tbuckley/cabot-search huggingface dataset:
Tasigna for Chronic and Accelerated Phase Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia Resistant to or Intolerant of Imatinib
Authors: Maitreyee Hazarika, Xiaoping Jiang, Qi Liu, Shwu-Luan Lee, Roshni Ramchandani, Christine Garnett, Micheal S. Orr, Rajeshwari Sridhara, Brian Booth, John K. Leighton, William Timmer, Ravi Harapanhalli, Ramzi Dagher, Robert Justice, Richard Pazdur
Journal: Clinical Cancer Research (2008)

Abstract Purpose: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib. Experimental Design: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response. Results: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling. Conclusions: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.
Multiple UPGMA and Neighbor-joining Trees and the Performance of Some Computer Packages
Authors: T. Backeljau, L. De Bruyn, H. De Wolf, K. Jordaens, S. Van Dongen, B. Winnepennincks
Journal: Molecular Biology and Evolution (1996)

*Royal Belgian Institute of Natural Sciences, Brussels; and TDepartments of Biology and SBiochemistry, University of Antwerp Although the unweighted pair-group method using arithmetic averages (UPGMA) and neighbor-joining (NJ) algo- rithms are designed to produce single trees, they may derive more than one topology from a single matrix, depending on the order of data entry. This “chaotic” behavior is due to ties, the effects of which are rarely considered. Therefore we present examples of ties and show that multiple UPGMA and NJ trees cannot be neglected with molecular data based on allozyme distances or “binary” distances derived from random amplified polymorphic DNA, restriction fragments, DNA fingerprints, or general protein patterns. We also compare the performance of 15 computer packages with respect to ties. Five programs recognize the problem (PHYLIP MVSP SAS, SYN-TAX, and NTSYS) but deal with it in different ways. We further point out that if ties are not properly taken into account, they might affect bootstrap and jackknife confidence estimates. Finally, we observed that NTSYS, PHYLIP MVSP and MVSP87 have different efficiencies in finding ties, and that some programs, including MEGA, may produce single alternative UPGMA topologies, probably due to their different rounding precisions or tie tolerances.
Elevated Transforming Growth Factor- α Levels in Bronchoalveolar Lavage Fluid of Patients with Acute Respiratory Distress Syndrome
Authors: DAVID K. MADTES, GORDON RUBENFELD, LAWRENCE D. KLIMA, JOHN A. MILBERG, KENNETH P. STEINBERG, THOMAS R. MARTIN, GANESH RAGHU, LEONARD D. HUDSON, JOAN G. CLARK
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The acute respiratory distress syndrome (ARDS) frequently results in a fibroproliferative response that precludes effective alveolar repair. Transforming growth factor-alpha (TGF-alpha), a potent epithelial and mesenchymal cell mitogen, may modulate the response to lung injury. In this study, we determined whether bronchoalveolar lavage fluid (BALF) concentrations of TGF-alpha are increased during the first 2 wk after the onset of ARDS and, if so, whether increased TGF-alpha levels in lavage fluid are associated with increased levels of procollagen peptide III (PCP III), a biological marker of fibroproliferation, and with increased fatality rates. We enrolled 74 consecutive patients with ARDS prospectively identified on admission to the intensive care unit of a tertiary care hospital, and 11 patients with chronic interstitial lung disease. Thirteen healthy volunteers served as control subjects. TGF-alpha concentrations were measured in BALF recovered on Days 3, 7, and 14 after the onset of ARDS (total of 130 lavage samples). TGF-alpha was detected in the lavage fluid of 90% of patients with ARDS (67 of 74), and in 100% of patients with idiopathic pulmonary fibrosis (IPF) (10 of 10), but in none of 13 normal volunteers. At each day tested, the median lavage TGF-alpha level of patients with ARDS was significantly higher than that of normals. The overall fatality rate was 45% (33 of 74 patients). In a univariate analysis, the median TGF-alpha levels in nonsurvivors were 1.5-fold higher at Day 7 (p = 0.06) and 1.8-fold higher at Day 14 (p = 0.048). The fatality rate was 4 times higher (CI 1.6, 17.5) for patients with both increased lavage TGF-alpha and PCP III concentrations at Day 7 than for patients with low TGF-alpha and PCP III values, indicating a synergistic relationship between TGF-alpha and PCP III. We conclude that increased levels of TGF-alpha in BALF are common in patients with ARDS and that lavage TGF-alpha is associated with a marker of the fibroproliferative response in sustained ARDS.
18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) visualizes follicular lymphoma irrespective of grading
Authors: S. Wöhrer, U. Jaeger, K. Kletter, A. Becherer, A. Hauswirth, K. Turetschek, M. Raderer, M. Hoffmann
Journal: Annals of Oncology (2006)
Role of flow cytometry immunophenotyping in the diagnosis of leptomeningeal carcinomatosis
Authors: Dolores Subirá, Cristina Serrano, Susana Castañón, Raquel Gonzalo, Julia Illán, Javier Pardo, María Martínez-García, Esther Millastre, Francisco Aparisi, Miguel Navarro, Manuel Dómine, Ignacio Gil-Bazo, Pedro Pérez Segura, Miguel Gil, Jordi Bruna
Journal: Neuro-Oncology (2011)

