tbuckley/cabot-search huggingface dataset:
Arbitrary-Pressure Continuous Positive Airway Pressure for Obstructive Sleep Apnea Syndrome
Authors: Craig A. Hukins
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Current resources are inadequate to meet the demand for polysomnography, resulting in long waiting lists. This study aimed to evaluate the role of arbitrary-pressure continuous positive airway pressure (CPAP) as a method to reduce delays in commencing treatment. The study was of an open, randomized, parallel design. Ninety-one subjects with obstructive sleep apnea syndrome were randomized to either arbitrary-pressure CPAP based on body mass index before treatment polysomnography or to CPAP at settings determined by polysomnography. Both interventions resulted in similar improvements in clinical outcomes as determined by Epworth Sleepiness Score, Short Form-36 Quality of Life questionnaire, objective compliance, and subjective attitudes to treatment. There was higher sleep efficiency at treatment polysomnography in the group commenced at arbitrary pressure (81.8 +/- 10.1% [mean +/- SD] compared with 72.2 +/- 18.0%, p = 0.01). Subjects unable to tolerate CPAP were identified by the use of arbitrary pressure, leading to a reduction in the proportion of "wasted" treatment polysomnograms (studies performed in subjects not persisting with treatment) relative to commencing therapy after treatment polysomnography (3 of 39 compared with 12 of 35, p = 0.01). This approach to initiating treatment with CPAP appears feasible when there are long waiting lists for polysomnography.
Aspirin Intake and Survival After Breast Cancer
Authors: Michelle D. Holmes, Wendy Y. Chen, Lisa Li, Ellen Hertzmark, Donna Spiegelman, Susan E. Hankinson
Journal: Journal of Clinical Oncology (2010)

Animal and in vitro studies suggest that aspirin may inhibit breast cancer metastasis. We studied whether aspirin use among women with breast cancer decreased their risk of death from breast cancer.This was a prospective observational study based on responses from 4,164 female registered nurses in the Nurses' Health Study who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 and were observed until death or June 2006, whichever came first. The main outcome was breast cancer mortality risk according to number of days per week of aspirin use (0, 1, 2 to 5, or 6 to 7 days) first assessed at least 12 months after diagnosis and updated.There were 341 breast cancer deaths. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks (RRs) for 1, 2 to 5, and 6 to 7 days of aspirin use per week compared with no use were 1.07 (95% CI, 0.70 to 1.63), 0.29 (95% CI, 0.16 to 0.52), and 0.36 (95% CI, 0.24 to 0.54), respectively (test for linear trend, P < .001). This association did not differ appreciably by stage, menopausal status, body mass index, or estrogen receptor status. Results were similar for distant recurrence. The adjusted RRs were 0.91 (95% CI, 0.62 to 1.33), 0.40 (95% CI, 0.24 to 0.65), and 0.57 (95% CI, 0.39 to 0.82; test for trend, P = .03) for 1, 2 to 5, and 6 to 7 days of aspirin use, respectively.Among women living at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death.
We need better data on smoking in pregnancy
Authors: Carmel O’Gorman
Journal: BMJ (2008)

My work as a smoking cessation midwife involved me directly with the initial national target to reduce smoking in pregnancy from 23% in 1995 to 18% by 2005 and now to 15% by 2010. An additional requirement is to reduce the rate of mothers who are smoking at delivery by 1% year on year, specifically focusing on disadvantaged women to tackle inequalities in infant mortality. There is considerable pressure to meet this target, which the Healthcare Commission is monitoring. Reducing smoking in pregnancy is also a health objective for Sure Start Children’s Centres.

The 1% annual target was set centrally but has not been discussed with key stakeholders involved in its implementation. These stakeholders are now concerned by how realistic the target is and whether it is achievable within the required time scale. How was the target derived? Why has good practice guidance not been issued in support? Each primary care trust has a plan specifying how it intends to decrease the percentage of mothers who are smoking at delivery year on year and this is how their performance is managed. However, there are concerns about the quality of current smoking data, making it difficult to set local targets and baselines and to monitor progress.

