tbuckley/cabot-search huggingface dataset:
The dl1520 Virus Is Found Preferentially in Tumor Tissue after Direct Intratumoral Injection in Oral Carcinoma
Authors: Stephen Morley, Gordon MacDonald, David Kirn, Stan Kaye, Robert Brown, David Soutar
Journal: Clinical Cancer Research (2004)

Abstract Purpose: dl1520 (also known as Onyx-015) is an E1B-deleted adenovirus designed to selectively lyse p53-deficient cancer cells. Clinical trials involving patients with recurrent squamous cell carcinoma of the head and neck have shown clinical efficacy, but no direct evidence as to the tumor or p53 selectivity of the virus was demonstrated. We wanted to determine whether dl1520 is selective for survival and replication within tumor tissue after direct injection and whether this is determined by p53 status of the tissues. We also wanted to ascertain whether the virus has any macroscopic effect on normal tissue. Experimental Design: An open-label Phase II trial was devised in which a fixed dose of the virus was administered to 15 patients via a direct intertumoral injection before surgery for untreated oral squamous cell carcinoma. The agent was also delivered into an area of adjacent normal buccal mucosa. Specimens of the excised tumor and of biopsies of the injected normal tissue were assessed for viral presence and p53 status. Results: We demonstrated that the virus replicates selectively in tumor as opposed to normal tissue after this direct injection. It was not possible to determine whether this selectivity was p53 related. It was found that dl1520 triggers an early rise in apoptosis levels in injected normal tissues. No adverse effects of viral injection were noted. Conclusions: This is the first report of injection of dl1520 into previously untreated squamous cell cancer. The data support the concept that dl1520 is replication deficient in normal, compared with cancerous, tissues and has potential as a selective anticancer agent against tumor tissues.
Targeting C4-Demethylating Genes in the Cholesterol Pathway Sensitizes Cancer Cells to EGF Receptor Inhibitors via Increased EGF Receptor Degradation
Authors: Anna Sukhanova, Andrey Gorin, Ilya G. Serebriiskii, Linara Gabitova, Hui Zheng, Diana Restifo, Brian L. Egleston, David Cunningham, Tetyana Bagnyukova, Hanqing Liu, Anna Nikonova, Gregory P. Adams, Yan Zhou, Dong-Hua Yang, Ranee Mehra, Barbara Burtness, Kathy Q. Cai, Andres Klein-Szanto, Lisa E. Kratz, Richard I. Kelley, Louis M. Weiner, Gail E. Herman, Erica A. Golemis, Igor Astsaturov
Journal: Cancer Discovery (2012)

Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa(1H/+) mice confirmed dramatic and selective loss of internalized platelet-derived growth factor receptor in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL.This work identifies a critical role for SC4MOL and NSDHL in the regulation of EGFR signaling and endocytic trafficking and suggests novel strategies to increase the potency of EGFR antagonists in tumors.
Use of permitted drugs in Italian professional soccer players
Authors: Emanuela Taioli
Journal: British Journal of Sports Medicine (2007)

Objectives: To assess the frequency and quantity of usage of permitted drugs by Italian professional soccer players. Methods: A cohort of 1041 professional soccer players from the two Italian major leagues was assembled during the season 2003–4; 743 of the 785 (94.6%) subjects available on the day of the interview answered an epidemiological questionnaire, which included questions on the type and frequency of use of several permitted drugs. Results: 92.6% of players reported having used oral anti-inflammatory products in the previous year, and most of them were current users (86.1%). 36% of the players, mostly current users, reported the use of analgesics. 82.8% of the players reported current use of supplements, and 28% reported using vitamins. Conclusions: The regular use of several permitted drugs is very high among professional soccer players. The description of players’ behaviour is the first step towards regular monitoring of the players’ need for, and use of, vitamins, supplements and other permitted drugs.
Incidence of asthma among workers exposed to sulphur dioxide and other irritant gases
Authors: E. Andersson, A. Knutsson, S. Hagberg, T. Nilsson, B. Karlsson, L. Alfredsson, K. Torén
Journal: European Respiratory Journal (2006)

