tbuckley/cabot-search huggingface dataset:
A Phase I Study of Sunitinib Plus Capecitabine in Patients With Advanced Solid Tumors
Authors: Christopher J. Sweeney, E. Gabriela Chiorean, Claire F. Verschraegen, Fa Chyi Lee, Suzanne Jones, Melanie Royce, Lesley Tye, Katherine F. Liau, Akintunde Bello, Richard Chao, Howard A. Burris
Journal: Journal of Clinical Oncology (2010)

This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors.Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m(2)) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts.Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m(2) twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m(2) twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1).The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.
Sorafenib Inhibits Non–Small Cell Lung Cancer Cell Growth by Targeting B-RAF in <i>KRAS</i> Wild-Type Cells and C-RAF in <i>KRAS</i> Mutant Cells
Authors: Ken Takezawa, Isamu Okamoto, Kimio Yonesaka, Erina Hatashita, Yuki Yamada, Masahiro Fukuoka, Kazuhiko Nakagawa
Journal: Cancer Research (2009)

Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non-small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G(1) arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G(1) arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G(1) arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G(1) arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G(1) arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS.
Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling
Authors: Katia M.S. Gomes, Juliane C. Campos, Luiz R.G. Bechara, Bruno Queliconi, Vanessa M. Lima, Marie-Helene Disatnik, Paulo Magno, Che-Hong Chen, Patricia C. Brum, Alicia J. Kowaltowski, Daria Mochly-Rosen, Julio C.B. Ferreira
Journal: Cardiovascular Research (2014)

AimsWe previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model.
Clinical Significance of Intracytoplasmic nm23-H1 Expression in Diffuse Large B-Cell Lymphoma
Authors: Nozomi Niitsu, Hirokazu Nakamine, Masataka Okamoto, Hiroko Akamatsu, Masaaki Higashihara, Yoshio Honma, Junko Okabe-Kado, Masami Hirano
Journal: Clinical Cancer Research (2004)

Recently, we established an ELISA technique for measuring nm23-H1 protein in serum and found that the serum nm23-H1 level is a potential prognostic factor for patients with non-Hodgkin's lymphoma.We used immunohistochemistry to examine the expression of nm23-H1 by the lymphoma cells in patients with diffuse large B-cell lymphoma (DLBCL).By analyzing a consecutive series of 172 untreated DLBCL patients, we found that 100 (58.1%) were strongly positive. The cytoplasmic nm23 expression in lymphoma cells correlated significantly with the serum nm23-H1 level. There was a significant correlation between patients with cytoplasmic nm23-positive lymphoma and those with performance status 2-4, stage III/IV, bulky mass, B symptoms, elevated serum level of soluble interleukin 2 receptor, and elevated serum level of C-reactive protein. Overall and progression-free survival rates were significantly lower in patients with nm23-H1-positive lymphomas than in those with nm23-H1-negative lymphomas. Similar difference was seen between patients with high and low serum levels of nm23-H1. Thus, the correlation between presence or absence of cytoplasmic nm23-H1 expression and serum nm23-H1 levels suggests that serum nm23-H1 is produced directly by lymphoma cells.We suggest that nm23-H1 expression is a prognostic factor for DLBCL, and that it is as important as serum nm23-H1, both of which are useful for planning a treatment strategy.
An active pregnancy for fetal well-being? The value of active living for most women and their babies
Authors: Zachary M Ferraro, Andree Gruslin, Kristi B Adamo
Journal: British Journal of Sports Medicine (2012)

Prenatal life is recognised as a critical period where vital physiological processes may be permanently transformed leading to altered susceptibility to disease risk later in life.1 Accordingly, fetal adaptive responses to the maternal milieu, including the in utero effect of a physically active pregnancy, may influence the long-term health and well-being of the developing child. Is there potentially lifelong significance of maternal exercise on fetal health?

