tbuckley/cabot-search huggingface dataset:
Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1α
Authors: Yang Lu, Ke Liang, Xinqun Li, Zhen Fan
Journal: Molecular Cancer (2007)

Abstract Background Searching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted. The purpose of the current study was to evaluate hypoxia-inducible factor-1α (HIF-1α) as a novel response marker compared with previously explored markers following treatment with an EGFR-blocking monoclonal antibody (cetuximab) and a small-molecule EGFR tyrosine kinase inhibitor (gefitinib) in a group of cancer cell lines containing wild-type or tyrosine kinase domain-mutated EGFR. Results We found that, compared with previously studied response markers, including EGFR per se and three EGFR downstream signal molecules (ERK, Akt, and STAT3), which showed variable post-treatment changes in levels of phosphorylation and no consistent link of the changes to therapeutic responses, HIF-1α showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1α downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1α mutant (HIF-1α/ΔODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1α/ΔODD-transfected cells remained sensitive to cetuximab-induced inhibition of Akt and ERK phosphorylation but were remarkably less responsive to cetuximab-induced growth inhibition compared with corresponding control cells. Conclusion Our data indicates that downregulation of HIF-1α is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1α as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting.
<i>O-</i>GlcNAc Cycling: A Link Between Metabolism and Chronic Disease
Authors: Michelle R. Bond, John A. Hanover
Journal: Annual Review of Nutrition (2013)

To maintain homeostasis under variable nutrient conditions, cells rapidly and robustly respond to fluctuations through adaptable signaling networks. Evidence suggests that the O-linked N-acetylglucosamine (O-GlcNAc) posttranslational modification of serine and threonine residues functions as a critical regulator of intracellular signaling cascades in response to nutrient changes. O-GlcNAc is a highly regulated, reversible modification poised to integrate metabolic signals and acts to influence many cellular processes, including cellular signaling, protein stability, and transcription. This review describes the role O-GlcNAc plays in governing both integrated cellular processes and the activity of individual proteins in response to nutrient levels. Moreover, we discuss the ways in which cellular changes in O-GlcNAc status may be linked to chronic diseases such as type 2 diabetes, neurodegeneration, and cancers, providing a unique window through which to identify and treat disease conditions.
[567] HCV HEPATITIS AND INTERFERON-RELATED DEPRESSION: AN ANALYSIS OF THE RETROSPECTIVE PHASE OF THE PROBE STUDY
Authors: P. Amodio, S. Montebianco Abenavoli, L. Cosco, C. Ferrari, R. Patriarchi, C. Coppola, F. Piccinino, S. Sani, N. Passariello, S. Babudieri, M. Sarracino, A. Alberti
Journal: Journal of Hepatology (2007)
Effect of inhaled corticosteroids on bronchial responsiveness in patients with "corticosteroid naive" mild asthma: a meta-analysis
Authors: P M van Grunsven, C P van Schayck, J Molema, R P Akkermans, C van Weel
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Inhaled corticosteroids are the most efficacious anti-inflammatory drugs in asthma. International guidelines also advocate the early introduction of inhaled corticosteroids in corticosteroid naive patients. A study was undertaken to assess the effects of inhaled corticosteroids on bronchial hyperresponsiveness in patients with corticosteroid naive asthma by conventional meta-analysis. <h3>METHODS</h3> A Medline search of papers published between January 1966 and June 1998 was performed and 11 papers were selected in which the patients had no history of treatment with inhaled or oral corticosteroids. Bronchial responsiveness to bronchoconstricting agents was considered as the main outcome parameter. Doubling doses (DD) of histamine or methacholine were calculated. <h3>RESULTS</h3> The total effect size of inhaled corticosteroids (average daily dose 1000 μg) versus placebo in the 11 studies was +1.16 DD (95% confidence interval (CI) +0.76 to +1.57). When only the eight short term studies (2–8 weeks) were analysed the effect size of the bronchoconstricting agent was +0.91 DD (95% CI +0.65 to +1.16). No relationship was found between the dose of inhaled corticosteroid used and the effect on bronchial responsiveness. <h3>CONCLUSION</h3> This meta-analysis in patients with corticosteroid naive asthma indicates that, on average, high doses of inhaled corticosteroids decrease bronchial hyperresponsiveness in 2–8 weeks. It remains unclear whether there is a dose-response relationship between inhaled corticosteroids and effect on bronchial hyperresponsiveness.
Advances in Blood Pressure Genomics
Authors: Patricia B. Munroe, Michael R. Barnes, Mark J. Caulfield
Journal: Circulation Research (2013)