The aim of the present study was to investigate whether repeated peak exposure (gassings) to sulphur dioxide (SO 2 ) and other irritant gases increases the risk of new-onset asthma. A questionnaire was sent to 4,112 sulphite workers, of whom 1,919 completed the questionnaire and 396 completed the short-form questionnaire, which was sent out as a last reminder. A sample of 130 nonrespondents completed a telephone interview using the short-form questionnaire. The incidence of adult-onset, physician-diagnosed asthma during employment duration was analysed in relation to exposure to SO 2 and gassings giving rise to respiratory symptoms. Incidence rates, as well as incidence rate ratios with 95% confidence interval (CI), were calculated. Further Cox regression models were used allowing assessment of hazard ratios (HR) stratified for sex and adjusted for atopy, smoking habits and age. The incidence rate for asthma among sulphite mill workers reporting gassings of SO 2 was 6.2 out of 1,000 person-yrs, compared with 1.9 out of 1,000 person-yrs among subjects unexposed to SO 2 and any gassings (HR (95% CI) 4.0 (2.1–7.7)). Among males reporting gassings to SO 2 , the HR (95% CI) for asthma was 5.8 (2.6–13) compared with unexposed males. In conclusion, repeated peak exposure to sulphur dioxide increased the incidence of asthma during work in sulphite pulp mills, which supports the hypothesis of irritant-induced asthma.
Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis
Authors: M Güler-Yüksel, C F Allaart, Y P M Goekoop-Ruiterman, J K de Vries-Bouwstra, J H L M van Groenendael, C Mallée, M H W de Bois, F C Breedveld, B A C Dijkmans, W F Lems
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To evaluate changes in bone mineral density (BMD) in the hands, hip and spine after 1 and 2 years of follow-up, in relation to antirheumatic and antiresorptive therapies and disease and demographic variables in patients with recent-onset rheumatoid arthritis (RA). Methods: Changes in BMD measured in metacarpals 2–4 by digital x -ray radiogrammetry and in the hip and spine by dual energy x -ray absorptiometry were assessed at baseline and after 1 and 2 years of follow-up in 218 patients with recent-onset RA from the BeSt study, who received one of four treatment strategies: sequential monotherapy (group 1); step-up combination therapy (group 2); initial combination therapy with tapered high-dose prednisone (group 3); or initial combination therapy with infliximab (group 4). Results: After 1 and 2 years, there was significant BMD loss in all locations, with significantly greater BMD loss in the hands than generalised BMD loss in the hip and spine. Initial combination therapy with prednisone or infliximab were associated with less hand BMD loss compared with initial monotherapy after 1 and 2 years (−0.9 and −1.6%, −0.6 and −1.4%, −1.7 and −3.3%, and −2.6 and −3.6% for group 4–1 after 1 and 2 years, overall p = 0.001 and p = 0.014, respectively). Progression in erosions was independently associated with increased BMD loss both in the hands and hip after 1 year. The use of bisphosphonates protected only against generalised BMD loss in the hip and spine. Conclusions: The association between joint damage progression and both hand and generalised BMD loss in RA suggests common pathways between these processes, with hand BMD loss occurring earlier in the disease course than generalised BMD loss.
Pointing B cells in the right direction
Authors: Michael Dustin
Journal: The Journal of Experimental Medicine (2015)

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Insight from Michael Dustin



One of the most elegant master regulatory cascades in cell biology is the system of small G proteins controlling actin-based structures and coordinating these with cell polarity and cell cycle: Cdc42, Rac, and Rho. In this issue, [Burbage et al.][2
Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide–mediated vascular smooth muscle relaxation
Authors: Jeff S. Isenberg, Fuminori Hyodo, Ken-Ichiro Matsumoto, Martin J. Romeo, Mones Abu-Asab, Maria Tsokos, Periannan Kuppusamy, David A. Wink, Murali C. Krishna, David D. Roberts
Journal: Blood (2006)
An incremental method to assess the linearity of gas flowmeters: application to Fleisch pneumotachographs
Authors: C Duvivier, R Peslin, C Gallina
Journal: European Respiratory Journal (1988)

A new method of studying the linearity of gas flowmeters was tested on different models of Fleisch pneumotachographs. The method applies a steady flow to the test flowmeter, which is increased in a stepwise manner by adding a constant flow-increment. This is achieved using two flow sources in parallel. The method does not require any reference flow channel and may be implemented with standard laboratory equipment. Using this method, the gain of Fleisch pneumotachographs, whatever their size, decreased by about 2-3% from low flows to about 40% of their nominal full scale (FS), and then increased almost linearly with increasing flow. The error was 8-13% at 200% FS. The following equation was devised to correct the data at high flow: Vc = Vt (1-K (Vt-S] where Vc and Vt are the corrected and measured flow respectively, K a gain correction factor and S a flow threshold below which no correction is needed. Applying this correction with suitable coefficients, the maximal error was below 3% from 0-200% FS.
Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry
Authors: Philip H. Quanjer, Danny J. Brazzale, Piotr W. Boros, Jeffrey J. Pretto
Journal: European Respiratory Journal (2013)

