tbuckley/cabot-search huggingface dataset:
Phase IB Study of the mTOR Inhibitor Ridaforolimus With Capecitabine
Authors: Antonella Perotti, Alberta Locatelli, Cristiana Sessa, Dagmar Hess, Lucia Viganò, Giuseppe Capri, Michela Maur, Thomas Cerny, Sara Cresta, Federico Rojo, Joan Albanell, Silvia Marsoni, Irene Corradino, Lori Berk, Victor M. Rivera, Frank Haluska, Luca Gianni
Journal: Journal of Clinical Oncology (2010)

Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine.Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m(2) or 1,800 mg/m(2) divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling.Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m(2) capecitabine and 50 mg ridaforolimus/1,800 mg/m(2) capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for ≥ 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus.Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination.
Diphtheria among Alcoholic Urban Adults
Authors: James P. Harnisch, Evelyn Tronca, Charles M. Nolan, Marvin Turck, King K. Holmes
Journal: Annals of Internal Medicine (1989)

Three outbreaks of Corynebacterium diphtheriae infection occurred in Seattle's Skid Road from 1972 through 1982. The first involved a single toxigenic, intermedius biotype clone, whereas the second and third outbreaks involved nontoxigenic mitis and gravis strains. Of 1100 total infections, 947 (86%) were cutaneous. The incidence was highest in winter and spring. In Skid Road, the estimated attack rate during 17 months in 1974 to 1975 was 5% for whites and 27% for native Americans. Streptococcus pyogenes was isolated from 73% of diphtheritic and 41% of nondiphtheritic skin lesions (P less than 0.001). Skin infection and environmental contamination by C. diphtheriae were correlated. Complications occurred in 21% of symptomatic nasopharyngeal and 3% of cutaneous toxigenic intermedius infections (P less than 0.001), and were significantly correlated with ages 60 years or more. Preferential use of erythromycin for diphtheria and pyodermas preceded plasmid-mediated resistance to erythromycin in C. diphtheriae. Diphtheria outbreaks in urban alcoholic persons are associated with poor hygiene, crowding, season, contaminated fomites, underlying skin disease, hyperendemic streptococcal pyoderma, and introduction of new strains from exogenous reservoirs.
Disability: Societal Responses to Difference and Interdisciplinary Interventions by Bioethicists
Authors: Sandra Anderson Garcia
Journal: The American Journal of Bioethics (2001)

(2001). Disability: Societal Responses to Difference and Interdisciplinary Interventions by Bioethicists. The American Journal of Bioethics: Vol. 1, No. 3, pp. 62-63.
Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria.
Authors: M Marre, H Leblanc, L Suarez, T T Guyenne, J Menard, P Passa
Journal: BMJ (1987)

The effects of a long term reduction in blood pressure on the kidney function of normotensive diabetic patients who had persistent microalbuminuria (30-300 mg albumin/24 hours) were studied in two groups of 10 such patients before and during six months of treatment with either 20 mg enalapril or placebo daily. Treatments were assigned randomly in a double blind fashion. Before treatment both groups had similar clinical characteristics, weight, diet, total glycosylated haemoglobin, median albumin excretion rate (enalapril group 124 mg/24 h, placebo group 81 mg/24 h), and mean arterial pressure (enalapril group 100 (SD 8) mm Hg, placebo group 99 (6) mm Hg). During treatment weight, urinary urea excretion, and total glycosylated haemoglobin remained unchanged. The mean arterial pressure decreased in the enalapril group but not in the placebo group (enalapril group 90 (10) mm Hg, placebo group 98 (8) mm Hg). The median albumin excretion rate also fell in the enalapril group but not in the placebo group (enalapril group 37 mg/24 h, placebo group 183 mg/24 h.) The glomerular filtration rate rose in the enalapril group from 130 (23) ml/min/1.73 m2 to 141 (24) ml/min/1.73 m2, and total renal resistances and fractional albumin clearance decreased while fractional albumin clearance increased in the placebo group. These results show that in patients who have diabetes but not hypertension a reduction in blood pressure by inhibition of converting enzyme for six months can reduce persistent microalbuminuria, perhaps by decreasing the intraglomerular pressure.
Emergency Revascularization-Reply
Authors: Steven J. Phillips
Journal: JAMA (1983)

