tbuckley/cabot-search huggingface dataset:
Comparison of lenalidomide plus dexamethasone therapy used at first relapse versus later salvage therapy in relapsed or refractory multiple myeloma patients
Authors: E. A. Stadtmauer, D. M. Weber, R. Nieszvizky, A. Belch, H. M. Prince, J. F. San Miguel, T. Facon, Z. Yu, R. D. Knight, M. A. Dimopoulos
Journal: Journal of Clinical Oncology (2009)

8594 Background: The benefit of initiating lenalidomide plus dexamethasone at first relapsed was evaluated in this subset analysis from phase III studies in patients with relapsed or refractory multiple myeloma (MM). Methods: Patients from the randomized, multicenter clinical trials MM-009 and MM-010 who had received at least 1 prior treatment and were not resistant to dexamethasone were treated with lenalidomide (25 mg daily for 21 days of every 28 day cycle) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20 every 28 days for 4 months, then 40 mg on days 1–4 every cycle thereafter until disease progression or intolerance), or dexamethasone (same dose and schedule) plus placebo. Baseline characteristics such as age, sex, ECOG score, and baseline β 2 -microglobulin levels between the 2 patient groups were similar, however, median time from diagnosis and prior therapy were statistically different. Results: Multivariate analysis showed that more prior therapies is associated with shorter time-to-progression (TTP). Patients who received 1 prior therapy demonstrated a significant improvement in outcomes such as TTP, progression-free survival (PFS), overall response rate (ORR), complete response/very good partial response rate (CR/VGPR), median duration of treatment and overall survival (OS) after first relapse compared with those who received ≥ 2 prior therapies ( Table ). Toxicity, rate of dose reduction, or treatment discontinuation in the cohort with 1 prior therapy did not increase, despite longer treatment. Conclusions: When used at first relapse compared with salvage therapy, lenalidomide plus dexamethasone treatment resulted in significantly prolonged TTP, PFS, and OS, and an improved quality of response. Lenalidomide plus dexamethasone should be considered at an early stage of therapy for patients with MM. [Table: see text] [Table: see text]
Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy
Authors: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu
Journal: Journal of Clinical Oncology (2007)

Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS.Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points.Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r(s)) between differences (Delta) in surrogate end points (DeltaPFS, DeltaTTP, and DeltaRR) and DeltaOS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r(s) for DeltaPFS was not significantly different from the r(s) DeltaTTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 +/- 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% +/- 1% risk reduction for OS.In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.
Effect of pulmonary rehabilitation on exhaled nitric oxide in patients with chronic obstructive pulmonary disease
Authors: E Clini
Journal: Thorax (2001)

Background-In patients with mild to moderate chronic obstructive pulmonary disease (COPD) the exercise induced increase in exhaled nitric oxide (eNO) parallels that observed in normal untrained subjects.There is no information on the eVects of the level of exercise tolerance on eNO in these patients.The aim of this study was to evaluate the eVect of a pulmonary rehabilitation programme including exercise training on eNO in patients with COPD.Methods-In 14 consecutive male patients with stable COPD of mean (SD) age 64 (9) years and forced expiratory volume in one second (FEV 1 ) 55 (14)% predicted, fractional eNO concentration (FeNO), peak work rate (Wpeak) and oxygen uptake (V ~O2 peak) were assessed at baseline (T-1), at the end of a 1 month run in period (T0), and after an 8 week outpatient multidisciplinary pulmonary rehabilitation programme (T1) including cycloergometer training.Results-FeNO did not significantly diVer at T-1 and T0 (mean (SE) 4.3 (0.6) and 4.4 (0.6) ppb, respectively), whereas it rose significantly at T1 to 6.4 (0.7) ppb (p<0.02).Compared with T0, both Wpeak and V ~O2 were significantly (p<0.05)increased at T1 (mean (SE) Wpeak from 89 (5.6) W to 109 (6.9) W); V ~O2 peak from 1.27 (0.1) l/min to 1.48 (0.1) l/min).A significant correlation was found between baseline FEV 1 and the change in FeNO following the rehabilitation programme (r=-0.71;p<0.05) and between changes in FeNO and Wpeak from T0 to T1(r=0.60;p<0.05).Conclusions-Pulmonary rehabilitation in patients with mild to moderate COPD is associated with an increase in exhaled nitric oxide.
Type I Collagen Receptor (α2β1) Signaling Promotes the Growth of Human Prostate Cancer Cells within the Bone
Authors: Christopher L. Hall, JinLu Dai, Kenneth L. van Golen, Evan T. Keller, Michael W. Long
Journal: Cancer Research (2006)