The aim of this study was to determine the diagnostic and interpretative consequences of adopting the Global Lungs Initiative (GLI) 2012 spirometric prediction equations. We assessed spirometric records from 17 572 subjects (49.5% females), aged 18–85 years, from hospitals in Australia and Poland. We calculated predicted forced expiratory volume in 1 s (FEV 1 ), forced expiratory volume (FVC), FEV 1 /FVC and lower limits of normal (LLN) using European Community for Steel and Coal (ECSC), National Health and Nutrition Examination Survey (NHANES) III and GLI 2012 equations. Obstruction was defined as FEV 1 /FVC&lt;LLN and a restrictive pattern as FEV 1 /FVC&gt;LLN and FVC&lt;LLN. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 and higher was defined as FEV 1 /FVC &lt;0.70 and FEV 1 &lt;80% pred. GLI 2012 equations produce similar predicted values for FEV 1 and FVC compared with NHANES, but produce larger values than ECSC. Differences in the LLN lead to an important increase in the prevalence rate of a low FVC compared to ECSC, and a significant decrease compared to NHANES prediction equations. Adopting GLI 2012 equations has small effects on the prevalence rate of airway obstruction. GOLD stages 2–4 lead to &gt;20% underdiagnosis of airway obstruction up to the age of 55 years and to 16–23% overdiagnosis in older subjects. GLI 2012 equations increase the prevalence of a “restrictive spirometric pattern” compared to ECSC but decrease it compared to NHANES.
Evaluating Clinical Improvement in Anxious Outpatients: A Comparison of Normal and Treated Neurotic Patients
Authors: KARL RICKELS, RONALD S. LIPMAN, CELSO-RAMON GARCIA, ELLEN FISHER
Journal: American Journal of Psychiatry (1972)

The emotional distress reported on the 64-item Patient Symptom Checklist by 133 anxious neurotic outpatients participating in a four-week drug trial was compared with that of 135 nonneurotic gynecological patients. Highly significant differences existed between the two patient groups before treatment. At the end of the trial period, those anxious patients who rated themselves as markedly improved had symptom distress levels that were not very different from those of the normal patients.
Complete Cytogenetic Response, Not Deep Molecular Response, Is Associated With Survival in Chronic Myeloid Leukemia
Authors: Hagop Kantarjian, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2014)

TO THEEDITOR:Hehlmannetal 1 recentlypublishedupdated results from the four-arm randomized study CML-Study IV (Imatinib Mesylate With or Without Interferon Alfa or Cytarabine Compared With Interferon Alfa Followed by Donor Stem Cell Transplant in Treating Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia). They concluded that a confirmed deep molecular response (MR 4.5 ; BCRABL transcript 0.0032% on the international scale) during receipt of imatinib therapy (regardless of dose) predicts for improved survival. The conclusion is based on a post hoc analysis of BCR-ABL transcript levels that were measured at 4 years (Fig 3A in the article by Hehlmann et al), showing that BCRABL transcripts 0.1% to 1%, 0.01% to 0.1%, 0.0032% to 0.01%, and 0.0032% were associated with estimated 8-year survival rates of 83%, 88%, 90%, and 92%, respectively (P .047). Figure 3A also shows that inability to achieve complete cytogeneticresponse(CCR)at4yearswasassociatedwithsignificantly worse outcome than the other four categories (estimated 8-year
Successful Discontinuation of Therapy for Disseminated Mycobacterium avium Complex Infection after Effective Antiretroviral Therapy
Authors: Stephen D. Shafran
Journal: Annals of Internal Medicine (2002)

