tbuckley/cabot-search huggingface dataset:
Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C
Authors: Paula Bonorino, Vincent Leroy, Tania Dufeu-Duchesne, Stefania Tongiani-Dashan, Nathalie Sturm, Martine Pernollet, Eric Vivier, Jean-Pierre Zarski, Patrice N. Marche, Evelyne Jouvin-Marche
Journal: Hepatology (2007)

CD8+ T cells represent a sizable component of the liver inflammatory infiltrate in chronic hepatitis C and are thought to contribute to immune-mediated tissue injury. Because chronic stimulation may promote the expression by CD8+ T cells of distinct human leukocyte antigen class I–specific natural killer cell receptors (NKRs) susceptible to both inhibiting effector functions and promoting cell survival, we examined the distribution and characteristics of CD8+ T cells with such receptors in chronic hepatitis C patients. NKR CD8+ T cells were detectable in liver and peripheral blood from hepatitis C virus (HCV)–infected patients but were not major subsets. However, the frequency of NKG2A+ CD8+ in the liver and in a lesser extent in the peripheral blood was positively correlated to histological activity in HCV-infected patients. No such correlation was found with KIR+ T cells in liver in HCV-infected patients and with the both NKR CD8+ T cells in hepatitis B virus (HBV) infected patients. Circulating CD8+ T cells expressing KIRs exhibited phenotypic features of memory T cells with exacerbated expression of the senescence marker CD57 in patients. NKG2A+CD8+ T cells were committed T cells that appeared less differentiated than KIR+CD8+ T cells. In HCV-infected patients, their content in perforin was low and similar to that observed in NKG2A−CD8+ T cells; this scenario was not observed in healthy subjects and HBV-infected patients. Both NKG2A and KIRs could inhibit the response of HCV-specific CD8+ T cells ex vivo. Conclusion: These results support the concept that an accumulation in the liver parenchyma of NKR+CD8+ T cells that have functional alterations could be responsible for liver lesions. They provide novel insights into the complexity of liver-infiltrating CD8+ T cells in chronic hepatitis C and reveal that distinct subsets of antigen-experienced CD8+ T cells are differentially sensitive to the pervasive influence of HCV
NF-κB–Dependent Plasticity of the Epithelial to Mesenchymal Transition Induced by <i>Von Hippel-Lindau</i> Inactivation in Renal Cell Carcinomas
Authors: Allan J. Pantuck, Jiabin An, Huiren Liu, Matthew B. Rettig
Journal: Cancer Research (2010)

Abstract The critical downstream signaling consequences contributing to renal cancer as a result of loss of the tumor suppressor gene von Hippel-Lindau (VHL) have yet to be fully elucidated. Here, we report that VHL loss results in an epithelial to mesenchymal transition (EMT). In studies of paired isogenic cell lines, VHL silencing increased the levels of N-cadherin and vimentin and reduced the levels of E-cadherin relative to the parental VHL+ cell line, which displayed the opposite profile. VHL+ cells grew as clusters of cuboidal and rhomboid cells, whereas VHL-silenced cells took on an elongated, fibroblastoid morphology associated with a more highly invasive character in Matrigel chamber assays. Based on earlier evidence that VHL loss can activate NF-κB, a known mediator of EMT, we tested whether NF-κB contributed to VHL-mediated effects on EMT. On pharmacologic or molecular inhibition of NF-κB, VHL-silenced cells regained expression of E-cadherin, lost expression of N-cadherin, and reversed their highly invasive phenotype. Introducing a pVHL-resistant hypoxia-inducible factor 1α (HIF1α) mutant (HIFαM) into VHL+ cells heightened NF-κB activity, phenocopying EMT effects produced by VHL silencing. Conversely, inhibiting the heightened NF-κB activity in this setting reversed the EMT phenotype. Taken together, these results suggest that VHL loss induces an EMT that is largely dependent on HIFα-induced NF-κB. Our findings rationalize targeting the NF-κB pathway as a therapeutic strategy to treat renal tumors characterized by biallelic VHL inactivation. Cancer Res; 70(2); 752–61
Socioeconomic Factors and Cancer Incidence Among Blacks and Whites
Authors: C. R. Baquet, J. W. Horm, T. Gibbs, P. Greenwald
Journal: JNCI Journal of the National Cancer Institute (1991)

