tbuckley/cabot-search huggingface dataset:
Clinical Characteristics and Outcome of Patients With Extracutaneous Mycosis Fungoides
Authors: Ellen C. de Coninck, Youn H. Kim, Anna Varghese, Richard T. Hoppe
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To identify prognostic factors predictive of outcome in patients with extracutaneous (stage IV) mycosis fungoides (MF) and to evaluate the risk of progression to extracutaneous disease by initial extent of skin involvement. PATIENTS AND METHODS: One hundred twelve patients with extracutaneous disease at presentation or with progression and 434 patients with initial cutaneous-only disease were identified. Actuarial survival curves were plotted according to the Kaplan-Meier technique. RESULTS: The median survival of all stage IV patients was 13 months from the date of first treatment for stage IV disease. Sex, race, age, extent of skin involvement, and peripheral blood Sezary cell involvement were not significant to survival outcome. Eleven patients (10%) had a complete response to therapy resulting in a significantly improved median survival compared with patients with a partial or no response (1.70 v 0.91 years, P = .047 and 1.70 v 0.57 years, P = .011, respectively). At 20 years from diagnosis, the risk for progression to extracutaneous disease by initial extent of skin involvement was 0% for limited patch/plaque, 10% for generalized patch/plaque, 35.5% for tumorous disease, and 41% for erythrodermic involvement. CONCLUSION: This was a larger scale study over a longer time period than had been completed previously on extracutaneous MF. Prognostic factors important in the cutaneous stages of disease are no longer significant once extracutaneous disease develops. Patients who had a more favorable response to therapy may have had a biologically less aggressive disease than their less fortunate counterparts. The risk of developing stage IV MF is highest in patients presenting with tumorous or erythrodermic skin disease and is lowest in patients with limited skin involvement.
Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer
Authors: Shunsuke Kondo, Satoshi Iwata, Taketo Yamada, Yusuke Inoue, Hiromi Ichihara, Yoshiko Kichikawa, Tomoki Katayose, Akiko Souta-Kuribara, Hiroto Yamazaki, Osamu Hosono, Hiroshi Kawasaki, Hirotoshi Tanaka, Yuichiro Hayashi, Michiie Sakamoto, Kazunori Kamiya, Nam H. Dang, Chikao Morimoto
Journal: Clinical Cancer Research (2012)

In a substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs.We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγ(null) mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival.Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis.
Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia
Authors: Mark A. Weiss, Peter G. Maslak, Joseph G. Jurcic, David A. Scheinberg, Timothy B. Aliff, Nicole Lamanna, Stanley R. Frankel, Steven E. Kossman, Denise Horgan
Journal: Journal of Clinical Oncology (2003)

Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs.We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m(2). Seventeen patients received cyclophosphamide 600 mg/m(2), and six patients received cyclophosphamide 900 mg/m(2). Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy.The cyclophosphamide 900 mg/m(2) dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m(2) as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy.Pentostatin 4 mg/m(2) with cyclophosphamide 600 mg/m(2) is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.
Computed Tomography Screening and Lung Cancer Outcomes
Authors: Peter B. Bach, James R. Jett, Ugo Pastorino, Melvyn S. Tockman, Stephen J. Swensen, Colin B. Begg
Journal: JAMA (2007)

