tbuckley/cabot-search huggingface dataset:
Individual Prediction of Heart Failure Among Childhood Cancer Survivors
Authors: Eric J. Chow, Yan Chen, Leontien C. Kremer, Norman E. Breslow, Melissa M. Hudson, Gregory T. Armstrong, William L. Border, Elizabeth A.M. Feijen, Daniel M. Green, Lillian R. Meacham, Kathleen A. Meeske, Daniel A. Mulrooney, Kirsten K. Ness, Kevin C. Oeffinger, Charles A. Sklar, Marilyn Stovall, Helena J. van der Pal, Rita E. Weathers, Leslie L. Robison, Yutaka Yasui
Journal: Journal of Clinical Oncology (2014)

Purpose To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer. Patients and Methods Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models. Results Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%). Conclusion Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions.
REGULATION OF THE IMMUNE RESPONSE
Authors: Nicholas R. StC. Sinclair
Journal: The Journal of Experimental Medicine (1969)

The ability of 7S and F(ab')2 antibody fragments to suppress priming with low doses of antigen was compared. The 7S preparation was approximately 100–1000 times more potent than the F(ab')2 preparation when the agglutinin titers of the two preparations were the same. The presence of any ability to suppress priming in the F(ab')2 preparation may reflect an inherent capacity of the F(ab')2 antibody or contamination with small amounts of 7S antibody. The difference between 7S and F(ab')2 antibody in ability to suppress priming is attributed to the lack of the Fc portion on the F(ab')2 antibody. The Fc portion may be needed to prevent rapid excretion of antibody from the body, to induce rapid phagocytosis of antigen-antibody complexes with consequent breakdown and elimination of antigen, or to inactivate or suppress the antigen-sensitive cells from reacting to antigenic determinants. More detailed studies will permit a better assessment of the importance of these three possible regulatory roles of the Fc portion of the immunoglobulin in the immune response.
Direct Visualization of Antigen-Specific Cytotoxic T Cells — A New Insight into Immune Defenses
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (1998)

Immunochemists have been making precise measurements of antibodies and antigens for many years, whereas cellular immunologists have had to rely on indirect and often clumsy methods for counting T cells with specificity for a particular antigen. Recently, several laboratories have shown how to enumerate antigen-specific T cells directly and have applied the method to clinical problems. With this medically important advance, physicians can obtain counts of circulating cytotoxic T cells with immunologic specificity for a given pathogenic virus. The method requires only existing equipment (a fluorescence-activated cell sorter) and reagents that will probably soon be commercially available. Knowledge of the . . .
Retrospective Analysis of Time to Recurrence in the ATAC Trial According to Hormone Receptor Status: An Hypothesis-Generating Study
Authors: Mitch Dowsett, Jack Cuzick, Chris Wale, Tony Howell, Joan Houghton, Michael Baum
Journal: Journal of Clinical Oncology (2005)

Arimidex, tamoxifen alone, or in combination (ATAC) trial of anastrozole (Arimidex) versus tamoxifen or a combination of the two in 9,366 postmenopausal patients with primary breast cancer found a significant improvement in disease-free survival and time to recurrence (TTR) for anastrozole compared with tamoxifen, that was restricted to patients with hormone receptor-positive (ie, estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+]) disease, the target population for these therapies. We retrospectively tested the hypothesis that this benefit might differ according to PgR status.TTR was compared between the three treatment groups for subgroups defined by ER and PgR status using Cox's proportional hazards model, with and without adjustment for baseline variables.The unadjusted hazard ratio (HR) for anastrozole versus tamoxifen for TTR was 0.74 (95% CI, 0.64 to 0.87) for women with either ER+ or PgR+ tumors. In the ER+/PgR+ subgroup (n = 3,834) the HR was 0.84 (95% CI, 0.69 to 1.02) compared with 0.43 (95% CI, 0.31 to 0.61) in the ER+/PgR-negative (PgR-) subgroup (n = 880). In the adjusted model the HRs were 0.83 and 0.45, respectively.Time to recurrence was longer for anastrozole- than tamoxifen-treated patients in both ER+/PgR+ and ER+/PgR- subgroups, but the benefit was substantially greater in the PgR- subgroup. As this was an "exploratory" analysis, this effect should be considered as hypothesis generating and assessed prospectively in other trials comparing the adjuvant use of an aromatase inhibitor with tamoxifen.
Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study
Authors: B. Koch, C. Schäper, T. Ittermann, T. Spielhagen, M. Dörr, H. Völzke, C. F. Opitz, R. Ewert, S. Gläser
Journal: European Respiratory Journal (2008)