Findings from previous studies suggest that differences in socioeconomic status may be responsible for some, if not all, of the elevated incidence of cancer among blacks as compared with whites. Using incidence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, we tested this hypothesis by correlating black and white cancer incidence rates in three US metropolitan areas between 1978 and 1982 with data from the 1980 census on socioeconomic status within individual census tracts. The study analyzed data on the incidence of cancer at all sites combined (>100 cancer sites) and at seven major sites separately. As in other studies, income and educational levels served as surrogates for socieconomic status. The present study also used census-tract data on population density as a surrogate factor. Each of these measures of socioeconomic status was analyzed independently. Before correlation with census-tract data, age-adjusted data on cancer incidence showed statistically significant elevated risks among blacks for cancer at all sites combined and at four of the seven separate sites; whites showed an elevated risk for cancer at two sites. Cancer at only one site, the colon, showed no significant association with race. When age-adjusted incidence data were correlated with socioeconomic status, the comparative black white risks changed: Whites showed an elevated risk of cancer at all sites combined and at three of the seven separate sites; blacks maintained their elevated risk at three sites. These findings suggest that the disproportionate distribution of blacks at lower socioeconomic levels accounts for much of the excess cancer burden among blacks. They also suggest that for both blacks and whites unidentified racial factors, which may be either cultural or genetic and which are not closely linked to socioeconomic status, may play a role in the incidence of some cancers. [J Natl Cancer Inst 83:551–557, 1991]
Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data
Authors: T De Backer, R Vander Stichele, P Lehert, L Van Bortel
Journal: BMJ (2009)

<b>Objective</b> To assess the efficacy of naftidrofuryl compared with placebo in treating the symptoms of intermittent claudication. <b>Design</b> Meta-analysis based on individual patient data. <b>Data sources</b> Medline, International Pharmaceutical Abstracts, Embase, Science Citation Index, and the Cochrane trial registers. Reference lists of retrieved articles were checked. Authors and companies were approached for additional information and individual patient data. <b>Inclusion criteria</b> Double blind, randomised controlled trials in patients with intermittent claudication receiving oral naftidrofuryl or placebo and with pain-free walking distance as primary outcome. <b>Data collection</b> Individual patient data were collected from electronic data or from case report forms and checked for integrity. <b>Analysis</b> All randomised patients were analysed following the intention to treat principle. Efficacy was assessed by the ratio of geometric mean of the relative improvement in pain-free walking distance after use of naftidrofuryl compared with placebo. In the analysis of responders, therapeutic success was defined as an improvement of walking distance at baseline by at least 50%. <b>Results</b> In total, 1266 patients were randomised (1083 in the main analysis). The ratio of relative improvement in pain-free walking distance after use of naftidrofuryl compared with placebo was 1.37 (95% confidence interval 1.27 to 1.49). The difference in response rate was 22.3% (95% confidence interval 17.1% to 27.6%) and the number needed to treat for relief of symptoms during six months of treatment was 4.48 (95% confidence interval 3.62 to 5.85). <b>Conclusion</b> This meta-analysis of individual patient data provides evidence that naftidrofuryl has a clinically meaningful effect compared with placebo in improving walking distance in patients with intermittent claudication.
Loss of an individual idiotype on chemical modification. A strategy for assigning idiotypic determinants.
Authors: J Dickerman, B Clevinger, B Friedenson
Journal: The Journal of Experimental Medicine (1981)

Two dextran-binding myeloma proteins, J558 and Hdex 24, which possess the same individual idiotype (IdI) were diazotized to low levels (1-3.3 groups per subunit) with 1-[14C]-p-aminobenzoate. Both proteins lost the IdI idiotype under these conditions with most of the label incorporated on the heavy chains of each protein. When the diazotization ws carried out in the presence of the hapten 1-O-methyl-alpha-D-glucopyranoside the loss of idiotypic reactivity could be prevented for J558 but not for Hdex 24. Under these conditions most of the label was incorporated on the light chains of J558, but on the heavy chains of Hdex 24. For J558, these results show that a major determinant of the individual idiotype is within the hypervariable positions of the heavy chain. For Hdex 24 the determinant being modified is on the heavy chain but not involved in hapten binding. These results are consistent with previous work showing that J558 and Hdex 24 differ in amino acid sequence in the D and the J segments of the heavy chain and offer an alternative and complementary strategy for assigning idiotypic determinants.
Assembly and Antigen-Presenting Function of MHC Class I Molecules in Cells Lacking the ER Chaperone Calreticulin
Authors: Bin Gao, Raju Adhikari, Mark Howarth, Kimitoshi Nakamura, Marielle C Gold, Ann B Hill, Rai Knee, Marek Michalak, Tim Elliott
Journal: Immunity (2002)
Characterization of avirulent mutant Legionella pneumophila that survive but do not multiply within human monocytes.
Authors: M A Horwitz
Journal: The Journal of Experimental Medicine (1987)

