tbuckley/cabot-search huggingface dataset:
Interleukin 2 receptors on human B cells. Implications for the role of interleukin 2 in human B cell function.
Authors: A Muraguchi, J H Kehrl, D L Longo, D J Volkman, K A Smith, A S Fauci
Journal: The Journal of Experimental Medicine (1985)

In the present study, we examined the expression of interleukin 2 (IL-2) receptors on normal human B cells as well as established B cell lines. Anti-Tac monoclonal antibody did not bind to freshly separated normal human B cells. Unexpectedly, with the appropriate activation of the normal B cells by anti-mu antibody, phorbol myristate acetate, or Staphylococcus aureus Cowan I (SAC), Tac antigen was induced on the activated B cells. Anti-Tac antibody showed consistent reactivity with two B cell lines that were infected by human T cell leukemia virus (HTLV) and some reactivity with two out of eight Epstein-Barr virus-transformed B cell lines established from normal adult donors. Immunoprecipitation analysis revealed that antigens of similar size with a molecular weight of 50,000-60,000 can be precipitated with anti-Tac antibody from phytohemagglutinin-stimulated normal T cell blasts and normal activated B cells, as well as a cloned B cell line. Binding assays of IL-2 on normal activated B cells and on the cloned B cell (HS1) revealed that B cells have significantly fewer sites and lower-affinity IL-2 receptors compared with phytohemagglutinin-stimulated normal T cell blasts. Finally, biological properties of the IL-2 receptor on B cells were examined by incubating B cells with recombinant IL-2. It was found that moderate concentrations of IL-2 induce significant enhancement of proliferation and differentiation in SAC-activated normal B cells. These results suggest that normal B cells may express functional IL-2 receptors or closely related proteins and thus IL-2 may play a significant role in the modulation of B cell function.
Characterization of Genetically Modified T-Cell Receptors that Recognize the CEA:691-699 Peptide in the Context of HLA-A2.1 on Human Colorectal Cancer Cells
Authors: Maria R. Parkhurst, Jayne Joo, John P. Riley, Zhiya Yu, Yong Li, Paul F. Robbins, Steven A. Rosenberg
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Carcinoembryonic antigen (CEA) is a tumor-associated protein expressed on a variety of adenocarcinomas. To develop an immunotherapy for patients with cancers that overexpress CEA, we isolated and genetically modified a T-cell receptors (TCRs) that specifically bound a CEA peptide on human cancer cells. Experimental Design: HLA-A2.1 transgenic mice were immunized with CEA:691-699. A CEA-reactive TCR was isolated from splenocytes of these mice and was genetically introduced into human peripheral blood lymphocytes via RNA electroporation or retroviral transduction. Amino acid substitutions were introduced throughout the complementarity determining regions (CDR1, CDR2, and CDR3) of both TCR α and β chains to improve recognition of CEA. Results: Murine lymphocytes bearing the CEA-reactive TCR specifically recognized peptide-loaded T2 cells and HLA-A2.1+ CEA+ human colon cancer cells. Both CD8+ and CD4+ human lymphocytes expressing the murine TCR specifically recognized peptide-loaded T2 cells. However, only gene-modified CD8+ lymphocytes specifically recognized HLA-A2.1+ CEA+ colon cancer cell lines, and tumor cell recognition was weak and variable. We identified two substitutions in the CDR3 of the α chain that significantly influenced tumor cell recognition by human peripheral blood lymphocytes. One substitution, T for S at position 112 (S112T), enhanced tumor cell recognition by CD8+ lymphocytes, and a second dually substituted receptor (S112T L110F) enhanced tumor cell recognition by CD4+ T cells. Conclusions: The modified CEA-reactive TCRs are good candidates for future gene therapy clinical trials and show the power of selected amino acid substitutions in the antigen-binding regions of the TCR to enhance desired reactivities.
Anastellin, a Fragment of the First Type III Repeat of Fibronectin, Inhibits Extracellular Signal-Regulated Kinase and Causes G1 Arrest in Human Microvessel Endothelial Cells
Authors: Anthony Ambesi, R. Matthew Klein, Kevin M. Pumiglia, Paula J. McKeown-Longo
Journal: Cancer Research (2005)

