tbuckley/cabot-search huggingface dataset:
Efficient Biased Estimation of Evolutionary Distances When Substitution Rates Vary Across Sites
Authors: Stéphane Guindon, Olivier Gascuel
Journal: Molecular Biology and Evolution (2002)

This paper deals with phylogenetic inference when the variability of substitution rates across sites (VRAS) is modeled by a gamma distribution.We show that underestimating VRAS, which results in underestimates for the evolutionary distances between sequences, usually improves the topological accuracy of phylogenetic tree inference by distance-based methods, especially when the molecular clock holds.We propose a method to estimate the gamma shape parameter value which is most suited for tree topology inference, given the sequences at hand.This method is based on the pairwise evolutionary distances between sequences and allows one to reconstruct the phylogeny of a high number of taxa (Ͼ1,000).Simulation results show that the topological accuracy is highly improved when using the gamma shape parameter value given by our method, compared with the true (unknown) value which was used to generate the data.Furthermore, when VRAS is high, the topological accuracy of our distance-based method is better than that of a maximum likelihood approach.Finally, a data set of Maoricicada species sequences is analyzed, which confirms the advantage of our method.
Cystic Fibrosis–Related Diabetes: Current Trends in Prevalence, Incidence, and Mortality
Authors: Antoinette Moran, Jordan Dunitz, Brandon Nathan, Asad Saeed, Bonnie Holme, William Thomas
Journal: Diabetes Care (2009)

Cystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database.Data were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992-1997, 1998-2002, and 2003-2008.CFRD is currently present in 2% of children, 19% of adolescents, and 40-50% of adults. Incidence and prevalence are higher in female subjects aged 30-39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992-1997 to 2003-2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003-2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia.Previously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed. We believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients.
Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non–Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups
Authors: Gary M. Strauss, James E. Herndon, Michael A. Maddaus, David W. Johnstone, Elizabeth A. Johnson, David H. Harpole, Heidi H. Gillenwater, Dorothy M. Watson, David J. Sugarbaker, Richard L. Schilsky, Everett E. Vokes, Mark R. Green
Journal: Journal of Clinical Oncology (2008)

Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043).Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.
Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes
Authors: Elisabetta Cerbai, Antonio Crucitti, Laura Sartiani, Petra De Paoli, Roberto Pino, Maria Luisa Rodriguez, GianFranco Gensini, Alessandro Mugelli
Journal: Cardiovascular Research (2000)

Objective: Cardiac hypertrophy due to pressure overload is associated with several cellular electrophysiological alterations such as prolongation of action potential duration (APD), decrease in transient outward current (Ito) and occurrence of the pacemaker current If. These alterations may play a role in sudden arrhythmic death, which is a major risk factor in myocardial hypertrophy and failure. Since angiotensin II is a key signal for myocyte hypertrophy, we tested if an 8-week treatment of old spontaneously hypertensive rats (SHR) with the antagonist of type-1 angiotensin II receptor (AT1), losartan (10 mg/kg/day), was able to influence the cellular electrophysiologic remodeling associated with cardiac hypertrophy. Methods: Left ventricular myocytes were isolated from control (CTR) or losartan-treated (LOS) 18-month old SHR. Patch-clamped LVM were superfused with a normal Tyrode's solution (to measure action potential) or appropriately modified Tyrode's solution (to measure Ito and If). Results: Heart weight to body weight ratio (HW/BW) was significantly smaller in LOS (5.69±0.25 mg/g) than in CTR rats (6.67±0.37 mg/g; P<0.05). Membrane capacitance, an index of cell size, was significantly reduced in LOS (342±12, n=92) vs. CTR (422±14 pF, n=96, P<0.001). APD was significantly shorter in LOS than in CTR (at −60 mV: 197±23 vs. 277±19 ms, n=28, P<0.001); this effect was paralleled by a larger maximum Ito density in the LOS group (LOS: 15.1±1.4 pA/pF, CTR: 10.0±0.8 pA/pF) (n=27, P<0.02). If, elicited by hyperpolarizing steps (range: −60 to −130 mV), was consistently recorded in SHR cells; however, its maximal specific conductance was significantly lower in LOS than in CTR rats (28.6±3.6 vs. 54.2±8.0 pS/pF, n=55, P<0.001). Voltage of half-maximal activation (V1/2) of both Ito and If was unchanged by the treatment. Conclusions: AT1 receptor blockade with losartan prevents the development of myocyte hypertrophy and associated electrophysiological alterations in old SHR.
Type 2 Diabetes in Youth: Epidemiology and Pathophysiology
Authors: Ebe D’Adamo, Sonia Caprio
Journal: Diabetes Care (2011)