Cardiopulmonary exercise testing (CPET) is a widely applied clinical procedure. The aim of the present study was to acquire a comprehensive set of reference values for cardiopulmonary responses to exercise and to evaluate possible associations with sex, age and body mass index (BMI). A standardised progressive incremental exercise protocol on a cycle ergometer was applied to 1,708 volunteers of a cross-sectional epidemiologic survey, called “Study of Health in Pomerania”. Individuals with cardiopulmonary disorders, or echocardiographic or lung function pathologies, were excluded. The influence of potential confounding factors, such as smoking, taking β-blockers, hypertension, diastolic dysfunction, BMI and physical activity, were analysed for their influencing power. Reference values of CPET parameters were determined by regression analyses. Of the volunteers, 542 current smokers and obese individuals were excluded for not being representative of a healthy population. The final sample size was 534 (253 males), with age 25–80 yrs. The current study provides a representative set of reference values for CPET parameters based on age and weight. Sex and age have a significant influence on exercise parameters. While addressing the problem of a selection bias, the current study provides the first comprehensive set of reference values obtained in a large number of healthy volunteers within a population-based survey.
Questionable Validity of Cardiac Risk Score on the Basis of the NSABP B-31 Model
Authors: Vincenzo Pitini, Carmela Arrigo, Patrizia Mondello, Giuseppe Altavilla
Journal: Journal of Clinical Oncology (2013)

TO THE EDITOR: Romond et al 1 presented the results of a 7-year follow-up of the cardiac function in the NSABP B-31 clinical trial. The authors concluded that the late development of chronic heart failure (CHF) after the addition of trastuzumab to paclitaxel after doxorubicin/cyclophosphamide chemotherapy is uncommon; furthermore, they developed a cardiac risk score that includes age and baseline left ventricular ejection fraction (LVEF) assessed by multigated acquisition scans for the prediction of the absolute risk of CHF in individual patients. Although a number of limitations have already been pointed out in the editorial by Mayer and Lin, 2 we would like to discuss some points in greater detail. Currently, there is no universally accepted gold standard for measuring LVEF that is widely used to monitor the cardiac systolic function after chemotherapy. Multigated acquisition scan is performed by labeling a patient’s RBCs with technetium 99m pertechnetate and measures changes in radioactivity in the left ventricle between end-diastole and end-systole rather than truly measuring left ventricle volumes. However, because the acquisition of counts is gated with the patient’s electrocardiogram, the accuracy of LVEF calculations in patients with arrhythmias will lead to artificially reduced counts and reduce the accuracy of LVEF calculations. In addition, poor labeling of the RBCs can occur. In one study, the average LVEF showed considerable variation (up to 8% differences in calculated means between institutions), using the same raw data but differ
The Loss of PTEN Allows TCR αβ Lineage Thymocytes to Bypass IL-7 and Pre-TCR–mediated Signaling
Authors: Thijs J. Hagenbeek, Marianne Naspetti, Fabrice Malergue, Fabien Garçon, Jacques A. Nunès, Kitty B.J.M. Cleutjens, Jan Trapman, Paul Krimpenfort, Hergen Spits
Journal: The Journal of Experimental Medicine (2004)

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates cell survival and proliferation mediated by phosphoinositol 3 kinases. We have explored the role of the phosphoinositol(3,4,5)P3-phosphatase PTEN in T cell development by analyzing mice with a T cell–specific deletion of PTEN. Ptenflox/floxLck-Cre mice developed thymic lymphomas, but before the onset of tumors, they showed normal thymic cellularity. To reveal a regulatory role of PTEN in proliferation of developing T cells we have crossed PTEN-deficient mice with mice deficient for interleukin (IL)-7 receptor and pre–T cell receptor (TCR) signaling. Analysis of mice deficient for Pten and CD3γ; Pten and γc; or Pten, γc, and Rag2 revealed that deletion of PTEN can substitute for both IL-7 and pre-TCR signals. These double- and triple-deficient mice all develop normal levels of CD4CD8 double negative and double positive thymocytes. These data indicate that PTEN is an important regulator of proliferation of developing T cells in the thymus.
Influenza A/H1N1_09: Australia and New Zealand's Winter of Discontent
Authors: Tom Kotsimbos, Grant Waterer, Christine Jenkins, Paul M. Kelly, Allen Cheng, Robert J. Hancox, Mark Holmes, Richard Wood-Baker, Simon Bowler, Louis Irving, Philip Thompson
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Section:ChooseTop of pageAbstract <<PAST PANDEMIC INFLUENZA A...BROAD CLINICAL SPECTRUM O...SPECIFIC H1N1_09 MANAGEME...PANDEMIC INFLUENZA, HEALT...ROLE OF RESPIRATORY COMMU...CONCLUSIONSReferencesCITING ARTICLES
A note on imaginability arguments: Building a bridge to the hard solution
Authors: Ralph Ellis
Journal: Behavioral and Brain Sciences (1999)

