tbuckley/cabot-search huggingface dataset:
T-Cell Receptor Gene–Modified T Cells with Shared Renal Cell Carcinoma Specificity for Adoptive T-Cell Therapy
Authors: Matthias Leisegang, Adriana Turqueti-Neves, Boris Engels, Thomas Blankenstein, Dolores J. Schendel, Wolfgang Uckert, Elfriede Noessner
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Adoptive therapy with genetically engineered T cells carrying redirected antigen specificity is a new option for the treatment of cancer. This approach is not yet available for metastatic renal cell carcinoma (RCC), due to the scarcity of therapeutically useful reagents. We analyzed tumor-infiltrating lymphocytes (TIL) from RCC to identify T-cell specificities with shared tumor-specific recognition to develop T-cell receptor (TCR)-engineered T lymphocytes for adoptive therapy of RCC. Experimental Design: We established a T-cell clone from TIL that recognized a human leukocyte antigen (HLA)-A2–restricted tumor antigen. The TCR α- and β-chain genes were isolated, modified by codon optimization and murinization, and retrovirally transduced into peripheral blood lymphocytes (PBL). A TCR-expressing indicator line (B3Z-TCR53) was established to screen for antigen prevalence in RCC, other malignancies, and normal cell counterparts. Results: TCR53-engineered PBL recapitulated the specificity of the TIL and showed tumor-specific HLA-A2–restricted effector activities (IFN-γ, tumor necrosis factor-α, interleukin-2, macrophage inflammatory protein-1β, cytotoxicity). PBL-TCR53 of healthy donors and RCC patients exhibited similar transduction efficiency, expansion, and polyfunctional profile. Using B3Z-TCR53 cells, 130 tumor and normal cells were screened and shared TCR53 peptide: MHC expression was found in &amp;gt;60% of RCC and 25% of tumor lines of other histology, whereas normal tissue cells were not recognized. Conclusions: To date, TCR53 is the only TCR with shared HLA-A2–restricted recognition of RCC. It fulfills the criteria for utilization in TCR gene therapy and advances T cell–based immunotherapy to patients with RCC and other malignancies expressing the TCR ligand. Clin Cancer Res; 16(8); 2333–43. ©2010 AACR.
mTOR: good, bad, or ugly?
Authors: Y. Zhang, T. Zhang, C.-M. Cao, R.-P. Xiao
Journal: Cardiovascular Research (2012)

This editorial refers to ‘Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress’ by S. Gratia et al ., pp. 290–299, this issue. 

Doxorubicin (DXR) is one of the most widely used chemotherapeutics in the treatment of a variety of cancers, including breast, prostate, stomach and liver tumours, soft tissue sarcomas, leukaemias, and lymphomas.1 The anti-malignancy effects of DXR are attributed to its interaction with the DNA helix and proteins involved in DNA replication and transcription, resulting in the inhibition of synthesis of DNA, RNA, and proteins and ultimately cell death.2 However, DXR causes severe cardiomyopathy and resultant congestive heart failure, especially in patients treated with a high dose or in high-risk populations such as children, adolescents, or patients with predisposed cardiac problems. DXR-induced cardiac injury is manifested as acute or chronic cardiomyopathy, and both can eventually develop into severe congestive heart failure.

Over the past few decades, extensive studies have been focused on the mechanisms underlying DXR-induced cardiotoxicity. Although multiple mechanisms have been implicated, oxidative stress-mediated death of cardiac myocytes has been identified as one of the most important. It is now well established that DXR-induced cardiomyopathy is associated with myocyte energetic stress, oxidative …
Impact of blood transfusions on outcome after pneumonectomy for thoracic malignancies
Authors: P. Thomas, P. Michelet, F. Barlesi, X. Thirion, C. Doddoli, R. Giudicelli, P. Fuentes
Journal: European Respiratory Journal (2006)

The aim of the present study was to determine the risk factors and impact on outcome of blood transfusions following pneumonectomy for thoracic malignancies. A retrospective analysis of 432 consecutive patients was carried out, of whom 183 (42.4%) were transfused post-operatively. The associations between blood transfusions and 20 variables were assessed by univariate and multivariate analysis. Survival analysis included log-rank test and Cox regression model. Patient age, neoadjuvant treatment, completion pneumonectomy and extended procedures were independent predictors of transfusion. It was found that 30-day mortality increased significantly from 2.4% (no transfusion) to 10.9 and 21.9% (≤2 and &gt;2 red blood cell packs, respectively). Blood transfusion was the strongest predictor of 30-day mortality (odds ratio (OR) 10; 95% confidence interval (CI): 3.7–27), respiratory failure (OR 19.2; 95% CI 7.4–49.4) and infectious complications (OR 3; 95% CI 1.5–6.2). In the 367 lung cancer patients, a significantly lower 5-yr survival was observed in univariate analysis of transfused patients (27.8±5.4% versus 39.4±4.5%). In a Cox regression analysis, blood transfusion was no longer found to be significant. A dose-related correlation is suggested between blood transfusion and early mortality through an increase of infectious and respiratory complications. In contrast, blood transfusion had no independent adverse impact on long-term survival.
Will My Patient Fall?
Authors: David A. Ganz, Yeran Bao, Paul G. Shekelle, Laurence Z. Rubenstein
Journal: JAMA (2007)