Abstract The most frequent site of prostate cancer metastasis is the bone. Adhesion to bone-specific factors may facilitate the selective metastasis of prostate cancer to the skeleton. Therefore, we tested whether prostate cancer bone metastasis is mediated by binding to type I collagen, the most abundant bone protein. We observed that only bone metastatic prostate cancer cells bound collagen I, whereas cells that form only visceral metastases failed to bind collagen. To confirm the relationship between collagen adhesion and bone metastatic potential, a collagen-binding variant of human LNCaP prostate cancer cells was derived through serial passage on type I collagen (LNCaPcol). Fluorescence-activated cell sorting analysis showed that LNCaPcol cells express increased levels of the integrin collagen I receptor α2β1 compared with LNCaP cells. Antibodies to the α2β1 complex inhibited LNCaPcol binding to collagen, confirming that integrins mediated the attachment. Correspondingly, LNCaPcol cells displayed enhanced chemotactic migration toward collagen I compared with LNCaP cells, an activity that could be blocked with α2β1 antibodies. To directly test the role of α2β1-dependent collagen binding in bone metastasis, LNCaP and LNCaPcol cells were injected into the tibia of nude mice. After 9 weeks, 7 of 13 (53%) mice injected with LNCaPcol developed bone tumors, whereas 0 of 8 mice injected with LNCaP cells had evidence of boney lesions. LNCaPcol cells were found to express increased levels of the metastasis-promoting RhoC GTPase compared with parental LNCaP. We conclude that collagen I attachment mediated by α2β1 initiates motility programs through RhoC and suggest a mechanism for prostate cancer metastasis to the bone. (Cancer Res 2006; 66(17): 8648-54)
Alpha-adrenergic blockade for variant angina: a long-term, double-blind, randomized trial.
Authors: M D Winniford, N Filipchuk, L D Hillis
Journal: Circulation (1983)

Recent reports have shown that beta-adrenergic blockade may exacerbate variant angina. On theoretical grounds, alpha-adrenergic blockade may be beneficial in these patients. To test this hypothesis, we assessed the efficacy of prazosin, an alpha-adrenergic blocking agent, in six men, mean age 49 years, with variant angina. Prazosin, 14.0 +/- 2.4 mg/day (mean +/- SD) in three equal doses, was compared with placebo in a double-blind, randomized, double-crossover trial lasting 4 1/2 months: 2 weeks of open-label prazosin followed by four 1-month periods of blinded alternating therapy. No other vasoactive medications were administered during the study. Prazosin reduced sitting systolic arterial pressure from 145 +/- 18 to 127 +/- 16 mm Hg (p = 0.02), but exerted no effect on diastolic arterial pressure or heart rate. Prazosin did not change the weekly number of episodes of chest pain (2.5 +/- 2.3 with placebo vs 3.1 +/- 3.0 with prazosin, NS), nitroglycerin tablets used (3.9 +/- 3.7 with placebo vs 4.6 +/- 4.2 with prazosin, NS), or transient ST-segment deviations (by calibrated two-channel Holter monitoring for 24 hours/week throughout the study) (6.5 +/- 10.1 with placebo vs 11.8 +/- 17.4 with prazosin, NS). During prazosin therapy, three patients had orthostatic dizziness and one patient had headache. Thus, in a long-term, randomized, double-blind trial, prazosin exerted no obvious beneficial effect in patients with variant angina.
Effect of 2 Years of Testosterone Replacement on Insulin Secretion, Insulin Action, Glucose Effectiveness, Hepatic Insulin Clearance, and Postprandial Glucose Turnover in Elderly Men
Authors: Rita Basu, Chiara Dalla Man, Marco Campioni, Ananda Basu, K. Sreekumaran Nair, Michael D. Jensen, Sundeep Khosla, George Klee, Gianna Toffolo, Claudio Cobelli, Robert A. Rizza
Journal: Diabetes Care (2007)

