tbuckley/cabot-search huggingface dataset:
Mutations in NPHS2 Encoding Podocin Are a Prevalent Cause of Steroid-Resistant Nephrotic Syndrome among Israeli-Arab Children
Authors: Yaacov Frishberg, Choni Rinat, Orli Megged, Eli Shapira, Sofia Feinstein, Annick Raas-Rothschild
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Steroid-resistant nephrotic syndrome (SRNS) represents a heterogeneous group of kidney disorders that are often resistant to other immunosuppressive agents and tend to progress to end-stage renal failure. Mutations in the gene NPHS2 that encode a protein named podocin have recently been found in a recessive form of SRNS. Ten children from two inbred families of Israeli-Arab descent presented with SRNS. Renal histologic findings were of diffuse mesangial proliferation. Six patients reached end-stage renal failure, but nephrotic syndrome did not recur after renal transplantation. Mutation analysis of NPHS2 revealed that they were homozygous for the C412T mutation (R138X). Eighteen children were subsequently analyzed with SRNS due to biopsy-proven focal segmental glomerulosclerosis (FSGS) from unrelated families of Israeli-Arab descent. Analysis disclosed six additional patients (33%) bearing the same mutation in a homozygous pattern. Three of them had no affected relatives, although they came from large families. Taken together, of the 27 patients tested (familial and nonfamilial), 15 patients (55%) were homozygous for the mutation (R138X). They all shared the same haplotype and were homozygous for the A1023G polymorphism, thus pointing to a possible founder effect. Thirteen children of Israeli-Jewish origin with SRNS and biopsy-proven FSGS and 15 children of both ethnic groups with steroid-responsive FSGS were tested, and none was found to have mutations in NPHS2. The results of this study demonstrate that mutations in NPHS2 are a common cause of SRNS in Israeli-Arab children. Mutations in NPHS2 may cause SRNS in nonfamilial cases. The interethnic differences in the occurrence of NPHS2 mutations may explain, in part, the previous observation that Arab patients with FSGS in Israel have a worse prognosis as compared with Jewish patients, despite similar presenting symptoms and medical management. Identifying the causing mutation will enable clinicians to avoid unnecessary immunosuppressive therapeutic trials in newly diagnosed patients and to provide prenatal diagnosis to families at risk.
ABT-888 Confers Broad<i>In vivo</i>Activity in Combination with Temozolomide in Diverse Tumors
Authors: Joann P. Palma, Yi-Chun Wang, Luis E. Rodriguez, Debra Montgomery, Paul A. Ellis, Gail Bukofzer, Amanda Niquette, Xuesong Liu, Yan Shi, Loren Lasko, Gui-Dong Zhu, Thomas D. Penning, Vincent L. Giranda, Saul H. Rosenberg, David J. Frost, Cherrie K. Donawho
Journal: Clinical Cancer Research (2009)

ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ.ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT).Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ.Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.
Association of Diabetes and Hemodialysis With Ankle Pressure and Ankle-Brachial Index in Japanese Patients With Critical Limb Ischemia
Authors: Mitsuyoshi Takahara, Hideaki Kaneto, Osamu Iida, Naoto Katakami, Taka-aki Matsuoka, Masahiko Ikeda, Iichiro Shimomura
Journal: Diabetes Care (2012)

To investigate whether diabetes and regular hemodialysis are associated with false elevation of ankle systolic blood pressure and ankle-brachial systolic pressure index (ABI) because of their arterial calcification in patients with critical limb ischemia (CLI).
A Population-Based Cohort Study of Premorbid Intellectual, Language, and Behavioral Functioning in Patients With Schizophrenia, Schizoaffective Disorder, and Nonpsychotic Bipolar Disorder
Authors: Abraham Reichenberg, Mark Weiser, Jonathan Rabinowitz, Asaf Caspi, James Schmeidler, Mordechai Mark, Zeev Kaplan, Michael Davidson
Journal: American Journal of Psychiatry (2002)

