tbuckley/cabot-search huggingface dataset:
The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens.
Authors: M J Bevan
Journal: The Journal of Experimental Medicine (1975)

Cytotoxic cells were generated by immunizing one strain of mouse with cells from an allogeneic strain which carries the same H-2 region. The effector cells assayed in a 4 h 51Cr release assay were shown to be T cells and indistinguishable, except in specificity, from cytotoxic T cells directed at H-2 alloantigens. Although the genetic differences between responder and stimulator cells responsible for the immunization did not code in H-2, the H-2 complex did restrict susceptibility of target cells. For example, BALB.B cytotoxic cells (H-2b) immunized against and capable of lysing C57BL/6 cells (H-2b) would not lyse B6.C/H-2d target cells. C57BL/6 and B6.C/H-2d are congenic and differ in the H-2 region. Two hypotheses are considered to explain the H-2 restriction of susceptibility to cytotoxic T cells generated by an H-2 identical alloimmunization. (a) The dual (self) recognition hypothesis states that the cytotoxic cell has two recognition units, one for H-2-coded structures and another clonally restricted receptor for the minor alloantigen. (b) The interaction antigen hypothesis states that all the surface alloantigenic determinants recognized by cytotoxic T cells are the result of interaction between H-2- and non-H-2-coded gene products. Two lines of evidence, one with F1 effector cells and the other a cold target competition experiment, are presented which argue strongly in favor of the interaction antigen hypothesis. The regions of H-2 required to be histocompatible were mapped to the D region and to the left of IC, probably the K region. These results, and recent work on the response to virus-infected and TNP-modified syngeneic cells, suggest that cytotoxic cells are restricted in specificity to preferentially recognizing alterations in structures that are coded in the major histocompatibility complex.
Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection?
Authors: Filippo Schepis, Calogero Cammà, Domenico Niceforo, Antonio Magnano, Socrate Pallio, Maurizio Cinquegrani, Gennaro D'Amico, Linda Pasta, Antonio Craxì, Antonino Saitta, Giovanni Raimondo
Journal: Hepatology (2001)

Our aims were to develop a noninvasive predictive tool to identify cirrhotic patients with esophageal varices and to evaluate whether portal Doppler ultrasonographic parameters may improve the value of other predictors. One hundred forty-three consecutive compensated cirrhotic patients underwent upper gastrointestinal endoscopy. Fourteen clinical, biochemical, ultrasonographic, and Doppler ultrasonographic parameters of each patient were also recorded. Esophageal varices were detected in 63 of the 143 patients examined (44%; 95% confidence interval [CI] 36.2-52.6). Medium and large esophageal varices were observed in 28 subjects (44%; 95% CI 31.4-58.4). Using stepwise logistic regression, presence of esophageal varices was independently predicted by prothrombin activity less than 70% (odds ratio [OR]: 5.83; 95% CI: 2.6-12.8), ultrasonographic portal vein diameter greater than 13 mm (OR: 2.92; 95% CI: 1.3-6.4), and platelet count less than 100 x 10(9)/L (OR: 2.83; 95% CI: 1.27-6.28). Variables included in the model were used to generate a simple incremental rule to evaluate each individual patient. The discriminating ability of the prediction rule was relevant (area under the curve: 0.80) and did not change by replacing ultrasonographic portal vein diameter with congestion index of portal vein. We concluded that compensated cirrhotic patients should be screened by upper gastrointestinal endoscopy when prothrombin activity less than 70%, platelet count less than 100 x 10(9)/L, and ultrasonographic portal vein diameter greater than 13 mm are observed, whereas those without any of these predictors should not undergo endoscopy. The contribution provided by portal Doppler ultrasonographic parameters does not appear of practical utility.
Ly-6C <sup>high</sup> Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium
Authors: Ingo Hilgendorf, Louisa M.S. Gerhardt, Timothy C. Tan, Carla Winter, Tobias A.W. Holderried, Benjamin G. Chousterman, Yoshiko Iwamoto, Ronglih Liao, Andreas Zirlik, Marielle Scherer-Crosbie, Catherine C. Hedrick, Peter Libby, Matthias Nahrendorf, Ralph Weissleder, Filip K. Swirski
Journal: Circulation Research (2014)

Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)(high) and reparative Ly-6C(low) monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C(low) monocyte production but dispensable to Ly-6C(low) macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity.This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios.We show that Ly-6C(high) monocytes infiltrate the infarcted myocardium and, unlike Ly-6C(low) monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C(high) monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C(high) monocytes give rise to reparative Ly-6C(low) F4/80(high) macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C(high) monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function.Ly-6C(high) monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
Aprataxin Tumor Levels Predict Response of Colorectal Cancer Patients to Irinotecan-based Treatment
Authors: Higinio Dopeso, Silvia Mateo-Lozano, Elena Elez, Stefania Landolfi, Francisco Javier Ramos Pascual, Javier Hernández-Losa, Rocco Mazzolini, Paulo Rodrigues, Sarah Bazzocco, Maria Josep Carreras, Eloy Espín, Manel Armengol, Andrew J. Wilson, John M. Mariadason, Santiago Ramon y Cajal, Josep Tabernero, Simo Schwartz, Diego Arango
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Irinotecan (CPT11) treatment significantly improves the survival of colorectal cancer patients and is routinely used for the treatment of these patients, alone or in combination with other agents. However, only 20% to 30% of patients show an objective response to irinotecan, and there is great need for new molecular markers capable of identifying the subset of patients who are unlikely to respond. Experimental Design: Here we used microarray analysis of a panel of 30 colorectal cancer cell lines and immunohistochemistry to identify and validate a new biomarker of response to irinotecan. Results: A good correlation was observed between irinotecan sensitivity and the expression of aprataxin (APTX), a histidine triad domain superfamily protein involved in DNA repair. Moreover, using an isogenic in vitro system deficient in APTX, we show that aprataxin directly regulates the cellular sensitivity to camptothecin, suggesting that it could be used to predict patient response to irinotecan. We constructed a tissue microarray containing duplicate tumor samples from 135 patients that received irinotecan for the treatment of advanced colorectal cancer. Immunohistochemical assessment of the tumor levels of aprataxin showed a significant association with treatment response and patient survival. Patients with low aprataxin had longer progression-free (9.2 versus 5.5 months; P = 0.03) and overall survival (36.7 versus 19.0 months; P = 0.008) than patients with high tumor aprataxin. No associations were found between coding APTX variants and aprataxin levels or camptothecin sensitivity. Conclusions: These results show that aprataxin tumor levels can be used to identify patients with low probability of response to irinotecan-based therapy who are ideal candidates to receive treatment with alternative agents in an attempt to improve patient survival. Clin Cancer Res; 16(8); 2375–82. ©2010 AACR.
The Serine/Threonine Protein Kinase, p90 Ribosomal S6 Kinase, Is an Important Regulator of Prostate Cancer Cell Proliferation
Authors: D.E. Clark, T.M. Errington, J.A. Smith, H.F. Frierson, M.J. Weber, D.A. Lannigan
Journal: Cancer Research (2005)

An increase in the activity of mitogen-activated protein kinase (MAPK) has been correlated with the progression of prostate cancer to advanced disease in humans. The serine/threonine protein kinase p90-kDa ribosomal S6 kinase (RSK) is an important downstream effector of MAPK but its role in prostate cancer has not previously been examined. Increasing RSK isoform 2 (RSK2) levels in the human prostate cancer line, LNCaP, enhanced prostate-specific antigen (PSA) expression, an important diagnostic marker for prostate cancer, whereas inhibiting RSK activity using a RSK-specific inhibitor, 3Ac-SL0101, decreased PSA expression. The RSK2 regulation of PSA expression occurred via a mechanism involving both RSK2 kinase activity and its ability to associate with the coactivator, p300. RNA interference of the androgen receptor (AR) showed that the AR was important in the RSK2-mediated increase in PSA expression. RSK levels are higher in approximately 50% of human prostate cancers compared with normal prostate tissue, which suggests that increased RSK levels may participate in the rise in PSA expression that occurs in prostate cancer. Furthermore, 3Ac-SL0101 inhibited proliferation of the LNCaP line and the androgen-independent human prostate cancer line, PC-3. These results suggest that proliferation of some prostate cancer cells is dependent on RSK activity and support the hypothesis that RSK may be an important chemotherapeutic target for prostate cancer.
Prognosis of “Masked” Hypertension and “White-Coat” Hypertension Detected by 24-h Ambulatory Blood Pressure Monitoring
Authors: Takayoshi Ohkubo, Masahiro Kikuya, Hirohito Metoki, Kei Asayama, Taku Obara, Junichiro Hashimoto, Kazuhito Totsune, Haruhisa Hoshi, Hiroshi Satoh, Yutaka Imai
Journal: Journal of the American College of Cardiology (2005)
Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients
Authors: C A McCune
Journal: Gut (2005)