ContextCurrent and former smokers are currently being screened for lung cancer with computed tomography (CT), although there are limited data on the effect screening has on lung cancer outcomes. Randomized controlled trials assessing CT screening are currently under way.ObjectiveTo assess whether screening may increase the frequency of lung cancer diagnosis and lung cancer resection or may reduce the risk of a diagnosis of advanced lung cancer or death from lung cancer.Design, Setting, and ParticipantsLongitudinal analysis of 3246 asymptomatic current or former smokers screened for lung cancer beginning in 1998 either at 1 of 2 academic medical centers in the United States or an academic medical center in Italy with follow-up for a median of 3.9 years.InterventionAnnual CT scans with comprehensive evaluation and treatment of detected nodules.Main Outcome MeasuresComparison of predicted with observed number of new lung cancer cases, lung cancer resections, advanced lung cancer cases, and deaths from lung cancer.ResultsThere were 144 individuals diagnosed with lung cancer compared with 44.5 expected cases (relative risk [RR], 3.2; 95% confidence interval [CI], 2.7-3.8; P&lt;.001). There were 109 individuals who had a lung resection compared with 10.9 expected cases (RR, 10.0; 95% CI, 8.2-11.9; P&lt;.001). There was no evidence of a decline in the number of diagnoses of advanced lung cancers (42 individuals compared with 33.4 expected cases) or deaths from lung cancer (38 deaths due to lung cancer observed and 38.8 expected; RR, 1.0; 95% CI, 0.7-1.3; P = .90).ConclusionsScreening for lung cancer with low-dose CT may increase the rate of lung cancer diagnosis and treatment, but may not meaningfully reduce the risk of advanced lung cancer or death from lung cancer. Until more conclusive data are available, asymptomatic individuals should not be screened outside of clinical research studies that have a reasonable likelihood of further clarifying the potential benefits and risks.
A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome
Authors: Guoqing Wei, Wanmao Ni, Jen-wei Chiao, Zhen Cai, He Huang, Delong Liu
Journal: Journal of Hematology & Oncology (2011)

The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched literature on CAG between 1995 and 2010 and performed a meta-analysis to determine its overall efficacy using a random-effects or fixed-effects model. Thirty five trials with a total of 1029 AML (n = 814) and MDS (n = 215) patients were included for analysis. The CR rate of AML (57.9%) was significantly higher than that of MDS (45.7%) (p < 0.01). No difference in CR was noted between the new (56.7%) and relapsed/refractory AML (60.1%) (p > 0.05). The CR rate was also significantly higher in patients with favorable (64.5%) and intermediate (69.6%) karyotypes than those with unfavorable one (29.5%) (p < 0.05). Remarkably, the CR rate of CAG was significantly higher than those of non-CAG regimens (odds ratio 2.43). CAG regimen was well tolerated, with cardiotoxicity in 2.3% and early death in 5.2% of the cases. In conclusion, CAG regimen was an effective and safe regimen for the treatment of AML, and may be more effective than non-CAG regimens. Randomized controlled trials are strongly recommended to evaluate its efficacy and safety in comparison with the current standard treatment.
Early Identification of Recipients With Progressive Histologic Recurrence of Hepatitis C After Liver Transplantation
Authors: Raghavakaimal Sreekumar, Alvaro Gonzalez-Koch, Yaakov Maor-Kendler, Kenneth Batts, Laura Moreno-Luna, John Poterucha, Lawrence Burgart, Russell Wiesner, Walter Kremers, Charles Rosen, Michael R. Charlton
Journal: Hepatology (2000)

Approximately half of patients undergoing liver transplantation (LT) for hepatitis C virus (HCV) develop histologic evidence of recurrence within the first postoperative year. Early identification of recipients at risk for more severe recurrence of HCV may be useful in selecting patients for antiviral therapy. We determined whether recipients at greatest risk for more severe recurrence of HCV can be identified by pre– and/or early post–LT HCV–RNA levels in serum or tissue. Serum and tissue samples were prospectively collected pre–LT and at 7 days, 4 months, 1 year, and at 3 years posttransplantation from patients undergoing LT for HCV. Hepatitis activity index (HAI) and fibrosis stage (FS) were assessed in all liver biopsies. Forty–seven patients (32 men) were studied. Higher HCV–RNA levels at 4 months post–LT (≥10 9 copies/mL, n = 29) were associated with higher HAI at 1 year and at 3 years post–LT. The HAI seen on protocol biopsies at 4 months correlated significantly with fibrosis stage (FS) at 1 year ( r = .56, P ≤ .001) and 3 years ( r = .53, P = .002). Higher HCV–RNA levels at 7 days and 4 months post–LT were sensitive (66% and 84%, respectively) and specific (92% and 63%, respectively) in identifying recipients with an HAI greater than 3 at 3 years. Higher pre– and early post–LT HCV–RNA levels are associated with more severe recurrence of HCV. The correlation of early HAI with subsequent FS suggests that higher mean HAI will eventually translate into more advanced stages of fibrosis. Patients at risk for more severe post–LT recurrence of HCV can be identified by early posttransplant HCV–RNA levels.
The HSP90 Inhibitor Ganetespib Synergizes with the MET Kinase Inhibitor Crizotinib in both Crizotinib-Sensitive and -Resistant MET-Driven Tumor Models
Authors: Naoto Miyajima, Shinji Tsutsumi, Carole Sourbier, Kristin Beebe, Mehdi Mollapour, Candy Rivas, Soichiro Yoshida, Jane B. Trepel, Ying Huang, Manabu Tatokoro, Nobuo Shinohara, Katsuya Nonomura, Len Neckers
Journal: Cancer Research (2013)

