tbuckley/cabot-search huggingface dataset:
AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease
Authors: Klaus Rave, Amparo de la Peña, Fabián S. Tibaldi, Liping Zhang, Bernard Silverman, Michaela Hausmann, Lutz Heinemann, Douglas B. Muchmore
Journal: Diabetes Care (2007)

In this open-label, randomized, crossover study, pharmacokinetic and glucodynamic responses were compared in healthy subjects versus subjects with moderate chronic obstructive pulmonary disease (COPD), following administration of 12 units equivalent AIR inhaled insulin versus 12 units subcutaneous insulin lispro.Three nonsmoking groups (n = 15 each)--healthy subjects (baseline mean +/- SD age 38 +/- 13 years, forced expiratory volume in 1 s [FEV1] 4.06 +/- 1.04 l), subjects with chronic bronchitis (aged 53 +/- 9 years, FEV1 2.14 +/- 0.60 l), and subjects with pulmonary emphysema (aged 58 +/- 6 years, FEV1 1.67 +/- 0.61 l)--were randomly assigned to one of three treatment sequences. Three euglycemic glucose clamp procedures were performed.In subjects with chronic bronchitis and emphysema, AIR inhaled insulin administration resulted in reduced insulin exposure (area under the serum insulin concentration curve from time zero until time of return to baseline [AUC(0-t')]) (55.7%, P = 0.13 and 78.5%, P < 0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P < 0.01 and 67.1%, P < 0.01, respectively) relative to healthy subjects. Subcutaneous insulin lispro administration resulted in similar responses across study groups for insulin exposure and metabolic effect. Intrasubject pharmacokinetic and glucodynamic variability ranged from 17 to 52% across groups. No significant differences were shown for pre- and postclamp pulmonary function tests. During clamps, FEV1 and forced vital capacity declined modestly in both COPD groups, with no difference between AIR insulin and subcutaneous insulin lispro.Short-term exposure to AIR inhaled insulin was well tolerated by COPD subjects, showing similar time-exposure and time-action profiles, but with reduced insulin absorption and metabolic effect compared with healthy subjects. Further clinical evaluation is warranted in patients with comorbid diabetes and COPD.
The Importance of Hyperglycemia in the Nonfasting State to the Development of Cardiovascular Disease
Authors: Steven M. Haffner
Journal: Endocrine Reviews (1998)

I. Introduction II. Correlation Between Hyperglycemia and CVD A. Type 2 diabetes B. Elevated glucose concentrations in the nondiabetic range C. Atherosclerosis in subjects with asymptomatic hyperglycemia III. Causal Relationship of Postprandial Hyperglycemia to CVD A. Direct effects of hyperglycemia B. Insufficient insulin production C. Insulin resistance and hyperinsulinemia D. Association with risk factors for CVD IV. Therapeutic Interventions for Type 2 Diabetes A. Insulin therapy B. Sulfonylureas C. Biguanides D. Acarbose V. Studies to Prevent Type 2 Diabetes VI. Conclusions
BRAF Inhibitor Vemurafenib Improves the Antitumor Activity of Adoptive Cell Immunotherapy
Authors: Richard C. Koya, Stephen Mok, Nicholas Otte, Kevin J. Blacketor, Begonya Comin-Anduix, Paul C. Tumeh, Aspram Minasyan, Nicholas A. Graham, Thomas G. Graeber, Thinle Chodon, Antoni Ribas
Journal: Cancer Research (2012)

Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. In this study, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer therapy with lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1 resulted in superior antitumor responses compared with either therapy alone. T-cell analysis showed that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased mitogen-activated protein kinase (MAPK) signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Taken together, our findings, derived from 2 independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma.
Combination antiretroviral therapy in population affected by conflict: outcomes from large cohort in northern Uganda
Authors: A. Kiboneka, R. J. Nyatia, C. Nabiryo, A. Anema, C. L Cooper, K. A. Fernandes, J. S G Montaner, E. J Mills
Journal: BMJ (2009)