Although the recent study published in BJSM by Salvesen et al 2 is timely with respect to the fetal response to extreme levels of maternal exertion in competitive Olympic hopefuls, it has limited applicability to the maternal population at large who are mostly inactive.3 The latter may benefit the most from a physically active, healthful pregnancy. In their study examining fetal response and utero-placental blood flow during strenuous treadmill running in the second trimester, Salvesen et al 2 note that fetal HR was within the normal range as long as maternal exertion was below 90% maternal HRmax; an exercise intensity that few women would routinely work at, nor would be encouraged in a typical maternal population. If maternal HR exceeded 90% of maximum value and uterine artery blood flow was simultaneously less than 50% the initial value, fetal bradycardia occurred. However, despite these concerns, following exercise cessation fetal HR reached baseline values, uterine artery flow volume improved to resting values in most women and all birthweights were within the lower normal range for Norwegian children, which is encouraging.

Salvasen and …
Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma
Authors: H Matsumoto
Journal: Thorax (2005)

The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction.Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by radicalBSA of a segmental bronchus (T/ radicalBSA), was examined.Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/ radicalBSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/ radicalBSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume.Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.
Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis
Authors: Eric Chevet, Claudio Hetz, Afshin Samali
Journal: Cancer Discovery (2015)

Abstract Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth. Significance: ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical efficacy with an acceptable safety profile. Cancer Discov; 5(6); 586–97. ©2015 AACR.
<i>Cgnz1</i> allele confers kidney resistance to damage preventing progression of immune complex–mediated acute lupus glomerulonephritis
Authors: Yan Ge, Chao Jiang, Sun-Sang J. Sung, Harini Bagavant, Chao Dai, Hongyang Wang, Carol C. Kannapell, Helen P. Cathro, Felicia Gaskin, Shu Man Fu
Journal: The Journal of Experimental Medicine (2013)

Cgnz1 and Agnz1 on the distal region of mouse chromosome 1 are associated with chronic glomerulonephritis (cGN) and acute GN (aGN). NZM2328.Lc1R27 (R27) was generated by introgressing a C57L/J region where Cgnz1 is located to NZM2328. R27 female mice developed aGN mediated by immune complex (IC) deposition and complement activation without progression to cGN with severe proteinuria. End stage renal disease (ESRD) was not seen in R27 mice as old as 15 mo. Thus, aGN and cGN are under separate genetic control, and IC-mediated proliferative GN need not progress to cGN and ESRD. NZM2328 and R27 female mice have comparable immune and inflammatory parameters. In contrast to NZM2328, R27 mice were resistant to sheep anti–mouse GBM serum-induced nephritis, supporting the hypothesis that aGN is mediated by autoimmunity and resistance to the development of cGN is mediated by end organ resistance to damage. Thus, autoimmunity should be considered distinct from end organ damage. The Cgnz1 region has been mapped to a 1.34 MB region with 45 genes. Nine candidate genes were identified. Clinical relevance of these observations is supported by case studies. Clinical implications and the significance to human lupus and other diseases are presented.
Prevalence and Impact of Bronchiectasis in α<sub>1</sub>-Antitrypsin Deficiency
Authors: David G. Parr, Peter G. Guest, John H. Reynolds, Lee J. Dowson, Robert A. Stockley
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: α1-Antitrypsin (AAT) deficiency is associated with increased risk of chronic obstructive pulmonary disease (COPD), in particular emphysema, but airway disease is less well described.Objectives: To assess the prevalence of airways disease in subjects with AAT deficiency and to identify the relationship between radiological airway abnormalities and clinical phenotype.Methods: We characterized the computed tomographic phenotype of 74 subjects (PiZ), using visual scoring of airway disease and densitometric assessment of emphysema. Computed tomographic measurements were related to physiology, health status (St. George's Respiratory Questionnaire), and emphysema severity, and the relative impact of airway disease and emphysema severity on health status and airflow obstruction was compared by stepwise regression.Measurements and Main Results: Bronchiectatic changes were seen in 70 subjects, and a subgroup with a bronchiectasis-predominant phenotype was identified. Clinically significant bronchiectasis (radiologic bronchiectasis in 4 or more bronchopulmonary segments together with symptoms of regular sputum production) occurred in 20 subjects (27%). AAT-deficient index cases had higher airway disease scores (P < 0.05), more severe emphysema (P < 0.001), and greater impairment of physiology (P < 0.001) and health status (P < 0.05) than nonindex cases. Airway disease scores correlated with health status, and bronchial wall thickening correlated with FEV1. Regression analysis indicated that emphysema severity had the strongest associations for health status (r = 0.505, P < 0.001) and FEV1 (r = 0.699, P < 0.001), but the addition of airway disease score improved the regression models (r = 0.596, P = 0.002 and r = 0.783, P < 0.001, respectively).Conclusions: Emphysema is the predominant component of COPD in AAT deficiency, but the prevalence and impact of airway disease are greater than currently recognized. Consequently, future therapeutic strategies in AAT deficiency should also target this component of COPD.
THE EFFECTS OF EXCLUSION OF THE RIGHT VENTRICLE FROM THE CIRCULATION IN DOGS 1
Authors: John C. Rose, Salvador J. Cosimano, Charles A. Hufnagel, Edmund A. Massullo
Journal: Journal of Clinical Investigation (1955)