The formation of a microvascular endothelium plays a critical role in the growth and metastasis of established tumors. The ability of a fragment from the first type III repeat of fibronectin (III(1C)), anastellin, to suppress tumor growth and metastasis in vivo has been reported to be related to its antiangiogenic properties, however, the mechanism of action of anastellin remains unknown. Utilizing cultures of human dermal microvascular endothelial cells, we provide evidence that anastellin inhibits signaling pathways which regulate the extracellular signal-regulated (ERK) mitogen-activated protein kinase pathway and subsequent expression of cell cycle regulatory proteins. Addition of anastellin to primary microvascular endothelial cells resulted in a complete inhibition of serum-dependent proliferation. Growth inhibition correlated with a decrease in serum-dependent expression of cyclin D1, cyclin A and the cyclin-dependent kinase, cdk4, key regulators of cell cycle progression through G(1) phase. Consistent with a block in G(1)-S transition, anastellin inhibited serum-dependent incorporation of [(3)H]-thymidine into S-phase nuclei. Addition of anastellin to serum-starved microvessel cells resulted in a time-dependent and dose-dependent decrease in basal levels of phosphorylated MEK/ERK and blocked serum-dependent activation of ERK. Adenoviral infection with Ad.DeltaB-Raf:ER, an inducible estrogen receptor-B-Raf fusion protein, restored levels of active ERK in anastellin-treated cells, rescued levels of cyclin D1, cyclin A, and cdk4, and rescued [(3)H]-thymidine incorporation. These data suggest that the antiangiogenic properties of anastellin observed in mouse models of human cancer may be due to its ability to block endothelial cell proliferation by modulating ERK signaling pathways and down-regulating cell cycle regulatory gene expression required for G(1)-S phase progression.
Fast Adaptive Coevolution of Nuclear and Mitochondrial Subunits of ATP Synthetase in Orangutan
Authors: Maria Pilar Bayona-Bafaluy, Stefan Müller, Carlos T. Moraes
Journal: Molecular Biology and Evolution (2004)

Nuclear and mitochondrial genomes have to work in concert to generate a functional oxidative phosphorylation (OXPHOS) system. We have previously shown that we could restore partial OXPHOS function when chimpanzee or gorilla mitochondrial DNA (mtDNA) were introduced into human cells lacking mtDNA. However, we were unable to maintain orangutan mitochondrial DNA in a human cell. We have now produced chimpanzee, gorilla, orangutan, and baboon cells lacking mtDNA and attempted to introduce mtDNA from different apes into them. Surprisingly, we were able to maintain human mtDNA in an orangutan nuclear background, even though these cells showed severe OXPHOS abnormalities, including a complete absence of assembled ATP synthetase. Phylogenetic analysis of complex V mtDNA-encoded subunits showed that they are among the most evolutionarily divergent components of the mitochondrial genome between orangutan and the other apes. Our studies showed that adaptive coevolution of nuclear and mitochondrial components in apes can be fast and accelerate in recent branches of anthropoid primates.
Two Distinct Pools of Mesenchyme Contribute to the Development of the Atrial Septum
Authors: Mathilda T.M. Mommersteeg, Alexandre T. Soufan, Frederik J. de Lange, Maurice J.B. van den Hoff, Robert H. Anderson, Vincent M. Christoffels, Antoon F.M. Moorman
Journal: Circulation Research (2006)

Closure of the primary atrial foramen is achieved by fusion of the atrioventricular cushions with the mesenchymal cap on the leading edge of the muscular primary atrial septum. A fourth component involved is the vestibular spine, originally described by His in 1880 as an intra-cardiac continuation of the extra-cardiac mesenchyme of the dorsal mesocardium. The morphogenesis of this area is of great clinical interest, because of the high incidence of atrial and atrioventricular septal defects. Nonetheless, the origin of the participating components is largely unknown. Here we report that the primary atrial foramen is surrounded in its entirety by mesenchyme derived from endocardium. A second population of mesenchyme not derived from endocardium was observed at the caudal margin of the mesenchymal atrial cap, entirely embedded within the mesenchyme derived from endocardium and contiguous with the mesenchyme of the dorsal mesocardium. Our reconstructions show this second population does indeed take the form of a short spine, albeit that it is the right pulmonary ridge, rather than this spine, that protrudes into the atrial lumen. From the stance of morphological description, therefore, there is little thus far to substantiate the existence of an atrial spine.
Lactic acid recovery profiles following exhaustive arm exercise on a canoeing ergometer.
Authors: S J Baker, N King
Journal: British Journal of Sports Medicine (1991)

