tbuckley/cabot-search huggingface dataset:
Randomized Trial of Two Induction Chemotherapy Regimens in Metastatic Colorectal Cancer: An Updated Analysis
Authors: G. Masi, E. Vasile, F. Loupakis, S. Cupini, L. Fornaro, G. Baldi, L. Salvatore, C. Cremolini, I. Stasi, I. Brunetti, M. A. Fabbri, M. Puglisi, P. Trenta, C. Granetto, S. Chiara, L. Fioretto, G. Allegrini, L. Crino, M. Andreuccetti, A. Falcone
Journal: JNCI Journal of the National Cancer Institute (2010)

In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI).From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups.Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.
Risk of Kaposi's Sarcoma-Associated Herpes Virus Transmission From Donor Allografts Among Italian Posttransplant Kaposi's Sarcoma Patients
Authors: Carlo Parravicini, Sonja J. Olsen, Maria Capra, Francesca Poli, Girolamo Sirchia, Shou Jiang Gao, Emilio Berti, Arcangelo Nocera, Edardo Rossi, Giovannina Bestetti, Massimo Pizzuto, Massimo Galli, Mauro Moroni, Patrick S. Moore, Mario Corbellino
Journal: Blood (1997)
Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial
Authors: Norbert Schmitz, Beate Pfistner, Michael Sextro, Markus Sieber, Angelo M Carella, Matthias Haenel, Friederike Boissevain, Reinhart Zschaber, Peter Müller, Hartmut Kirchner, Andreas Lohri, Susanne Decker, Bettina Koch, Dirk Hasenclever, Anthony H Goldstone, Volker Diehl
Journal: The Lancet (2002)
Gelatinase expression in pulmonary arteries during experimental pulmonary hypertension
Authors: E. Frisdal, V. Gest, A. Vieillard-Baron, M. Levame, H. Lepetit, S. Eddahibi, C. Lafuma, A. Harf, S. Adnot, M-P. d'Ortho
Journal: European Respiratory Journal (2001)

Structural remodelling of pulmonary vessels is an important feature of pulmonary hypertension (PH), which reflects distal artery muscularization and matrix remodelling. The matrix metalloproteinases (MMPs) are involved in extracellular matrix turnover and hence, in smooth muscle cell migration and endothelial cell migration and proliferation. Among the MMPs, gelatinases (MMP-;2 and MMP-;9) can degrade basement membrane components and promote cell proliferation and migration. This study evaluated gelatinases in pulmonary vessels during progressive PH in two rat models: exposure to hypoxia or monocrotaline. Zymography of tissue homogenates revealed an association of progression of hypoxic PH with a time-dependent increase in gelatinase MMP-;2 activity, specific to pulmonary vessels. Increased MMP-;2 activity was also found 30 days postmonocrotaline. Reverse transcription polymerase chain reaction demonstrated upregulation of MMP-;2 messenger ribonucleic acid. Immunolocalization showed MMP-;2 throughout the pulmonary vasculature, from the trunk to the distal vessels, with strong staining of the intima, media and adventitia. MMP-;2 was found in its active form and gelatinolytic activity was correlated to PH severity. Activity localization by <i>in situ</i> zymography corroborated with the immunolocalization findings. In conclusion, the authors demonstrated that matrix metalloproteinase-;2 activity is increased in pulmonary vessels during progression of pulmonary hypertension, probably as a result of involvement in the matrix turnover associated with vascular remodelling during pulmonary hypertension.
Regulation of DNA Methyltransferase 1 by the pRb/E2F1 Pathway
Authors: Michael T. McCabe, Joanne N. Davis, Mark L. Day
Journal: Cancer Research (2005)