The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers.
THE EFFECT OF PHYSICAL EXERCISE ON MUSCULO-SKELETAL METABOLISM: A SYSTEMATIC REVIEW OF THE ROLE OF RANK/RANKL/OPG PATHWAY
Authors: Nikolaos Keramaris, Nikolaos Malliaropoulos, Nat Padhiar, John King, Nicola Maffulli
Journal: British Journal of Sports Medicine (2013)

Background The effect of physical exercise on bone metabolism has been thoroughly discussed and a positive correlation between physical exercise and Bone Mineral Density (BMD) has been established. At the one hand many issues have not been entirely clarified: the impact of exercise on biochemical (especially novel like RANK/RANKL/OPG) markers of bone metabolism and mainly the type of exercise (high or low impact exercise, intensity of training). At the other hand, it is interesting to note that the aforementioned pathway is related not only to bone (and musculo-skeletal in general) metabolism, but also to cardiovascular metabolism and it is thought to be one of the possible causative links of the positive correlation between osteoporosis and cardiovascular disease. Methods The literature search was performed via the internet using the Medline, Scopus and Cochrane database. The key words which were searched in the abstracts were the terms “RANK”, “RANKL”, “OPG”, “physical exercise”, “sports”, “osteoporosis markers”, “bone turnover markers”. Results Our systematic review of the literature revealed 7 (seven) papers concerning the relationship of RANK/RANKL/OPG pathway with sports and physical exercise. The general trend observed in most papers was that physical exercise and sports activity have a positive impact in the RANK/RANKL/OPG pathway. It is important to note that extremely intense exercise (marathon running and beyond) might have detrimental effect on the pathway thus influencing negatively bone metabolism. Four (4) papers were focused on fit persons and intense training whether the rest three (3) papers were focused on exercise for obese or postmenopausal individuals. Conclusions The role of RANK/RANKL/OPG pathway in both bone/musculo-skeletal and cardiovascular metabolism has rather recently been studied. The possible positive influence of exercise on this pathway might have valuable positive effect on both metabolical systems. The further clarification of the exact pattern of exercise that might have the most significant impact on the RANK/RANKL/OPG pathway is needed, but our review points out that high impact (but not extremely intense) exercise is more beneficiary.
Spatial Analysis of Air Pollution and Mortality in California
Authors: Michael Jerrett, Richard T. Burnett, Bernardo S. Beckerman, Michelle C. Turner, Daniel Krewski, George Thurston, Randall V. Martin, Aaron van Donkelaar, Edward Hughes, Yuanli Shi, Susan M. Gapstur, Michael J. Thun, C. Arden Pope
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Although substantial scientific evidence suggests that chronic exposure to ambient air pollution contributes to premature mortality, uncertainties exist in the size and consistency of this association. Uncertainty may arise from inaccurate exposure assessment.To assess the associations of three types of air pollutants (fine particulate matter, ozone [O3], and nitrogen dioxide [NO2]) with the risk of mortality in a large cohort of California adults using individualized exposure assessments.For fine particulate matter and NO2, we used land use regression models to derive predicted individualized exposure at the home address. For O3, we estimated exposure with an inverse distance weighting interpolation. Standard and multilevel Cox survival models were used to assess the association between air pollution and mortality.Data for 73,711 subjects who resided in California were abstracted from the American Cancer Society Cancer Prevention II Study cohort, with baseline ascertainment of individual characteristics in 1982 and follow-up of vital status through to 2000. Exposure data were derived from government monitors. Exposure to fine particulate matter, O3, and NO2 was positively associated with ischemic heart disease mortality. NO2 (a marker for traffic pollution) and fine particulate matter were also associated with mortality from all causes combined. Only NO2 had significant positive association with lung cancer mortality.Using the first individualized exposure assignments in this important cohort, we found positive associations of fine particulate matter, O3, and NO2 with mortality. The positive associations of NO2 suggest that traffic pollution relates to premature death.
Molecular Pathways: Estrogen Pathway in Colorectal Cancer
Authors: Afsaneh Barzi, Annika Medea Lenz, Melissa J. Labonte, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2013)

