tbuckley/cabot-search huggingface dataset:
A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells
Authors: Sidonia B.G. Eckle, Richard W. Birkinshaw, Lyudmila Kostenko, Alexandra J. Corbett, Hamish E.G. McWilliam, Rangsima Reantragoon, Zhenjun Chen, Nicholas A. Gherardin, Travis Beddoe, Ligong Liu, Onisha Patel, Bronwyn Meehan, David P. Fairlie, Jose A. Villadangos, Dale I. Godfrey, Lars Kjer-Nielsen, James McCluskey, Jamie Rossjohn
Journal: The Journal of Experimental Medicine (2014)

Mucosal-associated invariant T (MAIT) cells express an invariant T cell receptor (TCR) α-chain (TRAV1-2 joined to TRAJ33, TRAJ20, or TRAJ12 in humans), which pairs with an array of TCR β-chains. MAIT TCRs can bind folate- and riboflavin-based metabolites restricted by the major histocompatibility complex (MHC)-related class I−like molecule, MR1. However, the impact of MAIT TCR and MR1-ligand heterogeneity on MAIT cell biology is unclear. We show how a previously uncharacterized MR1 ligand, acetyl-6-formylpterin (Ac-6-FP), markedly stabilized MR1, potently up-regulated MR1 cell surface expression, and inhibited MAIT cell activation. These enhanced properties of Ac-6-FP were attributable to structural alterations in MR1 that subsequently affected MAIT TCR recognition via conformational changes within the complementarity-determining region (CDR) 3β loop. Analysis of seven TRBV6-1+ MAIT TCRs demonstrated how CDR3β hypervariability impacted on MAIT TCR recognition by altering TCR flexibility and contacts with MR1 and the Ag itself. Ternary structures of TRBV6-1, TRBV6-4, and TRBV20+ MAIT TCRs in complex with MR1 bound to a potent riboflavin-based antigen (Ag) showed how variations in TRBV gene usage exclusively impacted on MR1 contacts within a consensus MAIT TCR-MR1 footprint. Moreover, differential TRAJ gene usage was readily accommodated within a conserved MAIT TCR-MR1-Ag docking mode. Collectively, MAIT TCR heterogeneity can fine-tune MR1 recognition in an Ag-dependent manner, thereby modulating MAIT cell recognition.
Sense of effort and other unpleasant sensations during exercise: clarifying concepts and mechanisms
Authors: Bruno de Paula Caraça Smirmaul
Journal: British Journal of Sports Medicine (2010)

Introduction The sense of effort is an essential component of all forms of exercise. Although extensively studied, exercise physiologists have failed to reach consensus about whether this sensation is based on afferent sensory feedback or is centrally generated and independent of such feedback. This confusion has led to misunderstandings regarding the neurological mechanisms responsible for the sense of effort as opposed to other specific sensations such as pain and temperature. Discussion A mechanism in which the sense of effort is centrally generated and independent of feedback had been proposed more than 150 years ago. However, a more recent concept of sense of effort as a subjective rating of exercise intensity based on various sensations experienced during exercise given by Borg may have caused confusion, especially among exercise physiologists. Many began to use and understand the sense of effort as a sensation that is generated by afferent sensory feedback. The information reviewed in this article, together with the examples given, constitutes a body of evidence in favour of a centrally generated sense of effort. Afferent sensory feedback is important for the conscious awareness of different sensations such as pain and temperature, and plays important roles in the control of homeostasis. However, peripheral sensory feedback does not seem to be important for the generation of the sense of effort. Conclusion The sense of effort and other specific sensations such as temperature, pain and other muscular sensations present two separate neurological mechanisms. While the former is centrally generated, the latter is based on afferent sensory feedback. An interaction of these sensations is likely the ultimate regulator of exercise performance. However, further investigation is required to fully understand these phenomena.
Nephrologists' reported attitudes about factors influencing recommendations to initiate or withdraw dialysis.
Authors: J L Holley, C J Foulks, A H Moss
Journal: Journal of the American Society of Nephrology (1991)