Effective multifactorial interventions reduce the frequent falling rate of older patients by 30% to 40%. However, clinical consensus suggests reserving these interventions for high-risk patients. Limiting fall prevention programs to high-risk patients implies that clinicians must recognize features that predict future falls.To identify the prognostic value of risk factors for future falls among older patients.Search of MEDLINE (1966-September 2004), CINAHL (1982-September 2004), and authors' own files to identify prospective cohort studies of risk factors for falls that performed a multivariate analysis of such factors.Two reviewers independently determined inclusion of articles and assessed study quality. Disagreements were resolved by consensus. Included studies were those identifying the prognostic value of risk factors for future falls among community-dwelling persons 65 years and older. Clinically identifiable risk factors were identified across 6 domains: orthostatic hypotension, visual impairment, impairment of gait or balance, medication use, limitations in basic or instrumental activities of daily living, and cognitive impairment.Eighteen studies met inclusion criteria and provided a multivariate analysis including at least 1 of the risk factor domains. The estimated pretest probability of falling at least once in any given year for individuals 65 years and older was 27% (95% confidence interval, 19%-36%). Patients who have fallen in the past year are more likely to fall again [likelihood ratio range, 2.3-2.8]. The most consistent predictors of future falls are clinically detected abnormalities of gait or balance (likelihood ratio range, 1.7-2.4). Visual impairment, medication variables, decreased activities of daily living, and impaired cognition did not consistently predict falls across studies. Orthostatic hypotension did not predict falls after controlling for other factors.Screening for risk of falling during the clinical examination begins with determining if the patient has fallen in the past year. For patients who have not previously fallen, screening consists of an assessment of gait and balance. Patients who have fallen or who have a gait or balance problem are at higher risk of future falls.
ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol
Authors: Allen J. Taylor, Steven M. Kent, Patrick J. Flaherty, Louis C. Coyle, Thor T. Markwood, Marina N. Vernalis
Journal: Circulation (2002)

Background— Whether marked LDL reduction to levels well below 100 mg/dL would further reduce the burden of cardiovascular disease is controversial. We compared the effects of 2 statins with widely differing potencies for LDL reduction (pravastatin 40 mg/d and atorvastatin 80 mg/d) on carotid intima-media thickness (CIMT). Methods and Results— This was a single-center, randomized, clinical trial of 161 patients (mean age, 60 years; 71.4% male; 46% with known cardiovascular disease) that met National Cholesterol Education Program (NCEP) II criteria for lipid-lowering therapy. The effects of atorvastatin (80 mg/d; n=79) and pravastatin (40 mg/d; n=82) on CIMT were compared using blinded, serial assessments of the far wall of the distal common carotid artery. Baseline CIMT and other characteristics were similar between study groups. As anticipated, atorvastatin was substantially more potent for LDL reduction after 12 months: in the atorvastatin group, LDL cholesterol was 76±23 mg/dL after 12 months (−48.5%); LDL cholesterol was 110±30 mg/dL in the pravastatin group (−27.2%; P &lt;0.001). Atorvastatin induced progressive CIMT regression over 12 months (change in CIMT, −0.034±0.021 mm), whereas CIMT was stable in the pravastatin group (change of 0.025± 0.017 mm; P =0.03). Conclusions— Marked LDL reduction (&lt;100 mg/dL) with a high-potency statin provides superior efficacy for atherosclerosis regression at 1 year. This early effect on CIMT, a surrogate for clinical benefit, suggests that marked LDL reduction with synthetic statins may provide enhanced reduction in clinical coronary event rates.
Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1
Authors: N. Mayuzumi, S. Ikeda, H. Kawada, P.S. Fan, H. Ogawa
Journal: British Journal of Dermatology (2005)

