tbuckley/cabot-search huggingface dataset:
Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cells
Authors: Hendrik Streeck, Zabrina L Brumme, Michael Anastario, Kristin W Cohen, Jonathan S Jolin, Angela Meier, Chanson J Brumme, Eric S Rosenberg, Galit Alter, Todd M Allen, Bruce D Walker, Marcus Altfeld
Journal: PLoS Medicine (2008)

Virus-specific CD8(+) T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8(+) T cells with a "polyfunctional" profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8(+) T cell responses on the single-epitope level over time, starting in primary HIV-1 infection.We longitudinally analyzed the polyfunctional epitope-specific CD8(+) T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8(+) T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8(+) T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%-72%) to 76% (56%-95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%-75%) to 56% (42%-70%) (SD of the effect size 0.18) (p < 0.05).These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.
Bladder Cancer Mortality of Workers Exposed to Aromatic Amines: A 58-Year Follow-up
Authors: Enrico Pira, Giorgio Piolatto, Eva Negri, Canzio Romano, Paolo Boffetta, Loren Lipworth, Joseph K. McLaughlin, Carlo La Vecchia
Journal: JNCI Journal of the National Cancer Institute (2010)

We previously investigated bladder cancer risk in a cohort of dyestuff workers who were heavily exposed to aromatic amines from 1922 through 1972. We updated the follow-up by 14 years (through 2003) for 590 exposed workers to include more than 30 years of follow-up since last exposure to aromatic amines. Expected numbers of deaths from bladder cancer and other causes were computed by use of national mortality rates from 1951 to 1980 and regional mortality rates subsequently. There were 394 deaths, compared with 262.7 expected (standardized mortality ratio = 1.50, 95% confidence interval = 1.36 to 1.66). Overall, 56 deaths from bladder cancer were observed, compared with 3.4 expected (standardized mortality ratio = 16.5, 95% confidence interval = 12.4 to 21.4). The standardized mortality ratio for bladder cancer increased with younger age at first exposure and increasing duration of exposure. Although the standardized mortality ratio for bladder cancer steadily decreased with time since exposure stopped, the absolute risk remained approximately constant at 3.5 deaths per 1000 man-years up to 29 years after exposure stopped. Excess risk was apparent 30 years or more after last exposure.
Rad As a Novel Regulator of Excitation–Contraction Coupling and β-Adrenergic Signaling in Heart
Authors: Gang Wang, Xiaojun Zhu, Wenjun Xie, Peidong Han, Kaitao Li, Zhongcui Sun, Yanru Wang, Chunlei Chen, Ruisheng Song, Chunmei Cao, Jifeng Zhang, Caihong Wu, Jie Liu, Heping Cheng
Journal: Circulation Research (2009)

Rad (Ras associated with diabetes) GTPase, a monomeric small G protein, binds to Ca(v)beta subunit of the L-type Ca(2+) channel (LCC) and thereby regulates LCC trafficking and activity. Emerging evidence suggests that Rad is an important player in cardiac arrhythmogenesis and hypertrophic remodeling. However, whether and how Rad involves in the regulation of excitation-contraction (EC) coupling is unknown.This study aimed to investigate possible role of Rad in cardiac EC coupling and beta-adrenergic receptor (betaAR) inotropic mechanism.Adenoviral overexpression of Rad by 3-fold in rat cardiomyocytes suppressed LCC current (I(Ca)), [Ca(2+)](i) transients, and contractility by 60%, 42%, and 38%, respectively, whereas the "gain" function of EC coupling was significantly increased, due perhaps to reduced "redundancy" of LCC in triggering sarcoplasmic reticulum release. Conversely, approximately 70% Rad knockdown by RNA interference increased I(Ca) (50%), [Ca(2+)](i) transients (52%) and contractility (58%) without altering EC coupling efficiency; and the dominant negative mutant RadS105N exerted a similar effect on I(Ca). Rad upregulation caused depolarizing shift of LCC activation and hastened time-dependent LCC inactivation; Rad downregulation, however, failed to alter these attributes. The Na(+)/Ca(2+) exchange activity, sarcoplasmic reticulum Ca(2+) content, properties of Ca(2+) sparks and propensity for Ca(2+) waves all remained unperturbed regardless of Rad manipulation. Rad overexpression, but not knockdown, negated betaAR effects on I(Ca) and Ca(2+) transients.These results establish Rad as a novel endogenous regulator of cardiac EC coupling and betaAR signaling and support a parsimonious model in which Rad buffers Ca(v)beta to modulate LCC activity, EC coupling, and betaAR responsiveness.
Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs
Authors: Karen E. Russell, Eva H. N. Olsen, Robin A. Raymer, Elizabeth P. Merricks, Dwight A. Bellinger, Marjorie S. Read, Bonita J. Rup, James C. Keith, Kyle P. McCarthy, Robert G. Schaub, Timothy C. Nichols
Journal: Blood (2003)
Foxp3+ regulatory T cells maintain immune homeostasis in the skin
Authors: Jan C. Dudda, Nikole Perdue, Eva Bachtanian, Daniel J. Campbell
Journal: The Journal of Experimental Medicine (2008)