A nationwide survey of nephrologists was performed to learn which patient factors and characteristics of nephrology fellowship training they reported as influencing their decisions to start or stop dialysis. One hundred seventy-four of 482 responses were received. Most respondents were men in private practice living in large communities (41% in communities over 1,000,000 population). Most had completed a 2-yr fellowship (88%) at a medical school hospital (75%). Few (9%) received formal instruction in medical ethics during fellowship training, and only one quarter had informally discussed life-sustaining treatments during training. Neurological status was the most, and age the least, important patient factor reported to influence decisions to start or stop dialysis. No respondent demographic factors correlated with ranking of patient factors in decisions to initiate or forego dialysis. Family wishes and preexisting medical conditions were significantly more important considerations in initiating than in stopping dialysis. Insights about the factors practicing nephrologists reportedly weigh most heavily in making the difficult decisions to withhold or withdraw dialysis are provided by this study. Additional study of the actual practices of nephrologists in decisions to initiate or withdraw dialysis and the factors influencing those decisions are needed. Formal instruction in these and other ethical problems confronting nephrologists should perhaps be included in fellowship programs.
Cytoplasmic Poly(Adenosine Diphosphate–Ribose) Polymerase Expression Is Predictive and Prognostic in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy
Authors: Gunter von Minckwitz, Berit Maria Müller, Sibylle Loibl, Jan Budczies, Claus Hanusch, Silvia Darb-Esfahani, Jörn Hilfrich, Erich Weiss, Jens Huober, Jens Uwe Blohmer, Andreas du Bois, Dirk-Michael Zahm, Fariba Khandan, Gerald Hoffmann, Bernd Gerber, Holger Eidtmann, Falko Fend, Manfred Dietel, Keyur Mehta, Carsten Denkert
Journal: Journal of Clinical Oncology (2011)

Poly(adenosine diphosphate-ribose) polymerase (PARP) plays a key role in DNA repair and cellular stress response. Inhibitors of PARP show promising clinical activity in metastatic, triple-negative or BRCA-mutated breast cancer.We investigated cytoplasmic PARP (cPARP) and nuclear PARP (nPARP) expression by immunohistochemistry in 638 pretreatment biopsies from patients on the GeparTrio study and evaluated its predictive and prognostic value after neoadjuvant anthracycline/taxane-based chemotherapy.cPARP expression was high in 23.7%, intermediate in 50.9%, and negative in 25.4% of tumors. High cPARP expression was significantly correlated with nonlobular histology (P < .001), undifferentiated grade (P < .001), positive nodal status (P = .049), and negative hormone receptor (HR) status (P < .001) but not with human epidermal growth factor receptor 2 (HER2) status. Expression was high in 35.5% of triple-negative tumors, 24.6% of HER2-positive tumors, and 18.0% of HR-positive/HER2-negative tumors (P < .001). Pathologic complete response (pCR) rates were 26.5%, 19.1%, and 8.0% in patients with high, intermediate, or negative expression, respectively (P < .001). This predictive effect was most prominent in HR-positive tumors (P = .035) or HER2-negative tumors (P < .001). High cPARP expression was a negative, but not independent, prognostic factor for disease-free survival (DFS; P = .0025) and overall survival (OS; P = .0022). cPARP expression was highly prognostic in patients without a pCR (DFS, P < .001; OS, P < .001) and in patients with HR-positive tumors (DFS, P < .001; OS, P < .001). No such correlations were found for nPARP expression.High cPARP expression correlates with aggressive tumor pattern and predicts high sensitivity to neoadjuvant taxane/anthracycline-based chemotherapy but also unfavorable long-term prognosis. As a potential target for PARP inhibitors, cPARP-positive breast cancer might become a new, clinically relevant entity.
Cardiac resynchronization therapy-induced left ventricular reverse remodelling is associated with reduced plasma annexin A5
Authors: Susana Ravassa, Ignacio García-Bolao, Amaia Zudaire, Alfonso Macías, Juan J. Gavira, Javier Beaumont, Teresa Arias, Ana Huerta, Javier Díez
Journal: Cardiovascular Research (2010)