The elucidation of genes implicated in Mendelian forms of hypertension demonstrates rare variants with substantial effects are responsible, and often these genes lie within pathways managing sodium homeostasis. More recently with advances in affordable high-throughput genotyping strategies, multiple common genetic variants with modest effects on blood pressure (&lt;1 mmHg systolic) have been discovered in the population. In aggregate, these common variants explain &lt;3% of the variance of blood pressure. Although these findings may offer new mechanistic insights into the biology of blood pressure, a key question is can these findings translate into patient benefit? It is timely to reflect on recent advances in genomics, and the use of new resources, such as the 1000 Genomes Project and the Encyclopedia of DNA Elements, to annotate likely causal variants, and their relevance to cardiovascular disease. In this review, we discuss the advances in relation to our knowledge of the genetic architecture of blood pressure, and whether gene discoveries might influence cardiovascular risk assessment, help to stratify patient response to medicine, or identify new biological pathways for novel therapeutic targets.
EXPERIMENTAL EPIDEMIOLOGY OF TUBERCULOSIS
Authors: David Perla
Journal: The Journal of Experimental Medicine (1927)

1. After intraperitoneal inoculation of guinea pigs with tubercle bacilli, the microorganisms may appear in the feces and elimination may persist during 1 week. Subsequently during several weeks no tubercle bacilli can be recovered from the feces. 2. When tuberculosis is widely disseminated in the body of guinea pigs, tubercle bacilli are discharged with the feces. 3. Tubercle bacilli are occasionally eliminated in the bile of guinea pigs immediately after inoculation but are almost constantly found in the bile after several weeks when the disease is well established. 4. Tubercle bacilli are eliminated in the urine of experimentally infected guinea pigs only when infection is far advanced.
Respiratory Syncytial Virus, Airway Inflammation, and FEV<sub>1</sub> Decline in Patients with Chronic Obstructive Pulmonary Disease
Authors: Tom M. A. Wilkinson, Gavin C. Donaldson, Sebastian L. Johnston, Peter J. M. Openshaw, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Respiratory syncytial virus (RSV) is increasingly recognized as an important pathogen in adults with cardiopulmonary disease. It has been associated with acute exacerbations of chronic obstructive pulmonary disease (COPD); however, it has also been detected in the lower airway in the stable state, but the consequences of RSV in stable disease have not previously been determined. We therefore studied the consequences of RSV persistence in adults with COPD and its effect on airway inflammation and lung function decline.A total of 241 sputum samples from 74 patients with COPD (FEV(1)% predicted, 39.2%; interquartile range, 29.6-57.8%) were collected quarterly in the stable state over 2 yr. RSV was detected by polymerase chain reaction (PCR), quantitative microbiology was performed, and inflammatory cytokines were quantified by ELISA.RSV RNA was detected in 32.8% of sputum samples. Patients in whom RSV was more frequently detected (> 50% of samples RSV PCR-positive, n=18) had higher airway inflammation and faster FEV(1) decline over the study (101.4 ml/yr [95% confidence interval, 57.1-145.8]) compared with those with less frequent detection of RSV (n=56; 51.2 ml/yr [31.7-70.8]; p=0.01). The observed relationship between RSV detection and accelerated lung function decline was independent of smoking status, exacerbation frequency, and lower airway bacterial load.Persistent RSV detection in patients with COPD is associated with airway inflammation and accelerated decline in FEV(1). Chronic RSV infection may be a novel therapeutic target to alter the natural history of COPD.
Corticosteroid Treatment in Critically Ill Patients with Pandemic Influenza A/H1N1 2009 Infection
Authors: Sung-Han Kim, Sang-Bum Hong, Sung-Choel Yun, Won-Il Choi, Jong-Joon Ahn, Young Joo Lee, Heung-Bum Lee, Chae-Man Lim, Younsuck Koh
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Administration of adjuvant corticosteroids to patients with pandemic influenza A/H1N1 2009 (pH1N1) may reduce inflammation and improve outcomes.To assess the effect of adjuvant corticosteroid treatment on the outcome of critically ill patients with pH1N1 infection.All adult patients with confirmed pH1N1 admitted to the intensive care unit of 28 hospitals in South Korea from September 2009 to February 2010 were enrolled. Patients with and without adjuvant corticosteroid treatment were retrospectively compared by two risk stratification models: (1) a retrospective cohort study that used propensity score analysis to adjust for confounding by treatment assignment and (2) a propensity-matched case-control study.A total of 245 patients were enrolled in the cohort study, 107 of whom (44%) received adjuvant steroid treatment. In the cohort study, the 90-day mortality rate of patients given steroids (58%, 62 of 107) was significantly higher than that of those not given steroids (27%, 37 of 138) (P < 0.001). The steroid group was more likely to have superinfection such as secondary bacterial pneumonia or invasive fungal infection, and had more prolonged intensive care unit stays than the no-steroid group. Multivariate analysis indicated that steroid treatment was associated with increased 90-day mortality when independent predictors for 90-day mortality and propensity score were considered (adjusted odds ratio, 2.20; 95% confidence interval, 1.03-4.71). In the case-control study, the 90-day mortality rate in the steroid group was 54% (35 of 65) and 31% (20 of 65) in the no-steroid group (McNemar test, P = 0.004).Adjuvant corticosteroids were significantly associated with higher mortality in critically ill patients with pH1N1 infection.
Sensitivity of the Dermatology Life Quality Index to clinical change in patients with psoriasis
Authors: E. Mazzotti, A. Picardi, F. Sampogna, F. Sera, P. Pasquini, D. Abeni
Journal: British Journal of Dermatology (2003)