Reducing inequalities is proving challenging; the latest infant feeding survey shows marked variations in smoking in pregnancy by mother’s socioeconomic …
Role of newly synthesized cholesterol or its metabolites on the regulation of bile acid biosynthesis after short-term biliary diversion in the rat
Authors: Reno Z. Vlahcevic, William M. Pandak, Philip B. Hylemon, Douglas M. Heuman
Journal: Hepatology (1993)

Cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the bile acid biosynthetic pathway, is thought to be regulated by hydrophobic bile acids through negative feedback control. The role of cholesterol in the regulation of cholesterol 7 alpha-hydroxylase is more controversial, in part because of incomplete understanding of the relationship between the pathways of cholesterol synthesis and degradation. The main objective of this study was to define the interaction between these two pathways in an experimental model in which the supply of newly synthesized cholesterol was interrupted by sustained infusion of mevinolin (lovastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) or accelerated by a continuous infusion of mevalonate, a cholesterol precursor. The study was carried out in rats subjected to short-term bile fistula. In one set of experiments, rats were treated postoperatively with mevinolin (5 mg/kg loading dose followed by 2 mg/kg/hr infusion), mevalonate (180 mumol/hr infusion) or both for up to 96 hr. In a separate set of experiments, rats were infused intraduodenally with taurocholate (36 mumol/100 gm/hr for up to 96 hr). We determined cholesterol 7 alpha-hydroxylase- and HMG-CoA reductase specific activities at those time intervals, whereas bile acid synthesis rates were determined throughout the study. Compared with rats not subjected to surgery, rats with short-term biliary diversion had increases in cholesterol 7 alpha-hydroxylase activity of 259% and 827% at 48 and 96 hr, respectively. The increase in bile acid biosynthesis was less pronounced. Continuous infusion of mevinolin completely prevented increases in cholesterol 7 alpha-hydroxylase specific activity and bile acid biosynthesis at both time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
Epidermal Growth Factor Receptor Signaling Synergizes with Hedgehog/GLI in Oncogenic Transformation via Activation of the MEK/ERK/JUN Pathway
Authors: Harald Schnidar, Markus Eberl, Stefan Klingler, Doris Mangelberger, Maria Kasper, Cornelia Hauser-Kronberger, Gerhard Regl, Renate Kroismayr, Richard Moriggl, Maria Sibilia, Fritz Aberger
Journal: Cancer Research (2009)

Abstract Persistent activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of a number of human cancers. The GLI zinc finger transcription factors act at the end of the HH signaling cascade to control gene expression, and recent studies have shown that the activity of GLI proteins can be additionally modified by integration of distinct signals, such as the MEK/extracellular signal-regulated kinase (ERK) and phosphinositide-3 kinase (PI3K)/AKT pathway. However, little is known about the identity of the upstream activators of these HH/GLI interacting signaling pathways in cancer. Here, we provide evidence that integration of the HH/GLI and epidermal growth factor receptor (EGFR) pathway synergistically induces oncogenic transformation, which depends on EGFR-mediated activation of the RAS/RAF/MEK/ERK but not of the PI3K/AKT pathway. EGFR/MEK/ERK signaling induces JUN/activator protein 1 activation, which is essential for oncogenic transformation, in combination with the GLI activator forms GLI1 and GLI2. Furthermore, pharmacologic inhibition of EGFR and HH/GLI efficiently reduces growth of basal cell carcinoma (BCC) cell lines derived from mice with activated HH/GLI signaling. The results identify the synergistic integration of GLI activator function and EGFR signaling as a critical step in oncogenic transformation and provide a molecular basis for therapeutic opportunities relying on combined inhibition of the HH/GLI and EGFR/MEK/ERK/JUN pathway in BCC. [Cancer Res 2009;69(4):1284–92]
Geographic Analysis of Disease and Care
Authors: Melinda S. Meade
Journal: Annual Review of Public Health (1986)