<h3>In Reply.—</h3> From 1975, until the advent of streptokinase and percutaneous transluminal coronary angioplasty, our only means for coronary reperfusion during evolving MI was direct revascularization. Since the advent of streptokinase and percutaneous transluminal coronary angioplasty, alternate means have become available. If these alternate means are successful—and in our experience they have been in a large percentage of the cases—then we see no need to invade the patients surgically, as suggested by Dr Reid in his letter. We also state unequivocally in our manuscript that if adequate reperfusion by nonsurgical means is unsuccessful (single-vessel disease) with streptokinase alone or combined with percutaneous transluminal coronary angioplasty, then immediate surgery is carried out. We certainly agree with Dr Reid that single coronary artery occlusion can be catastrophically fatal, and either our article did not state it strongly enough or he misread the fact that reperfusion is our therapeutic end point and goal.
Arnold Cecil Houghton
Authors: G. Houghton
Journal: BMJ (2003)

Former general practitioner Birmingham (b Birmingham 1913; q Birmingham 1936; OBE, TD), d 30 June 2003.

Known to his family as Mick and as Tim to his wife and friends, he went into partnership in Hall Green, Birmingham, in 1938 with his father. At the outbreak of the second world war, he joined the Royal Army Medical Corps and served in north Africa, Italy, Normandy, and Norway. He was mentioned in dispatches. His wife, Enid, became his GP partner from 1958 to 1975. He sat on various medical committees and was active in the BMA, being first elected a member of BMA Council in 1966 and later being made a BMA fellow. Predeceased by Enid, he leaves three children.
Symptoms of Sensory Neuropathy in Adults with NIDDM in the U.S. Population
Authors: Maureen Harris, Richard Eastman, Catherine Cowie
Journal: Diabetes Care (1993)

OBJECTIVE To ascertain the prevalence and determinants of sensory neuropathy symptoms through structured interview of a representative sample of people with diabetes in the U.S. population. RESEARCH DESIGN AND METHODS The 1989 National Health Interview Survey consisted of a representative sample of 84,572 persons in the U.S. ≥ 18 yr of age. A household respondent identified all people in the household believed to have diabetes (n = 2829). Subjects who could not be personally interviewed (n = 129) and individuals who stated they did not have diabetes (n = 295) were excluded. A detailed questionnaire was administered to 99.3% of the remaining 2405 subjects. Questions on symptoms of sensory neuropathy included whether during the past 3 mo the subjects had experienced numbness or loss of feeling, pain or tingling, or decreased ability to feel hot or cold. The neuropathy questions were also administered to a representative sample of 20,037 subjects who were not known to have diabetes. RESULTS Prevalence of symptoms of sensory neuropathy was 30.2% among people with IDDM. This prevalence was 36.0% for men with NIDDM and 39.8% for women with NIDDM, compared with 9.8 and 11.8% for nondiabetic men and women, respectively. In logistic regression, factors independently related to symptoms of sensory neuropathy in people with NIDDM included duration of diabetes, hypertension, hyperglycemia, and glycosuria. Long duration of NIDDM (&amp;gt;20 yr) was associated with a twofold increased risk of symptoms of sensory neuropathy compared with those with 0-4 yr of diabetes. Hypertension was associated with a 60% higher likelihood of symptoms. Diabetic individuals whose blood glucose was high all or most of the time or whose urine tests showed glucose all of the time were &amp;gt; 2 times as likely to have symptoms of sensory neuropathy than those who did not report hyperglycemia or glycosuria. Age, sex, ethnicity, cigarette smoking, and height were not determinants of sensory neuropathy. CONCLUSIONS Symptoms of sensory neuropathy affect 30–40% of diabetic patients in the U.S. Men and women are affected equally. Prevalence of these symptoms increases with longer duration of diabetes; hypertension and hyperglycemia predispose to symptoms of sensory neuropathy.
Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development
Authors: Jared R Mayers, Chen Wu, Clary B Clish, Peter Kraft, Margaret E Torrence, Brian P Fiske, Chen Yuan, Ying Bao, Mary K Townsend, Shelley S Tworoger, Shawn M Davidson, Thales Papagiannakopoulos, Annan Yang, Talya L Dayton, Shuji Ogino, Meir J Stampfer, Edward L Giovannucci, Zhi Rong Qian, Douglas A Rubinson, Jing Ma, Howard D Sesso, John M Gaziano, Barbara B Cochrane, Simin Liu, Jean Wactawski-Wende, JoAnn E Manson, Michael N Pollak, Alec C Kimmelman, Amanda Souza, Kerry Pierce, Thomas J Wang, Robert E Gerszten, Charles S Fuchs, Matthew G Vander Heiden, Brian M Wolpin
Journal: Nature Medicine (2014)
Impact of immune modulation with anti–T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies
Authors: Robert J. Soiffer, Jennifer LeRademacher, Vincent Ho, Fangyu Kan, Andrew Artz, Richard E. Champlin, Steven Devine, Luis Isola, Hillard M. Lazarus, David I. Marks, David L. Porter, Edmund K. Waller, Mary M. Horowitz, Mary Eapen
Journal: Blood (2011)
Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family
Authors: H. Michael Shepard, Cathleen M. Brdlik, Hans Schreiber
Journal: Journal of Clinical Investigation (2008)