<b>Objective</b> To measure the clinical and immunological outcomes of HIV positive adult patients receiving combination antiretroviral therapy in conflict affected northern Uganda. <b>Design</b> Prospective cohort study. <b>Setting</b> Gulu District, northern Uganda. <b>Participants</b> 1625 adults (aged over 14 years) receiving combination antiretroviral therapy. <b>Main outcome measures</b> Primary outcome: all cause mortality. Secondary outcomes: impact of covariates (sex, age, CD4 count at start, adherence, tuberculosis at start, duration of treatment, and internally displaced person status) on mortality. <b>Results</b> Sixty nine (4.2%) patients died during follow-up. The mortality incidence rate was 3.48 (95% confidence interval 2.66 to 4.31) per 100 person years. Patients started treatment with a median CD4 count of 157 (interquartile range 90-220) cells/μl; most (1009; 63%) had World Health Organization stage 2 defined illness. Sixty two patients had pulmonary tuberculosis at the start of treatment. Of the 1521 patients with adherence data, 118 (7.8%) had adherence of less than 95% and 1403 (92.2%) had adherence of 95% or above. <b>Conclusion</b> Patients receiving combination antiretroviral therapy in conflict affected northern Uganda had a mortality comparable to that of patients in peaceful, low income settings and better adherence than patients in higher income settings. These favourable findings highlight the need to expand access to combination antiretroviral therapy in populations affected by armed conflict.
Limitations of Screening for Lung Cancer with Low-Dose Spiral Computed Tomography
Authors: James R. Jett
Journal: Clinical Cancer Research (2005)

Abstract Past lung cancer screening trials in the United States with chest X-ray and sputum cytology were not able to show any decrease in lung cancer mortality; however, these trials are over 20 years old. Recent follow-up of the Mayo Lung Project showed a better survival from lung cancer in the screened arm, but no difference in overall mortality, suggesting an overdiagnosis of nonfatal cancers. Recent reports of low radiation dose spiral computed tomography (CT) chest screening for lung cancer have shown that CT screening detects cancers at a smaller size than chest X-rays. To date, there have been no randomized trials of CT versus observation or chest radiographs for screening purposes. All data available thus far on CT screening are from phase II proof-of-principle trials. The major limitations of CT screening, discussed here, include (a) a high rate of nodule detection: over 50% of participants will have at least one noncalcified nodule; (b) resulting follow-up CT scans, associated with increased costs; (c) cost and morbidity of biopsy or resection of benign noncalcified nodule (20-25% of such procedures in several trials); and (d) a small, but difficult to quantify, risk of cancer associated with multiple follow-up CT scans.
Serial Transcriptome Analysis and Cross-Species Integration Identifies <i>Centromere-Associated Protein E</i> as a Novel Neuroblastoma Target
Authors: Naomi J. Balamuth, Andrew Wood, Qun Wang, Jayanti Jagannathan, Patrick Mayes, Zhe Zhang, Zhongxue Chen, Eric Rappaport, Joshua Courtright, Bruce Pawel, Barbara Weber, Richard Wooster, Eric O. Sekyere, Glenn M. Marshall, John M. Maris
Journal: Cancer Research (2010)

Cancer genomic studies that rely on analysis of biopsies from primary tumors may not fully identify the molecular events associated with tumor progression. We hypothesized that characterizing the transcriptome during tumor progression in the TH-MYCN transgenic model would identify oncogenic drivers that would be targetable therapeutically. We quantified expression of 32,381 murine genes in nine hyperplastic ganglia harvested at three time points and four tumor cohorts of progressively larger size in mice homozygous for the TH-MYCN transgene. We found 93 genes that showed a linearly increasing or decreasing pattern of expression from the preneoplastic ganglia to end stage tumors. Cross-species integration identified 24 genes that were highly expressed in human MYCN-amplified neuroblastomas. The genes prioritized were not exclusively driven by increasing Myc transactivation or proliferative rate. We prioritized three targets [centromere-associated protein E (Cenpe), Gpr49, and inosine monophosphate dehydrogenase type II] with previously determined roles in cancer. Using siRNA knockdown in human neuroblastoma cell lines, we further prioritized CENPE due to inhibition of cellular proliferation. Targeting CENPE with the small molecular inhibitor GSK923295 showed inhibition of in vitro proliferation of 19 neuroblastoma cell lines (median IC(50), 41 nmol/L; range, 27-266 nmol/L) and delayed tumor growth in three xenograft models (P values ranged from P < 0.0001 to P = 0.018). We provide preclinical validation that serial transcriptome analysis of a transgenic mouse model followed by cross-species integration is a useful method to identify therapeutic targets and identify CENPE as a novel therapeutic candidate in neuroblastoma.
Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis
Authors: M. Aapro, V. Moebus, U. Nitz, J. O'Shaughnessy, P. Pronzato, M. Untch, D. Tomita, C. Bohac, B. Leyland-Jones
Journal: Annals of Oncology (2014)
Safety of Treatment of Metastatic Breast Cancer With Trastuzumab Beyond Disease Progression
Authors: Debu Tripathy, Dennis J. Slamon, Melody Cobleigh, Andrew Arnold, Mansoor Saleh, Joanne E. Mortimer, Maureen Murphy, Stanford J. Stewart
Journal: Journal of Clinical Oncology (2004)

