tbuckley/cabot-search huggingface dataset:
Can gene expression signatures of signaling pathway activation inform rational selection of potentially targetable molecules in lung cancer
Authors: Esther Black, Matthew McConnell, Justin Balko
Journal: Clinical Cancer Research (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

A23 

In this new age of utilizing complex biomarkers as metrics for describing disease types or making therapeutic decisions, translating discoveries at the benchtop to efficacious therapies in the clinic remains an overwhelming obstacle. Cancer of any tissue type is still a heterogeneous disease when evaluated among affected individuals. Developing new therapeutics requires understanding of the disease process, particularly avenues that lead to therapies appropriate for the heterogeneity observed in the clinic. We hypothesize that by combining knowledge-driven and data-driven approaches in analyzing gene expression data new pathways and targets for lung cancer therapeutics can be rationally ascertained.    Lung adenocarcinomas frequently have genetic lesions affecting EGFR or K-ras. The consequence of either mutation may be deregulation of one or more downstream signaling cascades, namely MAPK, PI3K/AKT, and STAT pathways. This knowledge was utilized to develop gene expression signatures of activation of each pathway in airway epithelial cells. The gene expression signatures derived from each dataset were compared to the genes in signatures that describe K-ras activity or sensitivity to EGFR inhibitors in lung cancer cell lines to determine co-expression. The genes that were found to be in common among the individual signatures may be potential hubs for normal control of the activity of PI3K/AKT, MAPK and STAT signaling cascades.    To test genes for activity among signaling pathways, the list of commonly-deregulated genes was narrowed to candidate genes chosen fit two criteria: 1) enzymatic activity and 2) likely regulation of activity by gene expression or protein turnover but not post-translational modification. Published data from similar gene expression studies, but using different cell systems, was evaluated to determine if our candidates are system specific. Following this evaluation, phosphatases that were deregulated in the gene expression signatures of pathway activity arose as an interesting subset of activities across all systems evaluated. Of the phosphatases screened by probesets on the array, the dual specificity phosphatases (DUSP) became the focus of our efforts, specifically DUSP4/MKP2.    DUSP4 activity was characterized among lung cancer cell lines and airway epithelial cells. The expression, localization and substrates of DUSP4 suggest that this phosphatase may link the MAPK and AKT pathways which are both deregulated in EGFR and K-ras active lung cancers. Thus, our proof-of-concept exercise in combining knowledge-driven and data-driven approaches to select targets for novel lung cancer therapeutics may yield a reasonable target.
Prevalence of hepatitis C and hepatitis B infection in the HIV-infected population of France, 2004
Authors: C Larsen, G Pialoux, D Salmon, D Antona, Y Le Strat, L Piroth, S Pol, E Rosenthal, D Neau, C Semaille, E Delarocque Astagneau
Journal: Eurosurveillance (2008)

Our objective was to estimate the prevalence of HCV and HBV co-infection among HIV-infected adults in France and describe the epidemiological characteristics of co-infected patients and their clinical management. A one-day national cross-sectional survey was conducted in 2004. A random and proportional probability sample design was used, based on the number of AIDS cases reported since 1999 by hospital wards. Weighted estimations were computed. HIV-infected adults (out/in-patients) were included after consent. Data were collected on demographic criteria, HIV, HCV and HBV infections, as well as on antiviral therapies. Overall, 1849 HIV-infected patients were included. The prevalence of anti-HCV or HCV RNA positivity (HCV co-infection) was 24.3% [95% confidence interval (CI): 21.3-27.6] and varied from 3.1% in men who had sex with men to 92.8% in injecting drug users (IDUs). The prevalence of positive HCV RNA was 17.0% [95% CI:14.7-19.4]. The prevalence of HBs antigen (Ag) or HBV DNA positivity was 7.0% [95% CI: 5.9-8.1] and varied with the continent of birth from 2.1% in Northern Africa to 10.8% in sub-Saharan Africa. The prevalence of HIV-HCV-HBV co-infection was 1.6% [95% CI: 1.0-2.4], mostly IDUs (83.3%). A severe liver disease (cirrhosis or hepatocellular carcinoma) was diagnosed in 24.7% of the positive HCV RNA patients.This study confirmed the burden of HCV infection in French HIV-infected patients and described for the first time in France the epidemiological characteristics of HIV-HBV co-infection. Furthermore, it stresses the severity of liver disease related to HCV in HIV-infected population.
Abstract 3570: Common Mitochondrial Haplogroups Do Not Predict Risk of Ischemic Cardiovascular Disease, Mortality, or Longevity in the General Population
Authors: Marianne Benn, Marianne Schwartz, Børge G Nordestgaard, Anne Tybjćrg-Hansen
Journal: Circulation (2007)

