tbuckley/cabot-search huggingface dataset:
Mechanisms of necroptosis in T cells
Authors: Irene L. Ch’en, Jennifer S. Tsau, Jeffery D. Molkentin, Masaaki Komatsu, Stephen M. Hedrick
Journal: The Journal of Experimental Medicine (2011)

Cell populations are regulated in size by at least two forms of apoptosis. More recently, necroptosis, a parallel, nonapoptotic pathway of cell death, has been described, and this pathway is invoked in the absence of caspase 8. In caspase 8–deficient T cells, necroptosis occurs as the result of antigen receptor–mediated activation. Here, through a genetic analysis, we show that necroptosis in caspase 8–deficient T cells is related neither to the programmed necrosis as defined by the requirement for mitochondrial cyclophilin D nor to autophagy as defined by the requirement for autophagy-related protein 7. Rather, survival of caspase 8–defective T cells can be completely rescued by loss of receptor-interacting serine-threonine kinase (Ripk) 3. Additionally, complementation of a T cell–specific caspase 8 deficiency with a loss of Ripk3 gives rise to lymphoproliferative disease reminiscent of lpr or gld mice. In conjunction with previous work, we conclude that necroptosis in antigen-stimulated caspase 8–deficient T cells is the result of a novel Ripk1- and Ripk3-mediated pathway of cell death.
Expression and role of TRPC proteins in human platelets: evidence that TRPC6 forms the store-independent calcium entry channel
Authors: Sheila R. Hassock, Michael X. Zhu, Claudia Trost, Veit Flockerzi, Kalwant S. Authi
Journal: Blood (2002)

Store-operated Ca(++) entry (SOCE) is thought to comprise the major pathway for Ca(++) entry in platelets. Recently, a number of transient receptor potential (TRP) proteins, which have been divided into 3 groups (TRPC, TRPM, and TRPV), have been suggested as SOCE channels. We report the expression and function of TRPC proteins in human platelets. TRPC6 is found at high levels and TRPC1 at low levels. Using purified plasma (PM) and intracellular membranes (IM), TRPC6 is found in the PM, but TRPC1 is localized to the IM. Using Fura-2-loaded platelets, we report that, in line with TRPC6 expression, 1-oleoyl-2-acetyl-sn-glycerol (OAG) stimulated the entry of Ca(++) and Ba(2+) independently of protein kinase C. Thrombin also induced the entry of Ca(++) and Ba(2+), but thapsigargin, which depletes the stores, induced the entry of only Ca(++). Thus, thrombin activated TRPC6 via a SOCE-independent mechanism. In phosphorylation studies, we report that neither TRPC6 nor TRPC1 was a substrate for tyrosine kinases. TRPC6 was phosphorylated by cAMP-dependent protein kinase (cAMP-PK) and associated with other cAMP-PK substrates. TRPC1 was not phosphorylated by cAMP-PK but also associated with other substrates. Activation of cAMP-PK inhibited Ca(++) but not Ba(2+) entry induced by thrombin and neither Ca(++) nor Ba(2+) entry stimulated by OAG. These results suggest that TRPC6 is a SOCE-independent, nonselective cation entry channel stimulated by thrombin and OAG. TRPC6 is a substrate for cAMP-PK, although phosphorylation appears to not affect cation permeation. TRPC1 is located in IM, suggesting a role at the level of the stores.
Prenatal PCB-153 Exposure and Decreased Birth Weight: Verner et al. Respond
Authors: Marc-André Verner, Melvin E. Andersen, Harvey J. Clewell, Matthew P. Longnecker
Journal: Environmental Health Perspectives (2014)

Verner et al. (2013) recently questioned whether the association between cord levels of PCB-153 (poly chlorinated biphenyl-153) and birth weight reported in our recent metaanalysis (Govarts et al. 2012) might be attributable to the influence of gestational weight gain (GWG), a factor that may be related to both PCB-153 concentrations and birth weight.By using simulated data in a physiologically based pharmaco kinetic (PBPK) model, Verner et al. (2013) concluded thatThe association between prenatal levels of PCBs and birth weight may be strongly confounded by the effect of [GWG] on both blood PCB levels and birth weight.
Age-dependent expression of the erythropoietin gene in rat liver and kidneys.
Authors: K U Eckardt, P J Ratcliffe, C C Tan, C Bauer, A Kurtz
Journal: Journal of Clinical Investigation (1992)