In a pivotal phase III trial, the addition of trastuzumab to chemotherapy significantly improved response rate, time to disease progression, and overall survival in women with HER2 overexpressing metastatic breast cancer. We conducted an extension study to this trial to obtain additional safety information and to provide trastuzumab following disease progression.A total of 247 patients with documented disease progression received weekly intravenous trastuzumab in the extension study. Concurrent therapies were administered at the discretion of the treating physician. Patient groups were based on initial study treatment: chemotherapy alone (group 1, n=154) or chemotherapy plus trastuzumab (group 2, n=93).Sixty-eight percent of group 1 and 76% of group 2 received chemotherapy plus trastuzumab in the extension trial; the remainder received trastuzumab alone or combined with palliative radiotherapy or hormonal therapy. Seventy-six percent of group 1 and 55% of group 2 experienced at least one adverse event, similar to effects observed in the pivotal trial. Symptomatic or asymptomatic cardiac dysfunction occurred in 9% of group 1 and 2% of group 2 patients. Overall objective response rates were 14% in group 1 and 11% in group 2; median durations of response exceeded 6 months in both groups.Our results suggest that prolonged use of trastuzumab therapy is safe and well tolerated. Longer durations of therapy did not appear to increase the risk of cardiac dysfunction. Patients progressing on trastuzumab-containing therapy demonstrate some response to a second trastuzumab-containing regimen. The independent contribution of trastuzumab in this setting merits further study.
N-terminal pro-brain natriuretic peptide in systemic sclerosis: a new cornerstone of cardiovascular assessment?
Authors: Y Allanore, K Wahbi, D Borderie, S Weber, A Kahan, C Meune
Journal: Annals of the Rheumatic Diseases (2008)

Cardiac involvement, a common and often fatal complication of systemic sclerosis (SSc), is currently detected by standard echocardiography enhanced by tissue Doppler echocardiography (TDE).The performance of the biomarker of cardiovascular disease, N-terminal pro-brain natriuretic peptide (NT-proBNP), in the detection of cardiac involvement by SSc was examined.A total of 69 consecutive patients with SSc (mean (SD) age 56 (13) years, 56 women) were prospectively studied with standard echocardiography and TDE measurements of longitudinal mitral and tricuspid annular velocities. Plasma NT-proBNP was measured in all patients.Overall, 18 patients had manifestations of cardiac involvement, of whom 7 had depressed left ventricular and 8 depressed right ventricular myocardial contractility, and 8 had elevated systolic pulmonary arterial pressure. Patients with reduced contractility had increased mean (SD) NT-proBNP (704 (878) pg/ml versus 118 (112) pg/ml in patients with normal myocardial contractility, p<0.001). Similarly, NT-proBNP was higher in patients with (607 (758) pg/ml) than in patients without (96 (78) pg/ml) manifestations of overall cardiac involvement (p<0.001). Receiver operating characteristic analysis showed NT-proBNP reliably detected depressed myocardial contractility and overall cardiac involvement (area under the curve 0.905 (95% CI 0.814 to 0.996) and 0.935 (95% CI 0.871 to 0.996), respectively). Considering patients with SSc with normal echocardiography and TDE as controls, and using a 125 pg/ml cut-off concentration, sensitivity and specificity were 92% and 71% in the detection of depressed myocardial contractility, and 94% and 78% for overall cardiac involvement.NT-proBNP reliably detected the presence of cardiac involvement and appears to be a very useful marker to risk stratify patients presenting with SSc.
Hippocrates: His Life and Writings
Authors: J. W. Begbie
Journal: BMJ (1872)

