tbuckley/cabot-search huggingface dataset:
Metallothionein Expression Is Suppressed in Primary Human Hepatocellular Carcinomas and Is Mediated through Inactivation of CCAAT/Enhancer Binding Protein α by Phosphatidylinositol 3-Kinase Signaling Cascade
Authors: Jharna Datta, Sarmila Majumder, Huban Kutay, Tasneem Motiwala, Wendy Frankel, Robert Costa, Hyuk C. Cha, Ormond A. MacDougald, Samson T. Jacob, Kalpana Ghoshal
Journal: Cancer Research (2007)

Reactive oxygen species (ROS) resulting from chronic inflammation cause liver injury leading to transformation of regenerating hepatocytes. Metallothioneins (MT), induced at high levels by oxidative stress, are potent scavengers of ROS. Here, we report that the levels of MT-1 and MT-2A are drastically reduced in primary human hepatocellular carcinomas (HCCs) and in diethylnitrosamine-induced liver tumors in mice, which is primarily due to transcriptional repression. Expression of the transcription factor, MTF-1, essential for MT expression, and its target gene Zn-T1 that encodes the zinc transporter-1 was not significantly altered in HCCs. Inhibitors of both phosphatidylinositol 3-kinase (PI3K) and its downstream target AKT increased expression of MT genes in HCC cells but not in liver epithelial cells. Suppression of MT-1 and MT-2A by ectopic expression of the constitutively active PI3K or AKT and their up-regulation by dominant-negative PI3K or AKT mutant confirmed negative regulation of MT expression by PI3K/AKT signaling pathway. Further, treatment of cells with a specific inhibitor of glycogen synthase kinase-3 (GSK-3), a downstream effector of PI3K/AKT, inhibited MT expression specifically in HCC cells. Short interfering RNA-mediated depletion of CCAAT/enhancer binding protein alpha (C/EBPalpha), a target of GSK-3, impeded MT expression, which could not be reversed by PI3K inhibitors. DNA binding activity of C/EBPalpha and its phosphorylation at T222 and T226 by GSK-3 are required for MT expression. MTF-1 and C/EBPalpha act in concert to increase MT-2A expression, which probably explains the high level of MT expression in the liver. This study shows the role of PI3K/AKT signaling pathway and C/EBPalpha in regulation of MT expression in hepatocarcinogenesis.
Bias in experimental study designs: randomised controlled trials with parallel groups
Authors: Philip Sedgwick
Journal: BMJ (2015)

Researchers investigated the effects of antenatal lifestyle advice on health outcomes in overweight and obese pregnant women. A randomised controlled trial with a parallel groups study design was used. The intervention consisted of a comprehensive dietary and lifestyle programme during pregnancy, which incorporated a combination of dietary, exercise, and behavioural strategies delivered by a research dietitian and trained research assistants. The control treatment was standard pregnancy care, which did not include such strategies. Participants were women with a singleton pregnancy, between 10 and 20 weeks’ gestation, and who had a body mass index (BMI) of 25 or more. The setting was three public maternity hospitals across South Australia.1

In total, 5474 eligible women were approached, of whom 2212 accepted the invitation and were randomly allocated to the intervention (n=1108) or control (n=1104) treatment. To ensure allocation concealment, a computer generated allocation sequence was delivered by a telephone randomisation service not involved with recruitment or clinical care. The primary outcome was the proportion of infants born large for gestational age (birth weight ≥90th centile for gestation and sex). Secondary outcomes included birth weight greater than 4000 g, hypertension, pre-eclampsia, and gestational diabetes. All outcomes were assessed by research staff blinded to the original treatment allocation.

Although the risk of infants being born large for gestational age was lower in the intervention group than in the control group, the difference was not significant (18.9% v 21%; adjusted relative risk 0.90, 95% confidence interval 0.77 to 1.07; P=0.24). Infants born to women after lifestyle advice were significantly less likely to have a birth weight above 4000 g (15.3% v 18.8%; 0.82, 0.68 to 0.99; P=0.04). There were no differences between the treatment groups for any of the other secondary outcomes. It was concluded that, in overweight or obese women, antenatal lifestyle advice …
The hamstring syndrome in endurance athletes
Authors: S Migliorini, M Merlo
Journal: British Journal of Sports Medicine (2011)

Hamstring syndrome is a gluteal sciatic pain, in which posttraumatic or congenital hard fibrotic bands irritate sciatic nerve at the insertion site of hamstring muscles to ischial tuberosity. Traction, mechanical compression and impingement of the sciatic nerve may occur in certain anatomopathological situations at the origin of the hamstrings on the ischial tuberosity. The symptoms include local pain at the ischial tuberosity irradiating to the posterior thigh which appears with the cyclic stress of running, after physical exercise, and typically during sitting. Hamstring syndrome diagnosis is basically done according to typical symptoms and finding. Differential diagnosis is required from piriformis syndrome, ischiogluteal bursitis, posterior femoral muscle compartment pain, scars in hamstring muscles and back originated symptoms. MRI is the best examination to detect abnormality at the ischial tuberosity area. The majority of the athletes with hamstring syndrome respond positively to conservative therapy but in the refractory cases the hamstring syndrome can be treated surgically by dividing the compressing band and by performing the sciatic neurolysis. This paper describes the results of the surgical treatment during the last 15 years of a personal series of 25 endurance athletes (middle and long distance running, marathon, triathlon, cycling) refractory to non operative treatments for a period of 1 to 6 years. Three bilateral operation have been made in different time; in two cases the operation has been performed after the failed piriformis surgery and in two cases was practised the miotomy of the hypertrofic quadratus femoris. Usually good results are seen in a few months after surgery, and all subjects returned to practice competitive sports except one patient with chronic lumbar back problems. The final healing may take 1/2 years in chronic cases. Hamstring syndrome is still misunderstood and it is often confused with other causes of sciatica despite its frequent occurrence in sports.
Hereditary persistence of alphafetoprotein (HPAFP). A new case of G a substitution in the promoter region of the gene
Authors: I. Catalan, R. Giner-Duran, J. Vidal, J.R. Blesa, M.L. Lacalle, J. Hernandez-Yago, L. Igual, M. Bixquert
Journal: Journal of Hepatology (2003)
Targeting the Oligomerization Domain of ETO Interferes with RUNX1/ETO Oncogenic Activity in t(8;21)-Positive Leukemic Cells
Authors: Christian Wichmann, Linping Chen, Markus Heinrich, Daniela Baus, Edith Pfitzner, Martin Zörnig, Oliver G. Ottmann, Manuel Grez
Journal: Cancer Research (2007)

Abstract About 12% of all de novo acute myeloid leukemias are characterized by the translocation t(8;21), which generates the oncogenic fusion protein RUNX1/ETO. RUNX1/ETO has a modular structure and contains several docking sites for heterologous proteins, including transcriptional corepressors like N-CoR, SMART, and mSIN3A. RUNX1/ETO is found in high molecular weight complexes, which are crucial for the block in myeloid differentiation observed in RUNX1/ETO–transformed cells. Essential for high molecular weight complex formation is the nervy homology region 2 (NHR2) within ETO, which serves as interacting surface for oligomerization as well as association with members of the ETO protein family. Here, we show that the expression of a fusion peptide consisting of 128 amino acids (NC128), including the entire NHR2 domain of ETO, disrupts the stability of the RUNX1/ETO high molecular weight complexes, restores transcription of RUNX1/ETO target genes, and reverts the differentiation block induced by RUNX1/ETO in myeloid cells. In the presence of NC128, RUNX1/ETO–transformed cells lose their progenitor cell characteristics, are arrested in cell cycle progression, and undergo cell death. Our results indicate that selective interference with the oligomerization domain of ETO could provide a promising strategy to inhibit the oncogenic properties of the leukemia-associated fusion protein RUNX1/ETO. [Cancer Res 2007;67(5):2280–9]
Sinoatrial Node Pacemaker Activity Requires Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II Activation
Authors: Tatiana M. Vinogradova, Ying-Ying Zhou, Konstantin Y. Bogdanov, Dongmei Yang, Meike Kuschel, Heping Cheng, Rui-Ping Xiao
Journal: Circulation Research (2000)

