tbuckley/cabot-search huggingface dataset:
Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins
Authors: Charlotte Ling, Pernille Poulsen, Emma Carlsson, Martin Ridderstråle, Peter Almgren, Jørgen Wojtaszewski, Henning Beck-Nielsen, Leif Groop, Allan Vaag
Journal: Journal of Clinical Investigation (2004)

Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPARγ coactivator 1α (PGC-1α) and PGC-1β genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1α gene. Insulin increased and aging reduced skeletal muscle PGC-1α and PGC-1β mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1α Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1α in a complex fashion. Whereas expression of PGC-1α in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1β expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1α and PGC-1β expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1α and PGC-1β on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
Compliance with oral corticosteroids during steroid trials in chronic airways obstruction.
Authors: M Q Hatton, M B Allen, S V Vathenen, M P Feely, N J Cooke
Journal: Thorax (1996)

Corticosteroid trials are an important part of the assessment of patients with chronic airways obstruction, but false negative results will occur if the treatment is not taken. To determine compliance low dose phenobarbitone has been used as a marker.Thirty six patients referred to a chest clinic for assessment of their airways obstruction were studied. They were instructed to take eight capsules (each containing 5 mg prednisolone and 0.5 mg phenobarbitone) per day for two weeks. The response was assessed by home peak flow monitoring and clinic spirometric tests. Plasma phenobarbitone levels were measured after the trial to enable calculation of the dose to plasma concentration ratio (level to dose ratio, LDR) and the result was compared with the reference range for fully compliant individuals.Five patients defaulted from follow up, 23 had LDR values within the expected range, and eight had low LDR values consistent with poor compliance. The nine patients with steroid responsive disease (> 20% improvement in peak flow or spirometric parameters) all had LDR values in the expected range.Excluding those who defaulted whose compliance must be questionable, eight (26%) patients did not fully comply with the steroid trial. Not all patients who fail to respond to a two week home steroid trial have a steroid "unresponsive" disease.
Exploring Patterns and Extent of Bias in Estimating Divergence Time from Mitochondrial DNA Sequence Data in a Particular Lineage: A Case Study of Salamanders (Order Caudata)
Authors: Y. Zheng, R. Peng, M. Kuro-o, X. Zeng
Journal: Molecular Biology and Evolution (2011)

In the practice of molecular dating, substitution saturation will bias the results if not properly modeled. Date estimates based on commonly used mitochondrial DNA sequences likely suffer from this problem because of their high substitution rate. Nevertheless, the patterns and extent of such expected bias remain unknown for many major evolutionary lineages, which often differ in ages, available calibrations, and substitution rates of their mitochondrial genome. In this case study of salamanders, we used estimates based on multiple nuclear exons to assess the effects of saturation on dating divergences using mitochondrial genome sequences on a timescale of ∼200–300 My. The results indicated that, due to saturation for older divergences and in the absence of younger effective calibration points, dates derived from the mitochondrial data were considerably overestimated and systematically biased toward the calibration point for the ingroup root. The overestimate might be as great as 3–10 times (about 20 My) older than actual divergence dates for recent splitting events and 40 My older for events that are more ancient. For deep divergences, dates estimated were strongly compressed together. Furthermore, excluding the third codon positions of protein-coding genes or only using the RNA genes or second codon positions did not considerably improve the performance. In the order Caudata, slowly evolving markers such as nuclear exons are preferred for dating a phylogeny covering a relatively wide time span. Dates estimated from these markers can be used as secondary calibrations for dating recent events based on rapidly evolving markers for which mitochondrial DNA sequences are attractive candidates due to their short coalescent time. In other groups, similar evaluation should be performed to facilitate the choice of markers for molecular dating and making inferences from the results.
Multimodality Therapy: Potentiation of High Linear Energy Transfer Radiation with Paclitaxel for the Treatment of Disseminated Peritoneal Disease
Authors: Diane E. Milenic, Kayhan Garmestani, Erik D. Brady, Kwamena E. Baidoo, Paul S. Albert, Karen J. Wong, Joseph Flynn, Martin W. Brechbiel
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Studies herein explore paclitaxel enhancement of the therapeutic efficacy of α-particle-targeted radiation therapy. Experimental Design: Athymic mice bearing 3 day i.p. LS-174T xenografts were treated with 300 or 600 μg paclitaxel at 24 h before, concurrently, or 24 h after [213Bi] or [212Pb]trastuzumab. Results: Paclitaxel (300 or 600 μg) followed 24 h later with [213Bi]trastuzumab (500 μCi) provided no therapeutic enhancement. Paclitaxel (300 μg) administered concurrently with [213Bi]trastuzumab or [213Bi]HuIgG resulted in median survival of 93 and 37 days, respectively; no difference was observed with 600 μg paclitaxel. Mice receiving just [213Bi]trastuzumab or [213Bi]HuIgG or left untreated had a median survival of 31, 21, and 15 days, respectively, 23 days for just either paclitaxel dose alone. Paclitaxel (300 or 600 μg) given 24 h after [213Bi]trastuzumab increased median survival to 100 and 135 days, respectively. The greatest improvement in median survival (198 days) was obtained with two weekly doses of paclitaxel (600 μg) followed by [213Bi]trastuzumab. Studies were also conducted investigating paclitaxel administered 24 h before, concurrently, or 24 h after [212Pb]trastuzumab (10 μCi). The 300 μg paclitaxel 24 h before radioimmunotherapy (RIT) failed to provide benefit, whereas 600 μg extended the median survival from 44 to 171 days. Conclusions: These results suggest that regimens combining chemotherapeutics and high linear energy transfer (LET) RIT may have tremendous potential in the management and treatment of cancer patients. Dose dependency and administration order appear to be critical factors requiring careful investigation.
Integrating Sequence Variation and Protein Structure to Identify Sites under Selection
Authors: Austin G. Meyer, Claus O. Wilke
Journal: Molecular Biology and Evolution (2012)