Quality of life is increasingly recognized as an important outcome measure in dermatology. The Dermatology Life Quality Index (DLQI) is a self-administered questionnaire designed to measure the impact of skin diseases on patients' quality of life.To assess the responsiveness of the DLQI to variations in clinical status as measured by the Self-Administered Psoriasis Area and Severity Index (SAPASI) in a large sample of in-patients with psoriasis.The SAPASI and the DLQI were completed by 359 in-patients with psoriasis at hospital admission and 4 weeks after discharge. Changes in SAPASI scores were used to categorize patients as improved, unchanged or worsened. Next, these groups were compared with one another with regard to the change in DLQI scores.Four weeks after discharge, both mean SAPASI scores and mean DLQI scores were significantly lower than at admission (P < 0.001). In improved patients, the DLQI score decreased significantly more than in worsened patients (P < 0.001), and tended to decrease more than in unchanged patients (P = 0.07). The difference in DLQI score change between improved patients and unchanged or worsened patients grouped together was highly significant (P < 0.001); also, it remained significant or nearly significant when the analysis was performed on subsets of patients based on gender and age range.This study contributes to building evidence of validity for the DLQI, because the instrument demonstrated the ability to detect small but meaningful changes in clinical status over time in a large sample of patients with psoriasis.
Hajj: journey of a lifetime
Authors: Abdul Rashid Gatrad, Aziz Sheikh
Journal: BMJ (2005)

Journeying to Mecca for Hajj (pilgrimage) is no ordinary undertaking for many Muslims (boxes 1 and 2; fig 1). Hajj represents the culmination of years of spiritual preparation and planning. Once they have completed the pilgrimage, pilgrims are given the honorific title Hajji (pilgrim).

Hajj commemorates the patriarch Abraham's readiness to sacrifice his son Ishmael in biblical times. Performing Hajj is one of the five pillars of Islam and is therefore obligatory for all adult Muslims who can afford to undertake the journey and are in good health. Hajj lasts for five days, and, as the Islamic calendar is lunar, the precise Gregorian calendar dates of the Hajj season will vary each year. Muslims travel to Mecca at other times to perform a lesser pilgrimage called Umrah.

Mecca's resident population of about 200 000 swells to well over two million during the Hajj season. This rapid increase in numbers poses many challenges, including ensuring adequate food, water, and sanitary facilities in Mecca and the neighbouring deserts of Mina and Arafat, which pilgrims must visit as part of the Hajj ritual.

Although the journey is incumbent on a Muslim only once in a lifetime, many Muslims, particularly those living in the West, will journey more often. For example, more than 20 000 Britons do the Hajj each year, and the current annual figure for Umrah stands at almost 29 000.3 In view of the very large numbers of people from disparate regions and the hostile climate of the Arabian desert, the chances of disease, particularly in elderly and infirm people, are high.

In this paper, we briefly describe the main rites of the Hajj before focusing on particular health risks associated with it and measures that may be taken to minimise them. Our main aim …
Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial
Authors: Raimund Jakesz, Walter Jonat, Michael Gnant, Martina Mittlboeck, Richard Greil, Christoph Tausch, Joern Hilfrich, Werner Kwasny, Christian Menzel, Hellmut Samonigg, Michael Seifert, Guenther Gademann, Manfred Kaufmann
Journal: The Lancet (2005)
Extraembryonic venous obstructions lead to cardiovascular malformations and can be embryolethal
Authors: B Hogers
Journal: Cardiovascular Research (1999)

