tbuckley/cabot-search huggingface dataset:
Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism.
Authors: P K Peterson, G Gekker, C C Chao, S X Hu, C Edelman, H H Balfour, J Verhoef
Journal: Journal of Clinical Investigation (1992)

Human cytomegalovirus (HCMV) is a potential cofactor in HIV-1 infection. To investigate the mechanism whereby HCMV promotes HIV-1 replication, a PBMC coculture assay which measures HIV-1 p24 antigen release was used as an index of viral replication. HCMV-stimulated PBMC were capable of inducing HIV-1 replication in cocultures with acutely infected PBMC; however, this occurred only when the PBMC were from HCMV-seropositive donors (598 +/- 207 versus 27 +/- 10 pg/ml p24 antigen with PBMC from HCMV-seronegative donors on day 6 of coculture). Upon stimulation with HCMV, PBMC obtained exclusively from HCMV-seropositive donors released tumor necrosis factor (TNF)-alpha (270 +/- 79 pg/ml at 18 h of culture). Monoclonal antibodies to TNF-alpha blocked the activity of HCMV-stimulated PBMC in cocultures both with acutely HIV-1-infected PBMC and with the chronically infected promonocytic line U1. Also, treatment of HCMV-stimulated PBMC with pentoxifylline, an inhibitor of TNF-alpha mRNA, markedly reduced HIV-1 replication in cocultures both with acutely and chronically infected cells. These results indicate that TNF-alpha is a key mediator of HIV-1 replication induced by HCMV-stimulated PBMC and support the concept that this cytokine plays an important role in the pathogenesis of HIV-1 infection.
Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma
Authors: Sith Sathornsumetee, Annick Desjardins, James J. Vredenburgh, Roger E. McLendon, Jennifer Marcello, James E. Herndon, Alyssa Mathe, Marta Hamilton, Jeremy N. Rich, Julie A. Norfleet, Sridharan Gururangan, Henry S. Friedman, David A. Reardon
Journal: Neuro-Oncology (2010)

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.
Persistent Overall Survival Benefit and No Increased Risk of Second Malignancies With Bortezomib-Melphalan-Prednisone Versus Melphalan-Prednisone in Patients With Previously Untreated Multiple Myeloma
Authors: Jesús F. San Miguel, Rudolf Schlag, Nuriet K. Khuageva, Meletios A. Dimopoulos, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria Teresa Petrucci, Antonio Palumbo, Olga S. Samoilova, Anna Dmoszynska, Kudrat M. Abdulkadyrov, Michel Delforge, Bin Jiang, Maria-Victoria Mateos, Kenneth C. Anderson, Dixie-Lee Esseltine, Kevin Liu, William Deraedt, Andrew Cakana, Helgi van de Velde, Paul G. Richardson
Journal: Journal of Clinical Oncology (2012)

This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients.After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates.VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.
Erythropoietic protoporphyria in the house mouse. A recessive inherited ferrochelatase deficiency with anemia, photosensitivity, and liver disease.
Authors: S Tutois, X Montagutelli, V Da Silva, H Jouault, P Rouyer-Fessard, K Leroy-Viard, J L Guénet, Y Nordmann, Y Beuzard, J C Deybach
Journal: Journal of Clinical Investigation (1991)

A viable autosomal recessive mutation (named fch, or ferrochelatase deficiency) causing jaundice and anemia in mice arose in a mutagenesis experiment using ethylnitrosourea. Homozygotes (fch/fch) display a hemolytic anemia, photosensitivity, cholestasis, and severe hepatic dysfunction. Protoporphyrin is found at high concentration in erythrocytes, serum, and liver. Ferrochelatase activity in various tissues is 2.7-6.3% of normal. Heterozygotes (+/fch) are not anemic and have normal liver function; they are not sensitive to light exposure; ferrochelatase activity is 45-65% of normal. Southern blot analysis using a ferrochelatase cDNA probe reveals no gross deletion of the ferrochelatase gene. This is the first spontaneous form of erythropoietic protoporphyria in the house mouse. Despite the presence in the mouse of clinical and biochemical features infrequent in the human, this mutation may represent a model for the human disease, especially in its severe form.
Persistent airway hyperresponsiveness and histologic alterations after chronic antigen challenge in cats.
Authors: P Padrid, S Snook, T Finucane, P Shiue, P Cozzi, J Solway, A R Leff
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

