tbuckley/cabot-search huggingface dataset:
Inhibition of MALT1 protease activity is selectively toxic for activated B cell–like diffuse large B cell lymphoma cells
Authors: Uta Ferch, Bernhard Kloo, Andreas Gewies, Vera Pfänder, Michael Düwel, Christian Peschel, Daniel Krappmann, Jürgen Ruland
Journal: The Journal of Experimental Medicine (2009)

Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell–like (ABC) subtype of DLBCL is characterized by constitutive NF-κB activity and requires signals from CARD11, BCL10, and the paracaspase MALT1 for survival. CARD11, BCL10, and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11–BCL10–MALT1 (CBM) complexes couple upstream events to IκB kinase (IKK)/NF-κB activation. MALT1 also possesses a recently recognized proteolytic activity that cleaves and inactivates the negative NF-κB regulator A20 and BCL10 upon antigen receptor ligation. Yet, the relevance of MALT1 proteolytic activity for malignant cell growth is unknown. Here, we demonstrate preassembled CBM complexes and constitutive proteolysis of the two known MALT1 substrates in ABC-DLBCL, but not in germinal center B cell–like (GCB) DLBCL. ABC-DLBCL cell treatment with a MALT1 protease inhibitor blocks A20 and BCL10 cleavage, reduces NF-κB activity, and decreases the expression of NF-κB targets genes. Finally, MALT1 paracaspase inhibition results in death and growth retardation selectively in ABC-DLBCL cells. Thus, our results indicate a growth-promoting role for MALT1 paracaspase activity in ABC-DLBCL and suggest that a pharmacological MALT1 protease inhibition could be a promising approach for lymphoma treatment.
THE EFFECTS OF l-EPINEPHRINE AND l-NOR-EPINEPHRINE UPON CEREBRAL CIRCULATION AND METABOLISM IN MAN 1
Authors: Benton D. King, Louis Sokoloff, Richard L. Wechsler
Journal: Journal of Clinical Investigation (1952)

Studies comparing the effects of epinephrine and nor-epinephrine, the two sympathomimetic amines which occur naturally in the mammalian body, show that these two closely related substances differ in many of their pharmacodynamic properties. The metabolic rate in man has been shown to increase after epinephrine (1, 2), whereas there is no significant change produced by nor-epinephrine (2). Systemic administration of epinephrine to man has been shown to result in a decrease in total peripheral resistance (1, 3), indicating that vasodilatation has occurred in many portions of the body; in contrast, nor-epinephrine appears to be predominantly vasoconstrictor in its action, for total peripheral resistance is increased (3). These differences may be manifestations of the specific functions which these substances perform in the body; von Euler (4) believes that nor-epinephrine is the sympathetic mediator for general purposes, while epinephrine acts as an adjuvant for more special functions, especially in regard to metabolic actions. In view of the importance of epinephrine and nor-epinephrine in physiological processes, their occurrence in pheochromocytomas, their use as therapeutic agents, and the possible relation of nor-epinephrine to essential hypertension (3), information regarding their effect on cerebral blood flow and cerebral metabolism is desirable. A preliminary report by Sensenbach, Madison, and Ochs (5) indicates that nor-epinephrine is a powerful cerebral vasoconstrictor. The animal studies upon epinephrine have yielded conflicting
Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction.
Authors: M S Lee, L Wogensen, J Shizuru, M B Oldstone, N Sarvetnick
Journal: Journal of Clinical Investigation (1994)

