tbuckley/cabot-search huggingface dataset:
Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma
Authors: Alison J. Moskowitz, Paul A. Hamlin, Miguel-Angel Perales, John Gerecitano, Steven M. Horwitz, Matthew J. Matasar, Ariela Noy, Maria Lia Palomba, Carol S. Portlock, David J. Straus, Tricia Graustein, Andrew D. Zelenetz, Craig H. Moskowitz
Journal: Journal of Clinical Oncology (2012)

Limited data exist regarding the activity of bendamustine in Hodgkin lymphoma (HL). This phase II study evaluated the efficacy of bendamustine in relapsed and refractory HL.Patients with relapsed and refractory HL who were ineligible for autologous stem-cell transplantation (ASCT), or for whom this treatment failed, received bendamustine 120 mg/m(2) as a 30-minute infusion on days 1 and 2 every 28 days with growth factor support. The primary end point was overall response rate (ORR). A secondary end point was referral rate to allogeneic stem-cell transplantation (alloSCT) for patients deemed eligible for alloSCT at the time of enrollment.Of the 36 patients enrolled, 34 were evaluable for response. Patients had received a median of four prior treatments, and 75% had relapsed after ASCT. The ORR by intent-to-treat analysis was 53%, including 12 complete responses (33%) and seven partial responses (19%). The response rate among evaluable patients was 56%. Responses were seen in patients with prior refractory disease, prior ASCT, and prior alloSCT; however, no responses were seen in patients who relapsed within 3 months of ASCT. The median response duration was 5 months. Five patients (20% of those eligible) proceeded to alloSCT after treatment with bendamustine. Grade ≥ 3 adverse events were infrequent and most commonly included thrombocytopenia (20%), anemia (14%), and infection (14%).This study confirms the efficacy of bendamustine in heavily pretreated patients with HL. These results support current and future studies evaluating bendamustine combinations in relapsed and refractory HL.
Increased Prevalence of Autoimmune Phenomena and Greater Risk for Alloreactivity in Female Heart Transplant Recipients
Authors: Katherine Lietz, Ranjit John, Alfred Kocher, Michael Schuster, Donna M. Mancini, Niloo M. Edwards, Silviu Itescu
Journal: Circulation (2001)

The influence of sex on alloreactivity and graft outcome after heart transplantation was evaluated.A retrospective review of 520 consecutive recipients of a primary cardiac allograft between 1992 and 2000 at a single center was performed. The influence of sex on alloreactivity, acute rejection, transplant-related coronary artery disease, and survival was determined. Statistical methods included logistic regression analysis and Kaplan-Meier actuarial survival analysis. Female recipients had an increased prevalence before transplant of idiopathic cardiomyopathy, antinuclear antibodies, and HLA-B8, DR3 haplotypes. After transplant, female sex predicted shorter duration to a first rejection, higher cumulative rejection frequency, and earlier posttransplant production of anti-HLA antibodies. Female recipients had higher early mortality rates (<6 months) that were due to infection. Fatal infections correlated with 2-fold higher cyclosporine levels in female recipients. However, the incidence of transplant-related coronary artery disease developing beyond 1 year after transplant was lower in female than in male recipients.Females undergoing cardiac transplantation are more likely to manifest features of an underlying autoimmune state. This may predispose to a higher posttransplant risk of allograft rejection and requirement for increased immunosuppression. Earlier diagnosis and management of alloreactivity in female recipients before development of acute rejection and the use of more focused and less globally immunosuppressive agents during established rejections may have a significant effect on the clinical outcome of female cardiac allograft recipients.
Bone quality and bone mass as assessed by quantitative ultrasound and dual energy x ray absorptiometry in women with rheumatoid arthritis: relationship with quadriceps strength
Authors: O R Madsen
Journal: Annals of the Rheumatic Diseases (2002)

