tbuckley/cabot-search huggingface dataset:
Critical Evaluation of Disease Stabilization As a Measure of Activity of Systemic Therapy: Lessons From Trials With Arms in Which Patients Do Not Receive Active Treatment
Authors: Christophe Le Tourneau, Xavier Paoletti, Elodie Coquan, Marie-Paule Sablin, Mustapha Zoubir, Ian F. Tannock
Journal: Journal of Clinical Oncology (2013)

by the heterogeneity of the designs of the trials included in the metaanalysis and by the results of the Radiotherapy With Cisplatin Versus Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation (TREMPLIN) randomized trial that failed to show a difference between cisplatin and cetuximab concomitant to radiotherapy after induction chemotherapy. 4 In our experience, the absence of parallelism between clinical and statistical heterogeneity is frequent. 5 Regarding the editorial by Forastiere et al, 6 we agree that knowing the sources of financial support are important to interpret the results of a study.However, in the present case, we would like to specify that this project was only modestly supported by an unrestricted grant by sanofi-aventis.sanofi-aventis had no role in the design of the metaanalysis, the analysis and interpretation of the data, nor the publication of this meta-analysis.For instance, they received
737 A PHASE-I, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF SINGLE ESCALATING ORAL DOSES OF GS-9620 IN HEALTHY SUBJECTS
Authors: U. Lopatin, G. Wolfgang, R. Kimberlin, D. Turnas, M. Cornprost, G. Chittick, C. Frey, J. Findlay, C. Ohmstede, B. Kearney, C. Barnes, J. McHutchinson, K. Hirsch
Journal: Journal of Hepatology (2011)
Seasonality of tuberculosis in an Eastern-Asian country with an extreme continental climate
Authors: N. Naranbat, P. Nymadawa, K. Schopfer, H. L. Rieder
Journal: European Respiratory Journal (2009)

Aggregate monthly notifications of incident sputum smear-positive tuberculosis (TB) in Mongolia, stratified by sex and age groups, were analysed separately for Ulaanbaatar, Mongolia, and the rest of the country for the 9-yr period from 1998 to 2006. TB notifications were compared with ambient surface temperature. More than twice as many TB cases were notified in the peak month (April) compared with the trough months (October–December), paralleling the temperature curve. The fluctuations recurred consistently over the entire observation period, were identical in the capital compared with the rest of the country, and were independent of age and sex. TB notifications parallel the temperature amplitudes and have a magnitude not reported elsewhere. We hypothesise that the influence of temperature on life either indoors or outdoors is consistent with the transmission probability of Mycobacterium tuberculosis and the subsequent delay to disease recognition and notification with the incubation period, possibly co-determined by other factors, rather than accessibility to services.
Anticoagulants as Inhibitors of Reverse Transcriptase Activity2
Authors: Bryan L. Kiehl, Phillip B. Stott, Andrew C. Huang, Darwin A. Buthala
Journal: JNCI Journal of the National Cancer Institute (1973)

Plasma collected by glass bead defibrination, citrate-phosphate-dextrose solution, or ethylenediaminetetraacetate inhibited reverse transcription to a lesser extent than did that collected in heparin. A dilution of the heparinized plasma >1:1000 was required to eliminate the inhibition. Heparin added to the reverse transcriptase reaction at 0, 5, or 15 minutes of incubation caused an immediate plateau of incorporation. The DNA product formed before addition of heparin was not degraded during the observation period.
Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial
Authors: Marjolein YV Homs, Ewout W Steyerberg, Wilhelmina MH Eijkenboom, Hugo W Tilanus, Lukas JA Stalpers, Joep FWM Bartelsman, Jan JB van Lanschot, Harm K Wijrdeman, Chris JJ Mulder, Janny G Reinders, Henk Boot, Berthe MP Aleman, Ernst J Kuipers, Peter D Siersema
Journal: The Lancet (2004)
Keys to Personalized Care in Pancreatic Oncology
Authors: Christopher H. Crane, Christine A. Iacobuzio-Donahue
Journal: Journal of Clinical Oncology (2012)