Recently there have been numerous reports suggesting a role for mitochondrial haplogroups, defined by common polymorphisms in the mitochondrial genome, in the pathogenesis of common multifactorial disease such as ischemic cardiovascular disease, and in longevity. These studies have in common that they are all case-control studies with a very limited number of participants, and therefore are prone to selection bias and have very limited power. In the present study, we therefore tested the hypothesis that mitochondrial haplogroups predict risk of ischemic cardiovascular disease, mortality, and longevity in a large prospective study of a general population of Northern European descent. We genotyped 9,254 individuals from the Danish general population, The Copenhagen City Heart Study, for six polymorphisms (mt7028, mt10398, mt11719, mt12308, mt12612, mt15607) defining eight mitochondrial haplogroups, and determined the ability of these haplogroups to predict risk of ischemic cardiovascular disease, mortality, and longevity with, respectively, 25 and 11 years follow-up. Haplogroup frequencies were: H(45.9%), U(15.9%), T(9.9%), J(9.1), K(6.2%), V(4.5%), W/I(3.8%), and Z(3.5%). Multifactorially adjusted hazard ratios for hospitalization due to ischemic heart disease and ischemic cerebrovascular disease as a function of haplogroups were not significantly different from the most common haplogroup H. Furthermore, multifactorially adjusted hazard ratios for death of all causes as well as for major causes of death including ischemic cardiovascular disease as a function of haplogroups were also not significantly different from haplogroup H. Finally, on survival plots, longevity defined as percent surviving as a function of age by haplogroups did not differ when comparing each haplogroup with haplogroup H. In conclusion, in this large prospective study of a general population of Northern European descent mitochondrial haplogroups did not predict risk of ischemic cardiovascular disease, mortality, or longevity. Thus, our results suggest that mitochondrial haplogroups are not major predictors of ischemic cardiovascular disease, overall mortality, mortality from ischemic cardiovascular disease, or longevity in the general population.
Abstract 207: The Prevalence and Significance of Abnormal Vital Signs Prior to In-Hospital Cardiac Arrest
Authors: Won Young Kim, Lars W Andersen, Sharri Mortensen, Maureen Chase, Katherine Berg, Michael N Cocchi, Michael Donino
Journal: Circulation (2014)

Background: The association between vital sign abnormalities prior to cardiac arrest and outcome has not been previously reported. In this study we investigated the prevalence of abnormal vital signs prior to in-hospital cardiac arrest and the association with mortality Methods: We utilized the Get With the Guidelines - Resuscitation national registry to identify adult patients with an in-hospital cardiac arrest between 2007-2010. We included index events and excluded patients with missing data on vital signs within 1-4 hours prior to arrest. We evaluated the prevalence of abnormal vital signs classified as mild, moderate or severe (Table 1). We determined the association between the number of abnormal vital signs per patient and in-hospital mortality using multivariate logistic regression with adjustment for multiple potential confounders including patient demographics and co-morbid conditions. Results: A total of 9,560 patients were included. Median age was 71 (60 - 81) years, 42% were female and overall mortality was 77%. The prevalence of vital sign abnormalities is shown in Table 1. As illustrated in Figure 1 we found a step-wise increase in mortality with increasing number of abnormal vital signs that remained in multivariable analysis across all categories (Mild: adjusted OR 1.37 [CI: 1.27 - 1.48], Moderate: adjusted OR 1.53 [CI: 1.35 - 1.73] and Severe: adjusted OR 1.43 [CI: 1.21 - 1.70], all p-values &lt; 0.0001). Conclusion: Abnormal vital signs are common within four hours before cardiac arrest on in-hospital wards. Our study demonstrates incremental increases in mortality with both increasing number of pre-arrest abnormal vital signs as well as increased severity.
Activation of PERK and endoplasmic reticulum signaling in response to anoikis
Authors: Sharon J. Sequeira, Julio A. Aguirre-Ghiso
Journal: Cancer Research (2005)

