tbuckley/cabot-search huggingface dataset:
Pilot Trial of Oral Rapamycin for Recalcitrant Restenosis
Authors: Prabhtej S. Brara, Mehran Moussavian, Mark A. Grise, John P. Reilly, Mindy Fernandez, Richard A. Schatz, Paul S. Teirstein
Journal: Circulation (2003)

Background— Sirolimus-coated stents are a promising new therapy for restenosis. We treated a select group of patients at especially high risk for restenosis with oral sirolimus. Methods and Results— Patients were treated with an oral sirolimus-loading dose of 6 mg after coronary angioplasty, followed by 2 mg/d for 4 weeks. Serum electrolytes, lipid profile, renal panel, and complete blood cell count were measured at 1, 3, and 5 weeks after drug initiation. Oral sirolimus was prescribed to 22 patients who had a total of 28 lesions and were at high risk for restenosis. Of the 22 study patients, 11 (50%) discontinued oral sirolimus early because of side effects or laboratory abnormalities. Hypertriglyceridemia and leukopenia were the most frequent adverse events, occurring in 3 patients each. All adverse drug effects were reversible after discontinuation. Follow-up was obtained in 100% of patients at a mean of 9.9±1.8 months, ranging from 6.5 to 11.8 months. Target lesion revascularization (TLR) occurred in 15 of 28 lesions (53.6%) and 13 of 22 patients (59.1%). There was no difference in TLR for patients receiving a complete course of sirolimus (n=8; 72.7%) compared with patients who terminated treatment prematurely (n=5; 45.5%; P =NS). Clinically driven repeat cardiac catheterization was obtained in 15 (68.2%) patients; restenosis (&gt;50% diameter stenosis at follow-up) was present in 13 (86.7%). Conclusion— Oral sirolimus does not appear to provide benefit to patients with recalcitrant restenosis. Adverse drug effects are frequent, underscoring the importance of local drug delivery to achieve high tissue concentrations without systemic adverse drug effects.
Oral Insulin: A Comparison With Subcutaneous Regular Human Insulin in Patients With Type 2 Diabetes
Authors: Christoph Kapitza, Eric Zijlstra, Lutz Heinemann, M. Cristina Castelli, Gary Riley, Tim Heise
Journal: Diabetes Care (2010)

OBJECTIVE To determine the pharmacokinetic and pharmacodynamic properties of an oral insulin (OI) formulation compared with subcutaneously injected regular human insulin (RHI). RESEARCH DESIGN AND METHODS Ten male patients with type 2 diabetes (means ± SD; A1C 7.0 ± 1.1%; BMI 28.3 ± 2.7 kg/m2) received either 300 units of insulin combined with 400 mg of delivery agent orally or 15 units RHI subcutaneously under isoglycemic clamp conditions. RESULTS Maximum insulin concentration was greater and onset of action was faster with OI (Cmax 93 ± 71 vs. 33 ± 11 μU/ml; AUCGIR(0−1h) 173 ± 86 vs. 27 ± 32 mg/kg; P &amp;lt; 0.05). Mean insulin concentration and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7 ± 4% (1st 2 h). CONCLUSIONS This proof-of-concept study demonstrated that absorption of OI is feasible under fasting conditions. OI has a fast onset and a short duration of action but also shows a rather high between-subject variability in absorption.
2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer
Authors: Christopher G. Azzoli, Sarah Temin, Timothy Aliff, Sherman Baker, Julie Brahmer, David H. Johnson, Janessa L. Laskin, Gregory Masters, Daniel Milton, Luke Nordquist, William Pao, David G. Pfister, Steven Piantadosi, Joan H. Schiller, Reily Smith, Thomas J. Smith, John R. Strawn, David Trent, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2011)

An American Society of Clinical Oncology (ASCO) focused update updates a single recommendation (or subset of recommendations) in advance of a regularly scheduled guideline update. This document updates one recommendation of the ASCO Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer (NSCLC) regarding switch maintenance chemotherapy.
Mitochondrial Reactive Oxygen Species Trigger Calcium Increases During Hypoxia in Pulmonary Arterial Myocytes
Authors: Gregory B. Waypa, Jeremy D. Marks, Mathew M. Mack, Chan Boriboun, Paul T. Mungai, Paul T. Schumacker
Journal: Circulation Research (2002)