thickening of the heart.I cannot but look upon it with veneration, but not with conviction.I think, with all deference to so great an authority, that the systemic capillaries, and, had it been possible, the entire man, should have been included in this vase, together with the heart and the kidneys; and then we should have had, I believe, a truer view of the causation of the cardiac hypertrophy, and of the disease of the kidney.
Study of extensor and flexor musculature in the knees of male and female volleyball players
Authors: D Rodríguez-Ruiz, D Rodríguez-Matoso, M E Quiroga, S Sarmiento, M E Da Silva-Grigoletto
Journal: British Journal of Sports Medicine (2011)

Objective The aim of the present study was to analyse differences in muscle response and mechanical characteristics of the vastus medialis (VM), rectus femoris (RF), vastus lateralis (VL) and biceps femoris (BF) in elite volleyball players of both sexes using tensiomyography (TMG). Setting 47 players of nine nationalities playing in teams belonging to the men's and women's Spanish Superleagues (elite division) were assessed. Participants 22 women (age 24.59±4.27 years; weight 72.14±10.06 kg; height 178.40±8.50 cm) and 25 men (age 25.04±4.29 years; weight 88.76±9.07 kg; height 194.71±7.84 cm). Methods TMG was used to assess muscular response, muscular mechanical characteristics, and gender differences. For this purpose, the following variables were analysed: maximum radial displacement of muscle belly or maximum deformation (Dm), and normalised response speed (Vrn). Results The findings show, both in men and women, a higher normalised response speed (Vrn) score in the VL and VM compared to the RF and BF. A marked lateral symmetry of maximum radial deformation or displacement of the muscle belly (Dm) was also observed in the musculature of the lower limbs, with no statistically-significant differences being detected in either men or women. There were, however, clear differences in terms of muscle response between male and female volleyball players: women displayed a more pronounced difference in the Vrn of the musculature responsible for extension (VM, RF and VL) and flexion (BF) of the knee joint than men. Conclusions TMG proved to be a highly sensitive tool for detecting changes in lower limb muscle activity.
A Guide to the Practical Use of Diuretics
Authors: Ray W. Gifford
Journal: JAMA (1976)

THE INTRODUCTION of potent orally administered diuretics has been one of the most significant therapeutic milestones of this century. It has had numerous unanticipated benefits, not the least of which is their key role in the management of hypertension. As with all potent agents, rational and safe use of these drugs is predicated on an understanding of their pharmacologic action and their potential side effects. <h3>DIURETIC AGENTS</h3><h3>Thiazide and Related Compounds</h3> All of the diuretics in Table 1 are sulfonamide derivatives although not all have the benzothiadiazine nucleus. Nevertheless, their pharmacologic properties and their effects on electrolyte excretion are so similar that they will be grouped together under the term "thiazide" for the purposes of this discussion. They inhibit sodium reabsorption in the cortical portion of the ascending tubule and in the distal convoluted tubule, where less than 10% of filtered sodium is reabsorbed. Consequently they are not as potent
Ethical, Behavioral, and Social Aspects of HIV Vaccine Trials in Developing Countries
Authors: P Lurie, M Bishaw, M A Chesney, M Cooke, M E Fernandes, N Hearst, E Katongole-Mbidde, S Koetsawang, C P Lindan, J Mandel
Journal: JAMA (1994)