The premorbid intellectual, language, and behavioral functioning of patients hospitalized for schizophrenia, schizoaffective disorder, or nonpsychotic bipolar disorder was compared with that of healthy comparison subjects.The Israeli Draft Board Registry, which contains measures of intellectual, language, and behavioral functioning for the unselected population of 16- to 17-year-olds, was merged with the National Psychiatric Hospitalization Case Registry, which contains diagnoses for all patients with psychiatric hospitalizations in Israel. The database was used to identify adolescents with no evidence of illness at their draft board assessment who were later hospitalized for nonpsychotic bipolar disorder (N=68), schizoaffective disorder (N=31), or schizophrenia (N=536). The premorbid functioning of these subjects was compared to that of nonhospitalized individuals matched for age, gender, and school attended at the time of the draft board assessment. The diagnostic groups of hospitalized subjects were also compared.Relative to the comparison subjects, subjects with schizophrenia showed significant premorbid deficits on all intellectual and behavioral measures and on measures of reading and reading comprehension. Subjects with schizophrenia performed significantly worse on these measures than those with a nonpsychotic bipolar disorder, who did not differ significantly from the comparison subjects on any measure. Subjects with schizoaffective disorder performed significantly worse than the comparison subjects only on the measure of nonverbal abstract reasoning and visual-spatial problem solving and performed significantly worse than subjects with nonpsychotic bipolar disorder on three of the four intellectual measures and on the reading and reading comprehension tests.The results support a nosologic distinction between nonpsychotic bipolar disease and schizophrenia in hospitalized patients.
PWE-124 Vap-1 Activity is Elevated in PSC and Modulates A4B7-Dependent Lymphocyte Adhesion to HSEC Under Flow
Authors: P J Trivedi, C Weston, C Corbett, E Liaskou, D Adams
Journal: Gut (2013)

<h3>Introduction</h3> Vascular adhesion protein (VAP)-1 is an adhesion molecule which possesses potent amine oxidase activity, and deaminates dietary amines resulting in the production of H<sub>2</sub>O<sub>2</sub>. Through this function, VAP-1 leads to activation of NFκB in hepatic sinusoidal endothelium (HSEC) resulting in the expression of mucosal-vascular cell-adhesion molecule-1 (MAdCAM-1); a mechanism proposed to contribute to the homing of gut-tropic lymphocytes expressing a4b7 to the liver. Given the putative role this pathway has in hepatic diseases complicating inflammatory bowel disease (IBD), we set out to quantify circulating/soluble (sVAP-1) and intrahepatic VAP-1 enzyme activity in primary sclerosing cholangitis (PSC), and evaluate the functional consequence of its inhibition on MAdCAM-1 dependent lymphocyte recruitment to HSEC. <h3>Methods</h3> Total VAP-1 concentration was measured by ELISA. VAP-1 amine oxidase activity was quantified in human serum and explanted liver tissue using the amplex red assay. Flow-based adhesion assays were performed using human HSEC isolated from liver explants, activated with TNFa and methylamine (VAP-1 substrate), and treated with VAP-1 antibody or semicarbazide (VAP-1 enzyme inhibitor). FAC-sorted peripheral blood leucocytes expressing a4b7 were perfused over HSEC under flow rates simulating physiological shear (0.05kPa) and adhesion and transmigration quantified. <h3>Results</h3> Patients with PSC had significantly higher circulating median VAP-1 enzyme activity (114.5pmol H2O2 produced/min/ml serum, IQR 100.6–134.7) than patients with IBD (60.3, IQR 38.5–73.0; <i>P</i> = 0.006), normal controls (84.0, IQR 77.7–105.7; <i>P</i> = 0.020) and individuals with PBC (53.9, IQR 33.0–90.9; <i>P</i> = 0.006), and trended higher than AIH (77.6, IQR 51.0–124.5; <i>P</i> = 0.200) (Mann-Whitney). Total sVAP-1 concentration correlated well with sVAP-1 enzyme activity (<i>R</i>2 = 0.75). Intrahepatic median VAP-1 activity was also significantly higher in PSC (97.6pmol H2O2/min/mg protein respectively, IQR 69.5–114.5) vs. PBC (24.6, IQR 18.7–27.8; <i>P</i> = 0.029) and AIH (32.3, IQR 23.3–35.6; <i>P</i> = 0.028) (Mann-Whitney). HSEC pretreatment with semicarbazide but not antibody led to a profound reduction in total a4b7+ lymphocyte adhesion (75%); however, both antibody and enzyme inhibition independently reduced transmigration by ~50% compared to untreated HSEC. <h3>Conclusion</h3> sVAP-1 enzyme activity is greater in PSC compared to IBD alone, normal controls, and other immune-mediated liver diseases. Intrahepatic VAP-1 enzyme activity is significantly higher in PSC compared to AIH and PBC. Inhibition of VAP-1 leads to abrogation of a4b7-mediated adhesion to HSEC, representing a putative target for therapeutic intervention in PSC. <h3>Disclosure of Interest</h3> None Declared.
The Dendritic Cell–like Functions of IFN-Producing Killer Dendritic Cells Reside in the CD11b+ Subset and Are Licensed by Tumor Cells
Authors: Magali Terme, Grégoire Mignot, Evelyn Ullrich, Mathieu Bonmort, Véronique Minard-Colin, Alexandra Jacquet, Joachim L. Schultze, Guido Kroemer, Claude Leclerc, Nathalie Chaput, Laurence Zitvogel
Journal: Cancer Research (2009)