Morethanadecadeago,investigatorsfromVirginiaMasonMedical Centerreportedapromising3-yearoverallsurvivalrateof64%(95%CI, 56% to 72%) in a group of 43 patients who received a novel adjuvant regimencomprisinginterferonalfa,infusionalfluorouracil,cisplatin,and external-beamradiationtherapy(45-54Gyover5to6weeks),followedby twomorecyclesoffluorouracil,afterresectionofpancreaticcancer.The GI toxicity in particular was significant, leading to a delay of chemoradiotherapyin70%ofthepatientsandhospitalizationin42%. 1 Two different institutions and one cooperative group have since reported similar findings with this regimen in single-arm prospective studies: potentially clinically relevant improvement in survival at the cost of significant but reversible acute toxicity. 2-4
Transforming Growth Factor–β Signaling in T Cells Promotes Stabilization of Atherosclerotic Plaques Through an Interleukin-17–Dependent Pathway
Authors: Anton Gisterå, Anna-Karin L. Robertson, John Andersson, Daniel F. J. Ketelhuth, Olga Ovchinnikova, Stefan K. Nilsson, Anna M. Lundberg, Ming O. Li, Richard A. Flavell, Göran K. Hansson
Journal: Science Translational Medicine (2013)

Enhanced TGF-β signaling may promote plaque stability and prevent clinical manifestations of atherosclerosis.
Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer
Authors: E. Van Cutsem, H. van de Velde, P. Karasek, H. Oettle, W.L. Vervenne, A. Szawlowski, P. Schoffski, S. Post, C. Verslype, H. Neumann, H. Safran, Y. Humblet, J. Perez Ruixo, Y. Ma, D. Von Hoff
Journal: Journal of Clinical Oncology (2004)

Purpose To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. Patients and Methods This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m 2 intravenously weekly × 7 for 8 weeks, then weekly × 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. Results Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P = .75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade ≥ 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. Conclusion The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.
Thymomodulin increases HLA-DR expression by macrophages but not T-lymphocyte proliferation in autologous mixed leucocyte reaction
Authors: B Balbi, MT Valle, S Oddera, F Manca, GA Rossi, L Allegra
Journal: European Respiratory Journal (1993)

Thymomodulin (TMD), a thymic biological response modifier, stimulates the release of tumour necrosis factor (TNF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) in macrophage-lymphocyte cultures. We investigated the effects of the cytokines released in cultures with TMD, on the expression of human leucocyte antigen-DR (HLA-DR) antigens by alveolar macrophages (AM) and the T-cell proliferation induced in autologous mixed leucocyte reaction (AMLR) cultures or by T-cell mitogens. Among freshly isolated AM, 84 +/- 4% were HLA-DR positive, and this proportion was significantly reduced after 24 h cultures (60 +/- 3%, p < 0.05). In cultures without peripheral blood (PBL) lymphocytes, TMD did not change HLA-DR expression by AM CHLA-DR+AM); whilst in the presence of autologous PBL lymphocytes, TMD induced an increase in the proportions of HLA-DR+AM (TMD 100 micrograms.ml-1 79 + 3%, p < 0.04 vs control cultures). However, TMD did not change the ability of AM to induce T-cell proliferation in AMLR between AM and PBL lymphocytes. In contrast, in PBL mononuclear cell cultures, TMD induced a further increase of the cell proliferation due to the T-cell mitogens interleukin-2 (IL-2) or phytohaemagglutinin (PHA) (p < 0.05 vs each control culture with mitogens) or anti-CD3 antibodies (p < 0.03 vs control cultures). Thus, the cytokines released in cultures with TMD enhance macrophage HLA-DR expression. Whilst this phenomenon is not associated with changes in the ability of AM to stimulate T-cell proliferation, TMD is able to increase the mitogen-induced T-cell proliferation.
Influence of autoregulation and capacitance on diastolic coronary artery pressure-flow relationships in the dog.
Authors: W P Dole, V S Bishop
Journal: Circulation Research (1982)

