tbuckley/cabot-search huggingface dataset:
Developmental Changes in Ionic Channel Activity in the Embryonic Murine Heart
Authors: M.P. Davies, R.H. An, P. Doevendans, S. Kubalak, K.R. Chien, R.S. Kass
Journal: Circulation Research (1996)

We have isolated murine embryonic atrial and ventricular cells derived from timed-pregnant females at different periods and used patch-clamp procedures to investigate age- and chamber-specific expression of ionic channels in the developing fetal mouse. Our data indicate that L-type Ca2+ channels play a dominant role in excitation during early murine cardiac embryogenesis and that Na+ channel expression increases dramatically just before birth. K+ channel expression is particularly sensitive to changes during development. Neither atrial nor ventricular cells express a slowly activating component of delayed rectification (IKs) until just before birth, and inwardly rectifying channel activity, associated with determination of cellular resting potential, is not markedly apparent until late stages of embryogenesis. Instead, we find robust expression of the ATP-regulated K+ channel at early and late states of embryonic development, which may indicate a novel functional role for this channel during morphogenesis of the heart. These results have important implications for the physiology and development of the murine cardiac conduction system and will also serve as a baseline for future studies designed to investigate developmental changes of ion channel expression in the myocardium of both wild-type and genetically modified mice.
Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL
Authors: Sandrine Le Noir, Raouf Ben Abdelali, Marc Lelorch, Julie Bergeron, Stephanie Sungalee, Dominique Payet-Bornet, Patrick Villarèse, Arnaud Petit, Céline Callens, Ludovic Lhermitte, Laurence Baranger, Isabelle Radford-Weiss, Marie-José Grégoire, Hervé Dombret, Norbert Ifrah, Salvatore Spicuglia, Serge Romana, Jean Soulier, Bertrand Nadel, Elizabeth Macintyre, Vahid Asnafi
Journal: Blood (2012)
Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents
Authors: Muling Mao, Feng Tian, John M. Mariadason, Chun C. Tsao, Robert Lemos, Farshid Dayyani, Y.N. Vashisht Gopal, Zhi-Qin Jiang, Ignacio I. Wistuba, Xi M. Tang, William G. Bornman, Gideon Bollag, Gordon B. Mills, Garth Powis, Jayesh Desai, Gary E. Gallick, Michael A. Davies, Scott Kopetz
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAFV600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models. Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification. Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. Clin Cancer Res; 19(3); 657–67. ©2012 AACR.
Cross-Genome Screening of Novel Sequence-Specific Non-LTR Retrotransposons: Various Multicopy RNA Genes and Microsatellites Are Selected as Targets
Authors: K. K. Kojima
Journal: Molecular Biology and Evolution (2003)

Although most LINEs (long interspersed nuclear elements), which are autonomous non–long-terminal-repeat retrotransposons, are inserted throughout the host genome, three groups of LINEs, the early-branched group, the Tx group, and the R1 clade, are inserted into specific sites within the target sequence. We previously characterized the sequence specificity of the R1 clade elements. In this study, we screened the other two groups of sequence-specific LINEs from public DNA databases, reconstructed elements from fragmented sequences, identified their target sequences, and analyzed them phylogenetically. We characterized 13 elements in the early-branched group and 13 in the Tx group. In the early-branched group, we identified R2 elements from sea squirts and zebrafish in this study, although R2 has not been characterized outside the arthropod group to date. This is the first evidence of cross-phylum distribution of sequence-specific LINEs. The Dong element also occurs across phyla, among arthropods and mollusks. In the Tx group, we characterized five novel sequence-specific families: Kibi for TC repeats, Koshi for TTC repeats, Keno for the U2 snRNA gene, Dewa for the tRNA tandem arrays, and Mutsu for the 5S rRNA gene. Keno and Mutsu insert into the highly conserved region within small RNA genes and destroy the targets. Several copies of Dewa insert different positions of tRNA tandem array, which indicates a certain "site specifier" other than sequence-specific endonuclease. In all three groups, LINEs specific for the rRNA genes or microsatellites can occur as multiple families in one organism. This indicates that the copy number of a target sequence is the primary factor to restrict the variety of sequence specificity of LINEs.
Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex.
Authors: R M Green, G L Stiles
Journal: Journal of Clinical Investigation (1986)