<b>Background and aims:</b> Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60). <b>Methods:</b> All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2). <b>Results:</b> In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives. <b>Conclusions:</b><i>HFE</i> C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.
Pioglitazone and Bladder Cancer
Authors: Chin-Hsiao Tseng
Journal: Diabetes Care (2011)

The association between pioglitazone and bladder cancer has not been investigated in Asians. We aimed to investigate this association.A total of 1,000,000 individuals were randomly sampled from the National Health Insurance database, and incident cases of bladder cancer during the period from 1 January 2006 to 31 December 2009 were analyzed among 54,928 patients with type 2 diabetes and without previous bladder cancer.Among 165 incident case subjects, 10 (0.39%) were ever users and 155 (0.30%) were never users of pioglitazone (adjusted hazard ratio in full model 1.305 [95% CI 0.661-2.576]). All bladder cancer in ever users occurred within a duration of therapy <24 months, suggesting an early effect of pioglitazone on bladder cancer or late use of pioglitazone in high-risk patients.The association between pioglitazone and bladder cancer was not significant. However, confirmation of this finding is required because of the possible lack of statistical power owing to the small number of events.
PREVALENCE, PREDICTORS AND PROGNOSIS OF IRON DEFICIENCY IN PATIENTS WITH CHRONIC HEART FAILURE: AN INTERNATIONAL POOLED ANALYSIS OF 1,506 PATIENTS
Authors: IJsbrand Thomas Klip, Josep Comin Colet, Adriaan Voors, Piotr Ponikowski, Dirk van Veldhuisen, Piotr Rozentryt, Waldemer Banasiak, Peter Van der Meer, Ewa Jankowska
Journal: Journal of the American College of Cardiology (2012)
Effects of <i>Helicobacter pylori</i> Eradication on Methylation Status of <i>E-Cadherin</i> Gene in Noncancerous Stomach
Authors: Wai K. Leung, Ellen P.S. Man, Jun Yu, Minnie Y.Y. Go, Ka-fai To, Yoshio Yamaoka, Victoria Y.Y. Cheng, Enders K.W. Ng, Joseph J.Y. Sung
Journal: Clinical Cancer Research (2006)

Promoter hypermethylation of E-cadherin plays an important role on gastric cancer development. Whereas E-cadherin methylation was frequently detected in the stomach of Helicobacter pylori-infected individuals, we tested whether eradication of H. pylori alters the methylation status of the noncancerous gastric epithelium.Endoscopic biopsies were taken from the antrum and corpus of H. pylori-infected subjects without gastric cancer. Presence of methylated E-cadherin sequences in the gastric specimens was detected by methylation-specific PCR. Bisulfite DNA sequencing was done to determine the topographical distribution and changes in methylation profiles with H. pylori eradication.Among the 28 H. pylori-infected subjects (median age, 44.5 years), 15 (53.6%) had E-cadherin methylation detected in stomach at baseline. Discordant methylation patterns between the antrum and corpus were noted in six patients. One year after successful H. pylori eradication, there was a significant reduction in the methylation density of the promoter region and exon 1 of the E-cadherin gene as detected by bisulfite DNA sequencing (P < 0.001).Promoter methylation in E-cadherin was frequently detected in the stomach of H. pylori-infected individuals. Eradication of H. pylori might possibly reduce the methylation density in E-cadherin gene and the chance of subsequent neoplastic transformation.
Idiopathic thrombocytopenic purpura occurring in Hodgkin disease after splenectomy: Report of two cases and review of the literature
Authors: Caroline C. Waddell, Philip L. Cimo
Journal: American Journal of Hematology (1979)

Abstract The occurrence of idiopathic thrombocytopenic purpura (ITP) in Hodgkin disease is uncommon. Even more unusual is the development of ITP in Hodgkin disease following splenectomy. This report describes two patients with Hodgkin disease who developed severe ITP with negative platelet antibody studies very soon after splenectomy (20 days in one and three months in the other). A review of the literature of 21 other patients with well‐documented ITP and Hodgkin diesease indicated that ITP occurring in Hodgkin disease may be more severe and refractory to therapy than ITP unassociated with Hodgkin. Nodular sclerosis or mixed cellularity histologic types of Hodgkin disease were present in all but one of the patients with ITP and Hodgkin disease, and males constituted 65% of cases. There appeared to be no correlation between the onset of ITP and activity of Hodgkin disease. Of five splenectomized patients with Hodgkin disease who developed ITP and were treated with immunosuppressive drugs for thrombocytopenia, three had an excellent response and two had a good response, suggesting that the combination of corticosteroids and immunosuppressive drugs may be indicated at the outset in patients with Hodgkin disease who develop ITP following splenectomy.
Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas
Authors: Koichi Shimizu, Masayoshi Shichiri, Peter Libby, Richard T. Lee, Richard N. Mitchell
Journal: Journal of Clinical Investigation (2004)

Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-γ, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-γ receptor–deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti–IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-γ– or IL-4–dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis.
The neurobiology of attention-deficit/hyperactivity disorder (ADHD) as a model of the neurobiology of personality
Authors: Bonnie J. Kaplan
Journal: Behavioral and Brain Sciences (1999)

The Depue &amp; Collins model is intended to explain a normal human personality trait: extraversion. In contrast, attention-deficit/hyperactivity disorder (ADHD) is generally considered to be a type of psychopathology not found in so-called normals; however, the clinical and neurobiological research done on ADHD seems to amplify and support Depue &amp; Collins's model.
Paralympics--Barcelona 1992.
Authors: J Reynolds, A Stirk, A Thomas, F Geary
Journal: British Journal of Sports Medicine (1994)

The British Team at the 9th Paralympic Games in September 1992 in Barcelona comprised 151 men and 54 women athletes in a total of 15 sports. They were supported by a staff of 86 including a 12-strong medical team. The athletes were selected from the National Championships of the five disability organizations: British Wheelchair Sports Federation; British Blind Sport; Cerebral Palsy Sport; British Amputee Sports Association; and the British Les Autres Sports Association. This article outlines the organization and experience of the medical support team. The injury/illness profile was similar to those in able bodied sport. The team went on to achieve 40 gold, 47 silver and 41 bronze medals, maintaining third place on the medal table as achieved in Seoul in 1988.
The centrosome protein NEDD1 as a potential pharmacological target to induce cell cycle arrest
Authors: Vanessa Tillement, Laurence Haren, Nicolas Roullet, Chantal Etievant, Andreas Merdes
Journal: Molecular Cancer (2009)

Abstract Background NEDD1 is a protein that binds to the gamma-tubulin ring complex, a multiprotein complex at the centrosome and at the mitotic spindle that mediates the nucleation of microtubules. Results We show that NEDD1 is expressed at comparable levels in a variety of tumor-derived cell lines and untransformed cells. We demonstrate that silencing of NEDD1 expression by treatment with siRNA has differential effects on cells, depending on their status of p53 expression: p53-positive cells arrest in G1, whereas p53-negative cells arrest in mitosis with predominantly aberrant monopolar spindles. However, both p53-positive and -negative cells arrest in mitosis if treated with low doses of siRNA against NEDD1 combined with low doses of the inhibitor BI2536 against the mitotic kinase Plk1. Simultaneous reduction of NEDD1 levels and inhibition of Plk1 act in a synergistic manner, by potentiating the anti-mitotic activity of each treatment. Conclusion We propose that NEDD1 may be a promising target for controlling cell proliferation, in particular if targeted in combination with Plk1 inhibitors.
Sequential multimodality bronchoscopic investigation of peripheral pulmonary lesions
Authors: Daniel P. Steinfort, Asha Bonney, Katharine See, Louis B. Irving
Journal: European Respiratory Journal (2015)

Multiple guidance modalities may be combined during bronchoscopic investigation of peripheral pulmonary lesions (PPLs). The relative contribution of each modality to diagnostic performance remains uncertain.Endobronchial ultrasound (EBUS) with virtual bronchoscopy (VB) was routinely performed, with electromagnetic navigation (EMN) utilised only where EBUS was unable to locate PPLs or where the probe was adjacent to the lesion and on-site cytologic examination was nondiagnostic.236 consecutive patients with 245 PPLs had lesion size 22.8±12.4 mm (mean±sd). PPLs were localised using EBUS+VB alone in 188 (77%) and was diagnostic in 134 of these (71.3%). EBUS localisation was predicted by PPL size (23.7±10.5 versus 19.7±9.8 mm, p=0.003), but not by bronchus sign, PPL-hilum distance or PPL-pleura distance. EMN in 57 patients achieved EBUS localisation in a further 17 patients (30.9%), improving overall visualisation yield to 85%. Nine of these 57 procedures achieved a definitive diagnosis (16%), improving overall diagnostic yield to 58.4%. Probe position and lesion type influenced overall diagnostic yield. Sensitivity for diagnosis of lung cancer was 70% (131/188; 95% CI 63-76%).Localisation rate and diagnostic sensitivity of radial probe EBUS+VB alone for diagnosis of PPLs is high. EBUS localisation rates and procedural yield are improved only modestly (by 8% and 4%, respectively) with addition of EMN. Sampling following EMN should include all available methods to maximise diagnostic yield.