We studied the effect of chronic immune sensitization on the airway reactivity and associated cytologic and histologic alterations in initially nonatopic cats, a species that spontaneously develops idiopathic asthma. Seven cats were sensitized by intramuscular injection of Ascaris suum antigen (AA) for 4 wk, and four other cats served as sham controls. Airway sensitization was demonstrated by an increased response to nebulized AA in sensitized animals (RL = 45.9 +/- 6.1 cm H2O/L/s, versus a baseline response of 24.7 +/- 1.5 cm H2O/L/s, p < 0.01), and hyperresponsiveness was demonstrated by an increased response to acetylcholine (ACh)-challenge 24 h after AA (approximately 1.0 log decrease in PD200, p < 0.01). The number of eosinophils in the sensitized animals' bronchoalveolar lavage (BAL) fluid increased 12-fold (p < 0.01 versus control) in response to AA challenge; 32 +/- 5% of the BAL eosinophils had a specific density < 1.050, versus 8 +/- 2% prior to AA challenge (p < 0.05). There was no change in airway reactivity, eosinophil recovery, or density in the control group 24 h after sham challenge with saline. The same seven sensitized cats further received nebulized AA three times weekly for 4 to 6 wk, after which BAL samples were again obtained and ACh dose-response curves generated 72 h after the final administration of nebulized AA. Airway hyperresponsiveness increased (approximately 1.5 log decrease in PD200, p < 0.001) and the number of eosinophils recovered in BAL fluid was increased 11-fold (p < 0.05). Necropsy specimens demonstrated bronchoconstriction in AA-challenged animals but not controls; luminal narrowing was accompanied by: (1) a 29.0 +/- 0.34% increase in smooth-muscle thickness (p < 0.05); (2) goblet-cell and submucosal-gland hypertrophy and hyperplasia; and (3) epithelial erosion and eosinophilic infiltration. We demonstrate in nonhuman species persistent airway hyperreactivity associated with a complete constellation of histologic changes in epithelium, smooth muscle, and mucus glands, and cytologic changes in BAL fluid, all induced by immune sensitization. Our data suggest that chronic immune sensitization per se could be a salient factor in causing many of the changes associated with chronic bronchial asthma.
Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma
Authors: Wei-Gang Tong, Rong Chen, William Plunkett, David Siegel, Rajni Sinha, R. Donald Harvey, Ashraf Z. Badros, Leslie Popplewell, Steven Coutre, Judith A. Fox, Kristi Mahadocon, Tianling Chen, Peggy Kegley, Ute Hoch, William G. Wierda
Journal: Journal of Clinical Oncology (2010)

SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy.Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course.There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m(2), and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m(2), owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis.SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.
Reply to the letters to the editor ‘Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma’ by Diwakar et al.
Authors: B. Schilling, W. Sondermann, K.G. Griewank, E. Livingstone, L. Zimmer, U. Hillen, D. Schadendorf
Journal: Annals of Oncology (2014)
Mode of onset of ventricular fibrillation in patients with Brugada syndrome detected by implantable cardioverter defibrillator therapy
Authors: Mikio Kakishita, Takashi Kurita, Kiyotaka Matsuo, Atsushi Taguchi, Kazuhiro Suyama, Wataru Shimizu, Naohiko Aihara, Shiro Kamakura, Fumio Yamamoto, Junjiro Kobayashi, Yoshio Kosakai, Tohru Ohe
Journal: Journal of the American College of Cardiology (2000)
Polymorphisms of the <b> <i>CYP1B1</i> </b> Gene as Risk Factors for Human Renal Cell Cancer
Authors: Masahiro Sasaki, Yuichiro Tanaka, Steven T. Okino, Mitsuharu Nomoto, Suguru Yonezawa, Masayuki Nakagawa, Seiichiro Fujimoto, Noriaki Sakuragi, Rajvir Dahiya
Journal: Clinical Cancer Research (2004)