According to “imaginability arguments,” given any explanation of the physiological correlates of consciousness, it remains imaginable that all elements of that explanation could occur without consciousness, which thus remains unexplained. The O'Brien &amp; Opie connectionist approach effectively shows that perspicuous explanations can bridge this explanatory gap, but bringing in other issues – for example, involving biology and emotion – would facilitate going much further in this direction. A major problem is the ambiguity of the term “representation.” Bridging the gap requires perspicuously explaining not just how we form “representations” in the sense of outputs isomorphic to what is represented, but also what makes representations conscious; I sketch briefly what this would entail.
Diagnosis and Immunotherapy of Mould Allergy
Authors: H.‐J. Malling, B. Agrell, S. Croner, S. Dreborg, T. Foucard, M. Kjellman, A. Koivikko, A. Roth, B. Weeke
Journal: Allergy (1985)

In order to screen for mould allergy, extracts of five common atmospheric moulds ( Cladosporium, Alternaria, Penicillium, Aspergillus and Mucor ) from various manufacturers were investigated in 130 patients (5–60 years old) with clinical symptoms indicating possible mould allergy. The patients were screened by skin prick test (SPT) and radioallergosorbent test (RAST). SPT seemed to be more sensitive than RAST as a diagnostic screening procedure (80% positive reactions to one or more species compared to 50%). With a partially purified, standardized preparation of Cladosporium herbarum more positive reactions were obtained than with crude extracts without evidence of any unspecific reactions. The difference between commercial and standardized extracts is most probably a result of a variation of both the biological potency of allergenic determinants and the allergenic composition. A considerable number of negative RAST reactions with standard discs were found in patients with positive skin reactions to partially purified Cladosporium , but RAST seemed to be more sensitive than SPT with the other commercial mould extracts. Based on the screening, a very convincing tendency to IgE‐reactivity to other moulds was found in patients reacting to Cladosporium , the most common cause of mould allergy. The results confirm the inadequacy of most mould extracts used in diagnostic procedures and strengthen the value of using standardized extracts.
Genotype-Phenotype Correlation in the Long-QT Syndrome
Authors: Peter J. Schwartz, Silvia G. Priori, Carla Spazzolini, Arthur J. Moss, G. Michael Vincent, Carlo Napolitano, Isabelle Denjoy, Pascale Guicheney, Günter Breithardt, Mark T. Keating, Jeffrey A. Towbin, Alan H. Beggs, Paul Brink, Arthur A. M. Wilde, Lauri Toivonen, Wojciech Zareba, Jennifer L. Robinson, Katherine W. Timothy, Valerie Corfield, Duangrurdee Wattanasirichaigoon, Clive Corbett, Wilhelm Haverkamp, Eric Schulze-Bahr, Michael H. Lehmann, Ketty Schwartz, Philippe Coumel, Raffaella Bloise
Journal: Circulation (2001)

Background —The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions (“triggers”) associated with cardiac events may in large part be gene specific. Methods and Results —We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions —Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
Adenosine Primes the Opening of Mitochondrial ATP-Sensitive Potassium Channels
Authors: Toshiaki Sato, Norihito Sasaki, Brian O’Rourke, Eduardo Marbán
Journal: Circulation (2000)

Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (K(ATP)) channels have emerged as the likely effectors. We sought to determine the mechanistic interactions between these 2 observations.The mitochondrial flavoprotein oxidation induced by diazoxide (100 micromol/L) was used to quantify mitochondrial K(ATP) channel activity in intact rabbit ventricular myocytes. Adenosine (100 micromol/L) increased mitochondrial K(ATP) channel activity and abbreviated the latency to mitochondrial K(ATP) channel opening. These potentiating effects were entirely prevented by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (100 micromol/L) or by the protein kinase C inhibitor polymyxin B (50 micromol/L). The effects of adenosine and diazoxide reflected mitochondrial K(ATP) channel activation, because they could be blocked by the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (500 micromol/L). In a cellular model of simulated ischemia, adenosine mitigated cell injury; this cardioprotective effect was blocked by 5-hydroxydecanoate but not by the surface-selective K(ATP) channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial K(ATP) channel gating reproduced the major experimental findings.Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial K(ATP) channels in a protein kinase C-dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.
Combination of Rituximab, Bendamustine, and Cytarabine for Patients With Mantle-Cell Non-Hodgkin Lymphoma Ineligible for Intensive Regimens or Autologous Transplantation
Authors: Carlo Visco, Silvia Finotto, Renato Zambello, Rossella Paolini, Andrea Menin, Roberta Zanotti, Francesco Zaja, Gianpietro Semenzato, Giovanni Pizzolo, Emanuele S.G. D'Amore, Francesco Rodeghiero
Journal: Journal of Clinical Oncology (2013)