Using RNAse protection, we have made quantitative measurements of erythropoietin (EPO) mRNA in liver and kidneys of developing rats (days 1-54), to determine the relative contribution of both organs to the total EPO mRNA, to monitor changes which occur with development, and to compare the hypoxia-induced accumulation of EPO mRNA with the changes in serum EPO concentrations. To determine whether developmental and organ-specific responsiveness is related to the type of hypoxic stimulus, normobaric hypoxia was compared with exposure to carbon monoxide (functional anemia). Under both stimuli EPO mRNA concentration in liver was maximal on day 7 and declined during development. In contrast, EPO mRNA concentration in kidney increased during development from day 1 when it was 30-65% the hepatic concentration to day 54 when it was 12-fold higher than in liver. When organ weight was considered the liver was found to contain the majority of EPO mRNA in the first three to four weeks of life, and although, in stimulated animals, the hepatic proportion declined from 85-91% on day 1, it remained approximately 33% at day 54 and was similar for the two types of stimuli. When normalized for body weight the sum of renal and hepatic EPO mRNA in animals of a particular age was related linearly to serum hormone concentrations. However, the slope of this regression increased progressively with development, suggesting age-dependent alterations in translational efficiency or EPO metabolism.
Mixed Chimerism and Transplantation Tolerance
Authors: Thomas Wekerle, Megan Sykes
Journal: Annual Review of Medicine (2001)

▪ Abstract Achieving transplanatation tolerance is an important goal in the effort to reduce long-term morbidity and mortality in organ transplant recipients. Robust, lifelong, donor-specific tolerance can be reliably achieved by induction of mixed chimerism in various animal models. To date, the clinical application of these proto-cols has been impeded partly by the potential toxicity of the required host conditioning regimens and the lack of successful studies in large animals. This article reviews the progress achieved in recent years in developing considerably milder conditioning protocols in rodents, and in extending some of these models to achieve permanent mixed chimerism and tolerance in large animals. Advances in the induction of xenogeneic tolerance through mixed chimerism are also discussed.
Visualising E-selectin in the detection and evaluation of inflammatory bowel disease
Authors: M Bhatti, P Chapman, M Peters, D Haskard, H J F Hodgson
Journal: Gut (1998)

Vascular endothelial E-selectin expression is induced by proinflammatory cytokines and contributes to accumulation of leucocytes in tissues.To investigate the role of E-selectin in inflammatory bowel disease (IBD).E-selectin expression was assessed in patients with ulcerative colitis and Crohn's disease by measuring the concentration of circulating soluble E-selectin (sE-selectin) using ELISA, by immunohistochemistry of colonic biopsy specimens, and by abdominal immunoscintigraphy after injecting radiolabelled F(ab')2 fragment of a monoclonal anti-E-selectin antibody. The value of scintigraphy using anti-E-selectin was judged by a prospective comparative study of autologous leucocyte scanning and E-selectin antibody scanning in 17 patients with IBD.Circulating sE-selectin was elevated in patients with clinically active disease. Tissue expression of E-selectin was enhanced in patients with active inflammation, with weak or absent expression in inactive disease and healthy controls. In-111 labelled anti-E-selectin scintiscans were compared with Tc-99m labelled leucocyte scans performed 24 hours earlier. Twelve patients had areas of active inflammation on leucocyte scan while 11 patients had positive E-selectin scans. The results of the two scans were concordant in 14 patients, with those positive for both (10/17) showing similar disease localisation and extent.Tissue E-selectin and circulating sE-selectin are increased during active inflammatory bowel disease. Anti-E-selectin imaging with radiolabelled monoclonal antibody identified areas of inflammation in Crohn's disease and ulcerative colitis. The technique should prove useful clinically for identifying the site and extent of disease.
Regulation of Immunity by Butyrophilins
Authors: David A. Rhodes, Walter Reith, John Trowsdale
Journal: Annual Review of Immunology (2016)