Purpose: To explore the contribution of flow cytometry immunophenotyping (FCI) in detecting leptomeningeal disease in patients with solid tumors. Experimental design: Cerebrospinal fluid (CSF) samples from 78 patients who received a diagnosis of epithelial-cell solid tumors and had clinical data suggestive of leptomeningeal carcinomatosis (LC) were studied. A novel FCI protocol was used to identify cells expressing the epithelial cell antigen EpCAM and their DNA content. Accompanying inflammatory cells were also described. FCI results (positive or negative for malignancy) were compared with those from CSF cytology and with the diagnosis established by the clinicians: patients with LC (n = 49), without LC (n = 26), and undetermined (n = 3). Results: FCI described a wide range of EpCAM-positive cells with a hyperdiploid DNA content in the CSF of patients with LC. Compared with cytology, FCI showed higher sensitivity (75.5 vs 65.3) and negative predictive value (67.6 vs 60.5), and similar specificity (96.1 vs 100) and positive predictive value (97.4 vs 100). Concordance between cytology and FCI was high (Kp = 0.83), although misdiagnosis of LC did not show differences between evaluating the CSF with 1 or 2 techniques (P = .06). Receiver-operator characteristic curve analyses showed that lymphocytes and monocytes had a different distribution between patients with and without LC. Conclusion: FCI seems to be a promising new tool for improving the diagnostic examination of patients with suspicion of LC. Detection of epithelial cells with a higher DNA content is highly specific of LC, but evaluation of the nonepithelial cell compartment of the CSF might also be useful for supporting this diagnosis.
Evidence for Fusion Between Cardiac and Skeletal Muscle Cells
Authors: Hans Reinecke, Elina Minami, Veronica Poppa, Charles E. Murry
Journal: Circulation Research (2004)