Abstract IFN producing killer dendritic cells (IKDC) were originally defined as CD11cint B220+NK1.1+ (or CD49b+) cells that exert a potent tumoricidal activity in animals lacking B, T, and conventional natural killer effectors. MHC class II expression on tumor infiltrating IKDC prompted us to investigate their putative antigen presenting function. Here, we show that tumor cells license IKDC to acquire the properties of antigen presenting cells, i.e., expression of MHC class II and costimulatory CD86 molecules. We show that the CD11b+ subset of IKDC are able to prime naïve CD4+ T cells and cross-prime naïve CD8+ T lymphocytes. Licensing of IKDC by tumor cells was mandatory for the full differentiation of T cells into polarized effectors. IKDC could engulf and process soluble Ova protein in a CD206-dependent manner. Finally, we show that CD11b+IKDC is selectively endowed with CTLA4Ig-inhibitable antigen presenting capacities and that targeting this subset with the detoxified adenylate cyclase toxin of Bordetella pertussis fused to antigen resulted in efficient cross-presentation of antigen by IKDC to specific TCR transgenic CD8+T cells in vivo. Collectively, our data indicate that upon exposure to tumor cells, IKDC subserve DC-like functions. [Cancer Res 2009;69(16):6590–7]
Complex two-gene modulation of lung disease severity in children with cystic fibrosis
Authors: Ruslan Dorfman, Andrew Sandford, Chelsea Taylor, Baisong Huang, Daisy Frangolias, Yongqian Wang, Richard Sang, Lilian Pereira, Lei Sun, Yves Berthiaume, Lap-Chee Tsui, Peter D. Paré, Peter Durie, Mary Corey, Julian Zielenski
Journal: Journal of Clinical Investigation (2008)

Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-β1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
Carbon dioxide insufflation improves the intubation depth and total enteroscopy rate in single-balloon enteroscopy: a randomised, controlled, double-blind trial
Authors: Xuan Li, Yun-Jia Zhao, Jun Dai, Xiao-Bo Li, Han-Bin Xue, Yao Zhang, Guang-Su Xiong, Kazuo Ohtsuka, Yun-Jie Gao, Qiang Liu, Yan Song, Jing-Yuan Fang, Zhi-Zheng Ge
Journal: Gut (2014)

The total enteroscopy rate of single-balloon enteroscopy (SBE) using air insufflation is not satisfactory, and whether carbon dioxide (CO2) insufflation increases the total enteroscopy rate of SBE is unknown. This randomised controlled trial aimed to determine whether CO2 insufflation facilitates the intubation depth and total enteroscopy rate of SBE.A total of 214 eligible patients referred for SBE were randomised to receive either air or CO2 insufflation, and included in the intention-to-test (ITT) analysis. In addition, 199 patients in whom enteroscopy was completed were included in the per-protocol (PP) analysis. Both the patients and endoscopists were blinded, and the intubation depth and total enteroscopy rate were defined as the primary outcomes.The CO2 group showed a superiority of intubation in the ITT analysis (oral route: 323.8±64.2 vs 238.3±68.6 cm; anal route: 261.6±74.2 vs 174.7±62.1 cm, both p<0.001), and the total enteroscopy rate (34.9% vs 17.6%, p=0.006). Similar results were obtained in a PP analysis for both outcomes. In addition, in the PP analysis, the addition of circumference after the procedure was less in the CO2 group (0.8±0.6 vs 3.3±1.8 cm, p=0.005) for the oral route. No serious complications were reported. The overall percentage of procedures with significant pathological findings was 52.8%; the rates were 58.5% and 47.2% (p=0.100, ITT analysis) in the CO2 and air groups, respectively.CO2 insufflation improves the intubation depth and total enteroscopy rate in SBE with a good safety profile and acceptability compared with that of air, and thus is recommended for clinical utilisation.ClinicalTrial.gov identifier: NCT01758900.
VHL Inactivation Induces HEF1 and Aurora Kinase A
Authors: Jianyong Xu, Huapeng Li, Bo Wang, Yan Xu, Jiayin Yang, Xiaofei Zhang, Sarah K. Harten, Deepa Shukla, Patrick H. Maxwell, Duanqing Pei, Miguel A. Esteban
Journal: Journal of the American Society of Nephrology (2010)