IL-10 inhibits macrophage-dependent antigen presentation, cytokine production, and generation of allospecific cells in vitro. These findings have lead to the widespread expectation that IL-10 may be a useful immunosuppressive agent to inhibit allograft rejection or autoimmunity in vivo. We used two experimental paradigms to study effects of murine IL-10 on in vivo immune responses. First, fetal pancreata or adult pancreatic islets from transgenic mice expressing IL-10 in pancreatic beta cells (Ins-IL-10 mice) were grafted across the MHC barrier to examine if IL-10 could inhibit allograft rejection. Second, Ins-IL-10 mice were crossed with transgenic mice expressing lymphocytic choriomeningitis virus (LCMV) antigens in pancreatic beta cells. These mice were infected with LCMV to elicit autoimmune diabetes, allowing us to ask if IL-10 protects islets from autoimmune destruction. We observed that allografts from IL-10-transgenic donors were rejected with comparable kinetics to the rejection of control nontransgenic allografts, indicating that IL-10 does not inhibit allograft rejection. After LCMV infection, IL-10 and LCMV antigen double transgenic mice developed diabetes earlier than LCMV antigen single transgenic littermates, suggesting that IL-10 does not inhibit islet antigen presentation or recognition. Our results contrast to in vitro observations and suggest that IL-10 cannot overcome immune-mediated tissue destruction within the pancreas.
Phase II Study of Flavopiridol in Relapsed Chronic Lymphocytic Leukemia Demonstrating High Response Rates in Genetically High-Risk Disease
Authors: Thomas S. Lin, Amy S. Ruppert, Amy J. Johnson, Beth Fischer, Nyla A. Heerema, Leslie A. Andritsos, Kristie A. Blum, Joseph M. Flynn, Jeffrey A. Jones, Weihong Hu, Mollie E. Moran, Sarah M. Mitchell, Lisa L. Smith, Amy J. Wagner, Chelsey A. Raymond, Larry J. Schaaf, Mitch A. Phelps, Miguel A. Villalona-Calero, Michael R. Grever, John C. Byrd
Journal: Journal of Clinical Oncology (2009)

Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.
IMMUNOGLOBULIN ISOANTIGENS (ALLOTYPES) IN THE MOUSE
Authors: Leonard A. Herzenberg, Noel L. Warner, Leonore A. Herzenberg
Journal: The Journal of Experimental Medicine (1965)

Eight antigens of 7S gamma(2)-immunoglobulins controlled by alleles at a single locus Ig-1, have been identified in mice. This locus has previously been shown to determine antigenic specificities on the F fragments of 7S gamma(2a)-globulins. The reactions of these antigens with various isoantisera have shown that the antigens all cross react with one another. New methods for the analysis of antigenic specificities of soluble proteins are presented in detail. A sensitive method for detecting in the order of 0.01 microg of these isoantigens has been developed, based on the quantitative inhibition of precipitation of I(125)-labeled antigen. Cross-reactions of the antigens were analysed in inhibition assays and the data is compatible with the existence of a minimum of eight antigenic specificities. Each of the antigens is composed of different combinations of these specificities, with only one antigen having a specificity not present in any other. Sixty-eight mouse strains have been tested with specific isoantisera, and on the basis of the results, have been placed into the eight allele groups. Evidence for close genetic linkage of the Ig-1 locus and 11 chromosome markers has been sought and not found.
A Tumorigenic Factor Interactome Connected through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer
Authors: Christian Marin-Muller, Dali Li, Uddalak Bharadwaj, Min Li, Changyi Chen, Sally E. Hodges, William E. Fisher, Qianxing Mo, Mien-Chie Hung, Qizhi Yao
Journal: Clinical Cancer Research (2013)

The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLN-regulated miR-198 treatment in vivo.The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models.We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB-mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival.miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point.
Thrombocytosis of active rheumatoid disease.
Authors: M Farr, D L Scott, T J Constable, R J Hawker, C F Hawkins, J Stuart
Journal: Annals of the Rheumatic Diseases (1983)

Two cross-sectional and one longitudinal study of patients with rheumatoid arthritis showed that platelet number correlated with both clinical and laboratory parameters of disease activity, including erythrocyte sedimentation rate, zeta sedimentation ratio, viscosity of plasma and blood, white cell count, liver enzymes, rheumatoid factor, and several acute-phase proteins. There was also an inverse relationship between platelet number and the haemoglobin and serum albumin levels. III Indium-labelled platelet survival was reduced in 4 patients with active rheumatoid arthritis despite a raised platelet count, with labelled platelets being localised to inflamed joints in the 2 patients studied. Platelet aggregation was normal. We suggest that the raised platelet count of active rheumatoid arthritis may be a useful index of disease activity and may represent a bone marrow stress (syndrome) response to shortened platelet survival, with platelet sequestration occurring in areas of synovial inflammation.
Pulmonary Alveolar Blood Flow
Authors: Y. C. FUNG, S. S. SOBIN
Journal: Circulation Research (1972)