We studied the influence of initial coronary artery pressure on pressure-flow relationships during long diastoles in 22 closed-chest, anesthetized dogs under basal conditions and after maximum coronary vasodilation.The circumflex artery was perfused from a pressurized arterial reservoir through a cannula inserted in the carotid artery.Diastolic pressure-flow relations were obtained under two conditions: (1) when pressure was gradually decreasing (40 mm Hg/sec); and(2) when pressure and flow were constant beginning 500 msec after a rapid step decrease in pressure.Pressure-flow curves obtained with pressure gradually decreasing were linear in the basal state and during maximum coronary vasodilation [r = 0.98 ± 0.01 (SE)].In autoregulating animals, 25 mm Hg increments in coronary artery pressure from 75 to 125 mm Hg resulted in progressive decreases in the slope (2.2 ± 0.1 to 1.2 ± 0.1 ml/min per 100 g per mm Hg, P < 0.01) and increases in the zero flow pressure intercept (37.3 ± 1.4 to 51.2 ± 2.1 mm Hg, P < 0.01) of the pressure-flow curves.These changes were not observed when autoregulation was abolished with intracoronary adenosine.Diastolic pressure-flow curves obtained under constant pressure conditions were also linear in the basal state and during maximum coronary vasodilation (r = 0.98 ± 0.01).Increasing initial coronary artery pressure from 75 to 125 mm Hg resulted in a decrease in the slope (1.6 ± 0.1 to 0.9 ± 0.0 ml/ min per 100 g per mm Hg, P < 0.01) and an increase in the zero flow pressure intercept (21.1 ± 2.1 to 37.2 ± 2.3 mm Hg, P < 0.01) of the pressure-flow curves.With maximum coronary vasodilation, the slope increased to 4.7 ± 0.1 ml/min per 100 g per mm Hg (P < 0.001) and the zero flow pressure intercept decreased to 15.2 ± 0.7 mm Hg (P < 0.001).When pressure-flow curves obtained with pressure gradually decreasing were compared to ones obtained during constant pressure perfusion, the constant pressure values for slope averaged 10-25% lower (P < 0.01), whereas values for the zero flow pressure intercept were 8-12 mm Hg lower (P < 0.01).These data indicate that diastolic coronary artery pressure-flow relations obtained when pressure is continuously changing are influenced by coronary vascular capacitance.When capacitance effects were minimized, the slope and zero flow pressure intercept of the diastolic pressure-flow curves were dependent on coronary vasomotor tone, with the zero flow pressure intercept ranging from 15 to 37 mm Hg.These data are consistent with a vascular waterfall model of diastolic flow regulation.Based on such a model, we estimate that changes in coronary vascular resistance and zero flow pressure intercept can account for 70-80% and 20-30%, respectively, of the coronary autoregulation observed over the pressure range of 75 to 125 mm Hg.
MK5 activates <i>Rag</i> transcription via Foxo1 in developing B cells
Authors: Kwan T. Chow, Greg A. Timblin, Sarah M. McWhirter, Mark S. Schlissel
Journal: The Journal of Experimental Medicine (2013)

Foxo1 is a critical, direct regulator of Rag (recombination activating gene) transcription during B cell development and is thus essential for the generation of a diverse repertoire of antigen receptors. Although Foxo1 regulation has been widely studied in many cell types, pathways regulating Foxo1 in B cells have not been fully elucidated. By screening a panel of Foxo1 mutants, we identified serine 215 on Foxo1 as a novel phosphorylation site that is essential for the activation of Rag transcription. Mutation of S215 strongly attenuated transactivation of Rag but did not affect most other Foxo1 target genes. We show that MK5, a MAPK-activated protein kinase, is a previously unidentified upstream regulator of Foxo1. MK5 was necessary and sufficient to activate Rag transcription in transformed and primary pro–B cells. Together, our experiments show that MK5 positively regulates Rag transcription via phosphorylation of Foxo1 in developing B cells.
Metal-rich Ambient Particles (Particulate Matter<sub>2.5</sub>) Cause Airway Inflammation in Healthy Subjects
Authors: Frank Schaumann, Paul J. A. Borm, Andreas Herbrich, Johannes Knoch, Mike Pitz, Roel P. F. Schins, Birgit Luettig, Jens M. Hohlfeld, Joachim Heinrich, Norbert Krug
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Epidemiologic studies have shown an increased prevalence of allergic asthma in children living in a German smelter area (Hettstedt) compared with a cohort who live in a nonindustrialized area (Zerbst). However, it is not known whether ambient particles (particulate matter2.5 [PM2.5]) from these areas induce distinct lung inflammation, which might be an explanation for this difference. Therefore, 100 μg of PM2.5 suspensions, collected simultaneously in the two areas, were instilled through a bronchoscope into contralateral lung segments of 12 healthy volunteers. PM2.5 from both Hettstedt and Zerbst increased the number of leukocytes in the bronchoalveolar lavage performed 24 hours later. PM2.5 from Hettstedt, but not Zerbst, induced a significant influx of monocytes (Hettstedt: 7.0% vs. Zerbst: 4.3%) without influencing the expression of surface activation markers on monocytes and alveolar macrophages. Oxidant radical generation of bronchoalveolar lavage cells and cytokine concentration (interleukin-6 and tumor necrosis factor-α) in bronchoalveolar lavage fluid was significantly increased after instillation of Hettstedt PM2.5. We conclude that environmentally relevant concentrations of PM2.5 from the smelter area induced distinct airway inflammation in healthy subjects with a selective influx of monocytes and increased generation of oxidant radicals. The higher concentration of transition metals in PM2.5 from Hettstedt might be responsible for this increased inflammation.
Association of Diagnostic Radiation Exposure and Second Abdominal-Pelvic Malignancies After Testicular Cancer
Authors: Carl van Walraven, Dean Fergusson, Craig Earle, Nancy Baxter, Shabbir Alibhai, Blair MacDonald, Alan J. Forster, Ilias Cagiannos
Journal: Journal of Clinical Oncology (2011)