The prevalence of type 2 diabetes is significantly increased in the pediatric population, which is affected by obesity worldwide. The progression from normal glucose tolerance (NGT) to type 2 diabetes involves intermediate stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), also known as prediabetes. The pathophysiology underlying the development of these glucose metabolic alterations is multifactorial; however an alteration in the balance between insulin sensitivity and insulin secretion represents the most important player in the development of type 2 diabetes. Obese children and adolescents affected by IGT and type 2 diabetes are characterized by severe insulin resistance, which is associated with an increased lipid accumulation in visceral compartments, liver and muscle tissues and by reduced sensitivity of I²-cell of first and second-phase insulin secretion.

The progression in obese children of insulin resistance to type 2 diabetes has been shown to be faster than in adults; in addition, type 2 diabetes is already associated with several metabolic and cardiovascular complications in this age group.

In the present review, we summarize the most recent findings concerning the prevalence of type 2 diabetes in youth and in particular we explore the pathophysiology of type 2 diabetes and the natural history of this pathology in obese children and adolescents.

Concurrent with the worldwide epidemic increase of childhood obesity, type 2 diabetes and the two prediabetic conditions, IFG and IGT, are becoming increasingly more common in obese children and adolescents (1,2). Until 10 years ago, type 2 diabetes accounted for less than 3% of all cases of new-onset diabetes in adolescents. At present 45% of cases are attributed to it (3,4).

Type 2 diabetes occurs in youth more often during the second decade of life, coinciding with the physiological occurrence of pubertal insulin resistance (1). In addition, â€¦
Susceptibility of chimeric mice with livers repopulated by serially subcultured human hepatocytes to hepatitis B virus
Authors: Rie Utoh, Chise Tateno, Chihiro Yamasaki, Nobuhiko Hiraga, Miho Kataoka, Takashi Shimada, Kazuaki Chayama, Katsutoshi Yoshizato
Journal: Hepatology (2007)

We previously identified a small population of replicative hepatocytes in long-term cultures of human adult parenchymal hepatocytes (PHs) at a frequency of 0.01%-0.09%. These hepatocytes were able to grow continuously through serial subcultures as colony-forming parenchymal hepatocytes (CFPHs). In the present study, we generated gene expression profiles for cultured CFPHs and found that they expressed cytokeratin 19, CD90 (Thy-1), and CD44, but not mature hepatocyte markers such as tryptophan-2,3-dioxygenase (TO) and glucose-6-phosphatase (G6P), confirming that these cells are hepatic progenitor-like cells. The cultured CFPHs were resistant to infection with human hepatitis B virus (HBV). To examine the growth and differentiation capacity of the cells in vivo , serially subcultured CFPHs were transplanted into the progeny of a cross between albumin promoter/enhancer-driven urokinase plasminogen activator-transgenic mice and severe combined immunodeficient (SCID) mice. The cells were engrafted into the liver and were able to grow for at least 10 weeks, ultimately reaching a maximum occupancy rate of 27%. The CFPHs in the host liver expressed differentiation markers such as TO, G6P, and cytochrome P450 subtypes and could be infected with HBV. CFPH-chimeric mice with a relatively high replacement rate exhibited viremia and had high serum levels of hepatitis B surface antigen. Conclusion: Serially subcultured human hepatic progenitor-like cells from postnatal livers successfully repopulated injured livers and exhibited several phenotypes of mature hepatocytes, including susceptibility to HBV. In vitro –expanded CFPHs can be used to characterize the differentiation state of human hepatic progenitor-like cells. (Hepatology 2008.)
Quadriceps muscle strength in scoliosis
Authors: E. B. Swallow, E. Barreiro, H. Gosker, S. A. Sathyapala, F. Sanchez, N. S. Hopkinson, J. Moxham, A. Schols, J. Gea, M. I. Polkey
Journal: European Respiratory Journal (2009)