Abstract Purpose: CYP1B1 activates various environmental carcinogens in human tissues, including renal tissues. We hypothesize that certain polymorphisms of the CYP1B1 gene are risk factors for renal cell cancer. The rationale for this hypothesis is that chemical procarcinogenic compounds require metabolic activation by oxidative enzymes such as CYP1B1 to be transformed into potentially carcinogenic forms. To test this hypothesis, we investigated the genotypic distributions of six different loci on the CYP1B1 gene and their association with renal cell cancer. Experimental Design: DNA from 211 cases of human renal cell cancer and 200 healthy controls was analyzed by sequence-specific PCR and direct DNA sequencing to determine the genotypic frequencies of six different polymorphic loci on the CYP1B1 gene. Results: The results of this study demonstrate that the frequencies of genotype 119T/T and genotype 432G/G were significantly higher in renal cell cancer patients compared with healthy normal controls. The relative risks were calculated as 3.01 and 2.17 for genotypes 119T/T and 432G/G, respectively, in renal cell carcinoma patients. These genotypic distributions were also significantly different between male and female patients. The relative risks of genotype 119T/T were calculated as 3.95 in males and 1.92 in females, and the relative risks of genotype 432G/G were calculated as 2.81 in males and 1.35 in females. Conclusions: The present study demonstrates for the first time that the polymorphisms at codons 119 and 432 may be risk factors for renal cancer, especially in the male population.
Convulsions in Childhood
Authors: T. W. Buchan
Journal: BMJ (1950)

The following method was used.A small enema was given to constipated children a few hours before the pro- posed administration, to help the absorption of the drug and minimize the risk of its return after injection.No food was given for at least three hours before the thiopentone was due.A hypodermic injection of atropine, 1/150 or 1/100 gr. (0.43 or 0.65 mg.), was given half an hour before the thiopentone in almost all cases.This is not essential, but is useful in controlling salivation.The thiopentone was dissolved in 20 to 40 ml. of warm tap-water and injected with a syringe slowly into the rectum by a rubber catheter.This injection took at least five minutes to complete.Afterwards the buttocks were held or strapped together to prevent some of the drug being returned.When this was not prevented, half the original dose was given half an hour later, if the child was not sufficiently sedated.The dose employed was 1 g. per 50 lb. of body weight.A detailed schedule is given in the accompanying Table .Dosage Schedule of Thiopentone for Children Weighing up to 52+ lb. Weight of ChildDose of Thiopentone lb.kg.
Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Authors: M. Nitter, B. Norgård, S. de Vogel, S.J.P.M. Eussen, K. Meyer, A. Ulvik, P.M. Ueland, O. Nygård, S.E. Vollset, T. Bjørge, A. Tjønneland, L. Hansen, M. Boutron-Ruault, A. Racine, V. Cottet, R. Kaaks, T. Kühn, A. Trichopoulou, C. Bamia, A. Naska, S. Grioni, D. Palli, S. Panico, R. Tumino, P. Vineis, H.B. Bueno-de-Mesquita, H. van Kranen, P.H. Peeters, E. Weiderpass, M. Dorronsoro, P. Jakszyn, M. Sánchez, M. Argüelles, J.M. Huerta, A. Barricarte, M. Johansson, I. Ljuslinder, K. Khaw, N. Wareham, H. Freisling, T. Duarte-Salles, M. Stepien, M.J. Gunter, E. Riboli
Journal: Annals of Oncology (2014)
Tubercle Bacilli and Urea
Authors: S. L. Cummins
Journal: BMJ (1945)

MEDBRATSoURNAL841dysfunction, and recent infection.Pregnant and nursing mothers were also excluded.The apparatus used for the dark-adaptation test was that described by Yudkin (1941b), with the addition of a means of stabilizing the voltage.The procedure was as follows:Method.-Each subject was generally examined as indicated above, and the test explained and demonstrated.They were put into the dark-room at 10-minute intervals.Before entering the dark-room no subject had been in the hospital less than half an hour, to safe- guard against the effects of exposure to previous high brightnesses (Craik and Vernon, 1942).At the 'end of the first subject's 30 minutes' dark-adaptation time the test was made, and so on with the remainder at 10-minute intervals.By this arrangeme-nt the intervals between subjects entering the dark-room and being tested were balanced so that all were dark-adapted for 30 minutes.The test object (arrow) was first shown at a brightness which could be seen fairly easily, and the brightness decreased until the threshold reading was obtained.The test was then continued to 40 minutes.As under the conditions of the test the expected difference between the readings at 30 minutes' and 40 minutes' dark-adaptation time is not more than 0.1 pylll log unit, subjects showing greater amounts than this were re-tested.In addition all readings of 3.83 ,u,ul log units and over were confirmed.The threshold measurements of brightness seen at 30 minutes' dark-adaptation time expressed as log yybl were those taken.a
Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.
Authors: J Watkins, E C Abbott, C N Hensby, J Webster, C T Dollery
Journal: BMJ (1980)