In experiments bearing on the relationship of "backward failure" of the right ventricle to the elevated venous pressure of clinical heart failure, Starr, Jeffers, and Meade (1) found that exten- sive cauterization of the right ventricle in dogs was not followed by a significant elevation of venous pressure.Subsequent investigations of the effects of destructive procedures on the right ventricular myocardium have led further to the conclusion that actively functioning right ventricular muscle is not necessary for the maintenance of adequate blood flow through the low pressure pulmonary circulation (2, 3).Rodbard and Wagner (4) created right atriopulmonary artery anastomoses in dogs and occluded right ventricular outflow.Blood was observed to flow directly from the right auricle to the pulmonary artery, and these animals survived up to one hour.Despite these short survivals, and without quantitatively documenting the alterations produced by this acute procedure, these authors concluded that the venous pressure may drive venous return through the lungs without benefit of the right ventricular pump.If it is possible to by-pass the right ventricle, such observations have clinical as well as basic physiologic importance.However, experiments in progress ( 5) suggest an active role by the right ventricle in the regulation and maintenance of a normal peripheral venous pressure and adequate pulmonary blood flow.Therefore, it was decided to re-investigate the veno-pulmonary anastomoses briefly studied by Rodbard and Wagner (4).1Presented (in part) at the National Meeting, American Federation for Clinical Research, Atlantic City, May 1, 1955.Supported (in part) by a U.
Benefit and Timing of Second Transplantations in Multiple Myeloma: Clinical Findings and Methodological Limitations in a European Group for Blood and Marrow Transplantation Registry Study
Authors: C. Morris, S. Iacobelli, R. Brand, B. Bjorkstrand, M. Drake, D. Niederwieser, G. Gahrton
Journal: Journal of Clinical Oncology (2004)

To use European Group for Blood and Marrow Transplantation registry data to assess the benefit and optimal timing of a double-autologous transplantation strategy for patients with myeloma.7,452 transplantation patients described as being either in a multiple graft program ("planned") or not, were analyzed on an intention-to-treat basis. Subsequent multivariate analyses concentrated on the real occurrence of second transplantation, survival, relapse, and transplant-related mortality.Although the transplantation rate in the planned group failed to reach 60%, the median survival from transplantation is 60 months for the planned, compared with 51 months for the remainder group. While the hazard ratio of the planned group is 0.89 (95% CI, 0.79 to 1.00; P =.05) before approximately 70 months, this "effect" is reversed after 70 months, with the hazard ratio estimated as 3.01 (95% CI, 1.07 to 8.46; P =.04). A time-dependent multivariate Cox analysis shows that, taking patients without a second transplantation as a reference group, those receiving a second transplantation in first remission (ie, before relapse) show an increased probability of transplant-related mortality, especially if the transplantation is performed more than 12 months after the first, and the reduction of the risk of relapse is less than when the transplantation is performed earlier. Performing a second transplantation after relapse does not seem to prolong survival, though a second transplantation before relapse is associated with a higher probability of mortality.To improve survival of tandem autologous transplantation in multiple myeloma, the second transplantation should preferably be performed before relapse and within 6 to 12 months of the first transplantation.
Bone mineral density and joint cartilage: four clinical settings of a complex relationship in osteoarthritis
Authors: G. Herrero-Beaumont, J. A. Roman-Blas, R. Largo, F. Berenbaum, S. Castaneda
Journal: Annals of the Rheumatic Diseases (2011)