Darier disease (DD) and Hailey-Hailey disease (HHD) are autosomal dominantly inherited skin disorders that histologically share the characteristics of suprabasal separation and acantholysis of epidermal keratinocytes. Various mutations in the DD gene (ATP2A2) and the HHD gene (ATP2C1) (respectively encoding the calcium pumps of the sarco/endoplasmic reticulum and the Golgi apparatus) have recently been described in multiple families with DD and HHD. Mutations in ATP2A2 or ATP2C1 have been suggested as causing the conditions via the mechanism of haploinsufficiency. Ultraviolet (UV) B irradiation is thought to be an aggravating factor in both diseases.To examine the effects of various stimuli on ATP2A2 and ATP2C1 mRNA expression, and to examine the role of calcium pumps during keratinocyte differentiation.The effects of UVB irradiation, of UVB-inducible inflammatory cytokines produced by keratinocytes and of high-calcium medium (1.8 mmol L(-1) as opposed to 0.08 mmol L(-1) Ca2+) on ATP2A2 and ATP2C1 mRNA expression were quantified in cultured normal human keratinocytes using reverse transcription-polymerase chain reaction.Expression of ATP2A2 and ATP2C1 mRNA was suppressed immediately after exposure to UVB irradiation, and modulation of mRNA expression was achieved in keratinocytes cultured with proinflammatory cytokines. The mRNA expression of both genes was increased significantly after the shift to high extracellular Ca2+ concentration.The results suggest that modulation of ATP2A2 and ATP2C1 mRNA expression by UV or cytokines might contribute to the clinical presentations unique to DD and HHD, and that the controlled expression of these genes plays an important role in keratinocyte homeostasis, function and differentiation.
Exacerbations of chronic obstructive pulmonary disease: when are bacteria important?
Authors: M. Miravitlles
Journal: European Respiratory Journal (2002)

The progressive course of chronic obstructive pulmonary disease (COPD) is often aggravated by exacerbations, the majority of them produced by bronchial infection. Frequent exacerbations have been demonstrated to have a negative impact on quality of life and pulmonary function in patients with COPD, particularly in active smokers. Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with chronic lung disease. Evidence indicates that the number of patients with pathogenic bacteria in respiratory secretions and the bronchial bacterial load increase during exacerbations. Furthermore, the local inflammatory response of the host parallels the increase in bacterial load. From these observations, it can be speculated that, for symptoms of acute exacerbation to appear, there must be a minimum bacterial load in the airways, i.e. a threshold above which the inflammatory reaction is severe enough to elicit clinical symptoms of exacerbation. This threshold may vary from patient to patient owing to different modifying factors. Some of these factors may be the recognised risk factors for relapse, such as increasing age, impairment of lung function, comorbid conditions or frequent exacerbations in the past. Relapse rates after ambulatory treatment of acute exacerbation of COPD may be as high as 20–25% of cases. Relapses are associated with significant mordibity and increased costs. A number of unanswered questions remain regarding exacerbations of chronic obstructive pulmonary disease. These include the role of viral infection, the importance of residual bacterial colonisation and the impact of new antibiotics on the treatment of exacerbations.
A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by Culture<i>In vitro</i>
Authors: Vincent C. Daniel, Luigi Marchionni, Jared S. Hierman, Jonathan T. Rhodes, Wendy L. Devereux, Charles M. Rudin, Rex Yung, Giovanni Parmigiani, Marion Dorsch, Craig D. Peacock, D. Neil Watkins
Journal: Cancer Research (2009)

Abstract Traditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small-cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then reimplanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared with normal lung, primary tumors, xenografts, and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture and that was not regained when the tumors were reestablished as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development. [Cancer Res 2009;69(8):3364–71]
The Effect of Postprandial Exercise on Meal-related Glucose Intolerance in Insulin-dependent Diabetic Individuals
Authors: D Caron, P Poussier, E B Marliss, B Zinman
Journal: Diabetes Care (1982)

Although exercise is a central therapeutic modality in insulin-dependent diabetic patients, its prescription and expected effects have remained far less precise than the concurrent modalities of insulin and diet. To quantify the potential benefit of exercise on meal glycemic excursions, eight insulin-dependent diabetic subjects were studied on two separate days during breakfast and lunch, with and without 45 min of moderate exercise, starting 30 min after breakfast. All other variables were kept constant, including their usual insulin doses, which were given subcutaneously in the abdomen. Fasting glycemias were brought to comparable levels by overnight insulin infusion (rest day: 110 ± 9 mg/dl; exercise day: 105 ± 9 mg/dl). Postprandial exercise reduced peak glycemia for breakfast (270 ± 22 versus 203 ± 22 mg/dl) and lunch (270 ± 16 versus 170 ± 20 mg/dl, P &amp;lt; 0.05) for the group as a whole on rest day and exercise day, respectively. Three types of individual responses were seen. Five subjects showed an improved glycemic excursion with exercise during both breakfast and lunch. In two subjects only the lunch response was significantly improved. One subject showed no effect of exercise. The failure to demonstrate a lowering of glycemia with breakfast appears to be related to the persistent use of fatderived fuels in these subjects. This is suggested by a lower respiratory quotient (RQ), and elevated free fatty acid and 3-hydroxybutyrate concentrations. Plasma “free” insulin and glucagon concentrations could not account for these observations. Thus, the majority of subjects showed improved glucoregulation related to exercise performed postprandially. If adequately insulinized, conventionally treated diabetic individuals can benefit from strategically timed exercise.
Interleukin-17 and Interferon-γ Are Produced Concomitantly by Human Coronary Artery–Infiltrating T Cells and Act Synergistically on Vascular Smooth Muscle Cells
Authors: Raymond E. Eid, Deepak A. Rao, Jing Zhou, Sheng-fu L. Lo, Hooman Ranjbaran, Amy Gallo, Seth I. Sokol, Steven Pfau, Jordan S. Pober, George Tellides
Journal: Circulation (2009)