Cardiac beating arises from the spontaneous rhythmic excitation of sinoatrial (SA) node cells. Here we report that SA node pacemaker activity is critically dependent on Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). In freshly dissociated rabbit single SA node cells, inhibition of CaMKII by a specific peptide inhibitor, autocamtide-2 inhibitory peptide (AIP, 10 micromol/L), or by KN-93 (0.1 to 3.0 micromol/L), but not its inactive analog, KN-92, depressed the rate and amplitude of spontaneous action potentials (APs) in a dose-dependent manner. Strikingly, 10 micromol/L AIP and 3 micromol/L KN-93 completely arrested SA node cells, which indicates that basal CaMKII activation is obligatory to the genesis of pacemaker AP. To understand the ionic mechanisms of the CaMKII effects, we measured L-type Ca(2+) current (I(Ca, L)), which contributes both to AP upstroke and to pacemaker depolarization. KN-93 (1 micromol/L), but not its inactive analog, KN-92, decreased I:(Ca, L) amplitude from 12+/-2 to 6+/-1 pA/pF without altering the shape of the current-voltage relationship. Both AIP and KN-93 shifted the midpoint of the steady-state inactivation curve leftward and markedly slowed the recovery of I(Ca, L) from inactivation. Similar results were observed using the fast Ca(2+) chelator BAPTA, whereas the slow Ca(2+) chelator EGTA had no significant effect, which suggests that CaMKII activity is preferentially regulated by local Ca(2+) transients. Indeed, confocal immunocytochemical imaging showed that active CaMKII is highly localized beneath the surface membrane in the vicinity of L-type channels and that AIP and KN-93 significantly reduced CaMKII activity. Thus, we conclude that CaMKII plays a vital role in regulating cardiac pacemaker activity mainly via modulating I(Ca, L) inactivation and reactivation, and local Ca(2+) is critically involved in these processes.
Tumors and Mitochondrial Respiration: A Neglected Connection
Authors: Andrea Viale, Denise Corti, Giulio F. Draetta
Journal: Cancer Research (2015)

For decades, tumor cells have been considered defective in mitochondrial respiration due to their dominant glycolytic metabolism. However, a growing body of evidence is now challenging this assumption, and also implying that tumors are metabolically less homogeneous than previously supposed. A small subpopulation of slow-cycling cells endowed with tumorigenic potential and multidrug resistance has been isolated from different tumors. Deep metabolic characterization of these tumorigenic cells revealed their dependency on mitochondrial respiration versus glycolysis, suggesting the existence of a common metabolic program active in slow-cycling cells across different tumors. These findings change our understanding of tumor metabolism and also highlight new vulnerabilities that can be exploited to eradicate cancer cells responsible for tumor relapse.
Density analysis of hepatitis C virus particle population in the circulation of infected hosts: implications for virus neutralization or persistence
Authors: Tatsuya Kanto, Hayashi Norio, Tetsuo Takehara, Hagiwara Hideki, Mita Eiji, Naito Masafumi, Kasahara Akinori, Fusamoto Hideyuki, Kamada Takenobu
Journal: Journal of Hepatology (1995)
Normal electrocardiographic findings: recognising physiological adaptations in athletes
Authors: Jonathan A Drezner, Peter Fischbach, Victor Froelicher, Joseph Marek, Antonio Pelliccia, Jordan M Prutkin, Christian M Schmied, Sanjay Sharma, Mathew G Wilson, Michael John Ackerman, Jeffrey Anderson, Euan Ashley, Chad A Asplund, Aaron L Baggish, Mats Börjesson, Bryan C Cannon, Domenico Corrado, John P DiFiori, Kimberly G Harmon, Hein Heidbuchel, David S Owens, Stephen Paul, Jack C Salerno, Ricardo Stein, Victoria L Vetter
Journal: British Journal of Sports Medicine (2013)