Cardiomyoplasty with skeletal myoblasts may benefit cardiac function after infarction. Recent reports indicate that adult stem cells can fuse with other cell types. Because myoblasts are “fusigenic” cells by nature, we hypothesized they might be particularly likely to fuse with cardiomyocytes. To test this, neonatal rat cardiomyocytes labeled with LacZ and green fluorescent protein (GFP) were cocultured with unlabeled C2C12 myoblasts. After 3 days, we observed a small population of skeletal myotubes that expressed LacZ and GFP, indicating cell fusion. To test whether such fusion occurred in vivo, LacZ-expressing C2C12 myoblasts were grafted into normal nude mouse hearts. At 2 weeks after grafting, cells at the graft-host interface expressed both LacZ and cardiac-specific myosin light chain 2v (MLC2v). To test more definitively whether fusion between skeletal and cardiac muscle could occur, we used a Cre/lox reporter system that activated LacZ only upon cell fusion. When neonatal cardiomyocytes from α-myosin heavy chain promoter (α-MHC)-Cre mice were cocultured with myoblasts from floxed-lacZ reporter mice, LacZ was activated in a subset of cells, indicating cell fusion occurred in vitro. Finally, we grafted the floxed-lacZ myoblasts into normal hearts of α-MHC-Cre + and α-MHC-Cre − mice (n=5 each). Hearts analyzed at 4 days and 1 week after transplantation demonstrated activation of LacZ when the skeletal muscle cells were implanted into hearts of α-MHC-Cre + mice, but not after implantation into α-MHC-Cre − mice. These data indicate that skeletal muscle cell grafting gives rise to a subpopulation of skeletal-cardiac hybrid cells with a currently unknown phenotype. The full text of this article is available online at http://circres.ahajournals.org .
Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells
Authors: Hideaki Tanizaki, Gyohei Egawa, Kayo Inaba, Tetsuya Honda, Saeko Nakajima, Catharina Sagita Moniaga, Atsushi Otsuka, Toshimasa Ishizaki, Michio Tomura, Takeshi Watanabe, Yoshiki Miyachi, Shuh Narumiya, Takaharu Okada, Kenji Kabashima
Journal: Blood (2010)
Phase II Study of the Anti-Cytotoxic T-Lymphocyte–Associated Antigen 4 Monoclonal Antibody, Tremelimumab, in Patients With Refractory Metastatic Colorectal Cancer
Authors: Ki Y. Chung, Ira Gore, Lawrence Fong, Alan Venook, Stephen B. Beck, Prudence Dorazio, Peggy J. Criscitiello, Diane I. Healey, Bo Huang, Jesus Gomez-Navarro, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2010)

Safety and efficacy of tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer.A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status <or= 1 and measurable colorectal carcinoma for whom standard treatments for metastatic disease had failed. Patients received 15 mg/kg tremelimumab intravenously every 90 days until progression. Primary end point was objective response status (per Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival, and overall survival.Forty-seven patients who had received extensive prior therapies (all had received fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which resolved spontaneously or with interventions. Six patients discontinued because of an AE; two were considered treatment related. Of 45 response-evaluable patients, 44 did not reach second dose (43 progressive disease; one discontinuation). Twenty-one patients (45%) lived >or= 180 days after enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass (partial response). This patient received five tremelimumab doses; response duration was 6 months (enrollment to disease progression, 15 months).Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting. Further study of tremelimumab in combination with other agents may be warranted.
Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro
Authors: V M Diaz
Journal: Gut (2004)

Overexpression of tissue plasminogen activator (t-PA) in pancreatic cancer cells promotes invasion and proliferation in vitro and tumour growth and angiogenesis in vivo.To understand the mechanisms by which t-PA favours cancer progression, we analysed the surface membrane proteins responsible for binding specifically t-PA and studied the contribution of this interaction to the t-PA promoted invasion of pancreatic cancer cells.The ability of t-PA to activate plasmin and a fluorogenic plasmin substrate was used to analyse the nature of the binding of active t-PA to cell surfaces. Specific binding was determined in two pancreatic cancer cell lines (SK-PC-1 and PANC-1), and complex formation analysed by co-immunoprecipitation experiments and co-immunolocalisation in tumours. The functional role of the interaction was studied in Matrigel invasion assays.t-PA bound to PANC-1 and SK-PC-1 cells in a specific and saturable manner while maintaining its activity. This binding was competitively inhibited by specific peptides interfering with the interaction of t-PA with annexin II. The t-PA/annexin II interaction on pancreatic cancer cells was also supported by co-immunoprecipitation assays using anti-t-PA antibodies and, reciprocally, with antiannexin II antibodies. In addition, confocal microscopy showed t-PA and annexin II colocalisation in tumour tissues. Finally, disruption of the t-PA/annexin II interaction by a specific hexapeptide significantly decreased the invasive capacity of SK-PC-1 cells in vitro.t-PA specifically binds to annexin II on the extracellular membrane of pancreatic cancer cells where it activates local plasmin production and tumour cell invasion. These findings may be clinically relevant for future therapeutic strategies based on specific drugs that counteract the activity of t-PA or its receptor annexin II, or their interaction at the surface level.
Pulmonary Diseases and the Heart
Authors: MeiLan K. Han, Vallerie V. McLaughlin, Gerard J. Criner, Fernando J. Martinez
Journal: Circulation (2007)