The evidence associating cancer risk with diagnostic radiation exposure is unclear. Men recovering from low-grade testicular cancer frequently undergo serial abdominal-pelvic computerized tomography (CT) scanning to monitor for recurrent disease.We used population-based administrative data sets to identify every incident case of testicular cancer between 1991 and 2004 in Ontario, Canada. We excluded those with previous cancer, concurrent radiation therapy, retroperitoneal lymph node dissection, or fewer than 5 years observation. Patients were observed until the occurrences of death or development of a second abdominal-pelvic malignancy or until December 31, 2009.A total of 2,569 men (mean age, 34.7 years; standard deviation, 10.2) were observed for a median of 11.2 years (interquartile range [IQR], 8.3 to 14.3). During the first 5 years after diagnosis, men underwent a median of 10 computed tomography (CT) scans (IQR, 4 to 18) of the abdominal-pelvic area, and they were exposed to a median of 110 mSv of radiation from radiologic investigations (IQR, 44 to 190). After this, 14 men were diagnosed with a second abdominal-pelvic malignancy (rate, five per 10,000 patient-years observation, 95% CI, three to eight); the most common diagnoses were colorectal and kidney malignancies. Radiation exposure was not associated with an excess risk of second cancers (hazard ratio per 10 mSv increase, 0.99; 95% CI, 0.95 to 1.04). This association did not change if men observed for fewer than 5 years were included in the analysis (hazard ratio, 1.00; 95% CI, 0.96 to 1.04).Second malignancies of the abdomen-pelvis are uncommon in men with low-grade testicular cancer. In this study, the risk of second cancer was not associated with the amount of diagnostic radiation exposure.
Brugada Syndrome Behind Complete Right Bundle-Branch Block
Authors: Yoshiyasu Aizawa, Seiji Takatsuki, Motoaki Sano, Takehiro Kimura, Nobuhiro Nishiyama, Kotaro Fukumoto, Yoko Tanimoto, Kojiro Tanimoto, Mitsushige Murata, Takashi Komatsu, Hideo Mitamura, Satoshi Ogawa, Toshikazu Funazaki, Masahito Sato, Yoshifusa Aizawa, Keiichi Fukuda
Journal: Circulation (2013)