Quadriceps muscle weakness is an important component of chronic obstructive pulmonary disease (COPD). We hypothesised that quadriceps weakness would also be a feature of restrictive lung disease due to scoliosis. We studied 10 patients with severe scoliosis (median (interquartile range (IQR)) forced expiratory volume in 1 s (FEV 1 ) 35.3 (11)% predicted), 10 patients with severe COPD (FEV 1 26.5 (9.0)% pred) and 10 healthy age-matched adults. We measured quadriceps strength, exercise capacity and analysed quadriceps muscle biopsies for myosin heavy-chain (MyHC) isoform expression and the presence of oxidative stress. Both groups exhibited quadriceps weakness with median (IQR) maximal voluntary contraction force being 46.0 (17.0) kg, 21.5 (21.0) kg and 31.5 (11.0) kg, respectively (p = 0.02 and 0.04, respectively, for each patient group against controls). Oxidative stress was significantly greater in the quadriceps of both restrictive and COPD patients. The scoliosis patients exhibited a decrease in the proportion of MyHC type I compared with controls; median (IQR) 35.3 (18.5)% compared with 47.7 (9.3)%, p = 0.028. The scoliosis patients also showed an increase in MyHC IIx (26.3 (15.5)% compared with 11.3 (13.0)%, p = 0.01. Quadriceps weakness is a feature of severe scoliosis; the similarities between patients with scoliosis and patients with COPD suggest a common aetiology to quadriceps weakness in both conditions.
FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity
Authors: Manuela Fanciulli, Penny J Norsworthy, Enrico Petretto, Rong Dong, Lorraine Harper, Lavanya Kamesh, Joanne M Heward, Stephen C L Gough, Adam de Smith, Alexandra I F Blakemore, Philippe Froguel, Catherine J Owen, Simon H S Pearce, Luis Teixeira, Loic Guillevin, Deborah S Cunninghame Graham, Charles D Pusey, H Terence Cook, Timothy J Vyse, Timothy J Aitman
Journal: Nature Genetics (2007)
TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas
Authors: Chong-kui Sun, Xiao-bo Luo, Ya-ping Gou, Ling Hu, Kun Wang, Chao Li, Zhen-ting Xiang, Ping Zhang, Xiang-li Kong, Chao-liang Zhang, Qin Yang, Jing Li, Li-ying Xiao, Yan Li, Qian-ming Chen
Journal: Molecular Cancer (2014)

WRAP53, including α, β and γ isoforms, plays an important role not only in the stability of p53 mRNA, but also in the assembly and trafficking of the telomerase holoenzyme. It has been considered an oncogene and is thought to promote the survival of cancer cells. The aim of this study was to detect the role of TCAB1 (except WRAP53α) in the occurrence and development of head and neck carcinomas.Immunohistochemistry was used to detect the TCAB1 expression in clinical specimen sections and performed western blotting to check the TCAB1 expression levels in cell lines. TCAB1 was depleted using shRNA lentivirus and the knockdown efficiency was assessed using q-PCR and Western blotting. We performed CCK-8 assays and flow cytometry to check the cell proliferation potential and used the trans-well assay to test the invasion ability in vitro. Xenografts were used to detect the tumor formation potential in vivo. Moreover, we performed cDNA microarray to investigate the candidate factors involved in this process.We observed a notable overexpression of TCAB1 in head and neck carcinoma clinical specimens as well as in carcinoma cell lines. Knockdown of TCAB1 decreased the cellular proliferation potential and invasion ability in vitro. cDNA microarray analysis suggested the possible involvement of several pathways and factors associated with tumorigenesis and carcinoma development in the TCAB1-mediated regulation of cancers. Furthermore, the xenograft assay confirmed that the depletion of TCAB1 would inhibit tumor formation in nude mice. The immunohistochemistry results of the mice tumor tissue sections revealed that the cells in shTCAB1 xenografts showed decreased proliferation potential and increased apoptotic trend, meanwhile, the angiogenesis was inhibited in the smaller tumors form shTCAB1 cells.Our study demonstrated that depletion of TCAB1 decreased cellular proliferation and invasion potential both in vitro and in vivo. The data indicated that TCAB1 might facilitate the occurrence and development of head and neck carcinomas. In future, TCAB1 might be useful as a prognostic biomarker or a potential target for the diagnosis and therapy of head and neck carcinomas.
Control of Heart Rate by the Autonomic Nervous System
Authors: BRIAN F. ROBINSON, STEPHEN E. EPSTEIN, G. David BEISER, EUGENE BRAUNWALD
Journal: Circulation Research (1966)

