tbuckley/cabot-search huggingface dataset:
Acceleration of Smad2 and Smad3 Phosphorylation via c-Jun NH2-Terminal Kinase during Human Colorectal Carcinogenesis
Authors: Hideo Yamagata, Koichi Matsuzaki, Shigeo Mori, Katsunori Yoshida, Yoshiya Tahashi, Fukiko Furukawa, Go Sekimoto, Toshihiko Watanabe, Yoshiko Uemura, Noriko Sakaida, Kazuhiko Yoshioka, Yasuo Kamiyama, Toshihito Seki, Kazuichi Okazaki
Journal: Cancer Research (2005)

Conversion of normal epithelial cells to tumors is associated with a shift in transforming growth factor-beta (TGF-beta) function: reduction of tumor suppressor activity and increase of oncogenic activity. However, specific mechanisms of this functional alteration during human colorectal carcinogenesis remain to be elucidated. TGF-beta signaling involves Smad2/3 phosphorylated at linker regions (pSmad2/3L) and COOH-terminal regions (pSmad2/3C). Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and that pSmad2/3C were located predominantly in their nuclei. However, the linker regions of Smad2 and Smad3 were phosphorylated in 31 sporadic colorectal adenocarcinomas. In particular, late-stage invasive and metastatic cancers typically showed a high degree of phosphorylation of Smad2/3L. Their extent of phosphorylation in 11 adenomas was intermediate between those in normal epithelial cells and adenocarcinomas. Whereas pSmad2L remained in the cytoplasm, pSmad3L was located exclusively in the nuclei of Ki-67-immunoreactive adenocarcinomas. In contrast, pSmad3C gradually decreased as the tumor stage progressed. Activated c-Jun NH(2)-terminal kinase in cancers could directly phosphorylate Smad2/3L. Although Mad homology 2 region sequencing in the Smad4 gene revealed a G/A substitution at codon 361 in one adenocarcinoma, the mutation did not correlate with phosphorylation. No mutations in the type II TGF-beta receptor and Smad2 genes were observed in the tumors. In conclusion, pSmad3C, which favors tumor suppressor activity of TGF-beta, was found to decrease, whereas c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence.
Quantitative Study of Rauscher Virus Inactivation by Various Physical and Chemical Agents
Authors: J. P. Levy, S. Oppenheim, Ph. Chenaille, D. Silvestre, A. Tavitian, M. Boiron
Journal: JNCI Journal of the National Cancer Institute (1967)

The inactivation curves of Rauscher murine leukemia virus (RV) submitted to various physicochemical agents have been studied with repeated titrations. The agents involved were: temperature, pH, molarity, ionic composition of the medium, mechanical factors, ultraviolet light, trypsin, and formalin. They were classified into three groups: 1) factors rapidly inactivating RV: 56 C, ultraviolet light, mechanical agitation, pH 3, 0.50% trypsin, and 1/400 formalin; 2) agents inactivating RV with a lower rate: 37 C, 20 C, high molarity, NaCI 0.14 M, pH 4 and 5, formalin 1/1000 or 1/4000; 3) factors inducing no or little inactivation: 4C,–170C, low molarity, pH 9.3.
Collecting duct–specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance
Authors: Isabelle Rubera, Johannes Loffing, Lawrence G. Palmer, Gustavo Frindt, Nicole Fowler-Jaeger, Daniel Sauter, Tom Carroll, Andrew McMahon, Edith Hummler, Bernard C. Rossier
Journal: Journal of Clinical Investigation (2003)

Aldosterone controls the final sodium reabsorption and potassium secretion in the kidney by regulating the activity of the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). ASDN consists of the last portion of the distal convoluted tubule (late DCT), the connecting tubule (CNT), and the collecting duct (CD) (i.e., the cortical CD [CCD] and the medullary CD [MCD]). It has been proposed that the control of sodium transport in the CCD is essential for achieving sodium and potassium balance. We have tested this hypothesis by inactivating the α subunit of ENaC in the CD but leaving ENaC expression in the late DCT and CNT intact. Under salt restriction or under aldosterone infusion, whole-cell voltage clamp of principal cells of CCD showed no detectable ENaC activity, whereas large amiloride-sensitive currents were observed in control littermates. The animals survive well and are able to maintain sodium and potassium balance, even when challenged by salt restriction, water deprivation, or potassium loading. We conclude that the expression of ENaC in the CD is not a prerequisite for achieving sodium and potassium balance in mice. This stresses the importance of more proximal nephron segments (late DCT/CNT) to achieve sodium and potassium balance.
Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes.
Authors: L S Wicker, M C Appel, F Dotta, A Pressey, B J Miller, N H DeLarato, P A Fischer, R C Boltz, L B Peterson
Journal: The Journal of Experimental Medicine (1992)