Explicit results concerning blood flow, alveolar blood volume, regional differences, and transit time distribution are derived from the sheet-flow theory and compared with experimental evidence available in the literature. A general consistency is indicated. The theory exhibits in a simple form the effects on flow of the arterial, alveolar, and venous pressures, the alveolar area, the mean path length between arterioles and venules, and the tension in the alveolar membrane, both elastic and surface tension; thus the theory provides a quantitative understanding of a large number of factors.
Effects of Butylated Hydroxyanisole on the Metabolism of Benzo[a]pyrene by Mouse Liver Microsomes2
Authors: Luke K. T. Lam, Lee W. Wattenberg
Journal: JNCI Journal of the National Cancer Institute (1977)

The metabolites of tritium-labeled benzo[a]pyrene (BP) extracted from liver microsomes prepared from butylated hydroxyanisole (BHA)-fed and control female A/HeJ mice were analyzed by high-pressure liquid chromatography. There was an overall decrease in diol formation as well as an increase in the phenol formation in microsomal incubations from the BHA-fed mice compared to the controls. The dione region, when analyzed together with the BP-4,5-oxide peak, showed an overall decrease with BHA feeding. The BP-4,5-oxide was isolated and identified. It was present in both the BHA-fed and control microsomal incubations but was substantially reduced in the former. BP-9,10-oxide and BP-7,8-oxide were not directly demonstrated. Data based on summation of diols and phenols resulting from the breakdown of these oxides indicated that they were present in reduced amounts in the microsomal incubation from BHA-fed mice. The 3-hydroxybenzo[a]pyrene (3-HOBP) was the major metabolite in both microsomal incubations and was present in a significantly higher percentage in the incubations from the BHA-fed mice when compared to control mice. Thus BHA resulted in two metabolic alterations which could result in its exerting an inhibitory effect on BP-induced carcinogenesis. The first was an increase in 3-HOBP, a metabolite of detoxification, and the second was a decrease in epoxidation, which is an activation process.
Hippocampal atrophy in systemic lupus erythematosus
Authors: S Appenzeller, A D Carnevalle, L M Li, L T L Costallat, F Cendes
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> To determine the frequency and progression of hippocampal atrophy in systemic lupus erythematosus (SLE) and the clinical, laboratory and treatment features associated with its occurrence. <b>Methods:</b> 150 patients with SLE and 40 healthy volunteers were enrolled in our study. A complete clinical, laboratory and neurological evaluation was performed. Magnetic resonance imaging was carried out using a 2T scanner (Elscint Prestige) and coronal T1-weighted images were used for manual volumetric measurements. Atrophy was defined as values &lt;2 standard deviations from the means of controls. <b>Results:</b> At entry into the study, the mean right and left hippocampal volumes of patients were significantly smaller than the hippocampal volumes of controls (p&lt;0.001). After the follow-up magnetic resonance imaging, a significant progression of reduction in right and left hippocampal volumes in patients was observed (p&lt;0.001). At entry, atrophy was identified in 43.9% and at follow-up in 66.7% of patients with SLE. Hippocampal atrophy was related to disease duration (p&lt;0.001) total corticosteroid dose (p = 0.01) and history of central nervous system (CNS) manifestations (p = 0.01). Progression of atrophy was associated with cumulative corticosteroid dose (p = 0.01) and number of CNS events (p = 0.01). Patients with cognitive impairment had more severe hippocampal atrophy than those without. <b>Conclusion:</b> Disease duration, total corticosteroid dose and greater number of CNS manifestations were associated with hippocampal atrophy in patients with SLE. A significant progression of hippocampal atrophy related to total corticosteroid dose and number of CNS events was observed. Further studies are necessary to confirm these findings.
Laparoscopic Live Donor Right Nephrectomy: A New Technique to Maximize the Length of the Renal Vein Using a Modified Endo GIA Stapler
Authors: Renaud Bollens, Dimitri Mikhaski, Baldo P. Espinoza, Alberto Rosenblatt, Anh Dung Hoang, Daniel Abramowicz, Vincent Donckier, Claude C. Schulman
Journal: European Urology (2006)
Influenza A Infection Simulating Pulmonary Embolism
Authors: D. Joanne Lynn
Journal: JAMA (1977)