Butyrophilin molecules (commonly contracted to BTN), collectively take their name from the eponymous protein in cow's milk. They are considered to be members of the B7 family of costimulatory receptors, which includes B7.1 (CD80), B7.2 (CD86), and related molecules, such as PD-L1 (B7-H1, CD274), ICOS-L (CD275), and B7-H3 (CD276). These coreceptors modulate T cell responses upon antigen presentation by major histocompatibility complex and cognate αβ T cell receptor engagement. Molecules such as BTN3A1 (CD277), myelin oligodendrocyte glycoprotein, and mouse Skint1 and Btnl2, all members of the butyrophilin family, show greater structural and functional diversity than the canonical B7 receptors. Some butyrophilins mediate complex interactions between antigen-presenting cells and conventional αβ T cells, and others regulate the immune responses of specific γδ T cell subsets by mechanisms that have characteristics of both innate and adaptive immunity.
Phase III Randomized, Placebo-Controlled Study of Cetuximab Plus Brivanib Alaninate Versus Cetuximab Plus Placebo in Patients With Metastatic, Chemotherapy-Refractory, Wild-Type <i>K-RAS</i> Colorectal Carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial
Authors: Lillian L. Siu, Jeremy D. Shapiro, Derek J. Jonker, Chris S. Karapetis, John R. Zalcberg, John Simes, Felix Couture, Malcolm J. Moore, Timothy J. Price, Jehan Siddiqui, Louise M. Nott, Danielle Charpentier, Winston Liauw, Michael B. Sawyer, Michael Jefford, Nadine M. Magoski, Andrew Haydon, Ian Walters, Jolie Ringash, Dongsheng Tu, Chris J. O'Callaghan
Journal: Journal of Clinical Oncology (2013)

The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity.Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS).A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively.Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
Detection of intrahepatic hepatitis C virus replication by strand-specific semi-quntitative RT-PCR: preliminary application to the liver transplantation model
Authors: Francesco Negro, Emiliano Giostra, Krzysztof Krawczynski, Rafael Quadri, Laura Rubbia-Brandt, Gilles Mentha, Giuseppe Colucci, Luc Perrin, Antoine Hadengue
Journal: Journal of Hepatology (1998)
THE NATURE OF ANAPHYLATOXIN
Authors: J. Bronfenbrenner
Journal: The Journal of Experimental Medicine (1915)

1. The union of fresh serum of pregnant or immunized animals with the corresponding boiled protein (substratum) is accompanied by the formation of poisonous substances. 2. The poison originates from the serum as a result of its autodigestion, and not from the substratum. 3. The process of autodigestion may be determined by the specific or non-specific removal of the antitrypsin of the serum. 4. The poisons originating from the serum are toxic only for homologous animals. 5. The autodigestion of the serum, if allowed to proceed far enough, may go beyond the toxic stage. 6. The biological properties of these poisons indicate their close similarity to the anaphylatoxin, and suggest that the anaphylatoxin of Friedberger is a product of the autodigestion of serum, and not of the protein outside of the serum.
Meta-analysis: Chondroitin for Osteoarthritis of the Knee or Hip
Authors: Stephan Reichenbach, Rebekka Sterchi, Martin Scherer, Sven Trelle, Elizabeth Bürgi, Ulrich Bürgi, Paul A. Dieppe, Peter Jüni
Journal: Annals of Internal Medicine (2007)

Background: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. Purpose: To determine the effects of chondroitin on pain in patients with osteoarthritis. Data Sources: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. Study Selection: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. Data Extraction: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. Data Synthesis: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of −0.03 (95% CI, −0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event. Limitations: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable. Conclusions: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.
Making Bad Cells Go Good: The Promise of Epigenetic Therapy
Authors: Edward A. Sausville, Michael A. Carducci
Journal: Journal of Clinical Oncology (2005)

Among the prevailing explanations for the development of cancer over the past 50 years has risen the notion that clinically apparent cancers represent the failure of the tumor cells to differentiate along a pathway that would be expected for their tissues of origin. This point of view springs from and leads to the familiar characterization of epithelial neoplasms as well-, moderately, and poorly differentiated. This obviously orients our thinking about hematologic cancers, where the neoplastic cells frequently seem to be parodies of normal maturing marrow elements. Indeed, laboratory studies have demonstrated that exposure to various substances causes differentiation of certain hematopoietic tumor cells with their acquisition of more normal characteristics. Historically, the field received a tremendous boost—and a challenge—when Leder and Leder 1 demonstrated that high concentrations of sodium butyrate could cause marked differentiation of murine erythroleukemia cells. The implications that profound regulation of gene expression could be manipulated by so simple a molecule had tantalizing mechanistic and therapeutic implications. The subsequent demonstration that high concentrations of sodium butyrate caused marked change in the acetylation state of histones pointed toward modification of DNA or chromatin-associated proteins as correlating with the basis for this effect. 2 In parallel with these developments, longstanding observations that the methylation status of certain genes could influence their expression had arisen from the observations that there are actually five bases that could be detected in DNA. In addition to the familiar adenine, guanine, thymine, and cytosine, a variable proportion of cytosine existed as a methylated form. Moreover, the pattern of methylated cytosines was conserved from cycle to cycle of replication by the action of methyltransferases so that only one of the two chromosomes bearing certain genes was methylated. The methylated allele tended to be preferentially underexpressed. This nongenetic (in the sense that it did not arise from the sequence of the gene) but heritable feature was described as the mechanism ‘‘imprinting’’ certain maternally, as opposed to paternally, derived gene sets. 3 Methylation
Effects of sulfonylureas on the synthesis and secretion of plasminogen activator from bovine aortic endothelial cells.
Authors: B S Kuo, G Korner, T D Bjornsson
Journal: Journal of Clinical Investigation (1988)