In this study lactate removal rates were monitored in ten subjects during a 30-min recovery period following exhaustive arm exercise. Each subject experienced three recovery regimens on different occasions in random order. One recovery period consisted of supine rest while the other two were active, one incorporating low intensity arm exercise and the other consisting of low intensity leg exercise. Lactate clearance rates showed a significant difference between the recovery regimens, and a posteriori test indicated a significant difference between leg exercise and arm exercise in the recovery period and also between leg exercise and rest. There was no significant difference in lactate clearance between arm exercise and rest in the recovery period.
Remodeling of the rat right and left ventricles in experimental hypertension.
Authors: C G Brilla, R Pick, L B Tan, J S Janicki, K T Weber
Journal: Circulation Research (1990)

Pathological left ventricular hypertrophy in renovascular hypertension is associated with the accumulation of fibrillar collagen within the extracellular space and around intramyocardial coronary arteries. Even though the angiotensin converting enzyme inhibitor captopril was previously found to attenuate this interstitial and perivascular fibrosis, the relative importance of arterial and ventricular systolic pressures versus circulating angiotensin II (AII) and aldosterone (AL) in promoting hypertrophy and collagen accumulation in renovascular hypertension is uncertain. By drawing on the in-parallel arrangement of the right and left ventricles, with respect to their coronary circulation, and the in-series mechanical alignment of the ventricles, with a pressure-overloaded left and a normotensive right ventricle, this study sought to address this uncertainty. Three models of experimental hypertension, each having a different circulating AII and AL profile, were examined and compared with their controls: renovascular hypertension, where both AII and AL are increased; infrarenal aorta banding, where AII and AL are normal; and a chronic infusion of AL, where AII is suppressed or normal and AL is increased. In renovascular hypertension, as well as with AL, we found a significant rise in the interstitial collagen volume fraction and perivascular collagen area of the pressure-overloaded, hypertrophied left ventricle as well as the normotensive, nonhypertrophied right ventricle. This remodeling was not seen in either ventricle with infrarenal aorta banding despite comparable systemic hypertension and left ventricular hypertrophy. Thus, in experimental arterial hypertension in the rat, myocyte and nonmyocyte compartments of the myocardium are under separate controls: myocyte hypertrophy is most closely related to ventricular loading while circulating AII and AL, acting alone or in concert with other humoral factors, regulate the accumulation of collagen within the right and left ventricles.
Expression, localization and alternative splicing pattern of fibronectin messenger RNA in fibrotic human liver and hepatocellular carcinoma
Authors: Shigeru Matsui, Toru Takahashi, Yoshinari Oyanagi, Sumio Takahashi, Saihiro Boku, Kou Takahashi, Koichi Furukawa, Futoshi Arai, Hitoshi Asakura
Journal: Journal of Hepatology (1997)
Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3
Authors: Laura Rubbia-Brandt, Rafael Quadri, Karim Abid, Emiliano Giostra, Pierre-Jean Malé, Gilles Mentha, Laurent Spahr, Jean-Pierre Zarski, Bettina Borisch, Antoine Hadengue, Francesco Negro
Journal: Journal of Hepatology (2000)
Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group.
Authors: M G Pfreundschuh, U Rueffer, B Lathan, N Schmitz, O Brosteanu, D Hasenclever, R Haas, H Kirchner, P Koch, R Kuse
Journal: Journal of Clinical Oncology (1994)