Cardiac resynchronization therapy (CRT) diminishes cardiac apoptosis and improves systolic function in heart failure (HF) patients with ventricular dyssynchrony. Plasma annexin A5 (AnxA5), a protein related to cellular damage, is associated with systolic dysfunction. We investigated whether the response to CRT is associated with plasma AnxA5. We also studied AnxA5 overexpression effects in HL-1 cardiomyocytes.AnxA5 ELISA was performed in plasma from 57 patients with HF and ventricular dyssynchrony at baseline and after 1 year of CRT. Patients were categorized as responders if they presented both a reduction in left ventricular (LV) end-systolic volume index (LVESVi) >10% and an increase in LV ejection fraction (LVEF) >10%. HL-1 cells were transfected with human AnxA5 cDNA, and AnxA5, PKC, Akt, p38MAPK, Bcl-2, mitochondrial integrity, caspase-3, and ATP were assessed. At baseline, an increased plasma AnxA5 level was associated with decreased LVEF and increased LVEDVi values (P < 0.05). No differences in baseline AnxA5 were observed between responders and non-responders. After CRT, AnxA5 decreased (P = 0.001) in responders but remained unchanged in non-responders. Final values of AnxA5 were independently associated with LVEF (r = -0.387, P = 0.003) and LVESVi (r = 0.403, P = 0.004) in all patients. Compared with control cells, AnxA5-transfected cells exhibited AnxA5 overexpression, decreased PKC and Akt and increased p38MAPK and Bcl-2 phosphorylation, loss of mitochondrial integrity, caspase-3 activation, and decreased ATP.CRT-induced LV reverse remodelling is associated with reduction in plasma AnxA5. The excess of AnxA5 is detrimental for HL-1 cardiomyocytes. Collectively, these data suggest that the beneficial effects of CRT might be related to an AnxA5 decrease.
Manganese Superoxide Dismutase Modulates Hypoxia-Inducible Factor-1α Induction via Superoxide
Authors: Suwimol Kaewpila, Sujatha Venkataraman, Garry R. Buettner, Larry W. Oberley
Journal: Cancer Research (2008)

Abstract Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays an important role in O2 homeostasis. Numerous observations suggest that changes in reactive oxygen species affect HIF-1α stabilization and HIF-1α transcriptional activation in many cell types. The antioxidant enzyme manganese superoxide dismutase (MnSOD) modulates the cellular redox environment by converting superoxide (O2•−) to hydrogen peroxide and dioxygen. Previous results from our group have shown that overexpression of MnSOD in MCF-7 cells alters stabilization of HIF-1α under hypoxic conditions; however, the underlying mechanism(s) is not known. Here, we tested the hypothesis that MnSOD regulates the expression of HIF-1α by modulating the steady-state level of O2•−. We found that decreasing MnSOD with small interfering RNA in MCF-7 cells resulted in (a) an associated increase in the hypoxic accumulation of HIF-1α immunoreactive protein, (b) a significant increase in the levels of O2•− (P &amp;lt; 0.01), but (c) no significant change in the steady-state level of H2O2. Removal of O2•− using spin traps (α-4-pyridyl-1-oxide-N-tert-butylnitrone and 5,5-dimethyl-1-pyrroline N-oxide) or the O2•− scavenger Tempol or an SOD mimic (AEOL10113) resulted in a decrease in HIF-1α protein, consistent with the hypothesis that O2•− is an important molecular effector responsible for hypoxic stabilization of HIF-1α. The evidence from both genetic and pharmaceutical manipulation is consistent with our hypothesis that O2•− can contribute to the stabilization of HIF-1α. [Cancer Res 2008;68(8):2781–8]
Aberrantly Methylated <i>CDKN2A</i>, <i>MGMT</i>, and <i>MLH1</i> in Colon Polyps and in Fecal DNA from Patients with Colorectal Polyps
Authors: Zsolt Petko, Mahan Ghiassi, Anthony Shuber, Janice Gorham, Walter Smalley, M. Kay Washington, Stephen Schultenover, Shiva Gautam, Sanford D. Markowitz, William M. Grady
Journal: Clinical Cancer Research (2005)