The combination of bendamustine (B) and rituximab (R) is efficacious, with favorable toxicity in mantle-cell lymphoma (MCL). In this phase II study, we combined cytarabine with R and B (R-BAC) in patients with MCL age ≥ 65 years who were previously untreated or relapsed or refractory (R/R) after one prior immunochemotherapy treatment.In stage one, we established the maximum-tolerated dose (MTD) of cytarabine in R-BAC. In stage two, patients received R (375 mg/m(2) intravenously [IV] on day 1), B (70 mg/m(2) IV on days 2 and 3), and cytarabine (MTD IV on days 2 to 4) every 28 days for four to six cycles. The primary end point (overall response rate [ORR]) was evaluated by positron emission tomography. Secondary end points included safety, progression-free survival (PFS), response duration, and overall survival.Forty patients (median age, 70 years; 20 previously untreated patients) were enrolled; 93% had Ann Arbor stage III/IV disease; 49% had high Mantle Cell International Prognostic Index scores, with 15% blastoid histology. All R/R patients (35% refractory) had previously received R-containing regimens. The cytarabine MTD used in stage two was 800 mg/m(2), and R-BAC was well tolerated, with an 85% treatment completion rate. The major toxicity was transient grades 3 to 4 thrombocytopenia (87% of patients); febrile neutropenia occurred in 12%. The ORR was 100% (95% complete response [CR]) for previously untreated and 80% (70% CR) for R/R patients. The 2-year PFS rate (± standard deviation) was 95% ± 5% for untreated and 70% ± 10% for R/R patients.R-BAC is well tolerated and active against MCL.
Do steroids ameliorate bile acid malabsorption in Crohn's disease?
Authors: R S Kwon
Journal: Gut (2003)

Steroids may partially restore impaired bile salt absorption in Crohn’s disease patients, highlighting a new modus operandi for steroids as their beneficial effects have traditionally been attributed to immunomodulatory effects alone

Steroids are among the mainstays of medical therapy for Crohn’s disease but may lead to unfavourable long term complications. Recently, budesonide has been shown to be effective in inducing remission in mild to moderate disease while undergoing less systemic absorption compared with other corticosteroids.1 It is hypothesised that steroids exert their salutary effect through an immunomodulatory action on the small bowel mucosa.2 In this issue of Gut , Jung and colleagues3 shed light on the possibility of another potentially beneficial effect of steroid therapy—namely, the partial restoration of impaired bile salt absorption in Crohn’s patients with distal ileal involvement [see page 78] .

The integrity of the enterohepatic circulation of bile salts is dependent on active uptake from the ileum, which is mediated by SLC10A2, known previously as the apical sodium dependent bile acid transporter (ASBT).4 Given the malady’s proclivity for the distal ileum, one of the classic hallmarks of intestinal Crohn’s disease is bile salt malabsorption.5–7 Bile salt malabsorption occurs when intestinal transport is appreciably disrupted, and the degree to which this occurs depends on the length of ileal involvement and/or resection.8 Therefore, the activity and functioning of the remaining ASBT, as well as colonic compensation by passive absorption of bacterially modified (secondary) bile acids are essential for keeping the enterohepatic circulation of bile salts partially intact.9,10 Mild bile salt malabsorption may result in cholerrhoeic enteropathy that is easily controlled with low dose bile …
Clinical outcome and prognostic factors of acute respiratory failure due to pneumocystis pneumonia in non-HIV patients
Authors: Yousang Ko, Kyeongman Jeon
Journal: European Respiratory Journal (2012)

Pneumocystis pneumonia is a potentially life-threatening infection that occurs in immunocompromised individuals. While it is well-known that the clinical course of PCP in non-HIV patients differs in HIV-positive patients. But, the ICU mortality of patients with acute respiratory failure requiring mechanical ventilation dose not well known.  The objective of this study was to examine the outcome and prognostic factors of ICU mortality in patients with acute respiratory failure caused by Pneumocystis pneumoniat.  We conducted a five-year retrospective review (from October 2005 to December 2010) of all patients who had histologic evidence in the non-HIV patients. Of the 44 adult patients investigated, 25 patients (56%) had solid or hematologic malignancies, 17 (33%) had received transplantation and 43 (97%) had received corticosteroid. Median P/f ratio on day 1 was 139 (IQR:116-187), SAPS 3 score on day 1 was 46 (IQR:36058) and SOFA score on day 1 was 7 (IQR:5-9). The ICU mortality rates are 50% (22 patients were died) and associated with high SAPS 3 score (37 vs. 58, p   The mortality rate in patients with acute respiratory failure caused by pneumocystis pneumonia was high. Especially, the severity on ICU admission and newly developed shock after ICU admission were related to a poor prognosis.