Background— The characteristic ECG of Brugada syndrome (BS) can be masked by complete right bundle-branch block (CRBBB) and exposed by resolution of the block or pharmacological or pacing maneuvers. Methods and Results— The study consisted of 11 patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB, on the resolution of CRBBB, or from new characteristic ST-segment changes that could be attributable to BS. Structural heart diseases were excluded, and coronary spasm was excluded on the basis of a provocation test at catheterization. In 7 patients, BS was diagnosed before the development of CRBBB. BS was diagnosed when CRBBB resolved spontaneously (n=1) or by right ventricular pacing (n=3). The precipitating cause for the spontaneous resolution of CRBBB, however, was not apparent. On repeated ECGs, new additional upward-convex ST-segment elevation was found in V 2 or V 3 in 3 patients. In 2 patients, new ST-segment elevation was induced by class I C drugs. The QRS duration was more prolonged in patients with BS and CRBBB compared with age- and sex-matched controls: 170±13 versus 145±15 milliseconds in V 1 and 144±19 versus 128±7 milliseconds in V 5 (both P &lt;0.0001). The amplitude of R in V 1 was larger in the BS patients than in the control subjects ( P =0.0323), but that of R′ was similar ( P =0.0560). Conclusions— BS can coexist behind CRBBB, and CRBBB can completely mask BS. BS might be demonstrated by relief of CRBBB or by spontaneous or drug-induced ST-segment elevation. The prevalence, mechanism, and clinical significance of a combination of CRBBB and BS are yet to be determined.
Human Papillomavirus Type 16-Positive Cervical Cancer Is Associated with Impaired CD4+ T-Cell Immunity against Early Antigens E2 and E6
Authors: Annemieke de Jong, Mariëtte I. E. van Poelgeest, Jeanette M. van der Hulst, Jan Wouter Drijfhout, Gert Jan Fleuren, Cornelis J. M. Melief, Gemma Kenter, Rienk Offringa, Sjoerd H. van der Burg
Journal: Cancer Research (2004)

Abstract Cervical cancer is the possible outcome of genital infection with high-risk human papillomavirus (HPV) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Fortunately, the majority of genital HPV infections are cleared before the development of (pre)malignant lesions. Analysis of CD4+ T-helper (Th) immunity against the E2, E6, and E7 antigens of HPV16 in healthy women revealed strong proliferative E2- and E6-specific responses associated with prominent IFN-γ and interleukin 5 secretion. This indicates that the naturally arising virus-induced immune response displays a mixed Th1/Th2 cytokine profile. Of all HPV16+ cervical cancer patients, approximately half failed to mount a detectable immune response against the HPV16-derived peptides. The other half of the patients showed impaired HPV16-specific proliferative responses, which generally lacked both IFN-γ and interleukin 5. This indicates that the HPV16-specific CD4+ T-cell response in cervical cancer patients is either absent or severely impaired, despite a relatively good immune status of the patients, as indicated by intact responses against recall antigens. It is highly conceivable that proper CD4+ T-cell help is important for launching an effective immune attack against HPV because infection of cervical epithelia by this virus is, at least initially, not accompanied by gross disturbance of this tissue and/or strong proinflammatory stimuli. Therefore, our observations concerning the lack of functional HPV16-specific CD4+ T-cell immunity in patients with cervical cancer offer a possible explanation for the development of this disease.
Characterization of thrombin receptor expression during vascular lesion formation.
Authors: J N Wilcox, J Rodriguez, R Subramanian, J Ollerenshaw, C Zhong, D J Hayzer, C Horaist, S R Hanson, A Lumsden, T A Salam
Journal: Circulation Research (1994)

Blood vessels respond to injury by initiating cell proliferation and migration that result in vascular lesion formation. To determine the roles of thrombin and the thrombin receptor in this process, we characterized thrombin receptor expression in normal and injured arteries, thrombin receptor-mediated smooth muscle cell mitogenesis, and the regulation of thrombin receptor mRNA expression in vitro. Thrombin receptor mRNA was not detected in normal rat or baboon arteries by in situ hybridization. Immunohistochemistry using an antithrombin receptor antibody (TR-R9), directed against the thrombin cleavage site of the rat aortic smooth muscle cell thrombin receptor, revealed low-level staining for thrombin receptor protein in endothelial cells and smooth muscle cells of normal arteries. In contrast, balloon catheter injury increased thrombin mRNA expression in medial smooth muscle cells within 6 hours. This increased thrombin receptor expression continued within the media and in neointimal cells throughout vascular lesion formation, predominantly in areas of active cell proliferation. In vitro, alpha-thrombin stimulates rat aortic smooth muscle cell proliferation in a concentration-dependent manner. That thrombin receptor activation is required for the mitogenic response was confirmed by demonstrating that the polyclonal antibody TR-R9 inhibits thrombin-induced cell proliferation. Thrombin receptor mRNA synthesis was induced by both basic fibroblast growth factor (maximal stimulation of 1.8-fold at 1 hour) and platelet-derived growth factor (maximal stimulation of 2.4-fold at 8 and 24 hours) in quiesced cultured rat aortic smooth muscle cells. In summary, upregulation of smooth muscle cell thrombin receptor expression occurs very early after vascular injury and continues throughout neointimal development.(ABSTRACT TRUNCATED AT 250 WORDS)