The diagnosis of pulmonary embolism is generally established when the patient has characteristic pulmonary perfusion abnormalities in the setting of an appropriate clinical history and with no concurrent cardiopulmonary disease on chest x-ray film. The initial evaluation, including positive pulmonary perfusion scan, of four young black women suggested the diagnosis of pulmonary emboli. A syndrome of respiratory tract viral infection then developed, and further evaluation by angiography and perfusion scans contradicted the diagnoses of pulmonary emboli. Each patient had substantial convalescent-phase complement-fixation titers to influenza A. Thus, if reliance is placed in pulmonary perfusion scans, an erroneous diagnosis of pulmonary emboli may be made for patients with influenza A. (<i>JAMA</i>238:1166-1168, 1977)
Exposure to antidepressants and the risk of cryptogenic fibrosing alveolitis: a case-control study
Authors: R. Hubbard, A. Venn, J. Britton
Journal: European Respiratory Journal (2000)

The explanations for the emergence of cryptogenic fibrosing alveolitis as a new clinical entity during the second half of the 20th century are unclear. The authors have previously reported evidence of an increased risk of cryptogenic fibrosing alveolitis in relation to the use of antidepressant drugs. The authors have now tested this hypothesis a priori in an analysis of computerized general practice records for 890 cases of cryptogenic fibrosing alveolitis and 5,884 matched controls drawn from the UK General Practice Research Database. Exposure to antidepressants at the time of diagnosis was increased in cases compared to controls (odds ratio (OR) 1.52, 95% confidence interval (95% CI) 1.24-1.86), and this increase remained if the analysis was restricted to exposures 4 yrs prior to diagnosis (OR 1.50, 95% CI 0.98-2.30). However this increased prescribing was not specific to any particular class of antidepressant or individual drug, and there was no evidence of a dose-response relationship between exposure to amitriptyline (the most commonly prescribed antidepressant) and disease. The presented data do not allow any firm conclusion to be made as to whether there is a causal relationship between antidepressant exposure and cryptogenic fibrosing alveolitis, but it seems unlikely that exposure to tricyclic antidepressants shortly before diagnosis is a strong risk factor for cryptogenic fibrosing alveolitis.
Leukocyte Recruitment and Vascular Injury in Diabetic Nephropathy
Authors: Elena Galkina, Klaus Ley
Journal: Journal of the American Society of Nephrology (2006)

Different types of activated leukocytes play a crucial role in the pathogenesis of most kidney diseases from acute to chronic stages; however, diabetic nephropathy was not considered an inflammatory disease in the past. This view is changing now because there is a growing body of evidence implicating inflammatory cells at every stage of diabetic nephropathy. Renal tissue macrophages, T cells, and neutrophils produce various reactive oxygen species, proinflammatory cytokines, metalloproteinases, and growth factors, which modulate the local response and increase inflammation within the diabetic kidney. Although the precise mechanisms that direct leukocyte homing into renal tissues are not fully identified, it has been reported that intercellular adhesion molecule-1 and the chemokines CCL2 and CX3CL1 probably are involved in leukocyte migration in diabetic nephropathy. This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues.
T-helper function of parent leads to F1 chimeras. Presence of a separate T-cell subgroup able to stimulate allogeneic B cells but not syngeneic B cells.
Authors: J Sprent, H von Boehmer
Journal: The Journal of Experimental Medicine (1979)