Background: Highly active antiretroviral therapy (HAART) is associated with improvement or resolution of several HIV-associated opportunistic infections. Although prophylaxis against disseminated Mycobacterium avium complex infection may be successfully discontinued after a favorable response to HAART, the 1999 guidelines from the U.S. Public Health Service/Infectious Diseases Society of America recommend continuing therapy for disseminated M. avium complex infection, regardless of the response to HAART. Objective: To examine the outcome among patients with disseminated M. avium complex infection whose antimycobacterial therapy was discontinued after a favorable response to HAART. Design: Retrospective chart review between May 2000 and May 2001. Setting: 13 Canadian HIV clinics. Patients: 52 HIV-infected adults (43 men; mean age, 37.3 years) in whom successful antimycobacterial therapy for disseminated M. avium complex infection was discontinued after a favorable virologic response to HAART. Measurements: Survival, survival free of disseminated M. avium complex infection, and CD4+ cell count responses. Results: At the time of diagnosis of disseminated M. avium complex infection, the median CD4+ cell count was 0.016 × 109 cells/L, and the median plasma HIV RNA level was 90 000 copies/mL (plasma HIV RNA levels were available for only 21 patients). The patients received a median of 32 months of antimycobacterial therapy that included ethambutol plus either clarithromycin or azithromycin. When antimycobacterial therapy was discontinued, the median CD4+ cell count was 0.23 × 109 cells/L and the median plasma HIV RNA level was less than 50 copies/mL. A median of 20 months after discontinuation of antimycobacterial therapy, only 1 patient had developed recurrent M. avium complex disease (37 months after stopping antimycobacterial therapy). This patient had stopped HAART 2 months earlier because of uncontrolled HIV viremia. Twenty months after stopping antimycobacterial therapy, the other 51 patients had a median CD4+ cell count of 0.288 × 109 cells/L; 34 (67%) had undetectable plasma HIV RNA levels, and 8 (15%) had plasma HIV RNA levels of 50 to 1000 copies/mL. Conclusions: Discontinuation of successful disseminated M. avium complex therapy after a successful response to HAART is safe and reduces patients' pill burdens, potential drug adverse effects, drug interactions, and costs of therapy.
Hospital Ventilation and Risk for Tuberculous Infection in Canadian Health Care Workers
Authors: Dick Menzies
Journal: Annals of Internal Medicine (2000)

Background: The risk for and determinants of transmission of tuberculosis in hospitals caring for moderate numbers of patients with tuberculosis remain uncertain. Objective: To study the association of tuberculin conversion among health care workers with ventilation of patient care areas. Design: Cross-sectional observational survey. Setting: 17 acute-care community or university hospitals. Participants: All personnel who worked at least 2 days per week in the respiratory and physiotherapy departments or in selected nursing units. Measurements: Participating workers underwent tuberculin skin testing and completed self-administered questionnaires. Previous tuberculin tests and bacille Calmette-Guérin vaccinations were verified. Records of patients with tuberculosis who were hospitalized in the 3 years preceding the study were reviewed. Air exchanges per hour in patient care areas were measured by using a tracer gas technique. Multivariate proportional hazards regression was used to estimate the effect of occupational factors on documented tuberculin conversion, after adjustment for nonoccupa- tional factors, among participants with at least one previous negative result on tuberculin skin testing. Results: Tuberculin conversion was associated with ventilation of general or nonisolation patient rooms of less than 2 air exchanges per hour (adjusted hazard ratio, 3.4 [95% CI, 2.1 to 5.8]); with work in moderate- to high-risk hospitals (adjusted hazard ratio, 2.2 [CI, 1.3 to 3.5]); and with work in the nursing (adjusted hazard ratio, 4.3 [CI, 2.7 to 6.9]), respiratory therapy (adjusted hazard ratio, 6.1 [CI, 3.1 to 12.0]), and physiotherapy (adjusted hazard ratio, 3.3 [CI, 1.5 to 7.2]) departments or housekeeping (adjusted hazard ratio, 4.2 [CI, 2.3 to 7.6]). Conversion was not associated with inadequate ventilation of respiratory isolation rooms (adjusted hazard ratio, 1.0 [CI, 0.8 to 1.3]). Conclusion: Tuberculin conversion among health care workers was strongly associated with inadequate ventilation in general patient rooms and with type and duration of work, but not with ventilation of respiratory isolation rooms. *For members of the Canadian Collaborative Group in Nosocomial Transmission of TB, see Appendix.
H2-M3–restricted CD8+ T cells are not required for MHC class Ib–restricted immunity against <i>Listeria monocytogenes </i>
Authors: Sarah E.F. D'Orazio, Christine A. Shaw, Michael N. Starnbach
Journal: The Journal of Experimental Medicine (2006)