Abstract Colon cancer is the third leading cause of cancer-related death in the United States, affecting ∼147,000 people each year. Most colon cancers arise from benign neoplasms and evolve into adenocarcinomas through a stepwise histologic progression sequence that starts from adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations and, more recently, epigenetic alterations have been associated with specific steps in this polyp-adenocarcinoma sequence and likely drive the histologic progression of colon cancer. Consequently, we have assessed in colon adenomas and hyperplastic polyps the methylation status of MGMT, CDKN2A, and MLH1 to determine the timing and frequency of these events in the polyp-carcinoma progression sequence and subsequently to analyze the potential for these methylated genes to be molecular markers for adenomas and hyperplastic polyps. We have found that methylated MGMT, CDKN2A, and MLH1 occur in 49%, 34%, and 7% of adenomas and in 5%, 10%, and 7% of hyperplastic polyps, respectively, and that they are more common in histologically advanced adenomas. Furthermore, analysis of fecal DNA from persons who have undergone colonoscopic exams revealed methylated CDKN2A, MGMT, and MLH1 in fecal DNA from 31%, 48%, and 0% of individuals with adenomas and from 16%, 27%, and 10% of individuals with no detectable polyps, respectively. These results show that aberrant methylated genes can be detected frequently in sporadic colon polyps and that they can be detected in fecal DNA. Notably, improvements in the specificity and sensitivity of the fecal DNA-based assays will be needed to make them clinically useful diagnostic tests for polyps.
HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era
Authors: Silvia Montoto, Kate Shaw, Jessica Okosun, Shreyans Gandhi, Paul Fields, Andrew Wilson, Milensu Shanyinde, Kate Cwynarski, Robert Marcus, Johannes de Vos, Anna Marie Young, Melinda Tenant-Flowers, Chloe Orkin, Margaret Johnson, Daniella Chilton, John G. Gribben, Mark Bower
Journal: Journal of Clinical Oncology (2012)

The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL.From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS≥3: 68% v 26%, respectively; P<.001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy.The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P=not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P=not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P=not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status.This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS.
Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes
Authors: Peter Gæde, Pernille Vedel, Nicolai Larsen, Gunnar V.H. Jensen, Hans-Henrik Parving, Oluf Pedersen
Journal: New England Journal of Medicine (2003)

Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria.The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin.The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79).A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.
Transformation of Sporozoites into Early Exoerythrocytic Malaria Parasites Does Not Require Host Cells
Authors: Karine Kaiser, Nelly Camargo, Stefan H.I. Kappe
Journal: The Journal of Experimental Medicine (2003)

Malaria parasite species that infect mammals, including humans, must first take up residence in hepatic host cells as exoerythrocytic forms (EEF) before initiating infection of red blood cells that leads to malaria disease. Despite the importance of hepatic stages for immunity against malaria, little is known about their biology and antigenic composition. Here, we show that sporozoites, the parasites' transmission stage that resides in the mosquito vector salivary glands, can transform into early EEF without intracellular residence in host hepatocytes. The morphological sequence of transformation and the expression of proteins in the EEF appear indistinguishable from parasites that develop within host cells. Transformation depends on temperature elevation to 37°C and serum. Our findings demonstrate that residence in a host hepatocyte or specific host cell–derived factors are not necessary to bring about the profound morphological and biochemical changes of the parasite that occur after its transmission from vector to mammalian host.
Bronchogenic glomangiomyoma with local intravenous infiltration
Authors: M. Katabami, K. Okamoto, K. Ito, K. Kimura, H. Kaji
Journal: European Respiratory Journal (2006)