Parent leads to F1 chimeras were prepared by reconstituting sublethally irradiated H-2 heterozygous mice with marrow cells from one parental strain. Purified parental strain T cells prepared from unprimed chimeras were exposed to sheep erythrocytes in heavily irradiated mice of each of the two parental strains and recovered from thoracic duct lymph of the recipients at either day 1 or day 5 posttransfer. The lymphoborne cells were then tested for their capacity to collaborate in vivo with B cells of the two parental strains. From this approach it was concluded that parent leads to F1 chimera T cells contain two discrete subgroups of T-helper cells, one specific for self H-2 determinants and the other restricted to H-2 determinants of the opposite parental strain. The restrictions mapped to the K-end of the H-2 complex.
Impact of Population Management With Direct Physician Feedback on Care of Patients With Type 2 Diabetes
Authors: Richard W. Grant, Hope E. Hamrick, Christine M. Sullivan, Anil K. Dubey, Henry C. Chueh, Enrico Cagliero, James B. Meigs
Journal: Diabetes Care (2003)

Population-level strategies may improve primary care for diabetes. We designed a controlled study to assess the impact of population management versus usual care on metabolic risk factor testing and management in patients with type 2 diabetes. We also identified potential patient-related barriers to effective diabetes management.We used novel clinical software to rank 910 patients in a diabetes registry at a single primary care clinic and thereby identify the 149 patients with the highest HbA(1c) and cholesterol levels. After review of the medical records of these 149 patients, evidence-based guideline recommendations regarding metabolic testing and management were sent via e-mail to each intervention patient's primary care provider (PCP). Over a 3-month follow-up period, we assessed changes in the evidence-based management of intervention patients compared with a matched cohort of control patients receiving usual care at a second primary care clinic affiliated with the same academic medical center.In the intervention cohort, PCPs followed testing recommendations more often (78%) than therapeutic change recommendations (36%, P = 0.001). Compared with the usual care control cohort, population management resulted in a greater overall proportion of evidence-based guideline practices being followed (59 vs. 45%, P = 0.02). Most intervention patients (62%) had potential barriers to effective care, including depression (35%), substance abuse (26%), and prior nonadherence to care plans (18%).Population management with clinical recommendations sent to PCPs had a modest but statistically significant impact on the evidence-based management of diabetes compared with usual care. Depression and substance abuse are prevalent patient-level adherence barriers in patients with poor metabolic control.
Comparative Analysis of the Membrane Proteome of Closely Related Metastatic and Nonmetastatic Tumor Cells
Authors: Christoph Roesli, Beatrice Borgia, Christoph Schliemann, Maja Gunthert, Heidi Wunderli-Allenspach, Raffaella Giavazzi, Dario Neri
Journal: Cancer Research (2009)

The identification of proteins that are preferentially expressed on the membrane of metastatic tumor cells is of fundamental importance in cancer research. Here, we report the systematic comparison of the membrane proteome of two closely related murine teratocarcinoma cell lines (F9B9 and F9DR), of which only one (F9DR) is capable of forming liver metastases in vivo. The proteomic methodology used in this study featured the surface protein biotinylation on tumor cells followed by protein purification on streptavidin resin and relative quantification of corresponding tryptic peptides by mass spectrometric procedures. The study allowed the identification of 998 proteins and the determination of their relative abundance. Proteins previously known to be associated with metastatic spread were found to be either up-regulated (e.g., synaptojanin-2) or down-regulated (e.g., Ceacam1) in F9DR cells. A dramatic increase in abundance at the cell membrane was observed for a broad variety of proteins (e.g., high-mobility group protein B1), which were mainly thought to reside in intracellular compartments, a finding that was confirmed using confocal laser scanning microscopy and immunochemical analysis of cell cultures. Furthermore, we showed by microautoradiographic analysis that certain target proteins can readily be reached by intravenously administered radiolabeled antibodies. Finally, we showed that the most promising antigens for antibody-based pharmacodelivery approaches are strongly and selectively expressed on the surface of tumor cells in three different syngeneic mouse models of liver metastases. Taken together, our results indicate that the expression of intracellular proteins on the membrane of metastatic cells is a feature much more common than previously expected.