OBJECTIVE—We sought to determine whether, and if so the mechanism by which, testosterone replacement improves carbohydrate tolerance. RESEARCH DESIGN AND METHODS—Fifty-five elderly men with relative testosterone deficiency ingested a labeled mixed meal and underwent a frequently sampled labeled intravenous glucose tolerance test before and after either placebo or treatment with testosterone patch (5 mg/day) for 2 years. RESULTS—Despite restoring bioavailable testosterone to values observed in young men, the change (24 months minus baseline values) in fasting and postprandial glucose, insulin, and C-peptide concentrations and meal appearance, glucose disposal, and endogenous glucose production were virtually identical to those observed after 2 years of placebo. The change over time in insulin and C-peptide concentrations post–intravenous glucose injection also did not differ. Furthermore, the change over time in insulin action and glucose effectiveness (measured with the unlabeled and labeled “oral” and “intravenous” minimal models), as well as insulin secretion and hepatic insulin clearance (measured with the C-peptide model), did not differ in the testosterone and placebo groups. CONCLUSIONS—We conclude that 2 years of treatment with testosterone in elderly men does not improve carbohydrate tolerance or alter insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, or the pattern of postprandial glucose metabolism. Thus, testosterone deficiency is unlikely the cause of the age-associated deterioration in glucose tolerance commonly observed in elderly men.
Social Anxiety in Outpatients With Schizophrenia: A Relevant Cause of Disability
Authors: Stefano Pallanti, Leonardo Quercioli, Eric Hollander
Journal: American Journal of Psychiatry (2004)

Social anxiety is a frequent but often unrecognized feature in schizophrenia and is associated with a severe level of disability. To precisely define the assessment, impact, clinical correlates, and consequences of social anxiety in schizophrenia, the authors conducted a survey of schizophrenia patients and a comparison cohort of patients with social anxiety disorder.A consecutively enrolled group of 80 outpatients with DSM-IV schizophrenia and a consecutive comparison group of 27 patients with social anxiety disorder were recruited from an institutional psychiatric practice and assessed with the Liebowitz Social Anxiety Scale, Scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, Social Adjustment Scale, and the Medical Outcomes Study 36-item Short-Form Health Survey.Social anxiety scores of schizophrenia patients with comorbid social anxiety disorder (N=29, 36.3%) did not differ from those of subjects with social anxiety disorder as their primary diagnosis. Schizophrenia patients without social anxiety disorder had significantly lower total scores on the Liebowitz Social Anxiety Scale and lower social and performance anxiety subscale scores than did the other two groups. No differences in negative and positive symptom rates were found between schizophrenia patients with and without social anxiety disorder. Schizophrenia patients with social anxiety disorder had a higher lifetime rate of suicide attempts, greater lethality of suicide attempts, more past substance/alcohol abuse disorder, lower social adjustment, and lower overall quality of life.Social anxiety is a highly prevalent, disabling condition in outpatients with schizophrenia that is unrelated to clinical psychotic symptoms. The Liebowitz Social Anxiety Scale appeared adequate and reliable in assessing social anxiety disorder in patients with schizophrenia. If these data are confirmed, this study will make a contribution to the search for operational guidelines and adequate next-step treatments for social anxiety disorder in schizophrenia patients.
Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses
Authors: W Kruis
Journal: Gut (2001)