The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family–targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences.
Abstract 2274: The association of preoperative serum level of lipocalin2 with breast cancer prognosis
Authors: Hyuna Sung, Sang-Ah Lee, Kyoung-Mu Lee, Ji-Young Lee, Jungmin Oh, Yunhee Lee, Lian Li, Sue K. Park, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Daehee Kang
Journal: Cancer Research (2011)

Abstract Purpose: The association between the expression level of lipocalin2 with cancer progression has already been reported in several tumors such as lung, colon, and breast cancer. However, no previous study has examined the relationship between the circulating level of lipocalin2 and its effect on the prognosis of breast cancer. Thus, this study aimed at assessing whether the preoperative serum level of lipocalin2 is related to the risk of recurrence and death in patients who have undergone curative surgical treatment for breast cancer. Design: A total of 370 histologically proven breast cancer patients who had undergone curative resections of the tumor between Mar 2004 and Jan 2007 were included in this study. The median follow-up time of survivors was 4.35 years. The preoperative serum level of lipocalin2 was assayed by using enzyme-linked immunosorbent assay. Disease-free survival was defined as the time from surgery to the date of the first locoregional recurrence, first distant metastasis, or death from any cause. Univariate survival analysis was performed using the Kaplan-Meier method, and log-rank tests were employed for comparison of survival curves. Multivariate analyses were conducted using Cox's proportional hazard regression model adjusted for age, tumor size, lymph node metastasis, hormone receptor status, adjuvant chemotherapy and hormone therapy. Results: The Kaplan-Meier curve showed that patients with upper three-quarters of lipocalin2 concentration combined had lower survival rates than the patients with lowest quarter concentration (P=0.014). In multivariate analysis, lipocalin2 remained an independent prognostic marker for disease-free survival after adjusting for known prognostic factors. The hazard ratio comparing the uppermost quartile to the lowest quartile of lipocalin2 was 2.33 (95% confidence interval, 1.19-4.56; P=0.015). Conclusions: The results revealed that patients with higher level of lipocalin2 showed significantly lower disease-free survival than patients with lower level. Our study suggests that the higher preoperative level of lipocalin2 may be closely linked to poor prognosis in breast cancer. Further validation is required and functional studies are warranted to elucidate the underlying biological mechanisms for the association. Key words: Lipocalin2 (LCN), serum biomarker, breast cancer, prognosis Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2274. doi:10.1158/1538-7445.AM2011-2274
IgM anti-HBc in anti-HBe positive chronic type B hepatitis with acute exacerbations
Authors: Kazuhiko Koike, Shiro Iino, Kiyohiko Kurai, Keiji Mitamura, Yasuo Endo, Hiroshi Oka
Journal: Hepatology (1987)

IgM anti-HBc was measured by radioimmunoassay in serially collected serum samples during 20 acute exacerbations which developed in 14 patients with anti-HBe positive chronic type B hepatitis. IgM anti-HBc became positive in 12 of the 14 (86%) patients and in 18 of the 20 (90%) exacerbations, and elevation of IgM anti-HBc which was believed to be significant was also observed in the remaining two patients. In most of the patients who also had determinations of serum hepatitis B virus DNA, the hepatitis B virus DNA became positive. These results suggest that ALT elevation in anti-HBe positive chronic type B hepatitis is associated with active replication of hepatitis B virus. It is considered to be useful to measure IgM anti-HBc for the purpose of identifying the causes of ALT elevation in anti-HBe positive chronic type B hepatitis.
<i>Helicobacter pylori</i>Infection and the Development of Gastric Cancer
Authors: Naomi Uemura, Shiro Okamoto, Soichiro Yamamoto, Nobutoshi Matsumura, Shuji Yamaguchi, Michio Yamakido, Kiyomi Taniyama, Naomi Sasaki, Ronald J. Schlemper
Journal: New England Journal of Medicine (2001)

Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain.
Noninvasive Ventilation for Treatment of Acute Respiratory Failure in Patients Undergoing Solid Organ Transplantation
Authors: Massimo Antonelli, Giorgio Conti, Maurizio Bufi, Maria Gabriella Costa, Angela Lappa, Monica Rocco, Alessandro Gasparetto, Gianfranco Umberto Meduri
Journal: JAMA (2000)