Objective: To examine relationships of bone quality as assessed by quantitative ultrasound (QUS) and bone mineral density (BMD, g/cm<sup>2</sup>) with quadriceps strength (QS) in women with rheumatoid arthritis (RA). Methods: Sixty seven women with RA according to the 1987 American College of Rheumatology (ACR) criteria were examined. Mean (SD) age was 62 (13) years, mean disease duration 15 years. Most were or had been receiving glucocorticoid treatment. Calcaneal bone quality expressed as speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz), and stiffness was measured by QUS. BMD of the femoral neck, spine, and distal forearm was measured by dual energy <i>x</i> ray absorptiometry (DXA). Maximal voluntary isokinetic quadriceps strength (Nm) was assessed by isokinetic dynamometry. Pain was recorded on a visual analogue scale (VAS), disability was scored by the Stanford Health Assessment Questionnaire (HAQ), and the degree of physical impairment was expressed by the Steinbrocker index (SI). Results: In multiple regression analyses, QS predicted SOS, BUA, and stiffness (<i>r</i><sub>partial</sub> ranging from 0.36 to 0.45, p&lt;0.005) and femoral neck BMD (<i>r</i><sub>partial</sub>=0.30, p&lt;0.05) independently of age, height, weight, disease duration, HAQ, VAS, SI, and cumulative steroid dose. BMD of the spine and distal forearm was not associated with QS. After adjustment for covariates, women with subnormal BMD of the femoral neck (T score &lt;−1), had a 20% lower QS than those with normal BMD (p&lt;0.0001). Conclusions: Calcaneal bone quality and femoral neck BMD were associated with QS in women with RA. This finding indicates that physical activity including muscle strengthening exercises may play a part in the prevention of bone loss in these patients.
INSTITUTIONAL TREATMENT IN SURGICAL TUBERCULOSIS
Authors: C. L. Pattison
Journal: BMJ (1921)

In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3<i>H</i>)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s–1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human <i>α</i><sub>1,2,3,5</sub><i>β</i><sub>2,3</sub><i>γ</i><sub>2S</sub> GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs) expressed in <i>Xenopus</i> oocytes, whereas it displayed highly diverse functionalities at the <i>α</i><sub>4,6</sub><i>β</i><sub>1,2,3</sub><i>δ</i> GABA<sub>A</sub>R subtypes, ranging from inactivity (<i>α</i><sub>4</sub><i>β</i><sub>1</sub><i>δ</i>), through negative (<i>α</i><sub>6</sub><i>β</i><sub>1</sub><i>δ</i>) or positive allosteric modulation (<i>α</i><sub>4</sub><i>β</i><sub>2</sub><i>δ</i>, <i>α</i><sub>6</sub><i>β</i><sub>2,3</sub><i>δ</i>), to superagonism (<i>α</i><sub>4</sub><i>β</i><sub>3</sub><i>δ</i>). Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABA<sub>A</sub>R. Instead, the compound is proposed to act through the transmembrane <i>β</i><sup>(+)</sup>/<i>α</i><sup>(–)</sup> subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABA<sub>A</sub>R modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1–100 <i>μ</i>M concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABA<sub>A</sub>Rs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABA<sub>A</sub>Rs give rise to its effects as a therapeutic and recreational drug.
Genetic Polymorphism in <i>EGF</i> Is Associated with Prostate Cancer Aggressiveness and Progression-Free Interval in Androgen Blockade–Treated Patients
Authors: Ana L. Teixeira, Ricardo Ribeiro, Diana Cardoso, Daniela Pinto, Francisco Lobo, Avelino Fraga, Francisco Pina, Fernando Calais-da-Silva, Rui Medeiros
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Most prostate cancer patients develop resistance to androgen deprivation treatment, resulting in hormone resistance. Epidermal growth factor (EGF) activates several pro-oncogenic intracellular pathways inducing proliferation, differentiation, and tumorigenesis in epithelial cells. The EGF-EGF receptor pathway seems to be especially relevant in hormone-resistant prostate cancer stage. A single nucleotide polymorphism G&amp;gt;A in +61 locus of EGF gene has been described, in which A homozygous carriers express significantly less EGF protein compared with G allele carriers. Our purpose was to investigate the potential prognostic and predictive role of EGF functional genetic variant +61 G&amp;gt;A in prostate cancer patients submitted to androgen blockade therapy (ABT). Experimental Design: We conducted a case-control study in prostate cancer patients treated with ABT (n = 123) and in healthy controls without evidence of cancer (n = 152). Cumulatively, a follow-up study (median follow-up, 37 months) was undertaken to evaluate response to ABT therapy in prostate cancer patients. EGF +61 G&amp;gt;A genotypes were detected by PCR-RFLP. Results: We found increased risk in G carriers, after age-adjusted regression analysis, for being diagnosed with Gleason ≥7 and with metastatic disease compared with control group (CG; age-adjusted odds ratio, 3.37, P = 0.004 and age-adjusted odds ratio, 2.61, P = 0.043, respectively). Kaplan-Meier survival analysis and log-rank test showed an influence of EGF +61 G&amp;gt;A polymorphism in time to relapse during ABT (P = 0.018). Conclusions: EGF functional polymorphism may contribute to earlier relapse in ABT patients, supporting the involvement of EGF as an alternative pathway in hormone-resistant prostatic tumors. Furthermore, our results lend support to EGF-EGF receptor pathway as an additional therapeutic target during hormonal treatment.
Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions
Authors: Steven E. Lipshultz, M. Jacob Adams, Steven D. Colan, Louis S. Constine, Eugene H. Herman, Daphne T. Hsu, Melissa M. Hudson, Leontien C. Kremer, David C. Landy, Tracie L. Miller, Kevin C. Oeffinger, David N. Rosenthal, Craig A. Sable, Stephen E. Sallan, Gautam K. Singh, Julia Steinberger, Thomas R. Cochran, James D. Wilkinson
Journal: Circulation (2013)
Studies on experimental myocardial infarction: dogs or baboons?
Authors: W. FLAMENG, J. VANHAECKE, G. VANDEPLASSCHE
Journal: Cardiovascular Research (1986)