<h3>BACKGROUND</h3> Balsalazide is a new 5-aminosalicylic acid (5-ASA) containing prodrug. Its efficacy in comparison with standard mesalazine therapy and the optimum dose for maintaining remission of ulcerative colitis are still unclear. <h3>AIMS</h3> To compare the relapse preventing effect and safety profile of two doses of balsalazide and a standard dose of Eudragit coated mesalazine. <h3>METHODS</h3> A total of 133 patients with ulcerative colitis in remission were recruited to participate in a double blind, multicentre, randomised trial: 49 patients received balsalazide 1.5 g twice daily, 40 received balsalazide 3.0 g twice daily, and 44 received mesalazine 0.5 g three times daily. Efficacy assessments were clinical activity index (CAI) and endoscopic score according to Rachmilewitz, and a histological score. In addition, laboratory tests were performed and urinary excretion of 5-ASA and its metabolite<i>N</i>-Ac-5-ASA was analysed. The study lasted for 26 weeks. <h3>RESULTS</h3> Balsalazide 3.0 g twice daily resulted in a significantly higher clinical remission rate (77.5%) than balsalazide 1.5 g twice daily (43.8%) and mesalazine 0.5 g three times daily (56.8%) (p=0.006). The respective times to relapse were 161 days, 131 days (p=0.003), and 144 days (NS). Accordingly, pairwise contrasts of the final endoscopic score demonstrated a significant difference (p=0.005) between the two balsalazide treatment groups while differences between either of these two groups and mesalazine were not statistically significant. Patients treated with balsalazide excreted less 5-ASA and<i>N</i>-Ac-5-ASA than patients receiving mesalazine but these differences were not statistically significant. Discontinuation of the trial because of adverse effects occurred in nine patients: three in the balsalazide 1.5 g twice daily group, two in the balsalazide 3.0 g twice daily group, and four in the mesalazine 0.5 g three times daily group. No clinically important new drug safety related findings were identified in this study. <h3>CONCLUSIONS</h3> High dose balsalazide (3.0 g twice daily) was superior in maintaining remission in patients with ulcerative colitis compared with a low dose (1.5 g twice daily) or a standard dose of mesalazine (0.5 g three times daily). All three treatments were safe and well tolerated.
Predicting Development of Proliferative Diabetic Retinopathy
Authors: Kristen Harris Nwanyanwu, Nidhi Talwar, Thomas W. Gardner, James S. Wrobel, William H. Herman, Joshua D. Stein
Journal: Diabetes Care (2012)

Identifying individuals most at risk for diabetic retinopathy progression and intervening early can limit vision loss and reduce the costs associated with managing more advanced disease. The purpose of this study was to identify factors associated with progression from nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR).
GRANULOCYTE-MACROPHAGE COLONY STIMULATING FACTOR EXPANDS THE CIRCULATING HAEMOPOIETIC PROGENITOR CELL COMPARTMENT IN MAN
Authors: MarkA. Socinski, Anthony Elias, Lowell Schnipper, StephenA. Cannistra, KarenH. Antman, JamesD. Griffin
Journal: The Lancet (1988)
Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men
Authors: E. C. Thomson, V. M. Fleming, J. Main, P. Klenerman, J. Weber, J. Eliahoo, J. Smith, M. O. McClure, P. Karayiannis
Journal: Gut (2010)

<h3>Objective</h3> An epidemic of acute hepatitis C virus (HCV) infection in HIV-positive men-who-have-sex-with-men (MSM) is emerging in Europe, Australia and the USA. The aim of this study was to characterise the natural history of primary HCV in this setting and to assess host and viral factors which predict spontaneous clearance. <h3>Methods</h3> This prospective longitudinal cohort study was carried out in 112 HIV-positive patients who were followed in a single centre (the St Mary9s Acute HCV Cohort). Plasma and peripheral blood mononuclear cells (PBMCs) were obtained at monthly intervals for 3 months and at 3-monthly intervals thereafter for a median of 45 months (IQR=29–69 months). The primary end point was spontaneous clearance of HCV. Cox regression was used to assess the impact of clinical and virological variables on outcome, including liver function, CD4 count, rate of HCV RNA decline, T cell response and clonal sequence evolution within the HCV E2 envelope gene. <h3>Results</h3> 15% of patients cleared HCV spontaneously, while 85% progressed towards chronicity. The latter group included a significant proportion of 'fluctuating' progressors (37.5%), in whom a fall followed by a rise (&gt;1 log<sub>10</sub>) in viraemia was observed. This was associated with superinfection with new HCV strains and partially effective T cell responses. Spontaneous clearance was strongly associated with a 2.2 log<sub>10</sub> viral load drop within 100 days of infection (HR=1.78; p&lt;0.0001), elevated bilirubin (≥40 μmol/l; HR=5.04; p=0.006), elevated alanine aminotransferase (ALT; ≥1000 IU/ml; HR=2.62; p=0.048) and baseline CD4 count ≥650×10<sup>6</sup>/l (HR=2.66; p=0.045), and only occurred in patients with genotype 1 infection. Evolution to spontaneous clearance occurred in patients with low viral diversity in the presence of an early multispecific T cell response. <h3>Conclusions</h3> Spontaneous clearance of acute HCV in HIV-positive men can be predicted by a rapid decline in viral load, high CD4 count, elevated bilirubin and ALT, and is associated with low viral diversity and strong T cell responses.
Interferon γ Induction of Pulmonary Emphysema in the Adult Murine Lung
Authors: Zhongde Wang, Tao Zheng, Zhou Zhu, Robert J. Homer, Richard J. Riese, Harold A. Chapman, Steven D. Shapiro, Jack A. Elias
Journal: The Journal of Experimental Medicine (2000)