Electrocardiographic changes in athletes are common and usually reflect benign structural and electrical remodelling of the heart as a physiological adaptation to regular and sustained physical training (athlete's heart). The ability to identify an abnormality on the 12-lead ECG, suggestive of underlying cardiac disease associated with sudden cardiac death (SCD), is based on a sound working knowledge of the normal ECG characteristics within the athletic population. This document will assist physicians in identifying normal ECG patterns commonly found in athletes. The ECG findings presented as normal in athletes were established by an international consensus panel of experts in sports cardiology and sports medicine.
Neurophysiological Evidence of Corollary Discharge Dysfunction in Schizophrenia
Authors: Judith M. Ford, Daniel H. Mathalon, Theda Heinks, Sontine Kalba, William O. Faustman, Walton T. Roth
Journal: American Journal of Psychiatry (2001)

Speaking is hypothesized to generate a corollary discharge of motor speech commands transmitted to the auditory cortex, dampening its response to self-generated speech sounds. Event-related potentials were used to test whether failures of corollary discharge during speech contribute to the pathophysiology of schizophrenia.The N1 component of the event-related potential elicited by vowels was recorded while the vowels were spoken by seven patients with schizophrenia and seven healthy comparison subjects and while the same vowels were played back.In the healthy subjects, the N1 elicited by spoken vowels was smaller than the N1 elicited by played-back vowels. This reduction in N1 elicited by spoken vowels was not observed in the patients with schizophrenia.These findings provide direct neurophysiological evidence for a corollary discharge that dampens sensory responses to self-generated, relative to externally presented, percepts in healthy comparison subjects and its failure in patients with schizophrenia.
National Institutes of Health Pathways to Prevention Workshop: The Role of Opioids in the Treatment of Chronic Pain
Authors: David B. Reuben, Anika A.H. Alvanzo, Takamaru Ashikaga, G. Anne Bogat, Christopher M. Callahan, Victoria Ruffing, David C. Steffens
Journal: Annals of Internal Medicine (2015)

This National Institutes of Health (NIH) Pathways to Prevention Workshop was cosponsored by the NIH Office of Disease Prevention (ODP), the NIH Pain Consortium, the National Institute on Drug Abuse, and the National Institute of Neurological Disorders and Stroke. A multidisciplinary working group developed the workshop agenda, and an evidence-based practice center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the workshop discussion. During the 1.5-day workshop, invited experts discussed the body of evidence, and attendees had opportunities to provide comments during open discussion periods. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the ODP Web site for 2 weeks for public comment. This article is an abridged version of the panel's full report, which is available at https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/opioids-chronic-pain/workshop-resources#final report.
Vascular Endothelial Growth Factor-A–Induced Chemotaxis of Monocytes Is Attenuated in Patients With Diabetes Mellitus
Authors: Johannes Waltenberger, Juliane Lange, Andrea Kranz
Journal: Circulation (2000)

Background —Vascular endothelial growth factor-A (VEGF-A) acts on endothelial cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identify differences in individual responses to VEGF-A stimulation because of the lack of an ex vivo assay. Methods and Results —We report a chemotaxis assay using isolated monocytes from individual diabetic patients and from healthy, age-matched volunteers. The chemotactic response of individual monocyte preparations to VEGF-A, as mediated via Flt-1, was quantitatively assessed using a modified Boyden chamber. Although the migration of monocytes from healthy volunteers could be stimulated with VEGF-A (1 ng/mL) to a median of 148.4% of the control value (25th and 75th percentiles, 136% and 170%), monocytes from diabetic patients could not be stimulated with VEGF-A (median, 91.1% of unstimulated controls; 25th and 75th percentiles, 83% and 98%; P &lt;0.0001). In contrast, the response of monocytes to the chemoattractant formylMetLeuPhe remained intact in diabetic patients. The VEGF-A–inducible kinase activity of Flt-1, as assessed by in vitro kinase assays, remained intact in monocytes from diabetic patients. Moreover, the serum level of VEGF-A, as assessed by immunoradiometric assay, was significantly elevated in diabetic patients. Conclusions —The cellular response of monocytes to VEGF-A is attenuated in diabetic patients because of a downstream signal transduction defect. These data suggest that monocytes are important in arteriogenesis and that their ability to migrate might be critical to the arteriogenic response. Thus, we resolved a fundamental mechanism involved in the problem of impaired collateral formation in diabetic patients.
Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study
Authors: Birgit Gruenberger, Johannes Schueller, Ute Heubrandtner, Fritz Wrba, Dietmar Tamandl, Klaus Kaczirek, Rudolf Roka, Sandra Freimann-Pircher, Thomas Gruenberger
Journal: The Lancet Oncology (2010)
PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps
Authors: Pingxin Li, Ming Li, Michael R. Lindberg, Mary J. Kennett, Na Xiong, Yanming Wang
Journal: The Journal of Experimental Medicine (2010)

Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation. However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. Unlike PAD4(+/+) neutrophils, PAD4(-/-) neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious disease model of necrotizing fasciitis, PAD4(-/-) mice are more susceptible to bacterial infection than PAD4(+/+) mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.
John Anthony Spencer
Authors: Andrew Mason
Journal: BMJ (2015)

For as long as he was a radiologist, John Spencer was a committed and dedicated teacher who exuded enthusiasm for his specialism. His gift was the ability to transfer that sense to others, many of whom he inspired to achieve their career goals. John’s humour and generosity resonated with many, making him an extremely popular and approachable consultant. Part of his appeal lay in a Yorkshire grit and pragmatism that enabled him to simplify concepts and get them over in a straightforward and amusing way. His joy in friends, food, and conversation were a source of pleasure to many but shielded from view his inner thoughts, which later became such a heavy load.

John Anthony Spencer was born in Kingston upon Hull in the East Riding of Yorkshire. His mother’s family had a Dutch market gardening background, and his father worked in the automobile trade. This was a key factor in John’s lifelong fascination with all things petrol powered. From humble beginnings in the Anlaby area of Hull the family moved to the more rural setting of Skidby in the Wolds. From here John attended Beverley Grammar School. Here he had a reputation for entertaining the class with humorous impersonations and as an exceptional student. A skilled footballer, John’s chosen position of central defender was influenced by his boyhood heroes down the road at Boothferry Park. He described his devotion to Hull City Football Club as his longest affiliation with any club or society.

From Beverley, John followed the established path from northern direct grant pupil to Oxbridge scholar, arriving at Gonville and Caius in October 1976. Initially residing in Harvey Court—to which he subsequently donated generously for the restoration of his old room—John made his remaining Cambridge base in Green Street. Here his basso profundo could regularly be heard …
Complexity in Mathematical Models of Public Health Policies: A Guide for Consumers of Models
Authors: Sanjay Basu, Jason Andrews
Journal: PLoS Medicine (2013)

Sanjay Basu and colleagues explain how models are increasingly used to inform public health policy yet readers may struggle to evaluate the quality of models. All models require simplifying assumptions, and there are tradeoffs between creating models that are more "realistic" versus those that are grounded in more solid data. Indeed, complex models are not necessarily more accurate or reliable simply because they can more easily fit real-world data than simpler models can. Please see later in the article for the Editors' Summary
Obstructive Sleep Apnea
Authors: Sanjay R. Patel
Journal: Annals of Internal Medicine (2019)

Obstructive sleep apnea (OSA) is very common but is frequently undiagnosed. Symptoms include loud snoring, nocturnal awakening, and daytime sleepiness. Motor vehicle accidents due to drowsy driving are a particular concern. Evaluation and treatment should focus on symptomatic patients, both to alleviate symptoms and to potentially decrease cardiovascular risk. In recent years, a strategy of home sleep apnea testing followed by initiation of autotitrating continuous positive airway pressure therapy in the home has greatly reduced barriers to diagnosis and treatment and has also facilitated routine management of OSA by primary care providers.