5515  Tumor cells, unlike their normal counterpart, are capable of anchorage-independent growth, which results from their ability to circumvent death signals activated during suspension-induced cell death or ‘anoikis’. Signaling from the endoplasmic reticulum (ER) during ER-stress allows cells to decide between survival and apoptosis. However, whether the ER signaling machinery generates survival or apoptotic signals in response to adhesion signaling is still unclear. We decided to examine if the ER is capable of sensing loss of anchorage to a suitable substratum and its link to survival during anoikis. We monitored transcriptional activation of the promoter for CHOP/GADD153, a gene induced during ER-stress, in immortalized wild type (wt) and PERK -/- mouse embryo fibroblasts (MEFs) in adherent or suspended growth conditions. wtMEF cells transfected with a CHOP promoter driven-EGFP reporter plasmid, showed higher levels of EGFP expression than PERK -/- cells (p 2.5-fold in wt over PERK-/- cells within 24 hrs. Further, expression of a dominant negative PERK reduced CHOP activation in response to growth in suspension. Activation of PERK-CHOP signaling in suspended cells was dependent on p38SAPK signaling since co-transfection with dominant negative p38SAPK decreased CHOP activation in wtMEFS. Expression of GADD34, a phospho-eIF2α phosphatase, as well as eIF2αS51A, an eIF2α mutant which is not phosphorylated by PERK, inhibited CHOP-promoter activation in suspended wt cells, suggesting that activation of the CHOP promoter was dependent on PERK phosphorylation of eIF2α. We found that splicing of XBP-1 was not activated in response to suspension, suggesting that PERK but not IRE1α functions as a sensor of adhesion signals in the ER. Quantitation of cell viability by trypan blue staining of wt and PERK-/- MEFs revealed that while adherent PERK-/- and wt MEFs had similar and high viability (94.2 ±2.4% viable cells), when placed in suspension for 48hrs, CHOP-EGFP transfected PERK-/- cells were more susceptible (56.3 ±0.96%) to anoikis than CHOP-EGFP transfected wt cells (87.1 ±3.14%). Our preliminary results reveal a novel mechanism in which (i) the ER kinase PERK, is responsive to adhesion-dependent signals, (ii) suspension induces PERK activation and results in increased CHOP-promoter activity, (iii) these signals appear to be dependent on p38SAPK and eIF2α phosphorylation and, (iv) PERK appears to promote survival of cells grown for at least 72 hrs in suspension.
Air Pollution from Industrial Swine Operations and Blood Pressure of Neighboring Residents
Authors: Steve Wing, Rachel Avery Horton, Kathryn M. Rose
Journal: Environmental Health Perspectives (2012)

Industrial swine operations emit odorant chemicals including ammonia, hydrogen sulfide (H2S), and volatile organic compounds. Malodor and pollutant concentrations have been associated with self-reported stress and altered mood in prior studies.We conducted a repeated-measures study of air pollution, stress, and blood pressure in neighbors of swine operations.For approximately 2 weeks, 101 nonsmoking adult volunteers living near industrial swine operations in 16 neighborhoods in eastern North Carolina sat outdoors for 10 min twice daily at preselected times. Afterward, they reported levels of hog odor on a 9-point scale and measured their blood pressure twice using an automated oscillometric device. During the same 2- to 3-week period, we measured ambient levels of H2S and PM10 at a central location in each neighborhood. Associations between systolic and diastolic blood pressure (SBP and DBP, respectively) and pollutant measures were estimated using fixed-effects (conditional) linear regression with adjustment for time of day.PM10 showed little association with blood pressure. DBP [β (SE)] increased 0.23 (0.08) mmHg per unit of reported hog odor during the 10 min outdoors and 0.12 (0.08) mmHg per 1-ppb increase of H2S concentration in the same hour. SBP increased 0.10 (0.12) mmHg per odor unit and 0.29 (0.12) mmHg per 1-ppb increase of H2S in the same hour. Reported stress was strongly associated with BP; adjustment for stress reduced the odor-DBP association, but the H2S-SBP association changed little.Like noise and other repetitive environmental stressors, malodors may be associated with acute blood pressure increases that could contribute to development of chronic hypertension.
Elevation of thioridazine plasma levels by propranolol
Authors: J M Silver, S C Yudofsky, M Kogan, B L Katz
Journal: American Journal of Psychiatry (1986)