Legionella pneumophila, the causative agent of Legionnaires' disease, is a Gram-negative bacterium and a facultative intracellular parasite that multiplies in human monocytes and alveolar macrophages. In this paper, mutants of L. pneumophila avirulent for human monocytes were obtained and extensively characterized. The mutants were obtained by serial passage of wild-type L. pneumophila on suboptimal artificial medium. None of 44 such mutant clones were capable of multiplying in monocytes or exerting a cytopathic effect on monocyte monolayers. Under the same conditions, wild-type L. pneumophila multiplied 2.5-4.5 logs, and destroyed the monocyte monolayers. The basis for the avirulent phenotype was an inability of the mutants to multiply intracellularly. Both mutant and wild-type bacteria bound to and were ingested by monocytes, and both entered by coiling phagocytosis. Thereafter, their intracellular destinies diverged. The wild-type formed a distinctive ribosome-lined replicative phagosome, inhibited phagosome-lysosome fusion, and multiplied intracellularly. The mutant did not form the distinctive phagosome nor inhibit phagosome-lysosome fusion. The mutant survived intracellularly but did not replicate in the phagolysosome. In all other respects studied, the mutant and wild-type bacteria were similar. They had similar ultrastructure and colony morphology; both formed colonies of compact and diffuse type. They had similar structural and secretory protein profiles and LPS profile by PAGE. Both the mutant and wild-type bacteria were completely resistant to human complement in the presence or absence of high titer anti-L. pneumophila antibody. The mutant L. pneumophila have tremendous potential for enhancing our understanding of the intracellular biology of L. pneumophila and other parasites that follow a similar pathway through the mononuclear phagocyte. Such mutants also show promise for enhancing our understanding of immunity to L. pneumophila, and they may serve as prototypes in the development of safe and effective vaccines against intracellular pathogens.
Node-Negative Colorectal Cancer at High Risk of Distant Metastasis Identified by Combined Analysis of Lymph Node Status, Vascular Invasion, and Raf-1 Kinase Inhibitor Protein Expression
Authors: Inti Zlobec, Kristi Baker, Parham Minoo, Jeremy R. Jass, Luigi Terracciano, Alessandro Lugli
Journal: Clinical Cancer Research (2008)

To identify independent clinicopathologic factors and protein markers leading to the identification of colorectal cancer (CRC) patients with mismatch repair proficiency at risk of developing metastasis and, consequently, more likely to benefit from combined modality therapy.Immunohistochemistry for 22 tumor markers was done using a tissue microarray. A subset of 387 CRC patients with complete clinicopathologic data and TNM stage was analyzed. Univariate and multivariate analyses were done to identify independent predictive markers of metastasis. The results were validated on 810 CRC patients.In univariate analysis, T stage (P < 0.001), N stage (P < 0.001), tumor grade (P = 0.005), vascular invasion (P < 0.001), tumor budding (P < 0.001), positive expression of beta-catenin (P = 0.015), overexpression of RHAMM (P = 0.008), negative expression of Raf-1 kinase inhibitor protein (RKIP; P = 0.001), and absence of intraepithelial lymphocytes (P = 0.017) were significantly associated with the presence of distant metastasis. In multivariate analysis, higher N stage (P < 0.001), presence of vascular invasion (P = 0.009), and RKIP loss (P = 0.003) independently predicted distant metastatic disease. A subgroup of node-negative patients was identified as high risk for distant metastasis and showed a similar probability of metastatic risk and nearly identical survival times as node-positive patients with absence of vascular invasion and positive RKIP expression (metastatic risk, 24% and 22%; median survival time, 45.0 and 47.0 months, respectively).The combined analysis of N stage, vascular invasion, and RKIP expression is highly predictive of distant metastasis in patients with mismatch repair--proficient CRC. Additionally, a subgroup of more aggressive N(0) tumors can be identified by evaluating vascular invasion and RKIP expression.
Structure and Function of Cyclic Nucleotide-Gated Channels
Authors: W N Zagotta, S A Siegelbaum
Journal: Annual Review of Neuroscience (1996)