The effects of sulfonylureas on the production of plasminogen activator (PA) and antiactivator (PAI) were investigated using bovine aortic endothelial cells. All compounds studied stimulated PA release (1.3- to 5.2-fold), with glipizide being the most potent, followed by tolazamide, chlorpropamide, and tolbutamide, in that order, while glyburide was the least effective. Both tissue-type and urokinase-type PA production was enhanced. Studies using metabolic inhibitors indicated that both RNA and protein syntheses are required for the sulfonylurea-mediated stimulation of PA release. In addition to continuous release of the two PAs, there was also a continuous release of a single PAI, which did not show an increase after the sulfonylureas. These results suggest that, in addition to their beneficial effects in the treatment of diabetes mellitus, some sulfonylurea compounds may also have significant thrombolytic effects. These results also suggest that pharmacological enhancement of PA production by vascular endothelial cells may be a promising antithrombotic mechanism.
Mouse Rad1 deletion enhances susceptibility for skin tumor development
Authors: Lu Han, Zhishang Hu, Yuheng Liu, Xiangyuan Wang, Kevin M. Hopkins, Howard B. Lieberman, Haiying Hang
Journal: Molecular Cancer (2010)

Abstract Background Cells are constantly exposed to stresses from cellular metabolites as well as environmental genotoxins. DNA damage caused by these genotoxins can be efficiently fixed by DNA repair in cooperation with cell cycle checkpoints. Unrepaired DNA lesions can lead to cell death, gene mutation and cancer. The Rad1 protein, evolutionarily conserved from yeast to humans, exists in cells as monomer as well as a component in the 9-1-1 protein complex. Rad1 plays crucial roles in DNA repair and cell cycle checkpoint control, but its contribution to carcinogenesis is unknown. Results To address this question, we constructed mice with a deletion of Mrad1 . Matings between heterozygous Mrad1 mutant mice produced Mrad1 +/+ and Mrad1 +/- but no Mrad1 -/- progeny, suggesting the Mrad1 null is embryonic lethal. Mrad1 +/- mice demonstrated no overt abnormalities up to one and half years of age. DMBA-TPA combinational treatment was used to induce tumors on mouse skin. Tumors were larger, more numerous, and appeared earlier on the skin of Mrad1 +/- mice compared to Mrad1 +/+ animals. Keratinocytes isolated from Mrad1 +/- mice had significantly more spontaneous DNA double strand breaks, proliferated slower and had slightly enhanced spontaneous apoptosis than Mrad1 +/+ control cells. Conclusion These data suggest that Mrad1 is important for preventing tumor development, probably through maintaining genomic integrity. The effects of heterozygous deletion of Mrad1 on proliferation and apoptosis of keratinocytes is different from those resulted from Mrad9 heterozygous deletion (from our previous study), suggesting that Mrad1 also functions independent of Mrad9 besides its role in the Mrad9-Mrad1-Mhus1 complex in mouse cells.
Role in Tumor Growth of a Glycogen Debranching Enzyme Lost in Glycogen Storage Disease
Authors: Sunny Guin, Courtney Pollard, Yuanbin Ru, Carolyn Ritterson Lew, Jason E. Duex, Garrett Dancik, Charles Owens, Andrea Spencer, Scott Knight, Heather Holemon, Sounak Gupta, Donna Hansel, Marc Hellerstein, Pawel Lorkiewicz, Andrew N. Lane, Teresa W.-M. Fan, Dan Theodorescu
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundBladder cancer is the most common malignancy of the urinary system, yet our molecular understanding of this disease is incomplete, hampering therapeutic advances.
Efficacy of Sertraline in the Treatment of Children and Adolescents With Major Depressive Disorder—Reply
Authors: Karen D. Wagner, Christopher J. Wohlberg, Ruoyong Yang
Journal: JAMA (2004)

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