Abstract Tumor suppressor gene silencing by DNA hypermethylation contributes to tumorigenesis in many tumor types. This aberrant methylation may be due to increased expression and activity of DNA methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine to cytosines in CpG dinucleotides. Elevated expression of the maintenance DNA methyltransferase, DNA methyltransferase 1 (DNMT-1), has been shown in carcinomas of the colon, lung, liver, and prostate. Based on the nearly ubiquitous alterations of both DNA methylation and the retinoblastoma protein (pRb) pathway found in human cancer, we investigated a potential regulatory pathway linking the two alterations in murine and human prostate epithelial cells. Analysis of DNA methyltransferase levels in Rb−/− murine prostate epithelial cell lines revealed elevated Dnmt-1 levels. Genomic DNA sequence analysis identified conserved E2F consensus binding sites in proximity to the transcription initiation points of murine and human Dnmt-1. Furthermore, the Dnmt-1 promoter was shown to be regulated by the pRb/E2F pathway in murine and human cell lines of epithelial and fibroblast origin. In the absence of pRb, Dnmt-1 transcripts exhibited aberrant cell cycle regulation and Rb−/− cells showed aberrant methylation of the paternally expressed gene 3 (Peg3) tumor suppressor gene. These findings show a link between inactivation of the pRb pathway and induction of DNA hypermethylation of CpG island–containing genes in tumorigenesis.
Physiologic Consequences of Vasopeptidase Inhibition in Humans
Authors: Michel Azizi, Maxime Lamarre-Cliche, Agne[Combining Grave Accent]s Labatide-Alanore, Alvine Bissery, Than Tam Guyene, Joe[Combining Diaeresis]l Me[Combining Acute Accent]nard
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodium-depleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance. Email: [email protected]
A Phase I Study of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate in Patients with Advanced Hematologic Malignancies
Authors: Aaron D. Schimmer, Susan O'Brien, Hagop Kantarjian, Joseph Brandwein, Bruce D. Cheson, Mark D. Minden, Karen Yee, Farhad Ravandi, Francis Giles, Andre Schuh, Vikas Gupta, Michael Andreeff, Charles Koller, Hong Chang, Suzanne Kamel-Reid, Mark Berger, Jean Viallet, Gautam Borthakur
Journal: Clinical Cancer Research (2008)

The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose.Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies.A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence.Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial
Authors: W.W. Tan, D.W. Hillman, M. Salim, D.W. Northfelt, D.M. Anderson, P.J. Stella, R. Niedringhaus, A.M. Bernath, S.S. Gamini, F. Palmieri, E.A. Perez
Journal: Annals of Oncology (2009)
Cytokines derived from alveolar macrophages induce fever after bronchoscopy and bronchoalveolar lavage.
Authors: A Krause, B Hohberg, F Heine, M John, G R Burmester, C Witt
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

As much as one-third of patients develop fever and flu-like symptoms after fiberoptic bronchoscopy (FOB) and bronchoalveolar lavage (BAL) for yet unknown reasons. The aim of the present study was to investigate factors mediating these side effects. Fifty consecutive patients with various pulmonary diseases who underwent FOB without further interventions (n = 30) or combined with BAL (n = 20) were enrolled. Serum levels of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha were determined directly prior to (t0), directly after (t1), and 6 h after (t2) the procedures by ELISA. In parallel, blood cultures were drawn at t2. At to and t1, generally only low cytokine concentrations could be detected. At t2, however, significant increases of cytokine levels were found. IL-6 and TNF-alpha were significantly higher in patients after BAL than in patients after FOB. Comparing patients who developed fever (n = 12) with those who did not (n = 38), irrespective of the endoscopic procedures performed, dramatic increases of all three cytokines were detected in febrile patients that were significantly higher than in patients without fever. In the FOB group only patients who received local anesthesia by prilocaine bolus injection into the airways via the working channel of the bronchoscope developed fever and increases of IL-6 and IL-beta, whereas patients anaesthetized by inhalation of a prilocaine aerosol remained afebrile and had slight IL-6 increases only. There was a highly significant correlation between IL-6 values at t2 and the number of BAL alveolar macrophages (r = 0.98). All blood cultures remained sterile. These results indicate that fever after FOB and BAL is induced by proinflammatory cytokines derived from alveolar macrophages activated by instillation of fluid into the airways.
A comparative phenotypical analysis of rheumatoid nodules and rheumatoid synovium with special reference to adhesion molecules and activation markers
Authors: D. Elewaut, F. De Keyser, N. De Wever, D. Baeten, N. Van Damme, G. Verbruggen, C. Cuvelier, E. M Veys
Journal: Annals of the Rheumatic Diseases (1998)