Cyclic nucleotide-gated (CNG) channels play important roles in both visual (Yau & Baylor 1989) and olfactory (Zufall et al 1994) signal transduction. The cloning of the gene coding for a rod photoreceptor channel (Kaupp et al 1989) and the subsequent cloning of related genes from olfactory neurons (Dhallan et al 1990, Ludwig et al 1990, Goulding et al 1992) has sparked much progress over the past several years in elucidating the structural bases for the function of the CNG channels. One of the surprising features to emerge from these cloning studies was that the CNG channels are structurally homologous to the voltage-gated channels (Jan & Jan 1990) despite the fact that the CNG channels are gated by the binding of a ligand-cAMP or cGMP-and not by voltage. In this review we focus on recent studies of the relationship between the structure and function of the CNG channels. Given the homology between CNG channels and voltage-gated channels, such studies are likely to provide important general information about the structure and function of a wide variety of channel types.
Perinatal deaths: analysis by clinical cause to assess value of induction of labour.
Authors: M B McNay, G M McIlwaine, P W Howie, M C Macnaughton
Journal: BMJ (1977)

Over the 10 years 1966-75 the rate of induction of labour in the Glasgow Royal Maternity Hospital has increased from 16-3% of all births. During the same period perinatal mortality fell from 33 to 22 per 1000, mainly because of significantly fewer deaths due to antepartum haemorrhage; trauma; maternal diseases; and unknown causes in mature babies. The reduction in the number of deaths of unknown causes in mature fetuses was achieved by preventing deaths occurring after 40 weeks and was recorded in all age and parity groups. The results suggested that increased use of induction of labour has contributed to the improved perinatal mortality rate.
Mcl-1 Down-regulation Potentiates ABT-737 Lethality by Cooperatively Inducing Bak Activation and Bax Translocation
Authors: Shuang Chen, Yun Dai, Hisashi Harada, Paul Dent, Steven Grant
Journal: Cancer Research (2007)

Abstract The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which may confer resistance to this novel agent. Here, we show that Mcl-1 down-regulation by the cyclin-dependent kinase (CDK) inhibitor roscovitine or Mcl-1-shRNA dramatically increases ABT-737 lethality in human leukemia cells. ABT-737 induces Bax conformational change but fails to activate Bak or trigger Bax translocation. Coadministration of roscovitine and ABT-737 untethers Bak from Mcl-1 and Bcl-xL, respectively, triggering Bak activation and Bax translocation. Studies employing Bax and/or Bak knockout mouse embryonic fibroblasts (MEFs) confirm that Bax is required for ABT-737 ± roscovitine lethality, whereas Bak is primarily involved in potentiation of ABT-737–induced apoptosis by Mcl-1 down-regulation. Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737 + roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive. Finally, Mcl-1 knockout MEFs are extremely sensitive to Bak conformational change and apoptosis induced by ABT-737, effects that are not potentiated by roscovitine. Collectively, these findings suggest down-regulation of Mcl-1 by either CDK inhibitors or genetic approaches dramatically potentiate ABT-737 lethality through cooperative interactions at two distinct levels: unleashing of Bak from both Bcl-xL and Mcl-1 and simultaneous induction of Bak activation and Bax translocation. These findings provide a mechanistic basis for simultaneously targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia. [Cancer Res 2007;67(2):782–91]
Intravenous infusion of total dose iron is superior to oral iron in treatment of anemia in peritoneal dialysis patients
Authors: N Ahsan
Journal: Journal of the American Society of Nephrology (1998)