Noninvasive ventilation (NIV) has been associated with lower rates of endotracheal intubation in populations of patients with acute respiratory failure.To compare NIV with standard treatment using supplemental oxygen administration to avoid endotracheal intubation in recipients of solid organ transplantation with acute hypoxemic respiratory failure.Prospective randomized study conducted at a 14-bed, general intensive care unit of a university hospital.Of 238 patients who underwent solid organ transplantation from December 1995 to October 1997, 51 were treated for acute respiratory failure. Of these, 40 were eligible and 20 were randomized to each group.Noninvasive ventilation vs standard treatment with supplemental oxygen administration.The need for endotracheal intubation and mechanical ventilation at any time during the study, complications not present on admission, duration of ventilatory assistance, length of hospital stay, and intensive care unit mortality.The 2 groups were similar at study entry. Within the first hour of treatment, 14 patients (70%) in the NIV group, and 5 patients (25%) in the standard treatment group improved their ratio of the PaO2 to the fraction of inspired oxygen (FIO2). Over time, a sustained improvement in PaO2 to FIO2 was noted in 12 patients (60%) in the NIV group, and in 5 patients (25%) randomized to standard treatment (P = .03). The use of NIV was associated with a significant reduction in the rate of endotracheal intubation (20% vs 70%; P = .002), rate of fatal complications (20% vs 50%; P = .05), length of stay in the intensive care unit by survivors (mean [SD] days, 5.5 [3] vs 9 [4]; P = .03), and intensive care unit mortality (20% vs 50%; P = .05). Hospital mortality did not differ.These results indicate that transplantation programs should consider NIV in the treatment of selected recipients of transplantation with acute respiratory failure.
Allergic eosinophilic gastroenteritis (AEG) with protein-losing enteropathy (PLE): Intestinal pathological characteristics and long-term clinical follow-up
Authors: M. Chehade, S. Mofidi, M.S. Magid, A. Nowak-Wegrzyn, S.H. Sicherer, H.A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2005)
Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.
Authors: P W Stacpoole, H J Harwood, C E Varnado
Journal: Journal of Clinical Investigation (1983)

Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H2O incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (Ki 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (Ki 1.2 mM) and NADPH (Ki 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (Ki 5.6 mM). Monochloroacetate, glycollate, and ethylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.
A tale of two Germanys: Health problems in eastern Germany are clearly related to transition
Authors: Friedrich Wilhelm Schwartz, Kurt Buser
Journal: BMJ (2005)

A tale of two Germanys Health problems in eastern Germany are clearly related to transitionEditor-The fall of the Berlin Wall in 1989 marked the beginning of the end of communism in eastern Europe and in eastern Germany.As McKee and Fister point out, 1 certain constellations of epidemiological and demographic variables characterise the resultant process of political and economic transition: low or even decreasing life expectancy (especially for men) and higher prevalences of alcoholism and obesity.This has happened in the postcommunist Länder (federal states) of eastern Germany.East Germany is different from other east European countries in that its healthcare sector was not deconstructed, with periods of severe dysfunction: it simply adopted the healthcare system of West Germany.Despite this, life expectancy at birth is still lower in eastern Germany than in western Germany, although the difference had diminished at the end of the 1990s. 2 Alcoholic disease is a feature of the typical transition process.The number of people discharged from hospital with alcoholic disease was higher in eastern Germany in 1994 and 1999 than in western Germany. 3 Obesity is another transition related problem and a risk factor for many diseases. 4 The proportion of the population with obesity (body mass index > 29.9) is higher in eastern Germany than in western Germany.This difference has remained for over 10 years after the fall of the Berlin Wall.In the medium term, the situation is set to even out.But it is remarkable that in spite of the same, well equipped (curative) health system, health care does not strongly modify mainly lifestyle linked health effects in a population that is exposed to transition after communism.For eastern Germany, the end of this transition process is in sight.
ATHEROSCLEROSIS IS COMMON IN ANCIENT HUMANS: RESULTS OF THE HORUS STUDY OF ANCIENT EGYPTIAN MUMMIES
Authors: Gregory S. Thomas, Adel H. Allam, Randall C. Thompson, Abdelhalim Nureldin, Gomaa Abdel-maksoud, Ibrahem Badr, Muhammad Al-Tohamy Soliman, Hany Abdel Rahman Amer, M Linda Sutherland, James Sutherland, Michael I. Miyamoto, L Samuel Wann
Journal: Journal of the American College of Cardiology (2011)