The complex nature of interactions between the pulmonary and cardiovascular systems is becoming increasingly appreciated. Pulmonary vascular abnormalities are frequently present in patients with respiratory disorders, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, sarcoidosis, neuromuscular or chest wall disorders, and disorders of ventilatory control including sleep apnea syndromes and obesity hypoventilation syndrome. Pulmonary hypertension, classified as group III in the World Health Organization classification scheme for pulmonary hypertension, may result in severe right ventricular dysfunction caused by lung disease, also known as cor pulmonale. The development of cor pulmonale is generally associated with poorer prognosis and increased death. Systemic manifestations of lung disease, particularly obstructive disorders, are also particularly relevant because they are associated with increased cardiac death and impaired health status. This article will discuss the most common pulmonary diseases and disorders of ventilatory control that cause pulmonary vascular abnormalities and cor pulmonale, with particular concentration on how treatment of these diseases may affect the heart. In addition, the complex nature of cardiac and lung disease will also be explored, particularly with respect to the relationship between chronic obstructive pulmonary disease, systemic inflammation, atherosclerosis, and cardiovascular death, which is currently a very active focus of research.
A Quality-Based Review of Randomized Controlled Trials of Psychodynamic Psychotherapy
Authors: Andrew J. Gerber, James H. Kocsis, Barbara L. Milrod, Steven P. Roose, Jacques P. Barber, Michael E. Thase, Patrick Perkins, Andrew C. Leon
Journal: American Journal of Psychiatry (2010)

The Ad Hoc Subcommittee for Evaluation of the Evidence Base for Psychodynamic Psychotherapy of the APA Committee on Research on Psychiatric Treatments developed the Randomized Controlled Trial Psychotherapy Quality Rating Scale (RCT-PQRS). The authors report results from application of the RCT-PQRS to 94 randomized controlled trials of psychodynamic psycho-therapy published between 1974 and May 2010.Five psychotherapy researchers from a range of therapeutic orientations rated a single published paper from each study.The RCT-PQRS had good interrater reliability and internal consistency. The mean total quality score was 25.1 (SD=8.8). More recent studies had higher total quality scores. Sixty-three of 103 comparisons between psychodynamic psychotherapy and a nondynamic comparator were of "adequate" quality. Of 39 comparisons of a psychodynamic treatment and an "active" comparator, six showed dynamic treatment to be superior, five showed dynamic treatment to be inferior, and 28 showed no difference (few of which were powered for equivalence). Of 24 adequate comparisons of psychodynamic psychotherapy with an "inactive" comparator, 18 found dynamic treatment to be superior.Existing randomized controlled trials of psychodynamic psychotherapy are promising but mostly show superiority of psychodynamic psychotherapy to an inactive comparator. This would be sufficient to make psychodynamic psychotherapy an "empirically validated" treatment (per American Psychological Association Division 12 standards) only if further randomized controlled trials of adequate quality and sample size replicated findings of existing positive trials for specific disorders. We do not yet know what will emerge when other psychotherapies are subjected to this form of quality-based review.
Cancer cell-specific photoactivity of pheophorbide a–glycol chitosan nanoparticles for photodynamic therapy in tumor-bearing mice
Authors: In-hyeok Oh, Hyun Su Min, Li Li, Thanh Huyen Tran, Yong-kyu Lee, Ick Chan Kwon, Kuiwon Choi, Kwangmeyung Kim, Kang Moo Huh
Journal: Biomaterials (2013)
Superinfection of chimpanzees carrying hepatitis C virus of genotype II/1b with that of genotype III/2a or I/1a
Authors: Hiroaki Okamoto, Shunji Mishiro, Hajime Tokita, Fumio Tsuda, Yuzo Miyakawa, Makoto Mayumi
Journal: Hepatology (1994)