As part of a pilot study to assess the efficacy of propranolol in the treatment of aggression in psychiatric patients, drug interactions of propranolol with other agents were estimated by blood level monitoring. In the two patients taking a standard oral dose of thioridazine, the addition of propranolol caused a threefold and fivefold increase of plasma thioridazine levels, which placed them in a potentially toxic range. Although neither patient exhibited a toxic effect, these levels may be associated with an increased risk of thioridazine-induced irreversible pigmentary retinopathy, cardiac arrhythmias, and tardive dyskinesia. The authors suggest precautionary monitoring of thioridazine plasma and other relevant levels and clinical assessments when thioridazine and propranolol are used in combination.
Score Card Endoscopy: A Multicenter Study to Evaluate Learning Curves in 1-Week Courses Using the Erlangen Endo-Trainer
Authors: M Neumann, C Hahn, T Horbach, I Schneider, A Meining, W Heldwein, T Rösch, W Hohenberger
Journal: Endoscopy (2003)

The present study was carried out in the context of current discussions concerning ways in which simulation systems can be integrated sensibly and effectively into clinical educational structures, in order to shorten the training period for assistants and reduce potential risks for the patient. In our study, a number of centers used a standardized training approach, in 1 week courses, to investigate the learning curve improvement that can be achieved with a group of beginners in upper gastroduodenal endoscopy.The multicenter study used the Erlangen Endo-Trainer, with specially prepared biological specimens from pigs. Using this, the individual steps of diagnostic upper gastrointestinal endoscopy with biopsy can be carried out following a score-card system. After a theoretical introduction and a demonstration of the examination by an experienced endoscopist, an initial evaluation score for each participant was obtained on day 1. On the following days, the program consisted of 2 hours' training by a tutor, followed by a test run for each participant. On days 1, 2, 3, 4, and 5 the test run was directly followed by a self-assessment. In addition, on days 1, 3, and 5 the test run for each beginner was recorded on video, with each video assigned an encrypted code number. All the end of the study week, control assessments of these videos were carried out by an experienced endoscopist.Both the self-assessments and the control assessments showed significant improvements in the endoscopic parameters tested during the course (days 1-5; all parameters P < 0.001, Wilcoxon-test). However, it was found that the trainees tended to give themselves better marks than the marks given by experienced endoscopists.During 1 week of training, using the model and following the score card, a significant improvement in the learning curve was achieved in the beginners' group for the individual steps involved in diagnostic upper gastrointestinal endoscopy. When this approach is used with trainees who are also provided with the necessary theoretical background, this type of preparation may lead to a better, lower-risk start to supervised practical endoscopic examinations in patients.
Abstract P183: Physical Stress Does Not Increase Ventilation Rate during Resuscitation in a Manikin Model
Authors: Joar Eilevstjønn, Jon Nysæther, Helge Myklebust
Journal: Circulation (2008)

BACKGROUND: Studies indicate that trained medical personnel often deliver manual ventilations at excessive rates while performing advanced cardiac life support (ACLS). Excessive ventilation rates may contribute to increased mortality among these patients. We seek to uncover if physical stress affects our perception of ventilation rate. HYPOTHESIS: We hypothesized that physical stress would increase the ventilation rate during simulated cardiac arrest in a manikin model. METHOD: Six persons at Laerdal Medical were asked to ventilate an intubated manikin (Laerdal ResuciAnne PC SkillReporting system) for three minutes under two different conditions. For the first condition the participants were asked to perform strenuous physical exercise (running up and down a stairway for several minutes) immediately prior to ventilating the manikin. For the second condition all participants were allowed to rest before performing ventilations. Participants had to deliver ventilations at what they felt were 10 ventilations per minute (vpm). No clock or other time keeping means were available. Heart rate and breathing rate of the participants were measured using ECG and trans-thoracic impedance signals from a defibrillator (Philips HeartStart MRx). Statistics are derived using the average rate values from each participant. RESULTS: The participants did not ventilate faster after physical stress (Mean rate =7.00 vpm, SD =1.94) than during the condition at rest (Mean rate =7.14 vpm, SD =1.10; t (5) =−0.20, 95% CI of mean difference −1.83, 1.57; Cohen’s d =0.085; p =0.85). On the average, no participants ventilated faster than the recommended rate of 10–12 vpm during any condition. Both the participants’ heart rate and respiration rate were significantly different during the two conditions; mean (SD) heart rate 112 (10.7) vs. 82 (5.3) bpm (p=0.002), mean (SD) respiration rate 21.2 (5.98) vs. 14.5 (3.44) breaths per minute (p=0.010). CONCLUSIONS: Ventilation rates do not seem to be elevated by physical stress of the provider. Causes of hyperventilation should be sought elsewhere, e.g. amongst mental stressors.
Is general practice in need of a career structure?
Authors: M. Lough, M. Kelly, S. Murray, R. Walter, L. Smeeth, J. Harrison, T. van Zwanenberg, P. Bundred, T. Gibbs, M. J Thompson, S. Seigel
Journal: BMJ (1999)

