tbuckley/cabot-search huggingface dataset:
Kir6.2-deficient mice are susceptible to stimulated ANP secretion: K channel acts as a negative feedback mechanism?
Authors: N SAEGUSA, T SATO, T SAITO, M TAMAGAWA, I KOMURO, H NAKAYA
Journal: Cardiovascular Research (2005)

While atrial natriuretic peptide (ANP) has been shown to be released mainly from cardiac muscle cells in response to atrial distension, the regulatory mechanisms of ANP secretion are still not fully understood. We sought to determine whether the ATP-sensitive K+ (K(ATP)) channel modulates the secretion of ANP, using mice with homozygous knockout of the Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene.K(ATP) channel currents were recorded from isolated mouse atrial cells with patch-clamp techniques. Plasma ANP concentrations in anesthetized mice and ANP content and secretion in isolated atrial preparations were determined by radioimmunoassay. Action potentials were recorded from the isolated atria.Exposure to 2,4-dinitrophenol (100 microM) evoked a glibenclamide-sensitive K(ATP) channel current in atrial cells from wild-type (WT) but not Kir6.2 knockout (Kir6.2 KO) mice. Although there were no significant differences in the basal plasma ANP levels between WT and Kir6.2 KO mice, volume expansion caused a significant elevation of plasma ANP concentration in Kir6.2 KO but not WT mice with accompanying hypotension. When isolated left atria were stretched, ANP secreted into the bath from Kir6.2 KO atria was significantly higher than that from WT atria. Furthermore, stretching the atria from WT but not Kir6.2 KO mice significantly shortened the action potential duration. A hypotonic stretch of the membrane induced the glibenclamide-sensitive K(ATP) channel current in atrial cells from WT but not Kir6.2 KO mice.Kir6.2 is essential for the function of K(ATP) channel in mouse atrial cells. Given that Kir6.2 KO mice are susceptible to stretch-induced secretion of ANP, our results suggest that K(ATP) channels may act as a negative feedback mechanism for the control of ANP secretion.
Promotion of Bladder Cancer Development and Progression by Androgen Receptor Signals
Authors: H. Miyamoto, Z. Yang, Y.-T. Chen, H. Ishiguro, H. Uemura, Y. Kubota, Y. Nagashima, Y.-J. Chang, Y.-C. Hu, M.-Y. Tsai, S. Yeh, E. M. Messing, C. Chang
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundMales have a higher incidence of bladder cancer than females, but the reason remains unknown. Unlike prostate cancer, human bladder cancer is not generally considered to be dependent on hormone activity. We investigated the possible involvement of androgens and the androgen receptor (AR) in bladder cancer.
Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders
Authors: Amy F.T. Arnsten, Min Wang
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Medications to treat cognitive disorders are increasingly needed, yet researchers have had few successes in this challenging arena. Cognitive abilities in primates arise from highly evolved N-methyl-d-aspartate (NMDA) receptor circuits in layer III of the dorsolateral prefrontal cortex. These circuits have unique modulatory needs that can differ from the layer V neurons that predominate in rodents, but they offer multiple therapeutic targets. Cognitive improvement often requires low doses that enhance the pattern of information held in working memory, whereas higher doses can produce nonspecific changes that obscure information. Identifying appropriate doses for clinical trials may be helped by assessments in monkeys and by flexible, individualized dose designs. The use of guanfacine (Intuniv) for prefrontal cortical disorders was based on research in monkeys, supporting this approach. Coupling our knowledge of higher primate circuits with the powerful methods now available in drug design will help create effective treatments for cognitive disorders.
<i>Liquorstudien bei progressiver Paralyse, mit besonderer Berücksichtigung der veraänderungen Während der Impfmalaria.</i> (Investigations of the spinal fluid in general paresis, with special reference to the changes during inoculation malaria.) By Bernhard Jacobowsky (<i>Uppsala: Almquist &amp; Wiksells Boktryckeri, 1929</i>)
Authors: None Wertham
Journal: American Journal of Psychiatry (1930)
156Pro--&amp;gt;Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox.
Authors: J H Leusen, B G Bolscher, P M Hilarius, R S Weening, W Kaulfersch, R A Seger, D Roos, A J Verhoeven
Journal: The Journal of Experimental Medicine (1994)

