethyl-lysine specific histone lysine demethylase. To study the role of JMJD2A, we generated heart specific JMJD2A overexpression and deletion mouse lines. Our studies with these genetically modified mice indicated that JMJD2A is required for pathological cardiac hypertrophy. Furthermore, we show that the demethylase activity of JMJD2A is required for its transcriptional activity. These data suggests that targeting JMJD2A enzymatic activity may be used to suppress hypertrophic remodeling. To test this hypothesis, we tested a collection of small molecule inhibitors of JMJD2 in collaboration with Chemists in NIH and identified several small molecule inhibitors of JMJD2A that are active in cell-based assays. These small molecule inhibitors of JMJD2A inhibited the phenylephrine-stimulated cardiomyocyte hypertrophy in vitro. Our data suggests that JMJD2A enzymatic activity may act as a hypertrophic determinant and may be an innovative drug target for prevention and treatment of pathological cardiac hypertrophy and heart failure.
Acral lentiginous melanoma: a skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients
Authors: Y. Teramoto, U. Keim, A. Gesierich, G. Schuler, E. Fiedler, T. Tüting, C. Ulrich, U. Wollina, J.C. Hassel, R. Gutzmer, S. Goerdt, C. Zouboulis, U. Leiter, T.K. Eigentler, C. Garbe
Journal: British Journal of Dermatology (2017)

Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide. To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society. The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS. In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors. ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes.
Regulation of PHAS-1 by insulin and IGF-1 in skeletal muscle cells
Authors: Winnie Fung, Mei Yoke Chan, Chan Hon Chui
Journal: Clinical Cancer Research (2007)

A34  Introduction: Protein synthesis is a complex process and key steps in translational control occur at the level of elF4F and p70S6 kinase regulation in eukaryotic cells. PHAS-1 protein plays a vital role as a translational repressor by inhibiting the formation of the elF4F complex. Insulin and insulin-like growth factor-1 (IGF-1) play important roles in protein synthesis. Whereas their receptors (insulin receptors and IGF-1 receptors) may be structurally similar and that many of their downstream substrates may be alike; differences in the physiological functions of insulin and IGF-1 suggest that divergent signaling induced by insulin and IGF-1 may exist. Skeletal muscle cells are of particular interest, as they are both insulin-targeted cell types and are the normal counterpart of a childhood cancer, rhabdomyosarcoma (RMS), of skeletal muscle origin. Moreover, the physiological upstream kinases of PHAS-1 are presently unknown. Thus, the current studyaims to increase understanding of PHAS-1 regulation by insulin and IGF-1 at the molecular level by investigating the signaling pathways involved.   Methods: The protein expression patterns and their phosphorylation (activation) status of the several kinases upstream of PHAS-1 have been assessed in parallel to that of PHAS-1 by western blot analysis of stimulated skeletal muscle cells, namely C2C12 and L6. PHAS-1 susceptibility to pharmacological inhibitors of these kinases has also been investigated in these cells.  Results: Our results using skeletal muscle cells have shown that the phosphorylation of PHAS-1 begins within 10 minutes upon insulin and IGF-1 induction, while it is being activated throughout the 96-hour of stimulation period. In addition, PHAS-1 susceptibility to pharmacological inhibitors of the several upstream kinases has been investigated in these cells, and have confirmed that the PI3K/AKT/mTOR, and to a lesser extent, the ERK/MAPK pathways have been activated in response to the insulin and IGF-1 stimulation.  Conclusions: By the above means, we have assessed the contributions of each of the above kinases to the regulation of PHAS-1 under normal physiological circumstances. A corollary to the current study is that these upstream kinases (or targets) should also play a significant role in regulating protein synthesis induced by insulin and IGF-1 under pathological states. There is increasing evidence that insulin/IGF-1 are growth factors for tumor formation, of which mechanism may include enhanced DNA and protein synthesis, leading to dysregulated cell growth frequently observed in cancer. By defining these important targets, it is hoped that specific therapeutic pharmacological inhibitors can be developed for use in disease states such as cancer. The current data on skeletal muscle cells is anticipated to provide a vital underpinning for future investigation of PHAS-1 regulation by insulin/IGF-1 in RMS cells.