Studies using major histocompatibility complex (MHC)-Ia–deficient mice have shown that MHC-Ib–restricted CD8+ T cells can clear infections caused by intracellular pathogens such as Listeria monocytogenes. M3-restricted CD8+ T cells, which recognize short hydrophobic N-formylated peptides, appear to comprise a substantial portion of the MHC-Ib–restricted T cell response in the mouse model of L. monocytogenes infection. In this study, we isolated formyltransferase (fmt) mutant strains of L. monocytogenes that lacked the ability to add formyl groups to nascent polypeptides. These fmt mutant Listeria strains did not produce antigens that could be recognized by M3-restricted T cells. We showed that immunization of MHC-Ia–deficient mice with fmt mutant Listeria resulted in stimulation of a protective memory response that cleared subsequent challenge with wild-type L. monocytogenes, despite the fact that M3-restricted CD8+ T cells did not proliferate in these mice. These data suggest that M3-restricted T cells are not required for protection against L. monocytogenes and underscore the importance of searching for new antigen-presenting molecules among the large MHC-Ib family of proteins.
Recovery of Regional but Not Global Contractile Function by the Direct Intramyocardial Autologous Bone Marrow Transplantation
Authors: Marc Hendrikx, Karen Hensen, Christel Clijsters, Hanne Jongen, Remco Koninckx, Eric Bijnens, Michel Ingels, Axel Jacobs, Robert Geukens, Paul Dendale, Johan Vijgen, Dagmara Dilling, Paul Steels, Urbain Mees, Jean-Luc Rummens
Journal: Circulation (2006)

Background— Recent trials have shown that intracoronary infusion of bone marrow cells (BMCs) improves functional recovery after acute myocardial infarction. However, whether this treatment is effective in heart failure as a consequence of remodeling after organized infarcts remains unclear. In this randomized trial, we assessed the hypothesis that direct intramyocardial injection of autologous mononuclear bone marrow cells during coronary artery bypass graft (CABG) could improve global and regional left ventricular ejection fraction (LVEF) at 4-month follow-up. Methods and Results— Twenty patients (age 64.8±8.7; 17 male, 3 female) with a postinfarction nonviable scar, as assessed by thallium (Tl) scintigraphy and cardiac magnetic resonance imaging (MRI), scheduled for elective CABG, were included. They were randomized to a control group (n =10, CABG only) or a BMC group (CABG and injection of 60.10 6 ±31.10 6 BMC). Primary end points were global LVEF change and wall thickening changes in the infarct area from baseline to 4-month follow-up, as measured by MRI. Changes in metabolic activity were measured by Tl scintigraphy and expressed as a score with a range from 0 to 4, corresponding to percent of maximal myocardial Tl uptake (4 indicates &lt;50%, nonviable scar; 3, 50% to 60%; 2, 60% to 70%; 1, 70% to 80%; 0&gt;80%). Global LVEF at baseline was 39.5±5.5% in controls and 42.9±10.3% in the BMC group ( P =0.38). At 4 months, LVEF had increased to 43.1±10.9% in the control group and to 48.9±9.5% in the BMC group ( P =0.23). Systolic thickening had improved from −0.6±1.3 mm at baseline to 1.8±2.6 mm at 4 months in the cell-implanted scars, whereas nontreated scars remained largely akinetic (−0.5±2.0 mm at baseline compared with 0.4±1.7 mm at 4 months, P =0.007 control versus BMC-treated group at 4 months). Defect score decreased from 4 to 3.3±0.9 in the BMC group and to 3.7±0.4 in the control group ( P =0.18). Conclusions— At 4 months, there was no significant difference in global LVEF between both groups, but a recovery of regional contractile function in previously nonviable scar was observed in the BMC group.
Physiologic Evidence for a Dual A-V Transmission System
Authors: GORDON K. MOE, JAMES B. PRESTON, HAROLD BURLINGTON
Journal: Circulation Research (1956)

A study of the transmission of early premature contractions between atria and ventricles and in the retrograde direction in the dog heart suggests the existence of two parallel A-V conduction pathways communicating with each other over one or more branches. The evidence is based on the excessive delay of very early premature responses in traversing the node, suggesting that a slowly conducting pathway recovers earlier than the normal "fast" pathway; on the echoing back to the chamber of origin of early premature responses; and on ventricular electrograms of "abnormal" configuration obtained during early premature responses. These observations and the hypothesis to which they lead provide a natural explanation for reciprocal rhythm and nodal paroxysmal tachycardia.