In the treatment of anemia of chronic renal failure, the most common cause of recombinant human erythropoietin (rhEPO) resistance is iron deficiency. In peritoneal dialysis (PD) patients, oral iron therapy is an accepted and convenient method of iron supplementation. The effectiveness of oral iron, however, is limited by many factors, including gastrointestinal side effects and poor gastric absorption. This study prospectively compared the efficacy of single intravenous infusion of total dose iron (ITDI group) given in an outpatient setting with oral iron (oral group) for the treatment of anemia in PD patients. Twenty-five adult stable PD patients with baseline hematocrit 25 to 35% were entered into the study. Thirteen patients with serum transferrin saturation (TSAT) < 25% received ITDI, and 12 patients with TSAT between 25 and 35% received oral iron. One patient in the oral group received emergent blood transfusion and was excluded from analysis. Hematocrit and iron indices were measured at monthly intervals. Doses of rhEPO were adjusted monthly to maintain target hematocrit at 35%. At the end of the study (6 mo), despite similar baseline mean hematocrit (31.0 +/- 0.9 versus 33.0 +/- 1.0%), comparable mean baseline weekly rhEPO dose (7886 +/- 1449 versus 6370 +/- 1553 U/wk), and significantly lower level of mean TSAT (11.3 +/- 3.5 versus 30.1 +/- 3.5%; P < 0.05), the ITDI group when compared with the oral group had significantly higher mean hematocrit (36.0 +/- 1.0 versus 31.4 +/- 1.1%; P < 0.05) and TSAT (33.7 +/- 3.7 versus 22.6 +/- 4.0%; P < 0.05) values. In addition, the final mean dose of weekly rhEPO was significantly lower in the ITDI group (4799 +/- 981 versus 9998 +/- 1027 U/wk; P < 0.05). No patient in the ITDI group developed an adverse reaction to intravenous iron. It is concluded that ITDI represents a more efficacious method of iron supplementation in PD patients receiving rhEPO. Moreover, ITDI is safe and well tolerated and can be administered in an outpatient setting.
Epigenetically Deregulated microRNA-375 Is Involved in a Positive Feedback Loop with Estrogen Receptor α in Breast Cancer Cells
Authors: Pedro de Souza Rocha Simonini, Achim Breiling, Nibedita Gupta, Mahdi Malekpour, Mahmoud Youns, Ramesh Omranipour, Fatemeh Malekpour, Stefano Volinia, Carlo M. Croce, Hossein Najmabadi, Sven Diederichs, Özgür Sahin, Doris Mayer, Frank Lyko, Jörg D. Hoheisel, Yasser Riazalhosseini
Journal: Cancer Research (2010)

Abstract Estrogen receptor α (ERα) upregulation causes abnormal cell proliferation in about two thirds of breast cancers, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high expression of the microRNA miR-375 in ERα-positive breast cell lines is a key driver of their proliferation. miR-375 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypomethylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ERα with regulatory regions of miR-375. Inhibiting miR-375 in ERα-positive MCF-7 cells resulted in reduced ERα activation and cell proliferation. A combination of expression profiling from tumor samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigations revealed that miR-375 regulates RASD1 by targeting the 3′ untranslated region in RASD1 mRNA. Additionally, we found that RASD1 negatively regulates ERα expression. Our findings define a forward feedback pathway in control of ERα expression, highlighting new strategies to treat ERα-positive invasive breast tumors. Cancer Res; 70(22); 9175–84. ©2010 AACR.
β <sub>1</sub> -Adrenergic Receptor Blockade Attenuates Angiotensin II–Mediated Catecholamine Release Into the Cardiac Interstitium in Mitral Regurgitation
Authors: José Tallaj, Chih-Chang Wei, Gerald H. Hankes, Merrilee Holland, Patricia Rynders, A. Ray Dillon, Jeffrey L. Ardell, J. Andrew Armour, Pamela A. Lucchesi, Louis J. Dell’Italia
Journal: Circulation (2003)

This study tested the hypothesis that beta1-adrenoreceptor blockade modulates the angiotensin II (Ang II)-evoked neural release of norepinephrine (NE) and epinephrine (Epi) into the cardiac interstitial fluid (ISF) space in experimentally induced mitral regurgitation (MR) in the dog.Normal dogs (n=8) were compared with dogs with MR of 2 (n=8) and 4 (n=6) weeks' duration and with dogs with MR treated with beta1-receptor blockade (RB; extended-release metoprolol succinate, 100 mg QD; MR+beta1-RB) that was started 24 hours after MR induction for 2 (n=6) and 4 weeks (n=8). Left ventricular end-diastolic dimension increased 20% as plasma Ang II levels increased >5-fold in both MR and MR+beta1-RB dogs at 2 and 4 weeks. Ang II infusion into the left atrium produced increases in ISF NE and Epi in normal dogs, which were further increased in 2- and 4-week MR dogs but were restored to normal in 4-week MR+beta1-RB dogs. Ang II infusion produced 4-fold increases in circulating NE and Epi in 2- and 4-week MR dogs that returned to normal in 4-week+beta1-RB dogs. Left ventricular angiotensin-converting enzyme activity and ISF Ang II were increased in 4-week MR dogs but were decreased in 4-week MR+beta1-RB dogs.beta1-RB decreases renin-angiotensin system sympathostimulation and activation by attenuating the Ang II-mediated NE and Epi release into the cardiac ISF and circulation and by decreasing left ventricular angiotensin-converting enzyme expression in the early phases of volume overload.