Most glomus tumours occur in the dermis and subcutaneous tissues. Lung glomus tumours are quite rare. The current authors present the first reported case of a lung-derived glomangiomyoma, the rarest variant of glomus tumour. A 56-yr-old female was admitted with haemoptysis. Chest computed tomography showed an ∼5-cm-diameter mass in the right lower lobe with mucoid impaction. After a right lower lobectomy, a diagnosis of glomangiomyoma was made. The tumour had grown endobronchially and its maximal diameter was 5.5 cm. Although cytologically benign, glomus tumour cells had visibly infiltrated neighbouring vessels. These results suggest that a bronchogenic glomangiomyoma has a low-grade malignancy potential and warrants close follow-up.
Dietary Antioxidant Intake and Risk of Type 2 Diabetes
Authors: Fernando Granado-Lorencio, Begona Olmedilla-Alonso
Journal: Diabetes Care (2004)

The results by Montonen et al. (1) regarding the potential role of dietary antioxidants in the prevention of type 2 diabetes are of considerable interest. The authors identify β-cryptoxanthin as a preventive factor, regardless of adjustment for other potential confounding factors, and point out that data support the hypothesis that “a sufficient intake of antioxidants plays a role in type 2 diabetes prevention.”

Although the follow-up time and number of subjects are considerable, …
Node-Negative Breast Cancer: Tamoxifen and Chemosuppression
Authors: V. CRAIG JORDAN
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Node-Negative Breast Cancer: Tamoxifen and Chemosuppression Get access V. CRAIG JORDAN V. CRAIG JORDAN Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 12, 20 June 1990, Pages 1068–1069, https://doi.org/10.1093/jnci/82.12.1068 Published: 20 June 1990
ERCC1 and RRM1: Ready for Prime Time?
Authors: Benjamin Besse, Ken A. Olaussen, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2013)

The quest for markers of sensitivity to cytotoxic agents has been ongoing for decades. In non-small-cell lung cancer, platinum compounds represent the cornerstone of systemic therapy. They target DNA and induce damage that cancer cells struggle to overcome. Somatic excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), and ribonucleotide reductase M1 (RRM1) expression levels have been extensively explored as markers of DNA repair capacity in tumor cells. Although low ERCC1 and/or RRM1 expression is generally associated with sensitivity to platinum, the results published in retrospective and prospective studies are not always consistent. Against this background, we will examine in this review the function of these two biomarkers as well as the tools available for their assessment and the associated technical issues. Their prognostic and predictive values will be summarized and considered in terms of customizing systemic therapy according to biomarker (ERCC1 and RRM1) expression levels. We will also discuss why the use of both markers should at this point be restricted to clinical research and underline that functional readouts of DNA repair will help boost future strategies for biomarker discovery in the field.
CYP2C19 LOSS-OF-FUNCTION ALLELES ARE NOT ASSOCIATED WITH CLINICAL OUTCOME OF CLOPIDOGREL THERAPY IN PATIENTS TREATED WITH NEWER-GENERATION DRUG-ELUTING STENTS
Authors: Ik Jun Choi, Mineok Chang, Jin Jin Kim, Sungmin Lim, Minkyu Kang, Byung-Hee Hwang, Donggyu Moon, Jae Gyung Kim, Eun ho Choo, Tae-Hun Kim, Yoon Seok Koh, Chan Jun Kim, Pum Joon Kim, Kiyuk Chang, Wook Sung Chung, Ki-Bae Seung
Journal: Journal of the American College of Cardiology (2013)