We present a novel method to identify sites under selection in protein-coding genes. Our method combines the traditional Goldman–Yang model of coding-sequence evolution with the information obtained from the 3D structure of the evolving protein, specifically the relative solvent accessibility (RSA) of individual residues. We develop a random-effects likelihood sites model in which rate classes are RSA dependent. The RSA dependence is modeled with linear functions. We demonstrate that our RSA-dependent model provides a significantly better fit to molecular sequence data than does a traditional, RSA-independent model. We further show that our model provides a natural, RSA-dependent neutral baseline for the evolutionary rate ratio ω = dN/dS Sites that deviate from this neutral baseline likely experience selection pressure for function. We apply our method to the influenza proteins hemagglutinin and neuraminidase. For hemagglutinin, our method recovers positively selected sites near the sialic acid-binding site and negatively selected sites that may be important for trimerization. For neuraminidase, our method recovers the oseltamivir resistance site and otherwise suggests that few sites deviate from the neutral baseline. Our method is broadly applicable to any protein sequences for which structural data are available or can be obtained via homology modeling or threading.
Postcholecystectomy symptoms. A prospective study of gall stone patients before and two years after surgery.
Authors: E Ros, D Zambon
Journal: Gut (1987)

The results of cholecystectomy in terms of symptomatic improvement were prospectively evaluated in 124 unselected gall stone patients interviewed before and two years after elective surgery. Indications for cholecystectomy were biliary pain (n = 65), previous complications of gall stone disease (n = 52), and flatulent dyspepsia (n = 7). At two years 93 patients could be re-evaluated, of whom only 49 (53%) were completely symptom free. Postcholecystectomy symptoms occurring in the remaining 44 patients were mainly flatulent dyspepsia (which had relapsed in 22 of 46 patients who suffered it preoperatively), dull abdominal pain or diarrhoea. Incisional hernia was present in five patients and one had recurrence of pain because of retained common bile duct stones. Symptomatic cures after cholecystectomy decreased with the duration of the preoperative history. The results reconfirm that cholecystectomy eradicates specific symptoms and complications of gall stone disease, but they also show that nearly one half of operated patients are dissatisfied with the procedure because of mild but distressing 9postcholecystectomy9 symptoms. These are probably caused by previously undiagnosed functional gut disease associated with, but unrelated to, gall stones. A systemic approach to multisymptomatic patients with gall stones is recommended.
TIGIT predominantly regulates the immune response via regulatory T cells
Authors: Sema Kurtulus, Kaori Sakuishi, Shin-Foong Ngiow, Nicole Joller, Dewar J. Tan, Michele W.L. Teng, Mark J. Smyth, Vijay K. Kuchroo, Ana C. Anderson
Journal: Journal of Clinical Investigation (2015)

Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.
THE REACTION OF THE CAPILLARY BED OF THE NAILFOLD TO THE CONTINUOUS INTRAVENOUS INFUSION OF LEVO-NOR-EPINEPHRINE IN PATIENTS WITH NORMAL BLOOD PRESSURE AND WITH ESSENTIAL HYPERTENSION
Authors: Sheldon E. Greisman
Journal: Journal of Clinical Investigation (1954)