The importance to health of customs of diet, dress, types of settlement and housing and of physical environmental factors such as climate, vegetation, altitude, and topography have been widely recognized since the time of Hippo­ crates' Airs, Waters, and Places. Geographical variation has been studied as geographic pathology, medical ecology, medical topography, geographical epidemiology, geomedicine, and other rubrics, but only in the past 30 years has the discipline of geography itself applied its perspective and methodology to the study of health, disease, and care. After presenting an introduction to the field, I address some of the major geographic questions as they apply to medical geography and offer an explanation and critique of the methodology and theory currently being used to answer them.
Air pollution and daily mortality in three U.S. counties.
Authors: S H Moolgavkar
Journal: Environmental Health Perspectives (2000)

I used generalized additive models to analyze the time-series of daily total nonaccidental and cause-specific (cardiovascular, cerebrovascular, and chronic obstructive pulmonary disease) deaths over the period 1987-1995 in three major U.S. metropolitan areas: Cook County, Los Angeles County, and Maricopa County. In all three counties I had monitoring information on particulate matter [less than/equal to] 10 microm (PM(10)), carbon monoxide, sulfur dioxide, nitrogen dioxide, and ozone. In Los Angeles, monitoring information on particulate matter [less than/equal to] 2.5 microm (PM(2.5)) was available as well. I present the results of both single and multi-pollutant analyses. Air pollution was associated with each of the mortality end points. With respect to the individual components of the pollution mix, the results indicate considerable heterogeneity of air pollution effects in the different geographic locations. In general, the gases, particularly CO, but not ozone, were much more strongly associated with mortality than was particulate matter. This association was particularly striking in Los Angeles County.
Cystic fibrosis and survival to 40 years: a case-control study
Authors: N.J. Simmonds, S.J. MacNeill, P. Cullinan, M.E. Hodson
Journal: European Respiratory Journal (2010)

The clinical course of patients with cystic fibrosis (CF) is variable and probably determined by many interacting factors. We aimed to examine the influence of early social and clinical factors on long-term survival. A case–control study of adult CF patients was used to compare long-term survivors (aged ≥40 yrs) with patients who died before reaching 30 yrs of age. Each case (n = 78) was matched by birth date with at least one control (n = 152), after exclusion of “late diagnosis” patients. Probability-weighted logistic regression models were used to identify influences on survival. Factors resulting in increased probabilities of survival included high body mass index (OR 1.76, 95% CI 1.40–2.22), forced expiratory volume in 1 s (OR per 5% increase 1.54, 95% CI 1.32–1.80), and forced vital capacity (OR per 5% increase 1.54, 95% CI 1.33–1.78) at transfer to the adult clinic and the exclusive use of oral antibiotics (OR 8.31, 95% CI 3.02–22.88). Factors resulting in decreased probabilities of survival were Pseudomonas aeruginosa acquisition (OR 0.18, 95% 0.05–0.65) or pneumothorax before transfer to the adult clinic (OR 0.02, 95% CI 0.004–0.08) and referral from a paediatric clinic in a deprived area (OR 0.13, 95% CI 0.04–0.38). Long-term survival is associated with the clinical features present by the time of referral to an adult clinic. Even “early-diagnosis” disease appears to have different phenotypes, possibly independent of CF gene function, that have different survival patterns.
Pharmacokinetically Stabilized Cystine Knot Peptides That Bind Alpha-v-Beta-6 Integrin with Single-Digit Nanomolar Affinities for Detection of Pancreatic Cancer
Authors: Richard H. Kimura, Robert Teed, Benjamin J. Hackel, Marybeth A. Pysz, Courtney Z. Chuang, Ataya Sathirachinda, Jürgen K. Willmann, Sanjiv S. Gambhir
Journal: Clinical Cancer Research (2011)