OBJECTIVES (1)To analyse the in situ expression of adhesion molecules in rheumatoid nodules. (2) To compare the endothelial expression of adhesion molecules in synovial tissue and subcutaneous nodules obtained from the same patients. (3) To compare the expression of adhesion molecules and activation markers on T cell lines from nodules and synovium. METHODS (1) Immunohistochemical analysis by APAAP technique of E selectin, CD44, ICAM-1, PECAM-1, and VCAM-1 was performed on 10 rheumatoid nodules from seven patients with rheumatoid arthritis (RA); nodules and synovium were simultaneously analysed from three patients. (2) T cell lines were generated from RA nodules (n=7) and synovium (n=7) by interleukin 2 expansion, and subsequently characterised by flow cytometry for surface expression of αEβ7, α4β7, CD44, L selectin, LFA-1a, PECAM-1, and CD30. RESULTS (1) In rheumatoid nodules, the palisading layer strongly stains for ICAM-1 and PECAM-1, but less pronounced for CD44. VCAM-1 staining was usually negative. ICAM-1 is upregulated in the vessels surrounding the central zone of fibrinoid necrosis. The immunohistological picture in different nodules derived from the same patient was similar. (2) The endothelial expression of adhesion molecules is comparable in RA nodules and synovium on an individual level, except for E selectin, which is overexpressed in nodule endothelium. (3) T cell lines from nodules and synovium display similar adhesion molecule profiles. However, the expression of CD30, a T cell activation marker linked with Th2 subsets, is higher in nodules compared with synovium . CONCLUSION These data support a recirculation hypothesis of T cells between articular and extra-articular manifestations in RA, although the activation state of the T cells in each of these localisations may differ.
Mice Lacking Expression of the Chemokines Ccl21-Ser and Ccl19 (<i>plt</i> Mice) Demonstrate Delayed but Enhanced T Cell Immune Responses
Authors: Shigeyuki Mori, Hideki Nakano, Kentaro Aritomi, Chrong-Reen Wang, Michael D. Gunn, Terutaka Kakiuchi
Journal: The Journal of Experimental Medicine (2001)

The paucity of lymph node T cells (plt) mutation leads to a loss of CCL21 and CCL19 expression in secondary lymphoid organs. plt mice have defects in the migration of naive T cells and activated dendritic cells into the T cell zones of lymphoid organs, suggesting that they would have defects in T cell immune responses. We now demonstrate T cell responses in plt mice are delayed but ultimately enhanced. Responses to contact sensitization are decreased at day 2 after priming but increased at day 6. After subcutaneous immunization, antigen-specific T cell proliferation and cytokine production in plt mice are increased and remain markedly elevated for at least 8 wk. Compared with wild-type mice, a proportion of T cell response in plt mice are shifted to the spleen, and prior splenectomy reduces the T cell response in draining lymph nodes. After immunization of plt mice, T cells and dendritic cells colocalize in the superficial cortex of lymph nodes and in splenic bridging channels, but not in T cell zones. These results demonstrate that plt mice mount robust T cell responses despite the failure of naive T cells and activated dendritic cells to enter the thymus dependent areas of secondary lymphoid organs.
Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the Cervix
Authors: William A. Peters, P.Y. Liu, Rolland J. Barrett, Richard J. Stock, Bradley J. Monk, Jonathan S. Berek, Luis Souhami, Perry Grigsby, William Gordon, David S. Alberts
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma. PATIENTS AND METHODS: Patients with clinical stage IA 2 , IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m 2 and a 96-hour infusion of fluorouracil 1,000 mg/m 2 /d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT. RESULTS: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P = .003) and 1.96 (P = .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group. CONCLUSION: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.
Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study
Authors: Tjasa Hranjec, Laura H Rosenberger, Brian Swenson, Rosemarie Metzger, Tanya R Flohr, Amani D Politano, Lin M Riccio, Kimberley A Popovsky, Robert G Sawyer
Journal: The Lancet Infectious Diseases (2012)
Alemtuzumab As Consolidation After a Response to Fludarabine Is Effective in Purging Residual Disease in Patients With Chronic Lymphocytic Leukemia
Authors: Marco Montillo, Alessandra Tedeschi, Sara Miqueleiz, Silvio Veronese, Roberto Cairoli, Liliana Intropido, Francesca Ricci, Anna Colosimo, Barbara Scarpati, Michela Montagna, Michele Nichelatti, Mario Regazzi, Enrica Morra
Journal: Journal of Clinical Oncology (2006)