Caffeine consumption causes significant physiologic effects due to its antagonism of adenosine receptors. The A1 adenosine receptor is coupled in an inhibitory manner to adenylate cyclase. To study the effects of chronic caffeine ingestion, rats were provided with 0.1% caffeine drinking solution for 28 d. The A1 adenosine receptor agonist radioligand [3H]phenylisopropyladenosine identifies two affinity states in control rat cerebral cortex membranes with a high affinity dissociation constant (KH) of 0.40 +/- 0.08 nM and low affinity dissociation constant (KL) of 13.7 +/- 3.9 nM, with 33% of the receptors in the high affinity state. In membranes from caffeine-treated animals, all of the A1 receptors are shifted to the high affinity state with a dissociation constant (KD) of 0.59 +/- 0.06 nM. Guanylyl-imidodiphosphate (10(-4) M) decreases binding by 43% in control membrane, with no change in KH or KL, while membrane binding in caffeine-treated animals decreases by 45% with a threefold shift in KD to 1.5 +/- 0.3 nM. Concomitant with the enhanced high affinity A1 receptor state and increased sensitivity to guanine nucleotides, membranes from treated animals show a 35% enhancement in (-)-N6-(R-phenylisopropyl)adenosine-mediated inhibition of adenylate cyclase compared with controls (P less than 0.03). Photoaffinity crosslinking the receptors with [125I]N6-2-(3-iodo-4-aminophenyl)ethyladenosine reveals that A1 receptors from both groups migrate as Mr 38,000 proteins. beta-adrenergic receptor binding with [125I]iodocyanopindolol shows a decrease in the number of beta-receptors from 233 +/- 7 fmol/mg protein in control membranes to 190 +/- 10 fmol/mg protein in treated membranes (P = 0.01). These data indicate that the adenosine receptor antagonist, caffeine, induces a compensatory sensitization of the A1 receptor-adenylate cyclase system and downregulation of beta-adrenergic receptors, and provides a molecular mechanism for the caffeine withdrawal syndrome.
Pre-eclampsia and cardiovascular disease
Authors: C. W. Chen, I. Z. Jaffe, S. A. Karumanchi
Journal: Cardiovascular Research (2014)

Heart disease is the leading cause of death in women in all countries. A history of pre-eclampsia, one of the most deadly hypertensive complications of pregnancy, increases cardiovascular risk by two to four times, which is comparable with the risk induced by smoking. Substantial epidemiological data reveal that pregnancy-related hypertensive complications are associated with a predisposition to chronic hypertension, premature heart attacks, strokes, and renal complications. In this review, we summarize clinical studies that demonstrate this relationship and also discuss the pathogenesis of these long-term complications of pre-eclampsia. Future studies should focus on strategies to prevent the progression of cardiovascular disease in women exposed to pre-eclampsia, thereby improving long-term cardiovascular health in women.
Immunoglobulin allotype Gm(1,2;21) in ankylosing spondylitis with peripheral arthritis.
Authors: R Mierau, C.A von Mühlen, H Zarnowski, E Genth, P.W Hartl
Journal: Annals of the Rheumatic Diseases (1988)

Frequencies of immunoglobulin G (Gm) allotypes were determined in 240 patients with ankylosing spondylitis (AS). The uncommon phenotype Gm(1,2;21) was increased in frequency in 55 patients with AS and peripheral arthritis (14.5% v 3.5% of healthy blood donors; p less than 0.05). In 16 patients with arthritis only of wrist/hand or ankle/forefoot, or both, the Gm(1,2;21) frequency was even higher (31.3%; p less than 0.0005). Patients with AS negative for the HLA antigen B27 (n = 28) differed from the B27 positive patients (n = 205) with regard to the frequency of the Gm(1,2,3;5,21) phenotype (39.3% v 9.3%; p less than 0.0005). These findings support the notion of genetic heterogeneity among patients with AS.
Genetics of New-Onset Diabetes after Transplantation
Authors: Jennifer A. McCaughan, Amy Jayne McKnight, Alexander P. Maxwell
Journal: Journal of the American Society of Nephrology (2013)

New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic β-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in β-cell apoptosis. These results corroborate recent clinical evidence implicating β-cell dysfunction in the pathophysiology of new-onset diabetes after transplantation and support the pursuit of therapeutic strategies to protect β cells in the post-transplant period.
Transient Receptor Potential A1 and Cannabinoid Receptor Activity in Human Normal and Hyperplastic Prostate: Relation to Nerves and Interstitial Cells
Authors: Christian Gratzke, Philipp Weinhold, Oliver Reich, Michael Seitz, Boris Schlenker, Christian G. Stief, Karl-Erik Andersson, Petter Hedlund
Journal: European Urology (2009)
New York City Health and Nutrition Examination Survey
Authors: Peter W. F. Wilson, K. M. Venkat Narayan
Journal: Diabetes Care (2008)