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the alpha and beta chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing beta cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2b (NOD.H-2b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2b strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2+ T cells and B220+ B cells. In addition, autoantibodies are present in NOD.H-2b mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only approximately 3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis greater than cyclophosphamide-induced diabetes greater than spontaneous diabetes.
Restriction of Dietary Glycotoxins Reduces Excessive Advanced Glycation End Products in Renal Failure Patients
Authors: Jaime Uribarri, Melpomeni Peppa, Weijing Cai, Teresia Goldberg, Min Lu, Cijiang He, Helen Vlassara
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Advanced glycation endproduct (AGE) levels are elevated in renal failure patients and may contribute to the excessive cardiovascular disease in this population. Diet-derived AGE are major contributors to the total body AGE pool. It was postulated that a reduction in dietary AGE intake might impact on the high circulating AGE levels in renal failure patients. Twenty-six nondiabetic renal failure patients on maintenance peritoneal dialysis were randomized to either a high or a low AGE diet for 4 wk. Three-day dietary records, fasting blood, 24-h urine, and dialysis fluid collections were obtained at baseline and end of study. AGE levels were determined by ELISA for N<sup>ε</sup>-carboxymethyl-lysine (CML) and methylglyoxal-derivatives (MG). Eighteen patients completed the study. Low dietary AGE intake decreased serum CML (34%; <i>P</i> &lt; 0.002), serum MG (35%; <i>P</i> &lt; 0.008), CML-LDL (28%; <i>P</i> &lt; 0.011), CML-apoB (25%; <i>P</i> &lt; 0.028), dialysate CML (39%; <i>P</i> &lt; 0.03), and dialysate MG output (40%; <i>P</i> &lt; 0.04). High dietary AGE intake increased serum CML (29%; <i>P</i> &lt; 0.028), serum MG (26%; <i>P</i> &lt; 0.09), CML-LDL (50%; <i>P</i> &lt; 0.011), CML-apoB (67%; <i>P</i> &lt; 0.028), and dialysate CML output (27%; <i>P</i> &lt; 0.01). Serum AGE correlated with BUN (<i>r</i> = 0.6, <i>P</i> &lt; 0.002 for CML; <i>r</i> = 0.4, <i>P</i> &lt; 0.05 for MG), serum creatinine (<i>r</i> = 0.76, <i>P</i> &lt; 0.05 for CML; <i>r</i> = 0.55, <i>P</i> &lt; 0.004 for MG), total protein (<i>r</i> = 0.4, <i>P</i> &lt; 0.05 for CML; <i>r</i> = 0.4, <i>P</i> &lt; 0.05 for MG), albumin (<i>r</i> = 0.4, <i>P</i> &lt; 0.02 for CML; <i>r</i> = 0.4, <i>P</i> &lt; 0.05 for MG), and phosphorus (<i>r</i> = 0.5, <i>P</i> &lt; 0.006 for CML; <i>r</i> = 0.5, <i>P</i> &lt; 0.01 for MG). It is concluded that dietary glycotoxins contribute significantly to the elevated AGE levels in renal failure patients. Moreover, dietary restriction of AGE is an effective and feasible method to reduce excess toxic AGE and possibly cardiovascular associated mortality. E-mail: jaime.uribarri@mssm.edu
HUMAN HERPESVIRUS 6 IN LYMPH NODES
Authors: Y. Eizuru, T. Minematsu, Y. Minamishima, M. Kikuchi, K. Yamanishi, M. Takahashi, T. Kurata, BettinaBorisch Chappuis, Klaus Ellinger, Franz Neipel, Thomas Kirchner, Peter Kujath, Bernhard Fleckenstein, HansKonrad Müller-Hermelink
Journal: The Lancet (1989)
Coordinated Regulation of Polycomb Group Complexes through microRNAs in Cancer
Authors: Qi Cao, Ram-Shankar Mani, Bushra Ateeq, Saravana M. Dhanasekaran, Irfan A. Asangani, John R. Prensner, Jung H. Kim, J. Chad Brenner, Xiaojun Jing, Xuhong Cao, Rui Wang, Yong Li, Arun Dahiya, Lei Wang, Mithil Pandhi, Robert J. Lonigro, Yi-Mi Wu, Scott A. Tomlins, Nallasivam Palanisamy, Zhaohui Qin, Jindan Yu, Christopher A. Maher, Sooryanarayana Varambally, Arul M. Chinnaiyan
Journal: Cancer Cell (2011)
Gene therapy for colorectal cancer by an oncolytic adenovirus that targets loss of the insulin-like growth factor 2 imprinting system
Authors: Zhen-Lin Nie, Yu-Qin Pan, Bang-Shun He, Ling Gu, Li-Ping Chen, Rui Li, Ye-Qiong Xu, Tian-Yi Gao, Guo-Qi Song, Andrew R Hoffman, Shu-Kui Wang, Ji-Fan Hu
Journal: Molecular Cancer (2012)