Atherosclerosis is an inflammatory disease in which interferon (IFN)-gamma, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis.Circulating IL-17 and IFN-gamma were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-gamma/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1beta, IL-6, and IL-23. Both IL-17 and IFN-gamma were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-gamma but not IL-17 secretion. Blockade of IFN-gamma signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-gamma synthesis; production of both cytokines was inhibited by transforming growth factor-beta1. Approximately 10-fold fewer coronary artery-infiltrating T helper cells were IL-17 producers than IFN-gamma producers, and unexpectedly, IL-17/IFN-gamma double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-gamma to enhance IL-6, CXCL8, and CXCL10 secretion.Our findings demonstrate that IL-17 is produced concomitantly with IFN-gamma by coronary artery-infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.
Year in review in Intensive Care Medicine 2010: II. Pneumonia and infections, cardiovascular and haemodynamics, organization, education, haematology, nutrition, ethics and miscellanea
Authors: Massimo Antonelli, Elie Azoulay, Marc Bonten, Jean Chastre, Giuseppe Citerio, Giorgio Conti, Daniel De Backer, Herwig Gerlach, Goran Hedenstierna, Michael Joannidis, Duncan Macrae, Jordi Mancebo, Salvatore M. Maggiore, Alexandre Mebazaa, Jean-Charles Preiser, Jerôme Pugin, Jan Wernerman, Haibo Zhang
Journal: Intensive Care Medicine (2011)

Year in review in Intensive Care Medicine 2010 : II. Pneumonia and infections, cardiovascular and haemodynamics, organization, education, haematology, nutrition, ethics and miscellanea
Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages.
Authors: B K English, J N Ihle, A Myracle, T Yi
Journal: The Journal of Experimental Medicine (1993)

The hematopoietic cell kinase (hck) is a member of the src family of tyrosine kinases, and is primarily expressed in myeloid cells. Hck expression increases with terminal differentiation in both monocyte/macrophages and granulocytes and is further augmented during macrophage activation. Recent evidence has implicated src-related tyrosine kinases in critical signaling pathways in other hematopoietic lineages. Herein we demonstrate that manipulation of the level of hck expression in the murine macrophage cell line BAC1.2F5 alters the responsiveness of these cells to activation by bacterial lipopolysaccharide (LPS) but does not affect survival or proliferation. Overexpression of an activated mutant of hck in BAC1.2F5 cells augments tumor necrosis factor (TNF) production in response to LPS, whereas inhibition of endogenous hck expression, by antisense oligonucleotides, interferes with LPS-mediated TNF synthesis. Together, these observations suggest that hck is an important component of the signal transduction pathways in activated macrophages.
Association of Interstage Home Monitoring With Mortality, Readmissions, and Weight Gain
Authors: Matthew E. Oster, Alexandra Ehrlich, Eileen King, Christopher J. Petit, Martha Clabby, Sherry Smith, Michelle Glanville, Jeffrey Anderson, Lynn Darbie, Robert H. Beekman
Journal: Circulation (2015)

Daily home monitoring of oxygen saturation and weight has been reported to improve outcomes for patients with single-ventricle heart disease during the period between stage I palliation and stage II palliation. However, these studies have been limited to single institutions and used historical control subjects. Our objective was to determine the association of various interstage home monitoring strategies with outcomes using a multicenter cohort with contemporary control subjects.We performed a retrospective cohort study using prospectively collected data from the National Pediatric Cardiology Quality Improvement Collaborative from 2008 to 2012. We compared interstage mortality, unscheduled readmissions, and change in weight-for-age Z score for various home monitoring strategies of oxygen saturation (n=494) or weight (n=472), adjusting for sex, syndrome, tricuspid regurgitation, arch obstruction, and shunt type. Overall interstage mortality was 8.1%, and 47% had ≥1 unscheduled readmission. We did not find any associations of home oxygen saturation or weight monitoring with mortality or readmission. Although there was no difference in weight-for-age Z score for daily (0.33±0.12) versus weekly (0.34±0.18, P=0.98) weight monitoring, daily home weight monitoring was superior to no home weight monitoring (-0.15±0.18; P<0.01).Home weight monitoring is associated with improved weight gain during the interstage period, but we did not find any benefits in other clinical outcomes for either home oxygen saturation monitoring or home weight monitoring.