Thorpe et al. (1) are to be commended for undertaking a comprehensive evaluation of glycemic status in adults from New York City. Their article represents the efforts of a health and nutrition survey within a large metropolitan area, the New York City (NYC) Health and Nutrition Examination Survey (HANES), and provides very useful information concerning the prevalence of hyperglycemia and control of diabetes in an urban setting. Such efforts have been undertaken in the U.S. by way of national surveys of the populace in terms of lifestyle behaviors and risk factor levels over several decades (2–4), but a survey that used population-based methods in a single city is new, provides valuable information, and may well serve as a model for the future.

The study by Thorpe et al. reports that diabetes affects 12.5% of adults living in New York City and that the frequency of pre-diabetes, which was previously called “impaired fasting glucose,” was almost double that (23.5%). Using the 1997 American Diabetes Association criteria for diabetes and data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the investigators reported that the prevalence of impaired fasting glucose was 6.9%, undiagnosed diabetes 2.8%, and diagnosed diabetes 5.1% (5). Previously, Harris et al. expressed concern that the prevalence of diabetes in American adults aged 40–74 years had increased from 8.9% in 1976–1980 to 12.3% in 1988–1994. The 1999–2003 NHANES estimates of diabetes are generally 6.6% at ages 40–59 years and ∼15.5% after age 60 years, which suggests that the national prevalence of diabetes after age 40 …
Pulmonary function in sickle cell disease with or without acute chest syndrome
Authors: F Santoli, F Zerah, N Vasile, D Bachir, F Galacteros, G Atlan
Journal: European Respiratory Journal (1998)

Recurrent acute chest syndrome (ACS) has been suggested as a risk factor for chronic lung dysfunction in sickle cell disease. To investigate this hypothesis, lung function tests were performed in 49 sickle cell disease outpatients whose condition was stable, including 23 patients with a history of two to four episodes of ACS (ACS+) and 26 with no history of ACS (ACS-). The two groups were comparable regarding the sex ratio, body mass index, smoking history, physical characteristics, clinical history and usual lung function tests. Respiratory resistance (Rrs), measured using the forced oscillation technique, increased with the number of ACS episodes (r=0.55, p<0.0001) and a significant relationship was observed between Rrs as an independent variable and the expiratory flow rates at 25, 50 and 25-75% of the forced vital capacity as explanatory variables (r= 0.36, p<0.02; r=0.35, p<0.02; and r=0.4, p<0.006, respectively), with higher Rrs being associated with lower expiratory flow rates. The transfer factor (TL,CO) and transfer coefficient (KCO) for CO were significantly higher in the ACS+ group than in the ACS-group (TL,CO=84+/-4 versus 71+/-3%, p<0.004 and KCO=102+/-5 versus 90+/-3%, p<0.05, respectively). The data demonstrate that obstructive lung dysfunction is fairly common in sickle cell disease and suggest that recurrent acute chest syndrome may contribute specific obstructive defects. The increase in respiratory resistance associated with acute chest syndrome was accompanied by an increase in diffusion capacity, suggesting that it may have been related to an increase in lung blood volume.
Hepatocyte-specific<i>Ptpn6</i>deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: Potential role of PPARγ
Authors: Elaine Xu, Marie-Pier Forest, Michael Schwab, Rita Kohen Avramoglu, Emmanuelle St-Amand, Annabelle Z. Caron, Kerstin Bellmann, Michaël Shum, Gregory Voisin, Marilene Paquet, Alain Montoudis, Emile Lévy, Katherine A. Siminovitch, Benjamin G. Neel, Nicole Beauchemin, André Marette
Journal: Hepatology (2013)

Hepatocyte-specific Shp1 knockout mice ( Ptpn6H-KO ) are protected from hepatic insulin resistance evoked by high-fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that Ptpn6H-KO mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD-fed Ptpn6f/f counterparts. The livers from HFD-fed Ptpn6H-KO mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD-fed Ptpn6H-KO liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD-fed Ptpn6f/f littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up-regulation of peroxisome proliferator-activated receptor gamma ( PPARγ ) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell-autonomous manner. Conclusion : These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity. (Hepatology 2014;59:1803–1815)
Power-Law Behavior of Beat-Rate Variability in Monolayer Cultures of Neonatal Rat Ventricular Myocytes
Authors: Jan P. Kucera, Marc O. Heuschkel, Philippe Renaud, Stephan Rohr
Journal: Circulation Research (2000)