The intravenous infusion of l-nor-epinephrine in persons with normal cardiovascular systems produces a hemodynamic state which in many respects resembles that found in patients with essential hypertension. In the systemic circulation there is in each of the two conditions an elevation of the systolic, diastolic and mean arterial pressures, an unchanged or moderately decreased cardiac output, an increase in systemic peripheral resistance and usually an absence of subjective symptoms (1). This similarity in the two hemodynamic states has led to the suggestion that l-nor-epinephrine may be a humoral agent responsible for essential hypertension. If this were true, then the hypertensive state produced by l-nor-epinephrine should produce changes in all portions of the circulatory system similar to those found in essential hypertension. The dynamics of the pulmonary circulation have been shown to be different in the two states; the intravenous infusion of l-nor-epinephrine raises mean pulmonary arterial pressure whereas this pressure is normal in patients with uncomplicated essential hypertension (1). The present study was undertaken to determine whether the circulation in specific portions of the systemic vascular system, in this instance the peripheral cutaneous capillaries, is the same in subjects with l-nor-epinephrine induced hypertension as in patients with essential hypertension. Accordingly, the capillary circulation of the nailfold during the sustained hypertensive state induced in control subjects by continuous intravenous infusion of l-nor-epinephrine was compared with the nailfold capillary circulation of patients with essential hypertension. The observations indicate that for similar levels of elevated arterial pressure the capillary circulation of the nailfold is more reactive in the l-nor-epinephrine induced hypertension than in essential hypertension. A previous study indicated that the nailfold capillary circulation of subjects with essential hypertension was more reactive to single rapid injections of epinephrine than the similar capillary circulation of control subjects (2). The present study extends this observation to indicate that such hyper-reactivity persists over the several hours of a continuous infusion of l-nor-epinephrine.
Serum factor requirement for reactive oxygen intermediate release by rabbit alveolar macrophages.
Authors: G F Gerberick, J B Willoughby, W F Willoughby
Journal: The Journal of Experimental Medicine (1985)

Alveolar macrophages (AM) from pathogen-free rabbits were unable to release reactive oxygen intermediates (ROI) unless they were conditioned in serum for 24-48 h before triggering with membrane-active agents. The degree of serum conditioning of AM depended upon the concentration of serum used; optimal ROI release was obtained at or above 7.5% fetal bovine serum (FBS). FBS, autologous rabbit serum, pooled rabbit serum, and pooled human serum were each capable of conditioning AM for release of ROI. Serum conditioning of AM requires synthesis of new protein(s); and the enzyme required for ROI production, NADPH oxidase, was only detectable in serum-conditioned cells. Moreover, serum-conditioned cells lost their ability to release ROI after transfer to serum-free medium, while cells maintained in serum-free medium acquired the capacity to release ROI after their transfer to serum-containing medium, demonstrating the reversibility of the phenomenon. Initial purification data indicate that conditioning is mediated by a discrete serum constituent, which precipitates 40-80% saturated ammonium sulfate, does not bind to Cibacron Blue columns, and has a molecular weight of 30,000 to 50,000, as determined by molecular exclusion chromatography. Unlike gamma interferon, which also enhances ROI release by macrophages, our serum-conditioning factor is not acid labile, retaining 67% of its activity after 120 min incubation at pH 2.0. Moreover, it does not appear to be a contaminating endotoxin, since LPS neither conditioned AM for ROI production, nor triggered ROI production by serum-conditioned AM. We propose that such a conditioning requirement may normally protect the lung against ROI-mediated tissue injury. However, during a pulmonary inflammatory reaction initiated by other mediator systems, the resulting transudation of plasma proteins into the alveolar spaces may condition AM in situ for ROI production.
PROSTATECTOMY AND ITS POST-OPERATIVE MANAGEMENT
Authors: W. I. d. C. Wheeler
Journal: BMJ (1939)