Experimental and clinical data support the hypothesis that both high and low bone mineral density (BMD) conditions, including osteoporosis, may induce osteoarthritis. However, these conditions do not always predispose to osteoarthritis progression. Four clinical settings could arise from this relationship, and furthermore two phenotypes may be identified whether early osteoarthritis coexists with high or low BMD.
Differential Expression of Immune-Regulatory Genes Associated with PD-L1 Display in Melanoma: Implications for PD-1 Pathway Blockade
Authors: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, Suzanne L. Topalian
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Blocking the immunosuppressive PD-1/PD-L1 pathway has antitumor activity in multiple cancer types, and PD-L1 expression on tumor cells and infiltrating myeloid cells correlates with the likelihood of response. We previously found that IFNG (interferon-gamma) was overexpressed by tumor-infiltrating lymphocytes in PD-L1+ versus PD-L1(−) melanomas, creating adaptive immune resistance by promoting PD-L1 display. This study was undertaken to identify additional factors in the PD-L1+ melanoma microenvironment coordinately contributing to immunosuppression. Experimental Design: Archived, formalin-fixed paraffin-embedded melanoma specimens were assessed for PD-L1 protein expression at the tumor cell surface with IHC. Whole-genome expression analysis, quantitative (q)RT-PCR, IHC, and functional in vitro validation studies were used to assess factors differentially expressed in PD-L1+ versus PD-L1(−) melanomas. Results: Functional annotation clustering based on whole-genome expression profiling revealed pathways upregulated in PD-L1+ melanomas, involving immune cell activation, inflammation, and antigen processing and presentation. Analysis by qRT-PCR demonstrated overexpression of functionally related genes in PD-L1+ melanomas, involved in CD8+ T-cell activation (CD8A, IFNG, PRF1, and CCL5), antigen presentation (CD163, TLR3, CXCL1, and LYZ), and immunosuppression [PDCD1 (PD-1), CD274 (PD-L1), and LAG3, IL10]. Functional studies demonstrated that some factors, including IL10 and IL32-gamma, induced PD-L1 expression on monocytes but not tumor cells. Conclusions: These studies elucidate the complexity of immune checkpoint regulation in the tumor microenvironment, identifying multiple factors likely contributing to coordinated immunosuppression. These factors may provide tumor escape mechanisms from anti–PD-1/PD-L1 therapy, and should be considered for cotargeting in combinatorial immunomodulation treatment strategies. Clin Cancer Res; 21(17); 3969–76. ©2015 AACR.
Cancer Stem Cells in Radiation Resistance
Authors: Jeremy N. Rich
Journal: Cancer Research (2007)

Highly tumorigenic subpopulations of several solid cancers share characteristics with somatic stem cells. We showed recently that cancer stem cells, or tumor-initiating cells, derived from human glioblastoma surgical specimens and xenografts display resistance to radiation due to increased activation of the DNA damage checkpoint. We additionally showed that these same tumor subpopulations promote tumor angiogenesis through increased expression of vascular endothelial growth factor. These studies and subsequent reports from other researchers support critical roles for cancer stem cells in determining tumor response to therapy. Hypoxia and stem cell maintenance pathways may provide therapeutic targets to sensitize cancer stem cells to cytotoxic therapies to improve cancer patient treatments.
Extended Lymph-Node Dissection for Gastric Cancer
Authors: J.J. Bonenkamp, J. Hermans, M. Sasako, K. Welvaart, I. Songun, S. Meyer, J.T.M. Plukker, P. Van Elk, H. Obertop, D.J. Gouma, J.J.B. van Lanschot, C.W. Taat, P.W. de Graaf, M.F. von Meyenfeldt, H. Tilanus, C.J.H. van de Velde
Journal: New England Journal of Medicine (1999)

Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery.