tbuckley/cabot-search huggingface dataset:
Activation of PI3-Kinase Stimulates Endocytosis of ROMK via Akt1/SGK1-Dependent Phosphorylation of WNK1
Authors: Chih-Jen Cheng, Chou-Long Huang
Journal: Journal of the American Society of Nephrology (2011)

WNK kinases stimulate endocytosis of ROMK channels to regulate renal K+ handling. Phosphatidylinositol 3-kinase (PI3K)-activating hormones, such as insulin and IGF 1, phosphorylate WNK1, but how this affects the regulation of ROMK abundance is unknown. Here, serum starvation of ROMK-transfected HEK cells led to an increase of ROMK current density; subsequent addition of insulin or IGF1 inhibited ROMK currents in a PI3K-dependent manner. Serum and insulin also increased phosphorylation of the downstream kinases Akt1 and SGK1 as well as WNK1. A biotinylation assay suggested that insulin and IGF1 inhibit ROMK by enhancing its endocytosis, a process that WNK1 may mediate. Knockdown of WNK1 with siRNA or expression of a phospho-deficient WNK1 mutant (T58A) both prevented insulin-induced inhibition of ROMK currents, suggesting that phosphorylation at Threonine-58 of WNK1 is important to mediate the inhibition of ROMK by PI3K-activating hormones or growth factors. In vitro and in vivo kinase assays supported the notion that Akt1 and SGK1 can phosphorylate WNK1 at this site, and we established that Akt1 and SGK1 synergistically inhibit ROMK through WNK1. We used dominant-negative intersectin and dynamin constructs to show that SGK1-mediated phosphorylation of WNK1 inhibits ROMK by promoting its endocytosis. Taken together, these results suggest that PI3K-activating hormones inhibit ROMK by enhancing its endocytosis via a mechanism that involves phosphorylation of WNK1 by Akt1 and SGK1.
Nonspecific Inflammatory Bowel Disease in Two General Hospitals1
Authors: N A Buckell
Journal: Journal of the Royal Society of Medicine (1978)

During 1976, 50 patients were admitted to two general hospitals for the investigation or treatment of nonspecific inflammatory bowel disease. There were more patients admitted with Crohn's disease (23) than proctocolitis (11). Half of those patients admitted with Crohn's disease required surgical treatment, the majority for small bowel obstruction. Five patients were admitted for the treatment of an acute attack of proctocolitis; these patients were all previously undiagnosed, were all admitted urgently and all responded to medical treatment.
Transmembrane protein ESDN promotes endothelial VEGF signaling and regulates angiogenesis
Authors: Lei Nie, Xiaojia Guo, Leila Esmailzadeh, Jiasheng Zhang, Abolfazl Asadi, Mark Collinge, Xuan Li, Jun-Dae Kim, Melissa Woolls, Suk-Won Jin, Alexandre Dubrac, Anne Eichmann, Michael Simons, Jeffrey R. Bender, Mehran M. Sadeghi
Journal: Journal of Clinical Investigation (2013)

Aberrant blood vessel formation contributes to a wide variety of pathologies, and factors that regulate angiogenesis are attractive therapeutic targets. Endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a neuropilin-related transmembrane protein expressed in ECs; however, its potential effect on VEGF responses remains undefined. Here, we generated global and EC-specific Esdn knockout mice and demonstrated that ESDN promotes VEGF-induced human and murine EC proliferation and migration. Deletion of Esdn in the mouse interfered with adult and developmental angiogenesis, and knockdown of the Esdn homolog (dcbld2) in zebrafish impaired normal vascular development. Loss of ESDN in ECs blunted VEGF responses in vivo and attenuated VEGF-induced VEGFR-2 signaling without altering VEGF receptor or neuropilin expression. Finally, we found that ESDN associates with VEGFR-2 and regulates its complex formation with negative regulators of VEGF signaling, protein tyrosine phosphatases PTP1B and TC-PTP, and VE-cadherin. These findings establish ESDN as a regulator of VEGF responses in ECs that acts through a mechanism distinct from neuropilins. As such, ESDN may serve as a therapeutic target for angiogenesis regulation.
<scp>l</scp>-Arginine: An Ultradian-Regulated Substrate Coupled With Insulin Oscillations in Healthy Volunteers
Authors: Adrien Schaefer, Chantal Simon, Antoine Viola, François Piquard, Bernard Geny, Gabrielle Brandenberger
Journal: Diabetes Care (2003)

OBJECTIVE—Coupled oscillations of 50–110 min in insulin and glucose have been found previously in healthy men under continuous enteral nutrition. Because l-arginine induces insulin release as glucose does, we tested the hypothesis that l-arginine can also display such an ultradian rhythm. RESEARCH DESIGN AND METHODS—Seven healthy male subjects participated in one experimental night during which blood was sampled every 10 min from 2300 to 0700. Plasma glucose, C-peptide, and l-arginine levels were measured simultaneously. The insulin secretion rate (ISR) was calculated from plasma C-peptide levels by a deconvolution procedure. RESULTS—Plasma glucose followed the recognizable profiles, with oscillations closely linked to similar changes in the ISR. Pulse analysis of l-arginine profiles revealed significant oscillations linked to glucose and ISR oscillations, with the highest cross-correlation coefficients at time lag 0 ranging from 0.380 to 0.680 for glucose and l-arginine and from 0.444 to 0.726 for ISR and l-arginine (P &amp;lt; 0.01). The mean period of l-arginine oscillations was 77.2 ± 6.2 min, and their mean amplitude was 19.9 ± 1.7%, similar to that of glucose (17.0 ± 1.9%), when expressed as the percentage of mean overnight levels. CONCLUSIONS—This newly discovered ultradian rhythm of l-arginine and its coupling with glucose and ISR oscillations sheds new light on the regulation of l-arginine, the substrate of numerous metabolic pathways, including nitric oxide synthesis. These oscillations may be of significance in conditions of hyperinsulinemia or abnormal glucose tolerance.
Serum IgE, Tumor Epidermal Growth Factor Receptor Expression, and Inherited Polymorphisms Associated with Glioma Survival
Authors: Margaret Wrensch, John K. Wiencke, Joe Wiemels, Rei Miike, Joe Patoka, Michelle Moghadassi, Alex McMillan, Karl T. Kelsey, Kenneth Aldape, Kathleen R. Lamborn, Andrew T. Parsa, Jennette D. Sison, Michael D. Prados
Journal: Cancer Research (2006)

Abstract In population-based glioma patients, we examined survival in relation to potentially pertinent constitutive polymorphisms, serologic factors, and tumor genetic and protein alterations in epidermal growth factor receptor (EGFR), MDM2, and TP53. Subjects were newly diagnosed adults residing in the San Francisco Bay Surveillance Epidemiology and End Results Area during 1991 to 1994 and 1997 to 1999 with central neuropathology review (n = 873). Subjects provided blood for serologic studies of IgE and IgG to four herpes viruses and constitutive specimens for genotyping 22 polymorphisms in 13 genes (n = 471). We obtained 595 of 697 astrocytic tumors for marker studies. We determined treatments, vital status, and other factors using registry, interview, medical record, and active follow-up data. Cox regressions for survival were adjusted for age, gender, ethnicity, study series, resection versus biopsy only, radiation, and chemotherapy. Using a stringent P &amp;lt; 0.001, glioma survival was associated with ERCC1 C8092A [hazard ratio (HR), 0.72; 95% confidence limits (95% CL), 0.60-0.86; P = 0.0004] and GSTT1 deletion (HR, 1.64; 95% CL, 1.25-2.16; P = 0.0004); glioblastoma patients with elevated IgE had 9 months longer survival than those with normal or borderline IgE levels (HR, 0.62; 95% CL, 0.47-0.82; P = 0.0007), and EGFR expression in anaplastic astrocytoma was associated with nearly 3-fold poorer survival (HR, 2.97; 95% CL, 1.70-5.19; P = 0.0001). Based on our and others' findings, we recommend further studies to (a) understand relationships of elevated IgE levels and other immunologic factors with improved glioblastoma survival potentially relevant to immunologic therapies and (b) determine which inherited ERCC1 variants or other variants in the 19q13.3 region influence survival. We also suggest that tumor EGFR expression be incorporated into clinical evaluation of anaplastic astrocytoma patients. (Cancer Res 2006; 66(8): 4531-41)
ENUMERATION OF CELL-INFECTING PARTICLES OF NEWCASTLE DISEASE VIRUS BY THE FLUORESCENT ANTIBODY TECHNIQUE
Authors: E. Frederick Wheelock, Igor Tamm
Journal: The Journal of Experimental Medicine (1961)

A procedure has been developed for the determination of the concentration of infective Newcastle disease virus (NDV) based on the enumeration of singly infected and distributed HeLa cells which are visualized by staining with fluorescent antibody. Infective virus assayed by the fluorescent cell-counting procedure is expressed in terms of cell-infecting units (CIU). Adsorption of NDV to HeLa cell monolayers reached a plateau 1 to 1.5 hours after inoculation of coverslip cultures, and 12 per cent of the infective particles inoculated failed to adsorb. The half-life of NDV in protein-free Eagle's medium at 37 degrees C. was 2.1 hours. There was a linear relationship between virus concentration and the number of infected cells. The coefficient of variation of the mean of replicate determinations of infective NDV was 8.2 per cent. The distribution of single infected HeLa cells in the monolayer corresponded to the Poisson distribution. With NDV the cell-infecting unit (CIU) determined in HeLa cells is equivalent to the plaque-forming unit in chick embryo cells and the egg infective dose. In experiments on the mechanism of dissemination of NDV in monolayer cultures of HeLa cells, NDV was found to spread from cell to cell through the extracellular milieu.
Loss of Krüppel-like factor 6 cripples podocyte mitochondrial function
Authors: Jeffrey B. Kopp
Journal: Journal of Clinical Investigation (2015)

Krüppel-like factors (KLFs) are zinc finger transcription factors that share homology in three C-terminal zinc finger domains. KLF family members are expressed in most if not all tissues and have diverse roles in organismal development and cell differentiation, function, and death. The glomerular podocyte is particularly sensitive to mitochondrial dysfunction, as seen in various genetic disorders manifesting as progressive glomerulosclerosis. In this issue of the JCI, Mallipattu and coworkers show that KLF6 expression is reduced in mouse and human glomerular disease. Podocyte-specific deletion of Klf6 expression in mice leads to mitochondrial dysfunction and apoptosis, followed by glomerulosclerosis. This is the first demonstration that defective transcriptional regulation of nuclear-encoded mitochondrial genes can result in experimental glomerular disease.
Progress in the use of RNA interference as a therapy for chronic hepatitis B virus infection
Authors: Marc S Weinberg, Patrick Arbuthnot
Journal: Genome Medicine (2010)

Chronic infection with hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for hepatocellular carcinoma and cirrhosis. Current treatment regimens, which include interferon-alpha and nucleoside/nucleotide analogs, are only partially effective and new treatment methods remain an important objective. Harnessing the RNA interference (RNAi) pathway to achieve post-transcriptional silencing of rogue genetic elements is an exciting avenue for development of novel therapeutic strategies. The specific and potent suppression of HBV gene expression and replication is an attractive option as a novel and effective approach for the treatment of chronic HBV infection. However, despite significant and rapid progress, existing RNAi technologies require further refinement before clinical applications can be realized. Here, we review current efforts aimed at improving the efficiency of anti-HBV RNAi-based delivery systems, at limiting the toxicities associated with RNAi modalities and at preventing reactivation of viral replication. We discuss the progress towards clinical implementation of anti-HBV RNAi therapies.
Neuronal Calcium Sensor-1 Promotes Immature Heart Function and Hypertrophy by Enhancing Ca <sup>2+</sup> Signals
Authors: Tomoe Y. Nakamura, Andreas Jeromin, Katsuhiko Mikoshiba, Shigeo Wakabayashi
Journal: Circulation Research (2011)

Neuronal calcium sensor-1 (NCS-1) regulates various neuronal functions. Although it is expressed in the heart, very little is known about its cardiac functions.This study aimed to identify the physiological and pathological roles of NCS-1 in the heart.We characterized the cardiac functions of knockout mice (Ncs1(-/-)) and identified NCS-1 as a novel regulator of cardiac Ca(2+) signaling, specifically in immature and hypertrophic hearts. NCS-1 was highly expressed in young hearts, and its deletion decreased survival and contractile function in young mice. Intracellular Ca(2+) levels and sarcoplasmic reticulum Ca(2+) content were significantly lower in Ncs1(-/-) myocytes than in wild-type cells. This was due to reduced Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity in Ncs1(-/-) myocytes, which led to reduced sarcoplasmic reticulum Ca(2+) uptake and release. NCS-1 physically and functionally interacted with inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in the heart. In addition, IP(3)R stimulation resulted in phosphorylation of CaMKII-δ, which was enhanced by NCS-1 overexpression. These results suggest that a functional link exists between NCS-1, IP(3)R function, and CaMKII activation that may affect global Ca(2+) signals in the immature heart. Furthermore, NCS-1 was upregulated in hypertrophic hearts, and hormone-induced hypertrophy was largely prevented in Ncs1(-/-) hearts. Inhibitors of IP(3)Rs, CaMKII, and calcineurin all prevented NCS-1-induced hypertrophy, which suggests the involvement of these pathways.NCS-1 is an important regulator of immature heart function and hypertrophy, and it functions in part by promoting IP(3)R function, followed by CaMKII-dependent signal activation.
Validation of a Radiosensitivity Molecular Signature in Breast Cancer
Authors: Steven A. Eschrich, William J. Fulp, Yudi Pawitan, John A. Foekens, Marcel Smid, John W.M. Martens, Michelle Echevarria, Vidya Kamath, Ji-Hyun Lee, Eleanor E. Harris, Jonas Bergh, Javier F. Torres-Roca
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Previously, we developed a radiosensitivity molecular signature [radiosensitivity index (RSI)] that was clinically validated in 3 independent datasets (rectal, esophageal, and head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT)-treated breast cancer patients. Experimental Design: RSI was tested in 2 previously published breast cancer datasets. Patients were treated at the Karolinska University Hospital (n = 159) and Erasmus Medical Center (n = 344). RSI was applied as previously described. Results: We tested RSI in RT-treated patients (Karolinska). Patients predicted to be radiosensitive (RS) had an improved 5-year relapse-free survival when compared with radioresistant (RR) patients (95% vs. 75%, P = 0.0212), but there was no difference between RS/RR patients treated without RT (71% vs. 77%, P = 0.6744), consistent with RSI being RT-specific (interaction term RSI × RT, P = 0.05). Similarly, in the Erasmus dataset, RT-treated RS patients had an improved 5-year distant metastasis-free survival over RR patients (77% vs. 64%, P = 0.0409), but no difference was observed in patients treated without RT (RS vs. RR, 80% vs. 81%, P = 0.9425). Multivariable analysis showed RSI is the strongest variable in RT-treated patients (Karolinska, HR = 5.53, P = 0.0987, Erasmus, HR = 1.64, P = 0.0758) and in backward selection (removal α of 0.10), RSI was the only variable remaining in the final model. Finally, RSI is an independent predictor of outcome in RT-treated ER+ patients (Erasmus, multivariable analysis, HR = 2.64, P = 0.0085). Conclusions: RSI is validated in 2 independent breast cancer datasets totaling 503 patients. Including prior data, RSI is validated in 5 independent cohorts (621 patients) and represents, to our knowledge, the most extensively validated molecular signature in radiation oncology. Clin Cancer Res; 18(18); 5134–43. ©2012 AACR.
Diffusion-Weighted Magnetic Resonance Imaging for Predicting and Detecting Early Response to Chemoradiation Therapy of Squamous Cell Carcinomas of the Head and Neck
Authors: Sungheon Kim, Laurie Loevner, Harry Quon, Eric Sherman, Gregory Weinstein, Alex Kilger, Harish Poptani
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The aim of this study was to investigate the utility of apparent diffusion coefficient (ADC) for prediction and early detection of treatment response in head and neck squamous cell carcinomas (HNSCC). Experimental Design: Diffusion-weighted magnetic resonance imaging studies were performed on 40 patients with newly diagnosed HNSCC before, during, and after the end of chemoradiation therapy. Analysis was done on data from 33 patients after exclusion of 7 patients that had incomplete data. Results: Pretreatment ADC value of complete responders (1.04 ± 0.19 × 10−3 mm2/s) was significantly lower (P &amp;lt; 0.05) than that from partial responders (1.35 ± 0.30 × 10−3 mm2/s). A significant increase in ADC was observed in complete responders within 1 week of treatment (P &amp;lt; 0.01), which remained high until the end of the treatment. The complete responders also showed significantly higher increase in ADC than the partial responders by the first week of chemoradiation (P &amp;lt; 0.01). When pretreatment ADC value was used for predicting treatment response, the area under the receiver operating characteristic curve was 0.80 with a sensitivity of 65% and a specificity of 86%. However, change in ADC within the first week of chemoradiation therapy resulted in an area under the receiver operating characteristic curve of 0.88 with 86% sensitivity and 83% specificity for prediction of treatment response. Conclusions: These results suggest that ADC can be used as a marker for prediction and early detection of response to concurrent chemoradiation therapy in HNSCC.
Antibodies Against the Human Papillomavirus Type 16 Early Proteins in Human Sera: Correlation of Anti-E7 Reactivity With Cervical Cancer
Authors: I. Jochmus-Kudielka, A. Schneider, R. Braun, R. Kimmig, U. Koldovsky, K. E. Schneweis, K. Seedorf, L. Gissmann
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Antibodies Against the Human Papillomavirus Type 16 Early Proteins in Human Sera: Correlation of Anti-E7 Reactivity With Cervical Cancer Get access Ingrid Jochmus-Kudielka, Ingrid Jochmus-Kudielka * Deutsches Krebsforschungszentrum, Im Neuenheimer FeldHeidelberg, Federal Republic of Germany (FRG) *Ingrid Jochmus-Kudielka, M.D., Deutsches Krebsforschungszentrum. Im Neuenheimer Feld, 6900 Heidelberg, Federal Republic of Germany. Search for other works by this author on: Oxford Academic PubMed Google Scholar Achim Schneider, Achim Schneider Universitäts-FrauenklinikPrittwitzstrasse, Ulm, FRG Search for other works by this author on: Oxford Academic PubMed Google Scholar Rüdiger Braun, Rüdiger Braun Institut für Virologie, Im Neuenheimer FeldHeidelberg, Federal Republic of Germany (FRG) Search for other works by this author on: Oxford Academic PubMed Google Scholar Rainer Kimmig, Rainer Kimmig Universitäts-FrauenklinikGroβhadern, Marchioninistrasse, Munchen, FRG Search for other works by this author on: Oxford Academic PubMed Google Scholar Ursula Koldovsky, Ursula Koldovsky Universitäts-FrauenklinikMohrenstrasse, Düsseldorf, FRG Search for other works by this author on: Oxford Academic PubMed Google Scholar Karl Eduard Schneweis, Karl Eduard Schneweis Institut für Medizinische Mikrobiologie und ImmunologieVenusberg, Bonn, FRG Search for other works by this author on: Oxford Academic PubMed Google Scholar Klaus Seedorf, Klaus Seedorf Max-Planck-Institut für BiochemieAm Klopferspitz, Martin-sried, FRG Search for other works by this author on: Oxford Academic PubMed Google Scholar Lutz Gissmann Lutz Gissmann Deutsches Krebsforschungszentrum, Im Neuenheimer FeldHeidelberg, Federal Republic of Germany (FRG) Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 22, 15 November 1989, Pages 1698–1704, https://doi.org/10.1093/jnci/81.22.1698 Published: 15 November 1989 Article history Received: 17 July 1989 Revision received: 17 August 1989 Accepted: 31 August 1989 Published: 15 November 1989
Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART)
Authors: A. La Marca, G. Sighinolfi, D. Radi, C. Argento, E. Baraldi, A. C. Artenisio, G. Stabile, A. Volpe
Journal: Human Reproduction Update (2009)

In women, anti-Müllerian hormone (AMH) levels may represent the ovarian follicular pool and could be a useful marker of ovarian reserve. The clinical application of AMH measurement has been proposed in the prediction of quantitative and qualitative aspects in assisted reproductive technologies (ART). In men AMH is secreted in both the serum and seminal fluid. Its measurement may be useful in clinical evaluation of the infertile male. The PubMed database was systematically searched for studies published until the end of January 2009, search criteria relevant to AMH, ovarian reserve, ovarian response to gonadotrophin stimulation, spermatogenesis and azoospermia were used. AMH seems to be a better marker in predicting ovarian response to controlled ovarian stimulation than age of the patient, FSH, estradiol and inhibin B. A similar performance for AMH and antral follicular count has been reported. In clinical practice, AMH measurement may be useful in the prediction of poor response and cycle cancellation and also of hyper-response and ovarian hyperstimulation syndrome. In the male, the wide overlap of AMH values between controls and infertile men precludes this hormone from being a useful marker of spermatogenesis. As AMH may permit the identification of both the extremes of ovarian stimulation, a possible role for its measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in ovarian reserve testing. Regarding the role of AMH in the evaluation of infertile men, AMH as single marker of spermatogenesis does not seem to reach a satisfactory clinical utility.
Women's groups' perceptions of maternal health issues in rural Malawi
Authors: Mikey Rosato, Charles W Mwansambo, Peter N Kazembe, Tambosi Phiri, Queen S Soko, Sonia Lewycka, Beata E Kunyenge, Stefania Vergnano, David Osrin, Marie-Louise Newell, Anthony M de L Costello
Journal: The Lancet (2006)
Leukocytapheresis treatment for pyoderma gangrenosum
Authors: E. Fujimoto, N. Fujimoto, K. Kuroda, S. Tajima
Journal: British Journal of Dermatology (2004)

Journal Article Leukocytapheresis treatment for pyoderma gangrenosum Get access E. Fujimoto, E. Fujimoto Department of Dermatology, National Defence Medical College, 3‐2 Namiki, Tokorozawa, Saitama 359‐8513, Japan Eita Fujimoto. E‐mail: srg1936@gr.ndmc.ac.jp Search for other works by this author on: Oxford Academic Google Scholar N. Fujimoto, N. Fujimoto Department of Dermatology, National Defence Medical College, 3‐2 Namiki, Tokorozawa, Saitama 359‐8513, Japan Search for other works by this author on: Oxford Academic Google Scholar K. Kuroda, K. Kuroda Department of Dermatology, National Defence Medical College, 3‐2 Namiki, Tokorozawa, Saitama 359‐8513, Japan Search for other works by this author on: Oxford Academic Google Scholar S. Tajima S. Tajima Department of Dermatology, National Defence Medical College, 3‐2 Namiki, Tokorozawa, Saitama 359‐8513, Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 151, Issue 5, 1 November 2004, Pages 1090–1092, https://doi.org/10.1111/j.1365-2133.2004.06249.x Published: 01 November 2004 Article history Accepted: 29 March 2004 Published: 01 November 2004