PURPOSE A prospective phase II study was conducted to evaluate the efficacy of dexamethasone, carmustine, etoposide, cytarabine, and melphalan (Dexa-BEAM) as salvage chemotherapy for patients with Hodgkin's disease. PATIENTS AND METHODS Fifty-five patients progressing on or relapsing after eight- or 10-drug chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone plus doxorubicin, bleomycin, vinblastine, and dacarbazine [COPP+ABVD] or COPP+ABV+ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) were treated with Dexa-BEAM. Patients who responded after two cycles of Dexa-BEAM either continued treatment for another two to three cycles or received high-dose chemotherapy/autologous bone marrow transplantation (HDCT/ABMT) with cyclophosphamide, etoposide, and carmustine (BCNU) (CVB) as conditioning regimen. RESULTS Seventeen patients (31%) achieved a complete remission and 16 (29%) a partial remission, resulting in a response rate of 60% (95% confidence interval, 46% to 73%). Progressive disease developed in 18 patients. Toxicity of Dexa-BEAM was acceptable with pronounced, but temporary World Health Organization (WHO) grade III/IV granulocytopenia and thrombocytopenia occurring in more than 90% of all courses. Two patients died of sepsis during granulocytopenia. Three prognostic subgroups could be distinguished: (1) patients progressing on initial chemotherapy, (2) patients relapsing within 12 months, and (3) patients with late relapses. The response rates for these groups were 52%, 60%, and 83%, and the median survival duration 12, 29, and 40+ months, respectively. In a nonrandomized comparison, the survival of patients who responded to two cycles of Dexa-BEAM and had additional cycles of Dexa-BEAM (n = 14) was not different from those responding patients who underwent HDCT/ABMT (n = 19). However, the power to detect a 20% survival difference was only 33% in this comparison. CONCLUSION Dexa-BEAM is an effective salvage treatment for patients with Hodgkin's disease who fail to respond to multidrug chemotherapy. Efficacy and toxicity are comparable to HDCT/ABMT and underline the need for prospective randomized trials to define better the role of HDCT with and without ABMT in these patients.
Deregulation of the activin/follistatin system in hepatocarcinogenesis
Authors: Michael Grusch, Claudia Drucker, Barbara Peter-Vörösmarty, Natascha Erlach, Andreas Lackner, Annemarie Losert, Doris Macheiner, Wolfgang J. Schneider, Marcela Hermann, Nigel P. Groome, Wolfram Parzefall, Walter Berger, Bettina Grasl-Kraupp, Rolf Schulte-Hermann
Journal: Journal of Hepatology (2006)
Clinical studies of renal disease in Sjogren's syndrome.
Authors: S Shiozawa, K Shiozawa, S Shimizu, M Nakada, T Isobe, T Fujita
Journal: Annals of the Rheumatic Diseases (1987)

When 17 patients with Sjögren9s syndrome, without apparent clinical manifestations of renal disease, were examined renal function studies frequently indicated abnormalities in their renal phosphate handling. The percentage tubular reabsorption of phosphate (%TRP) was decreased in six (35.3%), and maximal tubular reabsorption rate for phosphate (TmPO4/GFR) was low in eight (47.1%). In contrast, indices of renal calcium handling and serum parathyroid hormone levels were normal, suggesting that the abnormalities of phosphate metabolism were due not to extrinsic, but rather to intrinsic disease processes occurring in the kidney in Sjögren9s syndrome. When the patients were divided into two groups according to the presence or absence of a renal tubular acidification defect (RTAD), patients with RTAD were younger (p less than 0.005), had longer disease duration (p less than 0.01), lower creatinine clearance (p less than 0.05), and higher incidence of low %TRP (p less than 0.05). Thus the patients with lower creatinine clearance generally had disease of longer duration at diagnosis and tended also to have defects in concentrating and acidifying the urine.
CD8 <sup>+</sup> T Lymphocytes Regulate the Arteriogenic Response to Ischemia by Infiltrating the Site of Collateral Vessel Development and Recruiting CD4 <sup>+</sup> Mononuclear Cells Through the Expression of Interleukin-16
Authors: Eugenio Stabile, Timothy Kinnaird, Andrea la Sala, Sue Kim Hanson, Craig Watkins, Umberto Campia, Matie Shou, Stephan Zbinden, Shmuel Fuchs, Hardy Kornfeld, Stephen E. Epstein, Mary Susan Burnett
Journal: Circulation (2005)