<h3>Abstract</h3> <h3>Background</h3> Chronic liver disease is a growing epidemic leading to fibrosis and cirrhosis. TGF-β is the pivotal pro-fibrogenic cytokine which activates hepatic stellate cells (HSC), yet, other molecules can substantially modulate TGF-β signalling in the course of liver fibrosis. Expression of the axon guidance molecules Semaphorins (SEMAs), which signal through Plexins and Neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. However, their function in the regulation of HSCs has not yet been described. <h3>Results</h3> SEMA3C is the most enriched member of the Semaphorin family in liver samples from cirrhotic patients. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis or HBV-induced hepatitis discriminates those with a more pro-fibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs upon activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-β-mediated myofibroblast activation, as shown by increased SMAD2/3 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained upon activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. <h3>Conclusion</h3> SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.
HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4
Authors: Karen E. Strunk, Carty Husted, Leah C. Miraglia, Melissa Sandahl, William A. Rearick, Debra M. Hunter, H. Shelton Earp, Rebecca S. Muraoka-Cook
Journal: Cancer Research (2007)

Abstract Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80HER4, containing nuclear localization sequences) and results in G2-M delay by unknown signaling mechanisms. We report herein that s80HER4 contains a functional cyclin B–like sequence known as a D-box, which targets proteins for degradation by anaphase-promoting complex (APC)/cyclosome, a multisubunit ubiquitin ligase. s80HER4 ubiquitination and proteasomal degradation occurred during mitosis but not during S phase. Inhibition of an APC subunit (APC2) using short interfering RNA knockdown impaired s80HER4 degradation. Mutation of the s80HER4 D-box sequence stabilized s80HER4 during mitosis, and s80HER4-dependent growth inhibition via G2-M delay was significantly greater with the D-box mutant. Polyomavirus middle T antigen–transformed HC11 cells expressing s80HER4 resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80HER4 or the empty vector. Cells expressing s80HER4 with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle–dependent degradation of s80HER4 limits its growth-inhibitory action, and stabilization of s80HER4 enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control. [Cancer Res 2007;67(14):6582–90]
Conventional-Dose Versus High-Dose Chemotherapy As First Salvage Treatment in Male Patients With Metastatic Germ Cell Tumors: Evidence From a Large International Database
Authors: Anja Lorch, Caroline Bascoul-Mollevi, Andrew Kramar, Lawrence Einhorn, Andrea Necchi, Christophe Massard, Ugo De Giorgi, Aude Fléchon, Kim Margolin, Jean-Pierre Lotz, Jose Ramon Germà-Lluch, Thomas Powles, Christian Kollmannsberger, Jörg Beyer
Journal: Journal of Clinical Oncology (2011)

Purpose Conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) may both be successfully used as salvage treatment for patients with metastatic germ cell tumors (GCTs) who experience progression with first-line treatment. Patients and Methods Data on 1,984 patients with GCTs who experienced progression after at least three cisplatin-based cycles and were treated with either cisplatin-based CDCT or carboplatin-based HDCT chemotherapy were collected from 38 centers or groups worldwide. Of 1,984 patients, 1,594 (80%) were eligible, and among the eligible patients, 1,435 (90%) could reliably be classified into one of the following five prognostic categories based on prior prognostic classification: very low (n = 76), low (n = 257), intermediate (n = 646), high (n = 351), and very high risk (n = 105). Within each of the five categories, the progression-free survival (PFS) and overall survival (OS) after CDCT and HDCT were compared using the Cox model adjusted for significant distributional differences between important variables. Results Overall, 773 patients received CDCT, and 821 patients received HDCT. Both treatment modalities were used with similar frequencies within each prognostic category. The hazard ratio for PFS was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for OS was 0.65 (95% CI, 0.56 to 0.75), favoring HDCT. These results were consistent within each prognostic category except among low-risk patients, for whom similar OS was observed between the two treatment groups. Conclusion This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.