The extrapolation to humans of results obtained in experimental studies is a major problem in cardiovascular research. It is generally believed that non-human primates provide a better model for the study of experimental myocardial infarction than the canine or porcine heart. In the present study the transmural distribution of myocardial infarction and collateral flow were compared between dogs and baboons. In the open chest model, the left anterior descending coronary artery was ligated for 4 h. In the subepicardial and subendocardial portions of the left ventricle myocardial blood flow was measured with tracer microspheres, and infarct size and site were determined using triphenyl tetrazolium chloride. In baboons, mean(SD) subendocardial collateral flow was higher than subepicardial collateral flow (41.8(24.6) ml . min-1 X 100 g-1 vs 28.6(21.3) ml . min-1 X 100 g-1 (p less than 0.05)). Subendocardial infarct size (expressed as a percentage of the perfusion area) was smaller than subepicardial infarct size (50.3(8.5)% vs 61.2(9.6)% (p less than 0.001)). In dogs, subendocardial collateral flow was less than subepicardial collateral flow (10.2(6.0) ml . min-1 vs 13.6(4.6) ml . min-1 X 100 g-1 (p less than 0.05)), and subendocardial infarct size was greater than subepicardial infarct size (67.3(12.9)% vs 38.3(18.0)% (p less than 0.01)). When, irrespective of the species or transmural localisation, infarct size is related to collateral flow, expressed as a percentage of normal flow, a weak but significant correlation is obtained (r = 0.61, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiovascular risk estimation: important but may be inaccurate
Authors: Vishnu Madhok, Tom Fahey
Journal: BMJ (2006)

Manuel and colleagues applied the recommendations from six national guidelines on statin treatment to the same Canadian population and measured each guideline's impact in terms of number of people recommended for treatment, potential number of deaths from coronary heart disease avoided, and the number needed to treat to avoid one death.1 They show that markedly different numbers of people are recommended for treatment when different guidelines are followed.