We hypothesized that mitochondria function as the O 2 sensors underlying hypoxic pulmonary vasoconstriction by releasing reactive oxygen species (ROS) from complex III of the electron transport chain (ETC). We have previously found that antioxidants or inhibition of the proximal region of the ETC attenuates hypoxic pulmonary vasoconstriction in rat lungs and blocks hypoxia-induced contraction of isolated pulmonary arterial (PA) myocytes. To determine whether the hypoxia-induced increases in mitochondrial ROS act to trigger calcium increases, we measured changes in cytosolic calcium ([Ca 2+ ] i ) using fura 2-AM (fluorescence at 340/380 nm) during perfusion with hypoxic media (P o 2 12 mm Hg). Hypoxia caused an increase in fura 2 fluorescence, indicating an increase in [Ca 2+ ] i . In superfused PA myocytes, diphenyleneiodonium, rotenone, and myxothiazol, which inhibit the proximal region of the ETC, attenuated hypoxia-induced calcium increases. Antimycin A and cyanide, which inhibit the distal region of the ETC, failed to abolish hypoxia-induced [Ca 2+ ] i increases. To test whether mitochondrial H 2 O 2 is required to trigger [Ca 2+ ] i increases, catalase was overexpressed in PA myocytes with the use of a recombinant adenovirus. Catalase overexpression attenuated hypoxia-induced increases in [Ca 2+ ] i , suggesting that H 2 O 2 acts upstream from calcium increases during hypoxia. These results support the conclusion that mitochondria function as O 2 sensors during hypoxia and demonstrate that ROS generated in the proximal region of the ETC act as second messengers to trigger calcium increases in PA myocytes during acute hypoxia.
Bone Morphogenetic Protein Receptor-2 Signaling Promotes Pulmonary Arterial Endothelial Cell Survival
Authors: Krystyna Teichert-Kuliszewska, Michael J.B. Kutryk, Michael A. Kuliszewski, Golnaz Karoubi, David W. Courtman, Liana Zucco, John Granton, Duncan J. Stewart
Journal: Circulation Research (2005)

Mutations in the bone morphogenetic protein (BMP) receptor-2 (BMPR2) have been found in patients with idiopathic pulmonary arterial hypertension (IPAH); however, the mechanistic link between loss of BMPR2 signaling and the development of pulmonary arterial hypertension is unclear. We hypothesized that, contrary to smooth muscle cells, this pathway promotes survival in pulmonary artery endothelial cells (ECs) and loss of BMPR2 signaling will predispose to EC apoptosis. ECs were treated with BMP-2 or BMP-7 (200 ng/mL) for 24 hours in regular or serum-free (SF) medium, with and without addition of tumor necrosis factor α, and apoptosis was assessed by flow cytometry (Annexin V), TUNEL, or caspase-3 activity. Treatment for 24 hours in SF medium increased apoptosis, and both BMP-2 and BMP-7 significantly reduced apoptosis in response to serum deprivation to levels not different from serum controls. Transfection with 5 μg of small interfering RNAs for BMPR2 produced specific gene silencing assessed by RT-PCR and Western blot analysis. BMPR2 gene silencing increased apoptosis almost 3-fold ( P =0.0027), even in the presence of serum. Circulating endothelial progenitor cells (EPCs) isolated from normal subjects or patients with IPAH were differentiated in culture for 7 days and apoptosis was determined in the presence and absence of BMPs. BMP-2 reduced apoptosis induced by serum withdrawal in EPCs from normal subjects but not in EPCs isolated from patients with IPAH. These results support the hypothesis that loss-of-function mutations in BMPR2 could lead to increased pulmonary EC apoptosis, representing a possible initiating mechanism in the pathogenesis of pulmonary arterial hypertension.
Differential Phospholamban Gene Expression in Murine Cardiac Compartments
Authors: Kimberly L. Koss, Sathivel Ponniah, W. Keith Jones, Ingrid L. Grupp, Evangelia G. Kranias
Journal: Circulation Research (1995)