The ciliary hypothesis for cystic renal diseases postulates that most of these conditions result from abnormalities in the primary cilium, a microtubule-based structure that acts as a sensor for extracellular cues. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to renal cysts and clear cell renal cell carcinoma. VHL plays a critical role in the formation of primary cilia in kidney epithelium, but the underlying mechanisms are poorly understood. Here, we demonstrate that VHL inactivation induces HEF1/Cas-L/NEDD9 and Aurora kinase A via the stabilization of hypoxia-inducible factors 1 and 2. Aurora kinase A is a mitotic kinase commonly upregulated in cancer that causes regression of the primary cilium by promoting histone deacetylase-dependent tubulin depolymerization of the ciliary axoneme. HEF1/Cas-L/NEDD9 is a component of focal adhesions that has a prominent role in inducing metastasis and that colocalizes with Aurora kinase A at the centrosome, thereby enhancing the harmful effect of Aurora kinase A on the cilium. Suppression of this pathway improved the formation of primary cilia and reduced cell motility in VHL-defective renal cancer cells. Our results highlight the gatekeeper role of VHL in the kidney epithelium.
PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells
Authors: Shiri Gur-Cohen, Tomer Itkin, Sagarika Chakrabarty, Claudine Graf, Orit Kollet, Aya Ludin, Karin Golan, Alexander Kalinkovich, Guy Ledergor, Eitan Wong, Elisabeth Niemeyer, Ziv Porat, Ayelet Erez, Irit Sagi, Charles T Esmon, Wolfram Ruf, Tsvee Lapidot
Journal: Nature Medicine (2015)
Impact of Antiretroviral Therapy on Incidence of Pregnancy among HIV-Infected Women in Sub-Saharan Africa: A Cohort Study
Authors: Landon Myer, Rosalind J. Carter, Monica Katyal, Patricia Toro, Wafaa M. El-Sadr, Elaine J. Abrams
Journal: PLoS Medicine (2010)

With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates.We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19-2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts.ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services. Please see later in the article for the Editors' Summary.
Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Authors: An Verrijken, Sven Francque, Ilse Mertens, Janne Prawitt, Sandrine Caron, Guy Hubens, Eric Van Marck, Bart Staels, Peter Michielsen, Luc Van Gaal
Journal: Hepatology (2013)

An independent role of nonalcoholic fatty liver disease (NAFLD) in the development of cardiovascular disease has been suggested, probably mediated through increased levels of prothrombotic factors. Therefore, we examined whether NAFLD is linked to a prothrombotic state, independently of metabolic risk factors in a large single-center cohort of overweight/obese patients. Patients presenting to the obesity clinic underwent a detailed metabolic and liver assessment, including an extensive panel of coagulation factors. If NAFLD was suspected, a liver biopsy was proposed. A series of 273 consecutive patients (65% female) with a liver biopsy were included (age, 44 ± 0.76 years; body mass index: 39.6 ± 0.40 kg/m2). Increase in fibrinogen, factor VIII, and von Willebrand factor and decrease in antithrombin III correlated with metabolic features, but not with liver histology. Levels of plasminogen activator inhibitor-1 (PAI-1) increased significantly with increasing severity of steatosis (P < 0.001), lobular inflammation (P < 0.001), ballooning (P = 0.002), and fibrosis (P < 0.001). Patients with nonalcoholic steatohepatitis had significantly higher PAI-1 values than those with normal liver (P < 0.001). In multiple regression, including anthropometric and metabolic parameters, steatosis remained an independent predictor of PAI-1 levels, explaining, together with fasting C-peptide and waist circumference, 21% of the variance in PAI-1. No consistent correlations with histology were found for the other coagulation factors. Conclusion: In obesity, NAFLD severity independently contributes to the increase in PAI-1 levels, whereas other coagulation factors are unaltered. This finding might, in part, explain the increased cardiovascular risk associated with NAFLD. (Hepatology 2014;58:121–129)
Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. IX. Characterization of Idiotype-specific effector-phase suppressor cells on plaque-forming cell responses in vitro.
Authors: D H Sherr, M E Dorf
Journal: The Journal of Experimental Medicine (1981)

The ability of T suppressor cells, induced by the intravenous injection of 4-hydroxy-3-nitrophenyl acetyl (NP)-modified syngeneic spleen cells, to affect an ongoing B cell response was studied in vitro. It was found that the expression of NPb idiotype-positive B cells could be selectively inhibited by the addition of antigen-induced suppressor cells in the last 24 h of the in vitro culture. This effector-phase suppression of B cell responses was antigen specific and mediated by an Lyt 1-, Lyt 2+, idiotype-binding, T cell population whose suppressive function was restricted by genes linked to the Igh locus.