Purpose: Detection of pancreatic cancer remains a high priority and effective diagnostic tools are needed for clinical applications. Many cancer cells overexpress integrin αvβ6, a cell surface receptor being evaluated as a novel clinical biomarker.Experimental Design: To validate this molecular target, several highly stable cystine knot peptides were engineered by directed evolution to bind specifically and with high affinity (3–6 nmol/L) to integrin αvβ6. The binders do not cross-react with related integrin αvβ5, integrin α5β1, or tumor-angiogenesis–associated integrin, αvβ3.Results: Positron emission tomography showed that these disulfide-stabilized peptides rapidly accumulate at tumors expressing integrin αvβ6. Clinically relevant tumor-to-muscle ratios of 7.7 ± 2.4 to 11.3 ± 3.0 were achieved within 1 hour after radiotracer injection. Minimization of off-target dosing was achieved by reformatting αvβ6-binding activities across various natural and pharmacokinetically stabilized cystine knot scaffolds with different amino acid content. We show that the primary sequence of a peptide scaffold directs its pharmacokinetics. Scaffolds with high arginine or glutamic acid content suffered high renal retention of more than 75% injected dose per gram (%ID/g). Substitution of these amino acids with renally cleared amino acids, notably serine, led to significant decreases in renal accumulation of less than 20%ID/g 1 hour postinjection (P < 0.05, n = 3).Conclusions: We have engineered highly stable cystine knot peptides with potent and specific integrin αvβ6-binding activities for cancer detection. Pharmacokinetic engineering of scaffold primary sequence led to significant decreases in off-target radiotracer accumulation. Optimization of binding affinity, specificity, stability, and pharmacokinetics will facilitate translation of cystine knots for cancer molecular imaging. Clin Cancer Res; 18(3); 839–49. ©2011 AACR.
Isolation of tryptic fragment of antigen from mitochondrial inner membrane proteins reacting with antimitochondrial antibody in sera of patients with primary biliary cirrhosis
Authors: Daisaku Muno, Eiki Kominami, Hideo Ishii, Koh Usui, Koji Saifuku, Yuji Sakakibara, Toshihiko Namihisa
Journal: Hepatology (1990)

Most of the sera from patients with primary biliary cirrhosis contains antimitochondrial antibodies, which react with four proteins of the mitochondrial inner membrane. We reported in a previous paper that when beef heart mitochondrial inner membrane proteins were digested by trypsin, a new reactive 36 kDa fragment with antimitochondrial antibody was obtained. This 36 kDa fragment derives from original 70 kDa protein because the monoclonal antibody specific to 70 kDa protein reacts with the 36 kDa band equivalent to 70 kDa band. The 36 kDa fragment was purified using an affinity column conjugated with an immunoglobulinrich fraction of primary biliary cirrhosis serum containing antimitochondrial antibody, preparative electrophoresis and high–performance liquid chromatography using a reverse phase column. The final preparation showed a single band in sodium dodecyl sulfate polyacrylamide gel electrophoresis. Its amino acid composition is in good agreement with that of the subunit binding domain of the pyruvate dehydrogenase complex E2 from bovine heart.
Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting.
Authors: G A Rooke, E O Feigl
Journal: Circulation Research (1982)

Neither stroke volume nor external cardiac work (the integral of pressure times flow during ejection) has been considered an important correlate of myocardial oxygen consumption. An initial set of experiments re-examined this question of independently varying heart rate, systolic blood pressure, and stroke volume in seven closed-chest, anesthetized dogs. This was achieved by cardiac pacing, a pressure control reservoir, phenylephrine infusion, and adjustment of arteriovenous shunts. Propranolol was used to minimize changes in contractility which might affect myocardial oxygen consumption. Stroke volume in the form of external work had a significant effect on oxygen consumption. From these results, a new pressure-work index of myocardial oxygen consumption was devised, and fitting parameters for the following indexes were determined: systolic pressure-rate product, estimated wall tension, external left ventricular work, triple product, mean pressure-rate product, Et (Bretschneider), and tension-time index. These indexes were prospectively applied to a second set of experiments in 11 closed-chest, anesthetized dogs given norepinephrine, isoproterenol, dobutamine, Nembutal, and propranolol to alter myocardial contractility. Inotropic oxygen wasting was observed with the tension-time, mean pressure-rate, triple product, and estimated wall tension indexes, but not with the pressure-work or systolic pressure-rate indexes. It is concluded that stroke work is an important correlate of myocardial oxygen consumption, and that the pressure-work of systolic pressure-rate indexes can account for catecholamine-induced, changes in myocardial oxygen consumption without postulating an oxygen-wasting effect.
B Cell–attracting Chemokine 1, a Human CXC Chemokine Expressed in Lymphoid Tissues, Selectively Attracts B Lymphocytes via BLR1/CXCR5
Authors: Daniel F. Legler, Marcel Loetscher, Regula Stuber Roos, Ian Clark-Lewis, Marco Baggiolini, Bernhard Moser
Journal: The Journal of Experimental Medicine (1998)