Background— Previous studies have demonstrated that macrophages and CD4 + T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8 + T cells also play a role. Thus, after acute cerebral ischemia, CD8 + T cells infiltrate the perivascular space and secrete interleukin-16 (IL-16), a potent chemoattractant for monocytes and CD4 + T cells. We tested whether CD8 + T lymphocytes contribute to collateral vessel development and whether the lack of circulating CD8 + T cells prevents IL-16 expression, impairs CD4 + mononuclear cell recruitment, and reduces collateral vessel growth after femoral artery ligation in CD8 −/− mice . Methods and Results— After surgical excision of the femoral artery, laser Doppler perfusion imaging demonstrated reduced blood flow recovery in CD8 −/− mice compared with C57/BL6 mice (ischemic/nonischemic limb at day 28, 0.66±0.04 versus 0.87±0.04, respectively; P &lt;0.01). This resulted in greater calf muscle atrophy (mean fiber area, 785±68 versus 1067±69 μm 2 , respectively; P &lt;0.01) and increased fibrotic tissue content (10.8±1.2% versus 7±1%, respectively; P &lt;0.01). Moreover, CD8 −/− mice displayed reduced IL-16 expression and decreased CD4 + T-cell recruitment at the site of collateral vessel development. Exogenous CD8 + T cells, infused into CD8 −/− mice immediately after femoral artery ligation, selectively homed to the ischemic hind limb and expressed IL-16. The restoration of IL-16 expression resulted in significant CD4 + mononuclear cell infiltration of the ischemic limb, faster blood flow recovery, and reduced hindlimb muscle atrophy/fibrosis. When exogenous CD8 + T cells deficient in IL-16 (IL-16 −/− ) were infused into CD8 −/− mice immediately after femoral artery ligation, they selectively homed to the ischemic hind limb but were unable to recruit CD4 + mononuclear cells and did not improve blood flow recovery. Conclusions— These results demonstrate that CD8 + T cells importantly contribute to the early phase of collateral development. After femoral artery ligation, CD8 + T cells infiltrate the site of collateral vessel growth and recruit CD4 + mononuclear cells through the expression of IL-16. Our study provides further evidence of the significant role of the immune system in modulating collateral development in response to peripheral ischemia.
Obstetrical Complications and Childhood-Onset Schizophrenia
Authors: R Nicolson, D Malaspina, J N Giedd, S Hamburger, M Lenane, J Bedwell, T Fernandez, A Berman, E Susser, J L Rapoport
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: Increased obstetrical complications have been reported in individuals with adult-onset schizophrenia, with several studies finding an association between such complications and an earlier age at onset. Consequently, obstetrical records were examined for individuals with childhood-onset schizophrenia to determine if birth complications were more prevalent. METHOD: The birth records of 36 patients with childhood-onset schizophrenia and 35 sibling comparison subjects were rated for birth complications by two psychiatrists who were unaware of group membership. RESULTS: There were no significant differences between the groups in rates of obstetrical complications. Patients with such complications did not have a relatively earlier age at onset of schizophrenia. CONCLUSIONS: A very early age at onset of schizophrenia is probably not due to birth complications.
<i>F12</i>‐46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema
Authors: M. Speletas, Á. Szilágyi, D. Csuka, N. Koutsostathis, F. Psarros, D. Moldovan, M. Magerl, M. Kompoti, L. Varga, M. Maurer, H. Farkas, A. E. Germenis
Journal: Allergy (2015)

Abstract The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1‐ INH deficiency (C1‐ INH ‐ HAE ) represent one of the oldest unsolved problems of the disease. Considering that factor XII ( FXII ) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12 ‐46C/T in disease phenotype. We studied 258 C1‐ INH ‐ HAE patients from 113 European families, and we explored possible associations of F12 ‐46C/T with clinical features and the SERPING 1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations ( GEE s), an extension of the generalized linear model accounting for the within‐subject correlation. F12 ‐46C/T carriers exhibited a significantly delayed disease onset ( P &lt; 0.001) and did not need long‐term treatment ( P = 0.02). In a GEE linear regression model, the presence of F12 ‐46C/T was significantly associated with a 7‐year delay in disease onset ( P &lt; 0.0001) regardless of SERPING 1 mutational status. It is concluded that F12 ‐46C/T carriage acts as an independent modifier of C1‐ INH ‐ HAE severity.
Intercellular heterogeneity of expression of the MGMT DNA repair gene in pediatric medulloblastoma
Authors: Brian R Rood, Huizhen Zhang, Philip H Cogen
Journal: Neuro-Oncology (2004)

DNA methylation and epigenetic inactivation of the O6-methylguanine methyltransferase (MGMT) gene induces MGMT deficiency, reducing the tumor cell's DNA repair capacity and increasing its susceptibility to alkylating chemotherapeutic agents. Consequently, adult patients whose tumors are deficient in MGMT have better outcomes with alkylator chemotherapy, and MGMT methylation has been proposed as a screening marker of deficient tumors. In order to test the feasibility of this approach for medulloblastoma, a common brain tumor in children, we determined the methylation status, mRNA expression pattern, and protein expression of MGMT in a panel of clinical specimens. Methylation-specific polymerase chain reaction analysis revealed methylation of MGMT in 28 of 37 tumor samples. Quantitative real-time reverse transcriptase-polymerase chain reaction showed a range of expression of MGMT mRNA varying more than 20-fold. However, there was no correlation found between MGMT methylation and mRNA expression. Immunohistochemistry demonstrated that all tumors were immunoreactive for MGMT in the nucleus of the medulloblastoma cells in a heterogeneous pattern. The intercell variability of MGMT complement explained the discordance between methylation and expression. Therefore, MGMT methylation as determined by methylation-specific polymerase chain reaction cannot be used as a marker for MGMT deficiency in medulloblastoma. Further, these findings support the use of pharmacological MGMT depletion as a rational approach for intensification of alkylator chemotherapy in the treatment of medulloblastoma.