Cutaneous immune responses must be tightly controlled to prevent unwanted inflammation in response to innocuous antigens, while maintaining the ability to combat skin-tropic pathogens. Foxp3+ regulatory T (T reg) cells are potent immune regulators and are found at high frequency in both human and mouse skin. Although T reg cells migrate to the skin and can dampen immune responses during experimentally induced inflammation or infection, the importance of cutaneous T reg cells for maintaining normal immune homeostasis in the skin has not been addressed. To selectively block T reg cell function in the skin, we restored the T reg cell compartment in Foxp3-deficient scurfy mice with cells whose ability to migrate to the skin was impaired because of targeted mutation of α-1,3-fucosyltransferase VII (Fut7). Although Fut7-deficient T reg cells were present at normal frequency and could function in all other tissues examined, these animals rapidly developed severe cutaneous inflammation. Thus, skin-resident T reg cell are essential for maintaining normal immune homeostasis at this site.
Serum B Vitamin Levels and Risk of Lung Cancer
Authors: Mattias Johansson
Journal: JAMA (2010)

B vitamins and factors related to 1-carbon metabolism help to maintain DNA integrity and regulate gene expression and may affect cancer risk.To investigate if 1-carbon metabolism factors are associated with onset of lung cancer.The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519,978 participants from 10 countries between 1992 and 2000, of whom 385,747 donated blood. By 2006, 899 lung cancer cases were identified and 1770 control participants were individually matched by country, sex, date of birth, and date of blood collection. Serum levels were measured for 6 factors of 1-carbon metabolism and cotinine.Odds ratios (ORs) of lung cancer by serum levels of 4 B vitamins (B(2), B(6), folate [B(9)], and B(12)), methionine, and homocysteine.Within the entire EPIC cohort, the age-standardized incidence rates of lung cancer (standardized to the world population, aged 35-79 years) were 6.6, 44.9, and 156.1 per 100,000 person-years among never, former, and current smokers for men, respectively. The corresponding incidence rates for women were 7.1, 23.9, and 100.9 per 100,000 person-years, respectively. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B(6) (fourth vs first quartile OR, 0.44; 95% confidence interval [CI], 0.33-0.60; P for trend <.000001), as well as for serum methionine (fourth vs first quartile OR, 0.52; 95% CI, 0.39-0.69; P for trend <.000001). Similar and consistent decreases in risk were observed in never, former, and current smokers, indicating that results were not due to confounding by smoking. The magnitude of risk was also constant with increasing length of follow-up, indicating that the associations were not explained by preclinical disease. A lower risk was also seen for serum folate (fourth vs first quartile OR, 0.68; 95% CI, 0.51-0.90; P for trend = .001), although this was apparent only for former and current smokers. When participants were classified by median levels of serum methionine and B(6), having above-median levels of both was associated with a lower lung cancer risk overall (OR, 0.41; 95% CI, 0.31-0.54), as well as separately among never (OR, 0.36; 95% CI, 0.18-0.72), former (OR, 0.51; 95% CI, 0.34-0.76), and current smokers (OR, 0.42; 95% CI, 0.27-0.65).Serum levels of vitamin B(6) and methionine were inversely associated with risk of lung cancer.
Accelerated apoptosis in the Timp-3–deficient mammary gland
Authors: Jimmie E. Fata, Kevin J. Leco, Evelyn B. Voura, Hoi-Ying E. Yu, Paul Waterhouse, Gillian Murphy, Roger A. Moorehead, Rama Khokha
Journal: Journal of Clinical Investigation (2001)