Src homology 3 (SH3) domains have been suggested to play an important role in the assembly of the superoxide-forming nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upon activation of phagocytes, which involves the association of membrane-bound and cytosolic components. We studied the translocation of the cytosolic proteins to the plasma membrane in neutrophils of a patient with a point mutation in the gene encoding the light chain of cytochrome b558. This mutation leads to a substitution at residue 156 of a proline into a glutamine in a putative SH3 binding domain of p22-phox (Dinauer, M., E. A. Pierce, R. W. Erickson, T. Muhlebach, H. Messner, R. A. Seger, S. H. Orkin, and J. T. Curnutte. 1991. Proc. Natl. Acad. Sci. 88:11231). In PMA-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, association of the cytosolic proteins p47-phox and p67-phox with the membrane fraction of the patient's neutrophils was virtually absent. In contrast, when solubilized membranes of the patient's neutrophils were activated with phospholipids in the absence of cytosol (Koshkin, V., and E. Pick. 1993. FEBS [Fed. Eur. Biochem. Soc.] Lett. 327:57), the rate of NADPH-dependent oxygen uptake was observed at a rate similar to that of control membranes. We suggest that the binding of an SH3 domain of p47-phox to p22-phox, and thus activation of the oxidase, does not occur in the neutrophils of this patient, although under artificial conditions, electron flow from NADPH to oxygen in cytochrome b558 is possible.
Clinical Significance and Molecular Characteristics of Circulating Tumor Cells and Circulating Tumor Microemboli in Patients With Small-Cell Lung Cancer
Authors: Jian-Mei Hou, Matthew G. Krebs, Lee Lancashire, Robert Sloane, Alison Backen, Rajeeb K. Swain, Lynsey J.C. Priest, Alastair Greystoke, Cong Zhou, Karen Morris, Tim Ward, Fiona H. Blackhall, Caroline Dive
Journal: Journal of Clinical Oncology (2012)

Purpose Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and “virtual” biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment. Patients and Methods Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined. Results CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean ± standard deviation = 1,589 ± 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood and 11.5 months (P &lt; .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM. Conclusion Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology.
USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy
Authors: Iraia García-Santisteban, Godefridus J Peters, Elisa Giovannetti, Jose Antonio Rodríguez
Journal: Molecular Cancer (2013)

Abstract Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.
The negativity bias: Conceptualization, quantification, and individual differences
Authors: John T. Cacioppo, Stephanie Cacioppo, Jackie K. Gollan
Journal: Behavioral and Brain Sciences (2014)

Abstract There is an extensive literature on the negativity bias, including its conceptualization, measurement, temporal stability (individual differences), and neural and genetic associations. Hibbing et al. posit that the difference across individuals in the negativity bias is a key factor in determining political predisposition. The measures and paradigms developed in this literature provide a means of testing this hypothesis.
Skeletal muscle: from molecules to movement
Authors: K Stokes
Journal: British Journal of Sports Medicine (2006)

By David Jones, Joan Round, Arnold de Haan. Published by Elsevier, 2004, £20.99, 202pp. softcover. ISBN 0443074275

At the beginning of each academic year the first question asked by my undergraduate students is not “did you have a good summer?” but rather “what book should I read for this unit?”. In the hope that it will encourage them to attend at least some of my sessions, my answer is always that they should not rely on text books but instead should use my lectures as a springboard from which to experience the …
Targeted Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Can There Be Too Many Active Drugs?
Authors: Sarat Chandarlapaty, Shanu Modi
Journal: Journal of Clinical Oncology (2011)

overall survival in colorectal cancer on the basis of phase II tumor dynamics. J Clin Oncol 27:4103-4108, 2009 12. Frances N, Claret L, Bruno R, et al: Tumor growth modeling from clinical trials reveals synergistic anticancer effect of the capecitabine and docetaxel combination in metastatic breast cancer. Cancer Chemother Pharmacol [epub ahead of print on April 8, 2011] 13. Stein WD, Gulley JL, Schlom J, et al: Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: The growth rate constant as an indicator of therapeutic efficacy. Clin Cancer Res 17:907-917, 2011 14. Tham LS, Wang L, Soo RA, et al: A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine carboplatin in non-small cell lung cancer patients. Clin Cancer Res 14:4213-4218, 2008 15. Maitland ML, Hudoba C, Snider KL, et al: Analysis of the yield of phase II combination therapy trials in medical oncology. Clin Cancer Res 16:5296-5302, 2010 16. Yap TA, Sandhu SK, Workman P, et al: Envisioning the future of early anticancer drug development. Nat Rev Cancer 10:514-523, 2010 17. Bruno R, Lu JF, Sun YN, et al: A modeling and simulation framework to support early clinical drug development decisions in oncology. J Clin Pharmacol 51:6-8, 2010 18. Barrett JS, Mondick JT, Narayan M, et al: Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy. BMC Med Inform Decis Mak 8:6, 2008
Transforming Growth Factor (TGF)-β1–producing Regulatory T Cells Induce Smad-mediated Interleukin 10 Secretion That Facilitates Coordinated Immunoregulatory Activity and Amelioration of TGF-β1–mediated Fibrosis
Authors: Atsushi Kitani, Ivan Fuss, Kazuhiko Nakamura, Fumiyuki Kumaki, Takashi Usui, Warren Strober
Journal: The Journal of Experimental Medicine (2003)

Interleukin (IL)-10 and transforming growth factor (TGF)-beta1 are suppressor cytokines that frequently occur together during a regulatory T cell response. Here we used a one gene doxycycline (Dox)-inducible plasmid encoding TGF-beta1 to analyze this association and test its utility. In initial studies, we showed that intranasal administration of this plasmid (along with Dox) led to the appearance of TGF-beta1-producing cells (in spleen and lamina propria) and the almost concomitant appearance of IL-10-producing cells. Moreover, we showed that these cells exert Dox-regulated suppression of the T helper cell (Th)1-mediated inflammation in trinitrobenzene sulfonic acid colitis. In subsequent in vitro studies using retroviral TGF-beta1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-beta1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-beta1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-beta1 plasmid administration ameliorates bleomycin-induced fibrosis in wild-type but not IL-10-deficient mice, strongly suggesting that the amelioration is IL-10 dependent and that IL-10 protects mice from TGF-beta1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-beta1 is not fortuitous, but instead fulfills important requirements of TGF-beta1 function after its secretion by regulatory T cells.
Accumulation of NH2-Terminal Fragment of Connective Tissue Growth Factor in the Vitreous of Patients With Proliferative Diabetic Retinopathy
Authors: David R. Hinton, Christine Spee, Shikun He, Stephen Weitz, William Usinger, Laurie LaBree, Noelynn Oliver, Jennifer I. Lim
Journal: Diabetes Care (2004)

OBJECTIVE—To evaluate the expression of connective tissue growth factor (CTGF) and its fragments in the vitreous of patients with proliferative diabetic retinopathy (PDR) and to localize CTGF expression in associated preretinal membranes. RESEARCH DESIGN AND METHODS—Vitreous was obtained from 24 patients with active PDR, 4 patients with quiescent PDR, and 23 patients with other retinal diseases and no diabetes, including 5 patients with vitreous hemorrhage. Enzyme-linked immunosorbent assay was used to determine levels of whole CTGF and its NH2- and COOH-terminal fragments. Preretinal membranes from three patients with active PDR were stained immunohistochemically for the presence of CTGF and cell type-specific markers. RESULTS—A significant increase in NH2-terminal CTGF fragment content was found in vitreous samples from patients with active PDR when compared with samples from nondiabetic patients (P &amp;lt; 0.0001) or patients with quiescent PDR (P = 0.02). Levels of NH2-terminal CTGF were also greater in vitreous samples from diabetic patients with vitreous hemorrhage compared with samples from nondiabetic patients with vitreous hemorrhage (P = 0.02). Vitreous levels of whole CTGF were similar in all groups. COOH-terminal fragments of CTGF were not detected. CTGF immunoreactivity was predominantly localized to smooth muscle actin-positive myofibroblasts within active PDR membranes. CONCLUSIONS—NH2-terminal CTGF fragment content is increased in the vitreous of patients with active PDR, suggesting that it plays a pathogenic role or represents a surrogate marker of CTGF activity in the disorder. The localization of CTGF in myofibroblasts suggests a local paracrine mechanism for induction of fibrosis and neovascularization.
SUCCESSFUL REMOVAL OF A TUMOUR IN THE ADRENAL GLAND
Authors: H. T. Mursell
Journal: BMJ (1912)

in a stage of rapid development.After the age of 6 the author's method lies almost regularly between the curves of male and female weights.For males, therefore, it gives a slightly higher dose than is necessary; for females a lower dose than is required.This latter feature is of importance, since, as already stated, females are, as a rule, more sensitive to drugs than males, especially at the age of,puberty, at which time this formula gives a dosage decidedly lower than that demanded by the weight of the average female.CONCLUSIONS.
Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps.
Authors: W B Gough, R Mehra, M Restivo, R H Zeiler, N el-Sherif
Journal: Circulation Research (1985)

Isochronal maps of ventricular activation were analyzed in dogs 3-5 days after ligation of the left anterior descending coronary artery utilizing a 64-channel multiplexer. Isochronal maps of the effective refractory period were determined from 62 epicardial sites and correlated with the activation maps. The ischemia occurring in the surviving epicardial layer prolonged refractoriness in a spatially nonuniform manner. The resulting pattern of refractoriness on the epicardial surface resembled concentric rings of isorefractoriness which increased in duration from the normal zone to the center of the ischemic zone. The formation of an arc of functional unidirectional conduction block occurred along the gradient of refractoriness and the exact location of the arc depended on the S1-S2 interval. When a short S1-S2 failed to induce reentry, fewer adjacent sites with sufficiently disparate refractoriness formed a smaller arc of block. A subsequent S3 encountered further nonuniformly shortened refractoriness (normal areas had shortened refractoriness greater than ischemic areas) and the arc of block was lengthened. This required a longer time for the wavefront to circulate around the arc. When it then reached the distal side of the arc, refractoriness had expired proximal to the arc and reentry occurred. Similarly, nonuniform shortening of refractoriness explained why one reentrant beat may or may not produce successive reentrant beats. Therefore, the spatial pattern of refractoriness forms the substrate for the arc of unidirectional conduction block that is fundamental to the development of ventricular reentry in this experimental model.
Cerebral Edema in Childhood Diabetic Ketoacidosis
Authors: Andrew B. Muir, Ronald G. Quisling, Mark C.K. Yang, Arlan L. Rosenbloom
Journal: Diabetes Care (2004)

Children who develop cerebral edema (CE) during diabetic ketoacidosis (DKA) exhibit definable signs and symptoms of neurological collapse early enough to allow intervention to prevent brain damage. Our objective was to develop a model for early detection of CE in children with DKA.A training sample of 26 occurrences of DKA complicated by severe CE and 69 episodes of uncomplicated DKA was reviewed. Signs of neurological disease were incorporated into a bedside evaluation protocol that was applied to an independent test sample of 17 patients previously reported to have developed symptomatic CE during treatment for DKA. Head computed tomograms and their reports were reviewed.The protocol allowed 92% sensitivity and 96% specificity for the recognition of CE sufficiently early for intervention. The diagnostic criteria were fulfilled in two temporal patterns, defining early- and late-onset CE. Although initial computed tomograms were often normal, the findings also included diffuse CE and focal brain injury, the latter only in patients with an early onset of abnormal neurological signs.CE may occur in the absence of acute changes on head computed tomograms. Early detection of CE at the bedside using an evidence-based protocol permits intervention in time to prevent permanent brain damage.
Mechanotransduction: how exercise heals at the tissue level
Authors: K Khan
Journal: British Journal of Sports Medicine (2011)

Purpose  This keynote presentation aims to empower clinicians to prescribe exercise confidently for a variety of musculoskeletal conditions. Specifically, interested attendees will (1) be able to explain the process of mechanotransduction because it is a key to enabling patients to adopt exercise as treatment, (2) embrace the term ‘mechanotherapy’ as either a useful term to share with patients and (3) confidently prescribe exercise to stimulate tissue repair.  Background  Mechanotransduction is the physiologic process where cells sense and respond to mechanical loads. I argue that clinicians should reclaim the term ‘mechanotherapy‘ – the use of therapeutic tissue loading to stimulate repair and remodelling in tendon, muscle, cartilage and bone. Thus, the talk has broad relevance to various conditions. In short, mechanotransduction is the process whereby the body converts mechanical loading into cellular responses which, in turn, promote structural change. I have summarised my thoughts in the following paper.1
Injury risk is low among world-class volleyball players: 4-year data from the FIVB Injury Surveillance System
Authors: Tone Bere, Jacek Kruczynski, Nadège Veintimilla, Yuichiro Hamu, Roald Bahr
Journal: British Journal of Sports Medicine (2015)

Background Little is known about the rate and pattern of injuries in international volleyball competition. Objective To describe the risk and pattern of injuries among world-class players based on data from the The International Volleyball Federation (FIVB) Injury Surveillance System (ISS) (junior and senior, male and female). Methods The FIVB ISS is based on prospective registration of injuries by team medical staff during all major FIVB tournaments (World Championships, World Cup, World Grand Prix, World League, Olympic Games). This paper is based on 4-year data (September 2010 to November 2014) obtained through the FIVB ISS during 32 major FIVB events (23 senior and 9 junior). Results The incidence of time-loss injuries during match play was 3.8/1000 player hours (95% CI 3.0 to 4.5); this was greater for senior players than for junior players (relative risk: 2.04, 1.29 to 3.21), while there was no difference between males and females (1.04, 0.70 to 1.55). Across all age and sex groups, the ankle was the most commonly injured body part (25.9%), followed by the knee (15.2%), fingers/thumb (10.7%) and lower back (8.9%). Injury incidence was greater for centre players and lower for liberos than for other player functions; injury patterns also differed between player functions. Conclusions Volleyball is a very safe sport, even at the highest levels of play. Preventive measures should focus on acute ankle and finger sprains, and overuse injuries in the knee, lower back and shoulder.