Editor—Elwyn et al’s article on general practice training carries a sense of foreboding.1 The current training structure has many strengths, though increased time in general practice is undoubtedly needed; but any model suggested as an alternative has to be deliverable.

The Joint Committee for Postgraduate Training for General Practice has laid down criteria for training, some of which are couched in woolly terms. The aim of each criterion is to provide the very structure for training that Elwyn et al state is lacking. The problem is in the implementation of these criteria. Formative assessments, carried out throughout the three years of vocational training, should allow any problem identified to be dealt with at an early stage. Communication skills as taught by formative video recording of consultations is an integral part of general practice training. Two surveys before and after the implementation of a pilot system for summative assessment in the west of Scotland showed the practice of using three formative videos in the training year increase from 76% to 94%.2,3

The audit project is part of the “onerous requirement” to which registrars have to submit themselves. It can be carried out at any time during the three years of training, but until last year all audits were completed in general practice. As a result of 67 hospital reaccreditation visits in the west of Scotland, which produced 10 audits, it was decided that all senior house officers on the scheme should submit a completed audit cycle or a significant event analysis in each of their six month posts. In the first six months to 31 July 1998, 21 completed audit cycles were submitted, 15 of which passed summative assessment. Much of the trainer’s report could similarly be devolved to the hospital component of training.

The only references relating to summative assessment in Elwyn et al’s article are from two critics of the process. Much remains to be done to improve summative assessment, but it has certainly flushed out basic structural problems—particularly organisational—in many regions. If we were willing to be more honest about the current three year training structure, in both hospital and general practice, we would not need to extend it as the authors suggest.

Training should be seen as a top priority in the career structure of general practice. The three years of training undoubtedly require closer scrutiny, and a realistic training grant should reflect this.
Glucosylceramide synthase, a modulator of drug resistance is overexpressed in metastatic breast cancer
Authors: Yong-Yu Liu, Bret Taback, Jin Yuan Yu, Ping Xie, Valerie Gouaze, Armando E. Giuliano, Myles C. Cabot
Journal: Cancer Research (2006)

1260   Chemotherapy resistance and its detection in breast cancer are major clinical problems. Knowing more about the tumor at diagnosis would enhance treatment options/outcomes and spare patients needless exposure to toxic anticancer agents. Markers to detect and or predict chemotherapy resistance early on and to gauge metastatic potential would enhance survival. Recent findings have shown that the efficacy of the front-line anticancer agent, doxorubicin (Adriamycin), is linked to the formation of ceramide (a lipid) in breast cancer cells and that rapid metabolic clearance of ceramide by the enzyme glucosylceramide synthase (GCS) renders cells insensitive to drug. To test our hypothesis that the levels of expression of ceramide-associated genes will be predictive of multidrug resistance, we used gene array analysis to measure gene expression in two models: i) cultured human breast cancer cells, and ii) clinical specimens. Our results show that GCS is overexpressed (>2-fold) in doxorubicin-, paclitaxel-(Taxol), and etoposide-resistant sublines of MCF-7cells (MCF-7-AdrR, MCF-7-PTX, MCF-7/VP) compared to MCF-7 wild-type, but not overexpressed in MCF-7/CP, cisplatin-resistant cells. Early results on gene profiling in clinical specimens showed that GCS was overexpressed in approximately 70% (7/9) of primary tumors from patients with metastatic disease. Although this is a relatively small study, these results provide early evidence that suggests GCS may serve as a valuable predictive marker for identifying patients at increased risk for treatment failure.