<h3>Issue.</h3> —Several investigators are preparing to conduct efficacy trials of human immunodeficiency virus (HIV) vaccines in the developing world. Failure to adequately address the unique ethical, behavioral, and social issues that surround vaccine testing in that setting will jeopardize the success of these trials and future acquired immunodeficiency syndrome (AIDS) research in the host nation. <h3>Description of the Project.</h3> —Twelve investigators from Africa, Asia, North America, and South America reviewed previous experience with HIV trials in developing countries and explored potential solutions to these issues. <h3>Conclusions.</h3> —Host country scientists, government officials, and media must be actively involved in all aspects of the trials. Minimum prerequisites for conducting the trial include the following: (1) researching vaccines active against developing world HIV isolates; (2) establishing and maintaining an adequate technological infrastructure; (3) assessing the feasibility of recruitment in countries where the existence of HIV may be denied; (4) designing methods to obtain informed consent from each individual subject, rather than exclusively from family members or community elders; (5) creating locally appropriate instruments to measure risk behavior; (6) identifying a behavioral intervention for placebo and treatment groups; (7) making available laboratory methods to distinguish between natural HIV infection and vaccine-induced seropositivity; and (8) guaranteeing that an effective vaccine is available free of charge to the placebo group and at affordable prices to other host country residents. (<i>JAMA</i>. 1994;271:295-301)
Developing Clinical Recommendations for Breast, Colorectal, and Lung Cancer Adjuvant Treatments Using the GRADE System: A Study From the Programma Ricerca e Innovazione Emilia Romagna Oncology Research Group
Authors: Rossana De Palma, Alessandro Liberati, Giovannino Ciccone, Elena Bandieri, Maurizio Belfiglio, Manuela Ceccarelli, Maurizio Leoni, Giuseppe Longo, Nicola Magrini, Maurizio Marangolo, Fausto Roila
Journal: Journal of Clinical Oncology (2008)

In the area of anticancer drugs, the legitimate search for effective interventions can be jeopardized by the strong pressure for accelerated approval, which may hinder the full assessment of their benefit-risk profile. We aimed to produce drug-specific recommendations using an explicit approach that separates the judgments on quality of evidence from the judgment about strength of recommendations.We used the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system to develop recommendations for the use of specific anticancer drugs/regimens; 12 clinical questions relevant to adjuvant treatment of breast (three), colorectal (four) and lung (five) cancer have been assessed by multidisciplinary panels supported by a group of methodologists.For nine of 12 questions, recommendations were produced (one strong and six weak in favor and one weak and one strong against the index treatment); for the remaining three questions no specific course of action could be recommended. The perceived benefits to risk balance of the treatment was the most important and statistically significant (P < .01) predictor of panels' recommendations and of their strength, whereas panelists' personal (age, sex) and professional (specialty) characteristics were not statistically associated.Because the GRADE system sets out an explicit process going from evaluation of the quality of evidence and benefit-risk profile to the judgment of the strength of recommendations, in this experience, it proved very useful to combine methodologic rigor with the interdisciplinary participation that is important in the definition of evidence based clinical policies.
Differential expression of transforming growth factor-beta receptors in squamous cell carcinoma.
Authors: M. Kubo, H. Ihn, K. Yamane, Y. Asano, M. Jinnin, K. Tamaki
Journal: British Journal of Dermatology (2001)

Journal Article Differential expression of transforming growth factor‐β receptors in squamous cell carcinoma Get access M. Kubo, M. Kubo Department of Dermatology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8655, Japan. Correspondence: H.IhnE‐mail: IN‐DER@h.u‐tokyo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar H. Ihn, H. Ihn Department of Dermatology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8655, Japan. Correspondence: H.IhnE‐mail: IN‐DER@h.u‐tokyo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Yamane, K. Yamane Department of Dermatology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8655, Japan. Correspondence: H.IhnE‐mail: IN‐DER@h.u‐tokyo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar Y. Asano, Y. Asano Department of Dermatology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8655, Japan. Correspondence: H.IhnE‐mail: IN‐DER@h.u‐tokyo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar M. Jinnin, M. Jinnin Department of Dermatology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8655, Japan. Correspondence: H.IhnE‐mail: IN‐DER@h.u‐tokyo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Tamaki K. Tamaki Department of Dermatology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8655, Japan. Correspondence: H.IhnE‐mail: IN‐DER@h.u‐tokyo.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 145, Issue 5, 1 November 2001, Pages 840–842, https://doi.org/10.1046/j.1365-2133.2001.04480.x Published: 01 November 2001