The success or otherwise of post-operative treatment depends upon the efficacy of pre-operative measures and upon the operative procedure.It will therefore be neces- sary to allude briefly to both the latter when discussing the former.It will not be possible to discuss the wide variations of treatment which are required after procedures such as the Harris complete closure operation, endoscopic resection, or operations performed through the perineal route.Attention will be directed to open operations of the orthodox type. General ConsiderationsThe surgery of the prostate gland as we know it had its birth in or about the year 1887.At this time McGill of Leeds read a paper on suprapubic prostatectomy.In those early days surgery was judged largely by the speed of operation.Onlookers in the operating theatre in- stinctively stood with one eye on the clock.Manual dexterity was of a high order, and in every department the Science of surgery was subordinated to the Art.Major amputations were completed in a few minutes.It was emphatically laid down that operations such as lithotrity must not occupy more than four minutes for the "first sitting."Prostatectomy was performed by pioneers such as Freyer with a celerity that has never been excelled.Speed must still be the watchword in conditions of danger and emergency, but the cost may be heavy in the form of post-operative complications, immediate and remote.Elderly patients are not necessarily bad surgical risks.They tolerate well such major operations as amputations, gastrectomy, and colectomy.It is recognized, however, that those advanced in years require the most detailed care in the pre-operative and post-operative periods.This point is, I think, made clear by the statistical figures collected by the late Sir John Thomson-Walker and other authorities.Wide variations in results following operations by expert surgeons are reported.These variations can be explained only by assuming that some surgeons were in a better position than others to give close personal attention to pre-operative and post-operative care.In a series of 472 cases in private practice Thomson- Walker's mortality was 5.2 per cent.Comparable statistics in hospital practice revealed a rise in this figure to 9.9 per cent.The figures obtained from hospitals further afield demonstrated a death rate as high as 20.4 per cent.following a single-stage operation, with a reduc-
Multiscale Cancer Modeling
Authors: Thomas S. Deisboeck, Zhihui Wang, Paul Macklin, Vittorio Cristini
Journal: Annual Review of Biomedical Engineering (2011)

Simulating cancer behavior across multiple biological scales in space and time, i.e., multiscale cancer modeling, is increasingly being recognized as a powerful tool to refine hypotheses, focus experiments, and enable more accurate predictions. A growing number of examples illustrate the value of this approach in providing quantitative insights in the initiation, progression, and treatment of cancer. In this review, we introduce the most recent and important multiscale cancer modeling works that have successfully established a mechanistic link between different biological scales. Biophysical, biochemical, and biomechanical factors are considered in these models. We also discuss innovative, cutting-edge modeling methods that are moving predictive multiscale cancer modeling toward clinical application. Furthermore, because the development of multiscale cancer models requires a new level of collaboration among scientists from a variety of fields such as biology, medicine, physics, mathematics, engineering, and computer science, an innovative Web-based infrastructure is needed to support this growing community.
Clinical Assessment and Management of Adult Obesity
Authors: Robert F. Kushner
Journal: Circulation (2012)

O verweight and obesity are the most common medical problems seen in primary care practice, affecting Ͼ68% of adults and 33.0% of children and adolescents in the United States. 1,2Obesity is a risk factor for several of the leading causes of preventable death, including cardiovascular disease, diabetes mellitus, and many types of cancer.Thus, successful treatment and control of obesity should be major imperatives.4][5][6] Thus, a gap exists between the need to provide obesity care and the actual provision of care.In this article, current recommendations for the medical evaluation of the obese adult patient are reviewed, followed by management approaches to using lifestyle therapy, pharmacotherapy, and surgery.
Circulating Vascular Progenitor Cells Do Not Contribute to Compensatory Lung Growth
Authors: Robert Voswinckel, Tibor Ziegelhoeffer, Matthias Heil, Sawa Kostin, Georg Breier, Tanja Mehling, Rainer Haberberger, Matthias Clauss, Andreas Gaumann, Wolfgang Schaper, Werner Seeger
Journal: Circulation Research (2003)

The biological principles that underlie the induction and process of alveolization in the lung as well as the maintenance of the complex lung tissue structure are one of the major obstacles in pulmonary medicine today. Bone marrow–derived cells have been shown to participate in angiogenesis, vascular repair, and remodeling of various organs. We addressed this phenomenon in the lung vasculature of mice in a model of regenerative lung growth. C57BL/6 mice were transplanted with bone marrow from one of three different reporter gene–transgenic strains. flk-1 +/lacZ mice, tie-2/lacZ transgenic mice (both exhibiting endothelial cell–specific reporter gene expression), and ubiquitously enhanced green fluorescent protein (eGFP)-expressing mice served as marrow donors. After hematopoietic recovery, compensatory lung growth was induced by unilateral pneumonectomy and led to complete restoration of initial lung volume and surface area. The lungs were consecutively investigated for bone marrow–derived vascular cells by lacZ staining and immunohistochemistry for phenotype identification of vascular cells. lacZ- or eGFP-expressing bone marrow–derived endothelial cells could not be found in microvascular regions of alveolar septa. Single eGFP-positive endothelial cells were detected in pulmonary arteries at very low frequencies, whereas no eGFP-positive vascular smooth muscle cells were observed. In conclusion, we demonstrate in a model of lung growth and alveolization in adult mice the absence of significant bone marrow–derived progenitor cell contribution to the concomitant vascular growth and remodeling processes.