Abstract Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% [95% confidence interval (CI), 0.38–0.81; P = 0.003]. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03–0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents. Clin Cancer Res; 19(21); 5842–8. ©2013 AACR.
RCAS/SCL-TVA Animal Model Allows Targeted Delivery of Polyoma Middle T Oncogene to Vascular Endothelial Progenitors <i>In vivo</i> and Results in Hemangioma Development
Authors: Justin Sausville, Alfredo A. Molinolo, Xiangfei Cheng, Jon Frampton, Naoko Takebe, J. Silvio Gutkind, Ricardo A. Feldman
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To recapitulate the generation of cancer stem cells in the context of an intact animal using a retroviral vector capable of in vivo delivery of oncogenes to primitive endothelial and hematopoietic stem cells. Experimental Design: Targeting of these progenitors was achieved using transgenic mice in which the avian TVA retroviral receptor was placed under the control of the stem cell leukemia (scl/tal-1) gene promoter and SCL +19 enhancer. Results: Injection of an avian retrovirus encoding polyoma middle T (PyMT), an oncogene that transforms endothelial cells, caused rapid lethality in all SCL-TVA mice but not in control TVA(−) littermates. The infected animals exhibited hemorrhagic foci in several organs. Histopathologic analysis confirmed the presence of hemangiomas and the endothelial origin of the PyMT-transformed cells. Surprisingly, the transformed endothelial cells contained readily detectable numbers of TVA(+) cells. By contrast, normal blood vessels had very few of these cells. The presence of TVA(+) cells in the lesions suggests that the cells originally infected by PyMT retained stem cell characteristics. Further analysis showed that the tumor cells exhibited activation of the phosphatidylinositol 3-kinase/Akt and S6/mammalian target of rapamycin pathways, suggesting a mechanism used by PyMT to transform endothelial progenitors in vivo. Conclusions: We conclude that this experimental system can specifically deliver oncogenes to vascular endothelial progenitors in vivo and cause a fatal neoplastic disease. This animal model should allow the generation of endothelial cancer stem cells in the natural environment of an immunocompetent animal, thereby enabling the recapitulation of genetic alterations that are responsible for the initiation and progression of human malignancies of endothelial origin.
Activation of the adhesive capacity of CR3 on neutrophils by endotoxin: dependence on lipopolysaccharide binding protein and CD14.
Authors: S D Wright, R A Ramos, A Hermanowski-Vosatka, P Rockwell, P A Detmers
Journal: The Journal of Experimental Medicine (1991)

Tumor necrosis factor alpha, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and formyl peptide were each found to cause a twofold increase in expression of CD14 on the surface of polymorphonuclear leukocytes (PMN). Upregulation of CD14 was complete by 20 min and thus appeared to result from expression of preformed stores of protein. The CD14 on the surface of PMN was shown to serve two biological functions. It bound particles coated with complexes of lipopolysaccharide (LPS) and LPS binding protein (LBP). This binding activity was enhanced by agonists that upregulated CD14 expression and may serve in the clearance of Gram-negative bacteria opsonized with LBP. Interaction of CD14 with LPS in the presence of LBP or serum also caused a dramatic, transient increase in the adhesive activity of CR3 (CD11b/CD18) on PMN. Enhanced activity of CR3 and other members of the CD11/CD18 family underlies many of the known physiological responses of PMN to LPS and may be a central feature of the in vivo responses of PMN to endotoxin.
Glucocorticoid response elements and 11β-hydroxysteroid dehydrogenases in the regulation of endothelial nitric oxide synthase expression
Authors: Yong Liu, Domagoj Mladinov, Jennifer L. Pietrusz, Kristie Usa, Mingyu Liang
Journal: Cardiovascular Research (2008)

AimsHypertensive and other effects of excess glucocorticoids might be in part mediated by the suppression of endothelial nitric oxide synthase (eNOS) expression. We studied the transcriptional and biochemical mechanisms that mediate or modulate the suppression of eNOS expression by glucocorticoids.