Deciding whether to prescribe statins for a patient for the primary prevention of coronary heart disease would seem to be a relatively straightforward issue in the broader context of decision making in primary care. …
Polycythemia Impairs Vasodilator Response to Acetylcholine in Patients with Chronic Hypoxemic Lung Disease
Authors: C. Defouilloy, E. Teiger, S. Sediame, P. Andrivet, F. Roudot-Thoraval, C. Chouaid, B. Housset, S. Adnot
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

To investigate whether polycythemia associated with chronic hypoxemic lung disease (CHLD) increases vascular resistance by altering endothelium-derived nitric oxide (NO), we examined the responses to acetylcholine (ACh) infusions (5, 10, and 15 mg/min) on hemodynamics and gas exchange in 21 patients with CHLD of varying severity. Patients were classified into two groups based on whether their hemoglobin (Hb) level was less or greater than 15.5 g/dl. In the normocythemic patients (Hb = 13.6 ± 0.3 g/100 ml, n = 10), ACh decreased pulmonary artery pressure (Ppa) from 30 ± 2 mm Hg 26 ± 2 mm Hg (p < 0.01); pulmonary vascular resistance (PVR), from 5.1 ± 0.4 U/m2 to 3.4 ± 0.3 U/m2 (p < 0.001); systemic arterial pressure (Psa), from 111 ± 4 mm Hg to 108 ± 4 mm Hg (p < 0.05); and systemic vascular resistance (SVR), from 27 ± 2 U/m2 to 22 ± 2 U/m2 (p < 0.01); and also increased the cardiac index (CI), from 3.8 ± 0.2 to 4.7 ± 0.3 L/min/m2 (p < 0.001). PaO2 fell from 59 ± 3 mm Hg to 48 ± 3 mm Hg (p < 0.001) whereas venous admixture (Qs/Qt) rose from 32 ± 4% to 44 ± 4% (p < 0.01). In contrast, in patients with polycythemia (17.7 ± 0.5 g/100 ml, n = 11) ACh failed to produce any changes in PaO2 (49 ± 2 mm Hg versus 51 ± 2 mm Hg, p = NS), Ppa (34 ± 1 mm Hg versus 33 ± 1 mm Hg, p = NS), PVR (6.7 ± 0.9 U/m2 versus 6.9 ± 0.8 U/m2, p = NS) or Psa, but slightly increased the CI, from 3.6 ± 0.3 L/min/m2 to 3.9 ± 0.3 L/min/m2 (p < 0.01), and Qs/Qt, from 40 ± 4% to 45 ± 3% (p < 0.05). In the 21 patients, negative correlations with Hb concentrations were found for ACh-induced changes in PVR (r = − 0.57, p < 0.01), Ppa (r = − 0.46, p < 0.01), CI (r = − 0.5, p < 0.05), PaO2 (r = − 0.79, p < 0.01), and Qs/Qt (r = − 0.79, p < 0.01). In the six polycythemic patients who received isovolemic hemodilution, with a decrease in Hb concentration from 18.6 ± 0.9 g/dl to 15.3 ± 0.3 g/dl as a result, infusion of ACh, which was without effect before hemodilution, caused decreases in Ppa from 28 ± 1 mm Hg to 23 ± 1 mm Hg (p < 0.05) and in PVR from 5.7 ± 0.8 U/m2 to 3.6 ± 0.5 U/m2 (p < 0.02), as well as an increase in CI from 3.4 ± 0.4 L/min/ m2 to 4.1 ± 0.4 L/min/m2 (p < 0.05). In contrast to ACh, inhaled NO (40 ppm) induced pulmonary vasodilation in both the normocythemic and polycythemic groups. Our results show that high hematocrit (Hct) levels inhibit endothelium-dependent vasodilation in response to ACh in patients with CHLD, possibly through inactivation of endothelial-derived NO by Hb.
Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma
Authors: Richard C. Bates, David I. Bellovin, Courtney Brown, Elizabeth Maynard, Bingyan Wu, Hisaaki Kawakatsu, Dean Sheppard, Peter Oettgen, Arthur M. Mercurio
Journal: Journal of Clinical Investigation (2005)