Phospholamban, the regulator of the Ca2+ pump in cardiac sarcoplasmic reticulum, is differentially expressed between murine atrial and ventricular muscles. Quantitative analyses of RNA isolated from atrial flaps and ventricular apices indicated that the phospholamban gene transcript copy number is 2.5-fold higher in the ventricle compared with the atrium of the FVB/N mouse and 6-fold higher in the ventricle compared with the atrium of the B6D2/F1 mouse strain. These findings were corroborated by in situ hybridization studies of cardiopulmonary sections from both murine strains, and phospholamban transcripts were also observed in pulmonary myocardia of both strains. Analyses of phospholamban transcript levels relative to alpha-myosin heavy chain (alpha-MHC) revealed a 3-fold higher phospholamban abundance in the ventricle compared with the atrium of the FVB/N murine strain. However, the relative mRNA level of Ca(2+)-ATPase (ratio of sarcoplasmic reticulum Ca(2+)-ATPase [SERCA2] to alpha-MHC) in the ventricle was 80% of that in the atrium. Consequently, the relative ratio of phospholamban to SERCA2 mRNA was 4.2-fold lower in the atrium than in the ventricle. The lower transcript ratio of phospholamban to SERCA2 in the atrium was associated with significantly shortened times to half-relaxation (17.40 +/- 0.71 milliseconds for atrium versus 30.58 +/- 2.04 milliseconds for ventricle), assessed in isolated superfused cardiac tissue preparations recorded at maximum length tension. Contraction times, measured as times to peak tension, were also significantly shortened in atrial muscle (27.36 +/- 0.82 milliseconds) compared with ventricular muscle (44.60 +/- 2.55 milliseconds), assessed in the same tissue preparations. These findings suggest that phospholamban gene expression is differentially regulated in murine atrial and ventricular muscles and that this differential expression may be associated with differences in the contractile parameters of these cardiac compartments.
Oxygen: the good, the bad, and the necessary...
Authors: T Troosters
Journal: Thorax (2004)

The use of oxygen therapy in COPD needs more careful study

Long term oxygen therapy (LTOT) is one of the few treatments which has significant survival benefits in patients with severe hypoxaemia. It may modify disease progression, as indicated by a slower progression of hypoxia induced pulmonary hypertension,1–4 and the acute reduction in pulmonary hypertension to oxygen administration has been suggested as predictive for the survival benefit in individual patients. Reduced pulmonary vascular resistance and hence the reduced load on the right heart is probably the most important working mechanism of LTOT. In less severe hypoxaemic patients the benefits of LTOT on survival are less clear.5 Other benefits of oxygen administration are generally accepted. Reduced ventilation, especially during exercise, helps to avoid dynamic hyperinflation and hence reduces symptoms and increases exercise tolerance in the majority of patients with chronic obstructive pulmonary disease (COPD), even in patients with mild hypoxaemia.6 There is also some evidence to support the suggestion that LTOT may improve cognitive function in hypoxaemic COPD patients7 and may improve health related quality of life.8

LTOT is therefore a recognised treatment in hypoxaemic patients …
A Prevalent Amino Acid Polymorphism at Codon 98 (Ala98Val) of the Hepatocyte Nuclear Factor-1α Is Associated With Maturity-Onset Diabetes of the Young and Younger Age at Onset of Type 2 Diabetes in Asian Indians
Authors: Shekher Anuradha, Venkatesan Radha, Raj Deepa, Torben Hansen, Bendix Carstensen, Oluf Pedersen, Viswanathan Mohan
Journal: Diabetes Care (2005)

OBJECTIVE—Among Europeans, mutations in the hepatocyte nuclear factor-1α (HNF1α) gene are associated with the most common form of maturity-onset diabetes of the young (MODY)3. In Asian Indians, type 2 diabetes occurs earlier and often overlaps with MODY, but the genetics of the latter are unknown. The aim of this study was to estimate the prevalence of Ala98Val polymorphism of the HNF1α gene in different types of diabetes in Asian Indians. RESEARCH DESIGN AND METHODS—Genotyping of Ala98Val was done by the PCR–restriction fragment–length polymorphism method in the following groups: 1) MODY, defined as non–insulin-dependent diabetes (age at onset &amp;lt;25 years) and vertical transmission of diabetes through at least three generations (n = 122); 2) very-early-onset type 2 diabetes (age at onset &amp;lt;25 years) without family history (n = 23); 3) early-onset type 2 diabetes (age at onset between 26 and 40 years, n = 171); 4) late-onset type 2 diabetes (age at onset &amp;gt;40 years, n = 133); 5) type 1 diabetes (n = 150); and 6) normal glucose tolerance (n = 130). The frequency of the Val genotypes was compared in the diabetic and control groups. RESULTS—The frequency of the Val allele was significantly higher in MODY patients (P = 0.0013) compared with control groups. Furthermore, in the total group of patients with type 2–like diabetes (groups 1–4), the Val allele was associated with an earlier diagnosis of diabetes (P = 0.0002). CONCLUSIONS—Among Asian Indians, the Ala98Val polymorphism of HNF1α gene is associated with MODY and with earlier age at onset of type 2 diabetes.
Lung volume reduction coil treatment restores lung compliance in patients with homogeneous emphysema
Authors: Dirk-Jan Slebos, Karin Klooster, Ina Franz, Alie Smidt, Huib A.M. Kerstjens, Nick H.T. Ten Hacken
Journal: European Respiratory Journal (2013)