The proapoptotic proteinase inhibitor TIMP-3 is the only molecule of this family thought to influence cell death. We examined epithelial apoptosis in TIMP-3–deficient mice during mammary gland involution. Lactation was not affected by the absence of TIMP-3, but glandular function, as measured by gland-to-body weight ratio and production of β-casein, was suppressed earlier during post-lactational involution than in controls. Histological examination revealed accelerated lumen collapse, alveolar-epithelial loss, and adipose reconstitution in Timp-3–/– females. Epithelial apoptosis peaked on the first day of involution in Timp-3–null glands but at day 3 in wild-type littermates. Unscheduled activation of gelatinase-A was evident by zymography and correlated with earlier fragmentation of fibronectin in Timp-3–/– mammary. To obtain independent evidence of the proapoptotic effects of TIMP-3 deficiency, we introduced recombinant TIMP-3–releasing pellets into regressing Timp-3–/– mammary tissue and showed that this treatment rescued lumen collapse and epithelial apoptosis. Ex vivo, involuting Timp-3–/– mammary tissue demonstrated accelerated epithelial apoptosis that could be reduced by metalloproteinase inhibition. The physiological relevance of TIMP-3 became apparent as Timp-3–/– dams failed to reestablish lactation after brief cessation of suckling. Thus, TIMP-3 is a critical epithelial survival factor during mammary gland involution.
Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor
Authors: Arthur J. Bergman, Josee Cote, Bingming Yi, Thomas Marbury, Suzanne K. Swan, William Smith, Keith Gottesdiener, John Wagner, Gary A. Herman
Journal: Diabetes Care (2007)

Sitagliptin is an oral, once-daily, potent, and highly selective dipeptidyl peptidase–4 inhibitor for the treatment of type 2 diabetes (1). In subjects with normal renal function (creatinine clearance >80 ml/min), 75–80% of an oral dose was excreted unchanged in urine. Renal clearance was ∼350 ml/min, indicating that active secretion of sitagliptin rather than only filtration is involved in renal excretion. Thus, renal excretion is the primary mechanism of elimination for sitagliptin (2). The purpose of this study was to evaluate the pharmacokinetics of single doses of sitagliptin in patients with various degrees of renal insufficiency (RI).

This was an open-label, two-part study in 30 otherwise healthy male and female subjects (18–75 years of age) with BMI ≤40 kg/m2. Subjects were assigned to one of five groups ( n = 6/group), based on the following criterion for degree of RI: mild (creatinine clearance 50–80 ml/min), moderate (30–50 ml/min), severe ( 80 ml/min). Healthy subjects ( n = 145) from 11 other studies were included in a historical control group to supplement those studied here. Creatinine clearance values were based on measured 24-h urinary creatinine excretion (this study) or calculated using the Cockroft-Gault formula (historical controls). Because sitagliptin plasma concentrations were expected to increase with RI, a 50-mg dose was expected to be well …
Stimulation of Id1 Expression by Bone Morphogenetic Protein Is Sufficient and Necessary for Bone Morphogenetic Protein–Induced Activation of Endothelial Cells
Authors: Gudrun Valdimarsdottir, Marie-José Goumans, Alexander Rosendahl, Martijn Brugman, Susumu Itoh, Franck Lebrin, Paschalis Sideras, Peter ten Dijke
Journal: Circulation (2002)

Bone morphogenetic proteins (BMPs) are multifunctional proteins that regulate the proliferation, differentiation, and migration of a large variety of cell types. Like other members of the transforming growth factor-beta family, BMPs elicit their cellular effects through activating specific combinations of type I and type II serine/threonine kinase receptors and their downstream effector proteins, which are termed Smads. In the present study, we investigated BMP receptor/Smad expression and signaling in endothelial cells (ECs) and examined the effects of BMP on EC behavior.Immunohistochemical analysis of tissue sections of human colon and mouse heart and aorta showed that BMP receptors are expressed in ECs in vivo. Bovine aortic ECs and mouse embryonic ECs were found to express BMP receptors and their Smads. BMP receptor activation induced the phosphorylation of specific Smad proteins and promoted EC migration and tube formation. Id1 was identified as a BMP/Smad target in ECs. Ectopic expression of Id1 mimicked BMP-induced effects. Importantly, specific interference with Id1 expression blocked BMP-induced EC migration.The BMP/Smad pathway can potently activate the endothelium. Id1 expression is strongly induced by BMP in ECs. Ectopic expression of Id1 induces EC migration and tube formation. Moreover, Id1 played a critical role in mediating BMP-induced EC migration.
Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis
Authors: Andreas Hermansson, Daniel F.J. Ketelhuth, Daniela Strodthoff, Marion Wurm, Emil M. Hansson, Antonino Nicoletti, Gabrielle Paulsson-Berne, Göran K. Hansson
Journal: The Journal of Experimental Medicine (2010)