It is known that extracardiac factors (nervous, humoral, and hemodynamic) participate in the power-law behavior of heart-rate variability. To assess whether intrinsic properties of cardiac tissue might also be involved, beat-rate variability was studied in spontaneously beating cell cultures devoid of extracardiac influences. Extracellular electrograms were recorded from monolayer cultures of neonatal rat ventricular myocytes under stable incubating conditions for up to 9 hours. The beat-rate time series of these recordings were examined in terms of their Fourier spectra and their Hurst scaling exponents. A non-0 Hurst exponent was found in 21 of 22 preparations (0.29+/-0.09; range, 0.11 to 0.45), indicating the presence of fractal self-similarity in the beat-rate time series. The same preparations exhibited power-law behavior of the power spectra with a power-law exponent of -1.36+/-0.24 (range, -1.04 to -1.96) in the frequency range of 0.001 to 1 Hz. Furthermore, it was found that the power-law exponent was nonstationary over time. These results indicate that the power-law behavior of heart-rate variability is determined not only by extracardiac influences but also by components intrinsic to cardiac tissue. Furthermore, the presence of power-law behavior in monolayer cultures of cardiomyocytes suggests that beat-rate variability might be determined by the complex nonlinear dynamics of processes occurring at the level of the cellular network, eg, interactions among a large number of cell oscillators or metabolic regulatory systems.
High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 are significant target antigens of perinuclear anti-neutrophil cytoplasmic antibodies in autoimmune hepatitis
Authors: J Sobajima, S Ozaki, H Uesugi, F Osakada, M Inoue, Y Fukuda, H Shirakawa, M Yoshida, A Rokuhara, H Imai, K Kiyosawa, K Nakao
Journal: Gut (1999)

BACKGROUND High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 have been identified as novel antigens of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs), and the existence of anti-HMG1 and anti-HMG2 antibodies in a population of patients with ulcerative colitis has been reported. AIMS To investigate whether HMG1 and HMG2 are target antigens for p-ANCAs in autoimmune hepatitis (AIH). PATIENTS Serum samples from 28 patients with AIH, 44 patients with primary biliary cirrhosis (PBC), 27 patients with chronic hepatitis C, and 23 patients with chronic hepatitis B were tested. METHODS ANCAs were detected by routine indirect immunofluorescence (IIF). Anti-HMG1 and anti-HMG2 antibodies were assayed by enzyme linked immunosorbent assay. RESULTS p-ANCAs were detected in 89% (25/28) of patients with AIH, 36% (16/44) of patients with PBC, 11% (3/27) of patients with chronic hepatitis C, and 13% (3/23) of patients with chronic hepatitis B. Anti-HMG1 and/or anti-HMG2 antibodies were detected in 89% (25/28) of patients with AIH, 70% (31/44) with PBC, 26% (7/27) with chronic hepatitis C, and 9% (2/23) with chronic hepatitis B. In AIH, anti-HMG1 and/or anti-HMG2 antibodies were detected in 96% (24/25) of p-ANCA positive patients. The p-ANCA staining pattern detected by IIF using sera from patients with AIH disappeared or decreased in titre after preincubation with a mixture of HMG1/HMG2. The presence and titres of those antibodies in AIH correlated significantly with those of p-ANCA, but not with those of anti-nuclear antibody or anti-smooth muscle antibody. CONCLUSIONS HMG1 and HMG2 are significant target antigens of p-ANCA in AIH.
The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma
Authors: M.J. Overman, L. Feng, B. Pro, P. McLaughlin, M. Hess, F. Samaniego, A. Younes, J.E. Romaguera, F.B. Hagemeister, L. Kwak, F. Cabanillas, M.A. Rodriguez, L.E. Fayad
Journal: Annals of Oncology (2007)
Control of Multidrug Resistance Gene <i>mdr1</i> and Cancer Resistance to Chemotherapy by the Longevity Gene <i>sirt1</i>
Authors: Fei Chu, Pauline M. Chou, Xin Zheng, Bernard L. Mirkin, Abdelhadi Rebbaa
Journal: Cancer Research (2005)

Abstract Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their ability to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA–mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.