The control of heart rate by the autonomic nervous system was investigated in conscious human subjects by observing the effects of β-adrenergic blockade with propranolol, of parasympathetic blockade with atropine, and of combined sympathetic and parasympathetic blockade. The increase in heart rate with mild exercise in supine men was mediated predominantly by a decrease in parasympathetic activity; at higher levels of work, however, sympathetic stimulation also contributed to cardiac acceleration. When the response to 80° head-up tilt was compared with the response to exercise in the same subject supine, it appeared that the attainment of an equivalent heart rate was associated with a significantly greater degree of sympathetic activity during tilting than during exercise. Although heart rate was always higher at any given pressure during exercise than it had been at rest, the changes in heart rate that followed alterations in arterial pressure were found to be of similar magnitudes at rest and during exercise; it was therefore concluded that the sensitivity of the baroreceptor system was not altered during exercise. Investigation of the efferent pathways concerned in mediating the baroreceptor-induced changes in heart rate suggested that the relative roles of the sympathetic and parasympathetic systems were nearly equal in the resting state. During exercise, on the other hand, changes in sympathetic activity appeared to be the predominant mechanism by which speeding and slowing of the heart was achieved. It thus appears that baroreceptor-induced alterations in heart rate may be mediated by increased or decreased activity of either efferent system; the ultimate balance, however, is critically dependent on the preexisting level of background autonomic activity.
Obesity Is a Critical Risk Factor for Worsening of Glucose Tolerance in a Family With the Mutant Insulin Receptor
Authors: Akihiko Ando, Toshimitsu Yatagai, Kumiko Rokkaku, Shoichiro Nagasaka, San-e Ishikawa, Shun Ishibashi
Journal: Diabetes Care (2002)

It is generally accepted that insulin resistance precedes the development of type 2 diabetes, but the precise mechanism that links insulin resistance to overt diabetes is not well understood. Genetic defects of the insulin receptor, although the prevalence is low, are regarded as one of the specific causes of diabetes (1). However, few studies have reported long-term observations of subjects with the insulin receptor mutation (2). Here, we describe a family with the abnormal insulin receptor who was followed-up for ∼20 years.

The proband is a 34-year-old Japanese woman. At 16 years of age, she noticed acanthosis nigricans in her axillae and groin. Her BMI was 19.0 kg/m2. Fasting glucose was normal, but fasting insulin concentration was as high as 240 pmol/l. Anti-insulin and anti–insulin receptor antibodies were negative. The 100-g oral glucose challenge …
Psychological influences on cancer and ischaemic heart disease.
Authors: H. M. Van der Ploeg
Journal: BMJ (1992)

referred to in the personal communication to Swedberg, but in our trial withdrawals for this reason were according to prespecified criteria and in line with usual clinical practice.The size of our trial was indeed based on a comparison of active with placebo treatment, but, as we pointed out, an assessment of the two active agents was an important secondary objective from the outset.The advantage of the diuretic over the 3 blocker was clear, particularly for coronary events, and is also suggested by other recent results.' Swedberg is surely not suggesting that findings of such immediate clinical relevance should remain unreported.
Increased serum alkaline phosphatase activity in ankylosing spondylitis.
Authors: N J Sheehan, B M Slavin, P R Kind, J A Mathews
Journal: Annals of the Rheumatic Diseases (1983)

Raised serum alkaline phosphatase (AP) levels were found in 13 of 76 patients (17 %) with ankylosing spondylitis (AS), and 1 1 of these 13 underwent further investigation to determine the origin of the increased enzyme activity.Three had levels within the normal reference range on re-estimation, and, of the remaining 8, AP isoenzyme studies indicated an increased liver fraction in 6. Serum gamma-glutamyl transpeptidase (GGT) was raised in only 3 patients.Increased AP activity did not appear to be directly related to disease activity or to drug therapy.These findings confirm the occurrence of increased serum AP activity in AS but challenge a previously reported suggestion that bone is the source of the increased enzyme.
A CpG-loaded tumor cell vaccine induces antitumor CD4+ T cells that are effective in adoptive therapy for large and established tumors
Authors: Matthew J. Goldstein, Bindu Varghese, Joshua D. Brody, Ranjani Rajapaksa, Holbrook Kohrt, Debra K. Czerwinski, Shoshana Levy, Ronald Levy
Journal: Blood (2010)
Dupilumab Monotherapy in Adults with Moderate-to-Severe Atopic Dermatitis: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study
Authors: Thomas R.M. Bieber, Diamant Thaci, Neil Graham, Gianluca Pirozzi, Ariel Teper, Haobo Ren, Allen Radin
Journal: Journal of Allergy and Clinical Immunology (2014)
Treatment of cold urticaria
Authors: ALLAN S. HIGHET, D. MICHAEL TITTERINGTON
Journal: British Journal of Dermatology (1979)

In a single patient with severe essential acquired cold urticaria, the following drug regimes were assessed: diphenhydramine, cyproheptadine, hydroxyzine, terbutaline, cimetidine, hydroxyzine plus cimetidine, and hydroxyzine plus terbutaline. Each regime showed favourable results, but a significance level of P ‐ 0.01 was reached only for (a) hydroxyzine plus cimetidine in the suppression of erythema, and (b) the histamine H1 antagonists in the suppression of wealing.