Treatment with alemtuzumab has resulted in negative responses for minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL). In a prior analysis we demonstrated that it is possible to achieved MRD negativity, as assessed by polyclonality of immunoglobulin heavy chain after consolidation with alemtuzumab. This phase II study evaluated 34 patients with CLL who received alemtuzumab consolidation in an effort to improve the quality of their response to fludarabine-based induction. Subsequent peripheral blood stem-cell (PBSC) collection and transplantation, tolerability, and pharmacokinetics also were assessed.Thirty-four patients younger than 65 years who had a clinical response to fludarabine-based induction therapy received alemtuzumab 10 mg subcutaneously three times per week for 6 weeks. PBSCs were collected after mobilization with cytarabine and granulocyte colony-stimulating factor. Blood samples for pharmacokinetics study were taken between days 1 and 31.The complete response rate improved from 35% after fludarabine induction to 79.4% after alemtuzumab consolidation, including 19 patients (56%) who achieved MRD negativity. The most common adverse events were injection-site reactions and fever. Cytomegalovirus reactivation occurred in 18 patients, all of whom were successfully treated with oral ganciclovir. PBSC collection was successful in 24 (92%) of 26 patients, and 18 patients underwent autologous PBSC transplantation. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks and accumulated more rapidly thereafter.Subcutaneously administered alemtuzumab was effective, safe, and well tolerated as consolidation therapy in patients with CLL who responded to fludarabine induction therapy. Subsequent PBSCT was feasible thereafter.
The Organellar Genome and Metabolic Potential of the Hydrogen-Producing Mitochondrion of Nyctotherus ovalis
Authors: Rob M. de Graaf, Guenola Ricard, Theo A. van Alen, Isabel Duarte, Bas E. Dutilh, Carola Burgtorf, Jan W. P. Kuiper, Georg W. M. van der Staay, Aloysius G. M. Tielens, Martijn A. Huynen, Johannes H. P. Hackstein
Journal: Molecular Biology and Evolution (2011)

It is generally accepted that hydrogenosomes (hydrogen-producing organelles) evolved from a mitochondrial ancestor. However, until recently, only indirect evidence for this hypothesis was available. Here, we present the almost complete genome of the hydrogen-producing mitochondrion of the anaerobic ciliate Nyctotherus ovalis and show that, except for the notable absence of genes encoding electron transport chain components of Complexes III, IV, and V, it has a gene content similar to the mitochondrial genomes of aerobic ciliates. Analysis of the genome of the hydrogen-producing mitochondrion, in combination with that of more than 9,000 genomic DNA and cDNA sequences, allows a preliminary reconstruction of the organellar metabolism. The sequence data indicate that N. ovalis possesses hydrogen-producing mitochondria that have a truncated, two step (Complex I and II) electron transport chain that uses fumarate as electron acceptor. In addition, components of an extensive protein network for the metabolism of amino acids, defense against oxidative stress, mitochondrial protein synthesis, mitochondrial protein import and processing, and transport of metabolites across the mitochondrial membrane were identified. Genes for MPV17 and ACN9, two hypothetical proteins linked to mitochondrial disease in humans, were also found. The inferred metabolism is remarkably similar to the organellar metabolism of the phylogenetically distant anaerobic Stramenopile Blastocystis. Notably, the Blastocystis organelle and that of the related flagellate Proteromonas lacertae also lack genes encoding components of Complexes III, IV, and V. Thus, our data show that the hydrogenosomes of N. ovalis are highly specialized hydrogen-producing mitochondria.