Objective: To expand our knowledge concerning the effect of placental blood flow on human heart development, we used an embryonic chicken model in which extraembryonic blood flow was manipulated. Methods: First, one of the three major vitelline veins was ligated, while blood flow was visualized with Indian ink. In this way, we could study the effect of different ligation positions on intracardiac flow patterns. Secondly, these vitelline veins were ligated permanently with a microclip until cardiac septation was completed, thereafter, the hearts were morphologically evaluated. In this way, we could study the impact of the ligation position on the severity and frequency of heart malformations. On combining the results, we were able to study the effect of different intracardiac flow patterns on heart development. Results: Although ligation of each vein resulted in different intracardiac flow patterns, long-term ligation resulted in similar cardiovascular malformations in survivors. These consisted mainly of ventricular septum defects (VSDs), semilunar valve anomalies, and pharyngeal arch artery malformations. There was no significant difference (p>0.05) between the ligation position and the incidence of cardiovascular malformations. However, the percentage mortality after clipping the left lateral vitelline vein was significantly higher (p<0.05) than after ligation of either the right lateral or posterior vitelline vein. Conclusions: Early extraembryonic venous obstruction leads to altered flow patterns, which probably result in shear stress changes. In postseptation stages, these result in a spectrum of cardiovascular malformations irrespective of the ligation position. A diminished incidence of VSDs in the oldest stage was attributed to delayed closure of the interventricular foramen.
Trends in the Aggressiveness of Cancer Care Near the End of Life
Authors: Craig C. Earle, Bridget A. Neville, Mary Beth Landrum, John Z. Ayanian, Susan D. Block, Jane C. Weeks
Journal: Journal of Clinical Oncology (2004)

To characterize the aggressiveness of end-of-life cancer treatment for older adults on Medicare, and its relationship to the availability of healthcare resources.We analyzed Medicare claims of 28,777 patients 65 years and older who died within 1 year of a diagnosis of lung, breast, colorectal, or other gastrointestinal cancer between 1993 and 1996 while living in one of 11 US regions monitored by the Surveillance, Epidemiology, and End Results Program.Rates of treatment with chemotherapy increased from 27.9% in 1993 to 29.5% in 1996 (P =.02). Among those who received chemotherapy, 15.7% were still receiving treatment within 2 weeks of death, increasing from 13.8% in 1993 to 18.5% in 1996 (P <.001). From 1993 to 1996, increasing proportions of patients had more than one emergency department visit (7.2% v 9.2%; P <.001), hospitalization (7.8% v 9.1%; P =.008), or were admitted to an intensive care unit (7.1% v 9.4%; P =.009) in the last month of life. Although fewer patients died in acute-care hospitals (32.9% v 29.5%; P <.001) and more used hospice services (28.3% v 38.8%; P <.001), an increasing proportion of patients who received hospice care initiated this service only within the last 3 days of life (14.3% v 17.0%; P =.004). Black patients were more likely than white patients to experience aggressive intervention in nonteaching hospitals but not in teaching hospitals. Greater local availability of hospices was associated with less aggressive treatment near death on multivariate analysis.The treatment of cancer patients near death is becoming increasingly aggressive over time.
Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase Cα/β Enhances Cardiac Contractility and Attenuates Heart Failure
Authors: Michael Hambleton, Harvey Hahn, Sven T. Pleger, Matthew C. Kuhn, Raisa Klevitsky, Andrew N. Carr, Thomas F. Kimball, Timothy E. Hewett, Gerald W. Dorn, Walter J. Koch, Jeffery D. Molkentin
Journal: Circulation (2006)

The conventional protein kinase C (PKC) isoform alpha functions as a proximal regulator of Ca2+ handling in cardiac myocytes. Deletion of PKCalpha in the mouse results in augmented sarcoplasmic reticulum Ca2+ loading, enhanced Ca2+ transients, and augmented contractility, whereas overexpression of PKCalpha in the heart blunts contractility. Mechanistically, PKCalpha directly regulates Ca2+ handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca2+ ATPase.In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKCalpha-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKCalpha cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKCalpha was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology.Pharmacological inhibition of PKCalpha, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure.
Development of Cd8α/α and Cd8α/β T Cells in Major Histocompatibility Complex Class I–Deficient Mice
Authors: Gobardhan Das, Charles A. Janeway
Journal: The Journal of Experimental Medicine (1999)

Peripheral CD8+ T cells mainly use CD8α/β, and their development is mainly dependent on the major histocompatibility complex (MHC) class I proteins Kb and Db in H-2b mice. In this report, we have shown that the development of CD8α/β TCR-α/β cells in lymphoid organs as well as in intestinal intraepithelial lymphocytes (iIELs) is dependent on the MHC class I Kb and Db proteins. In contrast, TCR-α/β CD8α/α cells are found mainly in iIELs, and their numbers are unaffected in KbDb double knockout mice. Most of the TCR-γ/δ cells in the iIELs also bear CD8α/α, and they are also unaffected in KbDb −/− mice. In β2-microglobulin (β2m)-deficient mice, all of the TCR-α/β CD8α/α and CD8α/β T cells disappear, but TCR-γ/δ cells are unaffected by the absence of β2m.