Rationale: Bronchoscopic Lung Volume Reduction Coil (LVRC) treatment has been shown to improve pulmonary function, exercise performance and QOL in patients with heterogeneous emphysema. The mechanism of action is yet not fully elucidated. LVRC has not been prospectively investigated in homogeneous emphysema before.  Aim: To investigate safety, efficacy and mechanisms of action of LVRC treatment in patients with homogeneous emphysema.  Methods: In this single-arm, open-label study, homogeneous emphysema patients(≤15% difference in destruction   Results: 10 patients with a mean age of 56.2 (±7.6)yrs, FEV1 23.4 (±4.3)%pred, RV 275 (±47)%pred, 6MWD 307 (±107)m were treated. At 6 months follow-up two COPD exacerbations were recorded as SAE. After 6 months ΔFEV1,%pred was +16.2% (±21.8) p=0.035; ΔFVC,%pred: +11.3% (±14.8) p=0.005; ΔRV,L: -0.66 (±0.41) p=0.0004; ΔRV/TLC,%: -7.3 (±4.6) p=0.0003; ΔRaw, kPa*s/L: -19.3% (±21.6) p=0.004; Δ6MWD,m: +52.9 (±40.3) p=0.002; ΔSGRQ,points: -11.5 (±11.7) p=0.0127. Forced oscillation at 5-20Hz, kPa/L/s improved from 0.36 (±0.17) to 0.25 (±0.11) p=0.018, and the responder dynamic lung compliance from 1.77 L/kPa (±0.57) to 2.47 L/kPa (±0.64) p=0.003.  Conclusion: The benefit of LVRC treatment is not limited to patients with heterogeneous emphysema; it significantly improves pulmonary function, exercise capacity and QOL also in patients with homogeneous emphysema. The coils probably exert their effect by improving lung compliance, thereby reducing airway resistance and improving hyperinflation.
Evolution of the TIR Domain-Containing Adaptors in Humans: Swinging between Constraint and Adaptation
Authors: Simona Fornarino, Guillaume Laval, Luis B. Barreiro, Jeremy Manry, Estelle Vasseur, Lluis Quintana-Murci
Journal: Molecular Biology and Evolution (2011)

Natural selection is expected to act strongly on immune system genes as hosts adapt to novel, diverse, and coevolving pathogens. Population genetic studies of host defense genes with parallel functions in model organisms have revealed distinct evolutionary histories among the different components—receptors, adaptors, and effectors—of the innate immune system. In humans, however, detailed evolutionary studies have been mainly confined to the receptors and in particular to Toll-like receptors (TLRs). By virtue of a toll/interleukin-1 receptor (TIR) domain, TLRs activate distinct signaling pathways, which are mediated by the five TIR-containing adaptors: myeloid differentiation factor-88 (MyD88), myeloid differentiation factor-88 adaptor-like protein (MAL), toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon (IFN)β (TRIF), toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNβ-related adaptor molecule (TRAM), and sterile α- and armadillo motif-containing protein (SARM). Here, we have examined the extent to which natural selection has affected immune adaptors in humans, using as a paradigm the TIR-containing adaptors. To do so, we characterized their levels of naturally occurring genetic variation in various human populations. We found that MyD88 and TRIF have mainly evolved under purifying selection, suggesting that their role in the early stages of signal transduction is essential and nonredundant for host survival. In addition, the adaptors have been targeted by multiple episodes of positive selection, differing in timing and spatial location. MyD88 and SARM display signatures of a selective sweep that has occurred in all humans, whereas for the other three adaptors, we detected signatures of adaptive evolution that are restricted to specific populations. Our study provides evidence that the contemporary diversity of the five TIR-containing adaptors results from the intermingling of different selective events, swinging between constraint and adaptation.
Sustained Complete Molecular Remissions After Treatment With Imatinib-Mesylate in Patients With Failure After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia: Results of a Prospective Phase II Open-Label Multicenter Study
Authors: Georg Hess, Donald Bunjes, Wolfgang Siegert, Rainer Schwerdtfeger, Georg Ledderose, Barbara Wassmann, Guido Kobbe, Martin Bornhäuser, Andreas Hochhaus, Andrew J. Ullmann, Thomas Kindler, Ulrike Haus, Harald Gschaidmeier, Christoph Huber, Thomas Fischer
Journal: Journal of Clinical Oncology (2005)