Abstract Background Colorectal cancer is one of the most common malignant tumors worldwide. Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) gene is an epigenetic abnormality observed in human colorectal neoplasms. Our aim was to investigate the feasibility of using the IGF2 imprinting system for targeted gene therapy of colorectal cancer. Results We constructed a novel oncolytic adenovirus, Ad315-E1A, and a replication-deficient recombinant adenovirus, Ad315-EGFP, driven by the IGF2 imprinting system by inserting the H19 promoter, CCCTC binding factor, enhancer, human adenovirus early region 1A (E1A) and enhanced green fluorescent protein (EGFP) reporter gene into a pDC-315 shuttle plasmid. Cell lines with IGF2 LOI (HCT-8 and HT-29), which were infected with Ad315-EGFP, produced EGFP. However, no EGFP was produced in cell lines with maintenance of imprinting (HCT116 and GES-1). We found that Ad315-E1A significantly decreased cell viability and induced apoptosis only in LOI cell lines in vitro. In addition, mice bearing HCT-8-xenografted tumors, which received intratumoral administration of the oncolytic adenovirus, showed significantly reduced tumor growth and enhanced survival. Conclusions Our recombinant oncolytic virus targeting the IGF2 LOI system inhibits LOI cell growth in vitro and in vivo, and provides a novel approach for targeted gene therapy.
The pennsylvania hemophilia program 1973–1978
Authors: M. Elaine Eyster, Jessica H. Lewis, Sandor S. Shapiro, Frances Gill, Mehdi Kajani, David Prager, Isaac Djerassi, Samuel Rice, Charles Lusch, Anne Keller
Journal: American Journal of Hematology (1980)

Abstract In Pennsylvania, the prevalence of hemophilia is one per 10,000 males. Factor VIII deficiency is five times more frequent than Factor IX deficiency, and 34% of the patients have no relatives affected with the disease. The mean age is 23 years old, and 50% of the patients are less than 20 years old. Approximately one‐third of the patients with Factor VIII deficiency and one fourth of the patients with Factor IX deficiency have levels of &lt; 0.01 μ/ml. By clinical criteria, 55% of those with Factor VIII deficiency are severe compared to 45% of those with Factor IX deficiency. Factor VIII‐deficient patients are treated an average of 18 times per year compared to ten times per year for patients with Factor IX deficiency. Hemarthroses account for 70% of the hemorrhages treated and for 40% of the concentrate usage. Home therapy patients use an average of 45,950 Factor VIII units per year at a cost of $4,170 per patient and their use accounts for 60% of the total Factor VIII usage of 1.7 million units. Less than five days per patient per year are lost from school or work because of bleeding, and patients are hospitalized for bleeding an average of only two to three days per patient per year. Adverse immediate reactions to therapy are infrequent. Five percent of patients have persistence of the hepatitis B virus, and 7.5% have inhibitors. The mortality rate is 0.04% per year, with half of the deaths being hemophilia‐related.
Growth Arrest–Specific Protein 6 Is Hepatoprotective Against Murine Ischemia/Reperfusion Injury
Authors: Laura Llacuna, Cristina Bárcena, Lola Bellido-Martín, Laura Fernández, Milica Stefanovic, Montserrat Marí, Carmen García-Ruiz, José C. Fernández-Checa, Pablo García de Frutos, Albert Morales
Journal: Hepatology (2010)

Growth arrest–specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild-type (WT) mice, Gas6 −/− mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hours of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AKT) phosphorylation in WT mice but not in Gas6 −/− mice without significant changes in c-Jun N-terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin-1β (IL-1β) and tumor necrosis factor (TNF) messenger RNA levels were higher in Gas6 −/− mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia-induced cell death, whereas GAS6 diminished lipopolysaccharide-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R-induced liver damage but also attenuated hepatic damage in WT mice after I/R. Conclusion: Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage. (Hepatology 2010;)
Effects of cycle length on atrial vulnerability.
Authors: C R Wyndham, F Amat-y-Leon, D Wu, P Denes, R Dhingra, R Simpson, K M Rosen
Journal: Circulation (1977)

The effect of cycle length on atrial vulnerability was studied in 14 patients manifesting reproducible repetitive atrial firing during atrial extra-stimulus (A2) testing. Repetitive atrial firing was defined as the occurrence of two or more premature atrial responses with return cycle (A2-A3) of 250 msec or less and subsequent mean cycle length of 300 msec or less, following A2. The zone of repetitive atrial firing could be defined in terms of its longest and shortest A1-A2 coupling intervals. Each patient was tested at a long cycle length (CL1) (mean 884 msec) and a short cycle length (CL2) (mean 557 msec). CL1 was sinus rhythm and CL2, an atrial paced rhythm. Repetitive atrial firing occurred in two patients at CL1 and in all patients at CL2. Of the former two patients (group 2), the zone of repetitive atrial firing was markedly widened in one at CL2 due to a shortening of atrial functional refractory period (FRP) at CL2. In the other, zone of repetitive atrial firing could not be totally defined due to induction of sustained atrial flutter preventing definition of atrial FRP. The occurrence of repetitive atrial firing at only CL2 in 12 patients (group 1) reflected: 1) a shortening of atrial FRP from 294 +/- 11 msec at CL1 to 242 +/- 10 msec at CL2 (mean +/- SEM; P less than 0.01), allowing delivery of A2 at shorter coupling intervals (9); 2) the new occurrence of repetitive atrial firing at A1-A2 coupling intervals achievable at both cycle lengths (1); or 3) both effects (2). In conclusion, decrease of cycle length potentiated atrial vulnerability. This demonstration implies that atrial pacing could potentiate occurrence of paroxysmal atrial fibrillation or flutter.
Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure
Authors: T. Douglas Bradley, Alexander G. Logan, R. John Kimoff, Frédéric Sériès, Debra Morrison, Kathleen Ferguson, Israel Belenkie, Michael Pfeifer, John Fleetham, Patrick Hanly, Mark Smilovitch, George Tomlinson, John S. Floras
Journal: New England Journal of Medicine (2005)