Three chimpanzees persistently infected with hepatitis C virus of genotype II/1b were challenged with hepatitis C virus of genotype III/2a and 6 wk later with hepatitis C virus of genotype I/1a. They were tested for titers of total and genotype-specific hepatitis C virus RNA, as well as for serum transaminase levels, until 52 wk after the first challenge. One chimpanzee (CH489) with intermittent low hepatitis C virus RNA titers of genotype II/1b in serum was superinfected with hepatitis C virus of genotype III/2a between wk 1 and 7 after the challenge; superinfection was accompanied by fluctuating high transaminase levels. Later, the animal was superinfected with hepatitis C virus of genotype I/1a. Superinfection was accompanied by persistently high transaminase levels immediately after the challenge. Hepatitis C virus of genotype I/1a persisted, whereas hepatitis C virus of genotype II/1b was undetectable 22 wk after the challenge and thereafter. In another chimpanzee (CH353) with intermittent low hepatitis C virus RNA titers of genotype II/1b, hepatitis C virus of genotype III/2a induced fluctuating high levels of serum transaminases without revealing itself in serum. Then, HCV of genotype I/1a superinfected her, induced persistently high transaminase levels and took over HCV of genotype II/1b at 22 wk after the challenge and thereafter. The third chimpanzee (CH451) with persistently high HCV RNA titers of genotype II/1b did not reveal HCV RNA of genotype III/2a in serum after the challenge, although transaminases sharply increased. Low-titered HCV RNA of genotype I/1a was detected at 18 wk after the challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
Early Intensive Care Sedation Predicts Long-Term Mortality in Ventilated Critically Ill Patients
Authors: Yahya Shehabi, Rinaldo Bellomo, Michael C. Reade, Michael Bailey, Frances Bass, Belinda Howe, Colin McArthur, Ian M. Seppelt, Steve Webb, Leonie Weisbrodt
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Choice and intensity of early (first 48 h) sedation may affect short- and long-term outcome.To investigate the relationships between early sedation and time to extubation, delirium, and hospital and 180-day mortality among ventilated critically ill patients in the intensive care unit (ICU).Multicenter (25 Australia and New Zealand hospitals) prospective longitudinal (ICU admission to 28 d) cohort study of medical/surgical patients ventilated and sedated 24 hours or more. We assessed administration of sedative agents, ventilation time, sedation depth using Richmond Agitation Sedation Scale (RASS, four hourly), delirium (daily), and hospital and 180-day mortality. We used multivariable Cox regression to quantify relationships between early deep sedation (RASS, -3 to -5) and patients' outcomes.We studied 251 patients (mean age, 61.7 ± 15.9 yr; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score, 20.8 ± 7.8), with 21.1% (53) hospital and 25.8% (64) 180-day mortality. Over 2,678 study days, we completed 14,736 RASS assessments. Deep sedation occurred in 191 (76.1%) patients within 4 hours of commencing ventilation and in 171 (68%) patients at 48 hours. Delirium occurred in 111 (50.7%) patients with median (interquartile range) duration of 2 (1-4) days. After adjusting for diagnosis, age, sex, APACHE II, operative, elective, hospital type, early use of vasopressors, and dialysis, early deep sedation was an independent predictor of time to extubation (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.94; P < 0.001), hospital death (HR, 1.11; 95% CI, 1.02-1.20; P = 0.01), and 180-day mortality (HR, 1.08; 95% CI, 1.01-1.16; P = 0.026) but not delirium occurring after 48 hours (P = 0.19).Early sedation depth independently predicts delayed extubation and increased mortality, making it a potential target for interventional studies.