In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial.As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. Forty-four patients were enrolled and received the BCR-ABL tyrosine kinase inhibitor imatinib (IM) at a starting dose of 400 mg/d. The quality of molecular responses achieved then decided on discontinuation of IM or dose escalation up to 800 mg/d, and finally, on application of donor lymphocyte infusions. Results Seventy percent of patients achieved a complete molecular response (CMR), defined as nested PCR-negativity for BCR-ABL in three consecutive samples. Interestingly, in four out of 10 patients who discontinued IM, CMR was durable even after cessation of IM with a median follow-up of 494 days. This suggests the possibility of long-term tumor control in a subset of patients.The treatment strategy showed that IM treatment was well-tolerated and highly efficacious in MRD after allogeneic SCT. Moreover, this study demonstrated that evaluation of a molecular end point within a multicenter trial can be a safe and effective tool for clinical decision making.
Co-localization of CENP-C and CENP-H to discontinuous domains of CENP-A chromatin at human neocentromeres
Authors: Alicia Alonso, Björn Fritz, Dan Hasson, György Abrusan, Fanny Cheung, Kinya Yoda, Bernhard Radlwimmer, Andreas G Ladurner, Peter E Warburton
Journal: Genome biology (2007)

Abstract Background Mammalian centromere formation is dependent on chromatin that contains centromere protein (CENP)-A, which is the centromere-specific histone H3 variant. Human neocentromeres have acquired CENP-A chromatin epigenetically in ectopic chromosomal locations on low-copy complex DNA. Neocentromeres permit detailed investigation of centromeric chromatin organization that is not possible in the highly repetitive alpha satellite DNA present at endogenous centromeres. Results We have examined the distribution of CENP-A, as well as two additional centromeric chromatin-associated proteins (CENP-C and CENP-H), across neocentromeric DNA using chromatin immunoprecipitation (ChIP) on CHIP assays on custom genomic microarrays at three different resolutions. Analysis of two neocentromeres using a contiguous bacterial artificial chromosome (BAC) microarray spanning bands 13q31.3 to 13q33.1 shows that both CENP-C and CENP-H co-localize to the CENP-A chromatin domain. Using a higher resolution polymerase chain reaction (PCR)-amplicon microarray spanning the neocentromere, we find that the CENP-A chromatin is discontinuous, consisting of a major domain of about 87.8 kilobases (kb) and a minor domain of about 13.2 kb, separated by an approximately 158 kb region devoid of CENPs. Both CENP-A domains exhibit co-localization of CENP-C and CENP-H, defining a distinct inner kinetochore chromatin structure that is consistent with higher order chromatin looping models at centromeres. The PCR microarray data suggested varying density of CENP-A nucleosomes across the major domain, which was confirmed using a higher resolution oligo-based microarray. Conclusion Centromeric chromatin consists of several CENP-A subdomains with highly discontinuous CENP-A chromatin at both the level of individual nucleosomes and at higher order chromatin levels, raising questions regarding the overall structure of centromeric chromatin.
Effect of aerobic and anaerobic exercise on basal metabolic-rate
Authors: Moradhvaj Singh, D K Dureha, Santosh Yaduvanshi, Pooja Mishra
Journal: British Journal of Sports Medicine (2010)

Lack of activity destroys the good condition of every human being, while moment and methodical physical exercise save it and preserve it. Psychic tensions, anxieties, obesity, BP, etc, in sedentary people have now swelled (grew larger) to enormous proportions. Exercise or physical activities help in handling all this by increasing basal metabolic rate (BMR). The research findings could remove several misconceptions about exercise and remove the mystical sheath over it. Many people do not perform any exercise and are unaware of this fact. Proper exercise profoundly improves our BMR. The exercise is intimately connected with our State of Health and improper BMR will often reflect various disturbances of body and mind. The purpose of the study was to investigate the effect of aerobic and anaerobic exercise on BMR. For this study, 40 male and 20 female students from BPE group were randomly selected as subjects from LNUPE, Gwalior. The subjects were divided into two groups, that is, one experimental group and one control group. Experimental group was administered with aerobic and anaerobic exercise and second group was control group that did not participate in training programme. The quantitative measurement of each subject was taken with the help of standard equipment, before and after the treatment period of 2 h. The selected physiological variables were resting BMR administered in the Laboratory of Health Science and Yoga, LNUPE, Gwalior. The random group design applied for the effect of exercise on BMR. The analysis of resting BMR changes on the practice was positive of aerobic and anaerobic exercise subjects.