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) β chain, TRBV31, with different Vα chains. Immunization of huB100tgxLdlr−/− mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.
Immunocytochemical analysis of human synovial lining cells: phenotypic relation to other marrow derived cells.
Authors: N A Athanasou, J Quinn
Journal: Annals of the Rheumatic Diseases (1991)

The antigenic phenotype of human synovial lining cells in normal and hyperplastic synovium intima was determined with a panel of monoclonal antibodies directed against a large number of well defined myeloid (macrophage/granulocyte associated) antigens. Synovial lining cells express numerous macrophage associated antigens, including CD11b (CR3), CD13, CD14, CD16 (FcRIII), CD18, CD32 (FcRII), CD45 (leucocyte common antigen), CD54 (ICAM-1), CD64 (FcRI), CD68, and CD71 (transferrin receptor). Few synovial lining cells expressed CD11a (LFA-1) and CD11c (p150,95). Subintimal macrophages expressed all the macrophage associated antigens which were present on synovial lining cells and, in addition, expressed CD15a, CD25 (interleukin-2 receptor), CD34, and CD35 (C3b receptor), none of which was present on synovial lining cells. Synovial lining cell expression of a wide range of macrophage antigens argues in favour of their marrow origin and membership of the mononuclear phagocyte system.
Cloning and Functional Expression of an Inwardly Rectifying K <sup>+</sup> Channel From Human Atrium
Authors: Barbara A. Wible, Mariella De Biasi, Kumud Majumder, Maurizio Taglialatela, Arthur M. Brown
Journal: Circulation Research (1995)

Abstract The cardiac inward rectifier current (I K1 ) contributes to the shape and duration of the cardiac action potential and helps to set the resting membrane potential. Although several inwardly rectifying K + channels (IRKs) from different tissues have been cloned recently, the nature and number of K + channels contributing to the cardiac I K1 are presently unknown. To address this issue in human heart, we have used the reverse-transcriptase–polymerase chain reaction (PCR) technique with human atrial total RNA as a template to identify two sequences expressed in heart that are homologous to previously cloned IRKs. One of the PCR products we obtained was virtually identical to IRK1 (cloned from a mouse macrophage cell line); the other, which we named hIRK, exhibited &lt;70% identity to IRK1. A full-length clone encoding hIRK was isolated from a human atrial cDNA library and functionally expressed in Xenopus oocytes. This channel, like IRK1, exhibited strong inward rectification and was blocked by divalent cations. However, hIRK differed from IRK1 at the single-channel level: hIRK had a single-channel conductance of 36 pS compared with 21 pS for IRK1. We have identified single channels of 41, 35, 21, and 9 pS in recordings from dispersed human atrial myocytes. However, none of these atrial inward rectifiers exhibited single-channel properties exactly like those of cloned hIRK expressed in oocytes. Our findings suggest that the cardiac I K1 in human atrial myocytes is composed of multiple inwardly rectifying channels distinguishable on the basis of single-channel conductance, each of which may be the product of a different gene.
New insights into oxygen sensing at a cellular level
Authors: S R Walmsley
Journal: Thorax (2004)

The oxygen sensing pathway offers a new set of therapeutic targets for conditions ranging from inflammatory lung disease to pulmonary hypertension

The ability of cells to detect and respond to a fall in oxygen tension is of fundamental importance for maintaining oxidative metabolism and tissue homeostasis. One of the challenges facing scientists working in this area has been that any proposed mechanism for oxygen sensing has to accommodate the very different tolerances of certain tissues to hypoxia and the extreme variation in the cellular responses observed. Hence, while skeletal muscle cells can recover function after 30 minutes of anoxia, the brain suffers irreparable damage after only 4–6 minutes of ischaemia.1 Moreover, while carotid body cells respond to changes in oxygen tension that barely register in non-chemosensory tissues (and do so within seconds),2 upregulation of erythropoietin synthesis in the interstitial peritubular cells is transcriptionally regulated and requires far more protracted periods of hypoxaemia.3 Despite such variances in oxygen sensitivity and response time, all cells appear capable of responding to hypoxia and the essential components of a universal oxygen sensing mechanism have at last begun to emerge. Moreover, from studies conducted in stroke and heart disease, it is apparent that therapeutic targeting of this novel pathway is set to transform our approach to pathology previously deemed intractable.

Initial clues into how cells respond to low oxygen came from studies undertaken in the early 1990s examining the hypoxic response element (HRE) of the erythropoietin (Epo) gene. This led to the identification of a transcriptional activator called hypoxia inducible factor (HIF).4 HIF is a …