We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the β6 integrin subunit and a consequent induction of αvβ6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-β and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of β6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of patients with high β6 expression. Elevated receptor expression did not simply reflect increasing tumor stage, since log-rank analysis showed a more significant impact on the survival of patients with early-stage, as opposed to late-stage, disease. Cox regression analysis confirmed that this integrin is an independent variable for these tumors. These findings define the αvβ6 integrin as an important risk factor for early-stage disease and a novel therapeutic candidate for colorectal cancer.
Identification of MAGE-3 Epitopes Presented by HLA-DR Molecules to CD4+ T Lymphocytes
Authors: Pascal Chaux, Valérie Vantomme, Vincent Stroobant, Kris Thielemans, Jurgen Corthals, Rosalie Luiten, Alexander M.M. Eggermont, Thierry Boon, Pierre van der Bruggen
Journal: The Journal of Experimental Medicine (1999)

MAGE-type genes are expressed by many tumors of different histological types and not by normal cells, except for male germline cells, which do not express major histocompatibility complex (MHC) molecules. Therefore, the antigens encoded by MAGE-type genes are strictly tumor specific and common to many tumors. We describe here the identification of the first MAGE-encoded epitopes presented by histocompatibility leukocyte antigen (HLA) class II molecules to CD4+ T lymphocytes. Monocyte-derived dendritic cells were loaded with a MAGE-3 recombinant protein and used to stimulate autologous CD4+ T cells. We isolated CD4+ T cell clones that recognized two different MAGE-3 epitopes, MAGE-3114–127 and MAGE-3121–134, both presented by the HLA-DR13 molecule, which is expressed in 20% of Caucasians. The second epitope is also encoded by MAGE-1, -2, and -6. Our procedure should be applicable to other proteins for the identification of new tumor-specific antigens presented by HLA class II molecules. The knowledge of such antigens will be useful for evaluation of the immune response of cancer patients immunized with proteins or with recombinant viruses carrying entire genes coding for tumor antigens. The use of antigenic peptides presented by class II in addition to peptides presented by class I may also improve the efficacy of therapeutic antitumor vaccination.
Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis
Authors: Claire Andréjak, Rikke Nielsen, Vibeke Ø Thomsen, Pierre Duhaut, Henrik Toft Sørensen, Reimar Wernich Thomsen
Journal: Thorax (2012)

<h3>Background</h3> Chronic respiratory disease and inhaled corticosteroid (ICS) therapy for chronic obstructive pulmonary disease (COPD) increase the risk of pneumonia. Few data are available on the association of these risk factors with non-tuberculous mycobacterial (NTM) pulmonary disease. <h3>Methods</h3> This study examined chronic respiratory diseases and ICS use as risk factors in a population-based case-control study encompassing all adults in Denmark with microbiologically confirmed NTM pulmonary disease between 1997 and 2008. The study included 10 matched population controls per case. Conditional logistic regression was used to compute adjusted ORs for NTM pulmonary disease with regard to chronic respiratory disease history. <h3>Results</h3> Overall, chronic respiratory disease was associated with a 16.5-fold (95% CI 12.2 to 22.2) increased risk of NTM pulmonary disease. The adjusted OR for NTM disease was 15.7 (95% CI 11.4 to 21.5) for COPD, 7.8 (95% CI 5.2 to 11.6) for asthma, 9.8 (95% CI 2.03 to 52.8) for pneumoconiosis, 187.5 (95% CI 24.8 to 1417.4) for bronchiectasis, and 178.3 (95% CI 55.4 to 574.3) for tuberculosis history. ORs were 29.1 (95% CI 13.3 to 63.8) for patients with COPD on current ICS therapy and 7.6 (95% CI 3.4 to 16.8) for patients with COPD who had never received ICS therapy. Among patients with COPD, ORs increased according to ICS dose, from 28.1 for low-dose intake to 47.5 for high-dose intake (more than 800 μg/day). The OR was higher for fluticasone than for budesonide. <h3>Conclusion</h3> Chronic respiratory disease, particularly COPD treated with ICS therapy, is a strong risk factor for NTM pulmonary disease.