The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure.
Disruption of Fibroblast Growth Factor Signal Pathway Inhibits the Growth of Synovial Sarcomas: Potential Application of Signal Inhibitors to Molecular Target Therapy
Authors: Tatsuya Ishibe, Tomitaka Nakayama, Takeshi Okamoto, Tomoki Aoyama, Koichi Nishijo, Kotaro Roberts Shibata, Yasuko Shima, Satoshi Nagayama, Toyomasa Katagiri, Yusuke Nakamura, Takashi Nakamura, Junya Toguchida
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Synovial sarcoma is a soft tissue sarcoma, the growth regulatory mechanisms of which are unknown. We investigated the involvement of fibroblast growth factor (FGF) signals in synovial sarcoma and evaluated the therapeutic effect of inhibiting the FGF signal. Experimental Design: The expression of 22 FGF and 4 FGF receptor (FGFR) genes in 18 primary tumors and five cell lines of synovial sarcoma were analyzed by reverse transcription-PCR. Effects of recombinant FGF2, FGF8, and FGF18 for the activation of mitogen-activated protein kinase (MAPK) and the growth of synovial sarcoma cell lines were analyzed. Growth inhibitory effects of FGFR inhibitors on synovial sarcoma cell lines were investigated in vitro and in vivo. Results: Synovial sarcoma cell lines expressed multiple FGF genes especially those expressed in neural tissues, among which FGF8 showed growth stimulatory effects in all synovial sarcoma cell lines. FGF signals in synovial sarcoma induced the phosphorylation of extracellular signal–regulated kinase (ERK1/2) and p38MAPK but not c-Jun NH2-terminal kinase. Disruption of the FGF signaling pathway in synovial sarcoma by specific inhibitors of FGFR caused cell cycle arrest leading to significant growth inhibition both in vitro and in vivo. Growth inhibition by the FGFR inhibitor was associated with a down-regulation of phosphorylated ERK1/2 but not p38MAPK, and an ERK kinase inhibitor also showed growth inhibitory effects for synovial sarcoma, indicating that the growth stimulatory effect of FGF was transmitted through the ERK1/2. Conclusions: FGF signals have an important role in the growth of synovial sarcoma, and inhibitory molecules will be of potential use for molecular target therapy in synovial sarcoma.
Comparative safety of anesthetic type for hip fracture surgery in adults: retrospective cohort study
Authors: E. Patorno, M. D. Neuman, S. Schneeweiss, H. Mogun, B. T. Bateman
Journal: BMJ (2014)

<b>Objective</b> To evaluate the effect of anesthesia type on the risk of in-hospital mortality among adults undergoing hip fracture surgery in the United States. <b>Design</b> Retrospective cohort study. <b>Setting</b> Premier research database, United States. <b>Participants</b> 73 284 adults undergoing hip fracture surgery on hospital day 2 or greater between 2007 and 2011. Of those, 61 554 (84.0%) received general anesthesia, 6939 (9.5%) regional anesthesia, and 4791 (6.5%) combined general and regional anesthesia. <b>Main outcome measure</b> In-hospital all cause mortality. <b>Results</b> In-hospital deaths occurred in 1362 (2.2%) patients receiving general anesthesia, 144 (2.1%) receiving regional anesthesia, and 115 (2.4%) receiving combined anesthesia. In the multivariable adjusted analysis, when compared with general anesthesia the mortality risk did not differ significantly between regional anesthesia (risk ratio 0.93, 95% confidence interval 0.78 to 1.11) or combined anesthesia (1.00, 0.82 to 1.22). A mixed effects analysis accounting for differences between hospitals produced similar results: compared with general anesthesia the risk from regional anesthesia was 0.91 (0.75 to 1.10) and from combined anesthesia was 0.98 (0.79 to 1.21). Findings were also consistent in subgroup analyses. <b>Conclusions</b> In this large nationwide sample of hospital admissions, mortality risk did not differ significantly by anesthesia type among patients undergoing hip fracture surgery. Our results suggest that if the previously posited beneficial effect of regional anesthesia on short term mortality exists, it is likely to be more modest than previously reported.
Trends in mild, moderate, and severe stunting and underweight, and progress towards MDG 1 in 141 developing countries: a systematic analysis of population representative data
Authors: Gretchen A Stevens, Mariel M Finucane, Christopher J Paciorek, Seth R Flaxman, Richard A White, Abigail J Donner, Majid Ezzati
Journal: The Lancet (2012)
The Deiodination of the Iodothyronines and of Their Derivatives in Man
Authors: DENNIS ENGLER, ALBERT G. BURGER
Journal: Endocrine Reviews (1984)

THYROIDAL secretion is the only source of thyroxine (T4) in the human systemic circulation, and in euthyroid man, T4 is the main secretory product of the gland. The metabolic fate of the hormone once thyroidal secretion has occurred is complex and involves deiodination, deamination and decarboxylation of the amino acid side chain, and esterification of the phenolic hydroxyl group with glucuronic or sulfuric acid. These pathways are not to be considered as mutually exclusive, but are interrelated in an exceedingly complex manner. Deiodination of T4 is the most important degradative pathway and accounts for up to 85% of the disposal of the hormone (1–3). At least two major mechanisms exist within the peripheral tissues by which the iodine atoms may be removed from the molecule. Of these, monodeiodination is quantitatively the most important pathway and has been subjected to the most intensive investigation.