Chronic inflammation containing CD8(+) lymphocytes, neutrophils, and macrophages, and pulmonary emphysema coexist in lungs from patients with chronic obstructive pulmonary disease. Although this inflammatory response is believed to cause the remodeling that is seen in these tissues, the mechanism(s) by which inflammation causes emphysema have not been defined. Here we demonstrate that interferon gamma (IFN-gamma), a prominent product of CD8(+) cells, causes emphysema with alveolar enlargement, enhanced lung volumes, enhanced pulmonary compliance, and macrophage- and neutrophil-rich inflammation when inducibly targeted, in a transgenic fashion, to the adult murine lung. Prominent protease and antiprotease alterations were also noted in these mice. They included the induction and activation of matrix metalloproteinase (MMP)-12 and cathepsins B, H, D, S, and L, the elaboration of MMP-9, and the selective inhibition of secretory leukocyte proteinase inhibitor. IFN-gamma causes emphysema and alterations in pulmonary protease/antiprotease balance when expressed in pulmonary tissues.
Efficient Presentation of Phagocytosed Cellular Fragments on the Major Histocompatibility Complex Class II Products of Dendritic Cells
Authors: Kayo Inaba, Shannon Turley, Fumiya Yamaide, Tomonori Iyoda, Karsten Mahnke, Muneo Inaba, Margit Pack, Marion Subklewe, Birthe Sauter, David Sheff, Matthew Albert, Nina Bhardwaj, Ira Mellman, Ralph M. Steinman
Journal: The Journal of Experimental Medicine (1998)

Cells from the bone marrow can present peptides that are derived from tumors, transplants, and self-tissues. Here we describe how dendritic cells (DCs) process phagocytosed cell fragments onto major histocompatibility complex (MHC) class II products with unusual efficacy. This was monitored with the Y-Ae monoclonal antibody that is specific for complexes of I-Ab MHC class II presenting a peptide derived from I-Eα. When immature DCs from I-Ab mice were cultured for 5–20 h with activated I-E+ B blasts, either necrotic or apoptotic, the DCs produced the epitope recognized by the Y-Ae monoclonal antibody and stimulated T cells reactive with the same MHC–peptide complex. Antigen transfer was also observed with human cells, where human histocompatibility leukocyte antigen (HLA)-DRα includes the same peptide sequence as mouse I-Eα. Antigen transfer was preceded by uptake of B cell fragments into MHC class II–rich compartments. Quantitation of the amount of I-E protein in the B cell fragments revealed that phagocytosed I-E was 1–10 thousand times more efficient in generating MHC–peptide complexes than preprocessed I-E peptide. When we injected different I-E– bearing cells into C57BL/6 mice to look for a similar phenomenon in vivo, we found that short-lived migrating DCs could be processed by most of the recipient DCs in the lymph node. The consequence of antigen transfer from migratory DCs to lymph node DCs is not yet known, but we suggest that in the steady state, i.e., in the absence of stimuli for DC maturation, this transfer leads to peripheral tolerance of the T cell repertoire to self.
Management of Human Immunodeficiency Virus Infection in Pregnancy
Authors: D. Heather Watts
Journal: New England Journal of Medicine (2002)

Globally, more than 16 million women are living with human immunodeficiency virus (HIV) infection. Each year, 600,000 children are infected, most of them through mother-to-child transmission. This review focuses on the management of HIV infection during pregnancy in developed countries in which antiretroviral therapy, scheduled cesarean delivery, and alternatives to breast-feeding are available; it discusses strategies for obtaining the best possible outcomes.