Although most leukocytes, T lymphocytes in particular, respond to several different chemokines, there is virtually no information on chemokine activities and chemokine receptors in B lymphocytes. A putative chemokine receptor, BLR1, that is expressed in Burkitt's lymphoma cells and B lymphocytes was cloned a few years ago. Deletion of the gene for BLR1 yielded mice with abnormal primary follicles and germinal centers of the spleen and Peyer's patches, reflecting the inability of B lymphocytes to migrate into B cell areas. By screening expressed sequence tag DNA sequences, we have identified a CXC chemokine, termed B cell–attracting chemokine 1 (BCA-1), that is chemotactic for human B lymphocytes. BCA-1 cDNA encodes a protein of 109 amino acids with a leader sequence of 22 residues. The mature protein shares 23–34% identical amino acids with known CXC chemokines and is constitutively expressed in secondary lymphoid organs. BCA-1 was chemically synthesized and tested for activity on murine pre–B cells 300-19 transfected with BLR1 and on human blood B lymphocytes. In transfected cells, BCA-1 induced chemotaxis and Ca2+ mobilization demonstrating that it acts via BLR1. Under the same conditions, no activity was obtained with 10 CXC and 19 CC chemokines, lymphotactin, neurotactin/fractalkine and several other peptide ligands. BCA-1 was also a highly effective attractant for human blood B lymphocytes (which express BLR1), but was inactive on freshly isolated or IL-2–stimulated T lymphocytes, monocytes, and neutrophils. In agreement with the nomenclature rules for chemokine receptors, we propose the term CXCR5 for BLR1. Together with the observed disturbance of B cell colonization in BLR1/ CXCR5-deficient mice, the present results indicate that chemotactic recruitment by locally produced BCA-1 is important for the development of B cell areas of secondary lymphoid tissues.
Synergy Between VEGF/VEGFR Inhibitors and Chemotherapy Agents in the Phase I Clinic
Authors: Chad Tang, Kenneth Hess, Denis Leonardo F. Jardim, Debora De Melo Gagliato, Apostolia M. Tsimberidou, Gerald Falchook, Siqing Fu, Filip Janku, Aung Naing, Sarina Piha-Paul, Vivek Subbiah, Jennifer Wheler, Ralph G. Zinner, Razelle Kurzrock, Lee M. Ellis, Funda Meric-Berstam, David S. Hong
Journal: Clinical Cancer Research (2014)

We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies.Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥ 6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors.All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5-2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1-2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3-0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5-4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1-0.3), Pinteraction = 0.004].VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class.
Interaction of E-cadherin and PTEN Regulates Morphogenesis and Growth Arrest in Human Mammary Epithelial Cells
Authors: Marcia V. Fournier, Jimmie E. Fata, Katherine J. Martin, Paul Yaswen, Mina J. Bissell
Journal: Cancer Research (2009)

Abstract Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a dual-function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two nonmalignant human mammary epithelial cell lines that form polarized, growth-arrested structures (acini) when cultured in three-dimensional laminin-rich extracellular matrix gels (lrECM). As acini begin to form, PTEN accumulates both in the cytoplasm and at cell-cell contacts where it colocalizes with the E-cadherin/β-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function–blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in Skbr-3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in three-dimensional lrECM, indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus seems to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells. [Cancer Res 2009;69(10):4545–52]