tbuckley/cabot-search huggingface dataset:
Bolus Versus Infusion Regimens of Etoposide and Cisplatin in Treatment of Non-Small Cell Lung Cancer: A Study of the North Central Cancer Treatment Group
Authors: R. M. Goldberg, J. R. Jett, T. M. Therneau, P. S. Johnson, L. K. Tschetter, J. E. Krook, M. H. Veeder, D. Owen, P. S Etzell, D. F. Andres
Journal: JNCI Journal of the National Cancer Institute (1990)

In an effort to test clinically the hypothesis that the duration of cellular exposure to etoposide (VP-16) and cisplatin (CDDP) is an important determinant of cytotoxicity, we performed a phase III randomized trial comparing an outpatient bolus regimen of combined VP-16 and CDDP with a sequential infusion over 72 hours of these same two drugs. All patients had stage IV non-small cell lung cancer, and survival was the primary end point Of 113 patients randomly allocated to the study, 108 were assessable for response, survival, and toxicity. A major response was observed in 20 (37%) of 54 patients on the bolus regimen and in 16 (30%) of 54 patients receiving infusion therapy. The median time to progression was 61 and 88 days for bolus and infusion therapy, respectively. The median survival time was 148 and 157 days, respectively ( P = .71). Study results were not consistent with the possibility that infusion therapy could be associated with a 50% improvement in median survival, ie, from 5 months to 7½ months. Toxicity was primarily myelosuppression and was significantly greater with the infusion regimen. We conclude that infusion therapy as tested in this protocol with VP-16 and CDDP does not offer any advantage in response rate, time to disease progression, or survival as compared with bolus therapy. In addition, infusion therapy is associated with a greater degree of neutropenia and more treatment-related deaths. [J Natl Cancer Inst 82:1899–1903,1990]
Changing Concepts: Menopausal Hormone Therapy and Breast Cancer
Authors: R. T. Chlebowski, G. L. Anderson
Journal: JNCI Journal of the National Cancer Institute (2012)

Hormone therapy is still used by millions of women for menopausal symptoms. Concerns regarding hormone therapy and breast cancer were initially based on case reports and retrospective case–control studies. However, recent results from large prospective cohort studies and the Women's Health Initiative (WHI) randomized placebo-controlled hormone therapy trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestin influence breast cancer. The preponderance of observational studies suggested that estrogen alone and estrogen plus progestin both increased the risk of breast cancer, with cancers commonly diagnosed at an early stage. However, substantially different results emerged from the WHI randomized hormone therapy trials. In the WHI trial evaluating estrogen plus progestin in postmenopausal women with an intact uterus, combined hormone therapy statistically significantly increased the risk of breast cancer and hindered breast cancer detection, leading to delayed diagnosis and a statistically significant increase in breast cancer mortality. By contrast, estrogen alone use by postmenopausal women with prior hysterectomy in the WHI trial did not substantially interfere with breast cancer detection and statistically significantly decreased the risk of breast cancer. Differential mammography usage patterns may explain differences between observational study and randomized trial results. In clinical practice, hormone therapy users have mammograms more frequently than nonusers, leading to more and earlier stage cancer detection. By contrast, in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups. Currently, the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely understood.
Independent component analysis of Alzheimer's DNA microarray gene expression data
Authors: Wei Kong, Xiaoyang Mou, Qingzhong Liu, Zhongxue Chen, Charles R Vanderburg, Jack T Rogers, Xudong Huang
Journal: Molecular Neurodegeneration (2009)

Abstract Background Gene microarray technology is an effective tool to investigate the simultaneous activity of multiple cellular pathways from hundreds to thousands of genes. However, because data in the colossal amounts generated by DNA microarray technology are usually complex, noisy, high-dimensional, and often hindered by low statistical power, their exploitation is difficult. To overcome these problems, two kinds of unsupervised analysis methods for microarray data: principal component analysis (PCA) and independent component analysis (ICA) have been developed to accomplish the task. PCA projects the data into a new space spanned by the principal components that are mutually orthonormal to each other. The constraint of mutual orthogonality and second-order statistics technique within PCA algorithms, however, may not be applied to the biological systems studied. Extracting and characterizing the most informative features of the biological signals, however, require higher-order statistics. Results ICA is one of the unsupervised algorithms that can extract higher-order statistical structures from data and has been applied to DNA microarray gene expression data analysis. We performed FastICA method on DNA microarray gene expression data from Alzheimer's disease (AD) hippocampal tissue samples and consequential gene clustering. Experimental results showed that the ICA method can improve the clustering results of AD samples and identify significant genes. More than 50 significant genes with high expression levels in severe AD were extracted, representing immunity-related protein, metal-related protein, membrane protein, lipoprotein, neuropeptide, cytoskeleton protein, cellular binding protein, and ribosomal protein. Within the aforementioned categories, our method also found 37 significant genes with low expression levels. Moreover, it is worth noting that some oncogenes and phosphorylation-related proteins are expressed in low levels. In comparison to the PCA and support vector machine recursive feature elimination (SVM-RFE) methods, which are widely used in microarray data analysis, ICA can identify more AD-related genes. Furthermore, we have validated and identified many genes that are associated with AD pathogenesis. Conclusion We demonstrated that ICA exploits higher-order statistics to identify gene expression profiles as linear combinations of elementary expression patterns that lead to the construction of potential AD-related pathogenic pathways. Our computing results also validated that the ICA model outperformed PCA and the SVM-RFE method. This report shows that ICA as a microarray data analysis tool can help us to elucidate the molecular taxonomy of AD and other multifactorial and polygenic complex diseases.
Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas
Authors: Philip Kunkel, Sabine Müller, Peter Schirmacher, Dimitrios Stavrou, Regina Fillbrandt, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2001)

Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic cytokine that has been implicated in glioma invasion and angiogenesis. The SF/HGF receptor, MET, has been found to be expressed in neoplastic astrocytes as well as in endothelial cells of the tumor vasculature. Both SF/HGF and MET expression have also been described to correlate with the malignancy grade of human gliomas. However, most glioblastoma cell lines lack SF/HGF expression, raising the question of the cellular origin of SF/HGF in vivo. Using in situ hybridization, we analyzed glioblastomas, anaplastic astrocytomas, diffuse astrocytomas, pilocytic astrocytomas, and normal brain for the expression of SF/HGF mRNA. We detected strong SF/HGF expression by the majority of the tumor cells and by vascular endothelial cells in all glioblastoma specimens analyzed. Combined use of in situ hybridization with fluorescence immunohistochemistry confirmed the astrocytic origin of the SF/HGF-expressing cells. In contrast, CD68-immunoreactive microglia/macrophages, as well as vascular smooth muscle cells reactive to -smooth muscle actin, lacked SF/HGF expression. In anaplastic, diffuse, and pilocytic astrocytomas, SF/HGF expression was confined to a subset of tumor cells, and signals were less intense than in glioblasto mas. In addition, we detected SF/HGF mRNA in cortical neurons. SF/HGF expression was not up regulated around necroses or at tumor margins. MET immunoreactivity was observed in GFAP-expressing astrocytic tumor cells and endothelial cells as well as in a subset of microglia/macrophages. We conclude that in vivo, both autocrine and paracrine stimulation of tumor cells and endothelium through the SF/HGF-MET system are likely to contribute to tumor invasion and angiogenesis. Lack of SF/HGF expression by most cultured glioblastoma cells is not representative of the in vivo situation and most likely represents a culture artifact.
Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: Comparison with uremic encephalopathy
Authors: Petra Steindl, Andreas Püspök, Wilfred Druml, Peter Ferenci
Journal: Hepatology (1991)

Hepatic encephalopathy is ameliorated by drugs acting on the central GABAA-benzodiazepine receptor complex. To investigate whether these effects are specific for hepatic encephalopathy or just reflect a nonspecific arousal reaction, various benzodiazepine antagonists like flumazenil or with inverse agonistic properties (Ro 15-4513, Ro 15-3505) were studied in uremic encephalopathy in rats after bilateral ureteral ligation (n = 20) and compared with hepatic encephalopathy caused by thioacetamide-induced acute liver failure (n = 33). As soon as the animals developed clear signs of metabolic encephalopathy, their motor activity was recorded in an animal activity meter for 10 min. Furthermore, a composite score was calculated by grading various behavioral signs from 0 = absent to 3 = apparently normal. Rats were then injected with coded preparations of Ro 15-4513 (0.5, 2.5 and 5 mg/kg body wt intraperitoneally), flumazenil (2.5, 10, 25 and 40 mg/kg), Ro 15-3505 (10 mg/kg) or vehicle, and the measurements were repeated. The code was broken after the completion of the study. Pretreatment motor activity was decreased both in hepatic and uremic encephalopathy (20.7 +/- 6.4 [S.E.M.] and 41.3 +/- 37.1 movements/10 min). In hepatic encephalopathy motor activity and the composite score were improved both by 5 mg/kg Ro 15-4513 (by 293%, p less than 0.05) and by 10 mg/kg Ro 15-3505 (by 509%, p greater than 0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status.(ABSTRACT TRUNCATED AT 250 WORDS)
Psychological disturbance and service provision in parentally bereaved children: prospective case-control study
Authors: L. Dowdney, R. Wilson, B Maughan, M Allerton, P Schofield, D Skuse
Journal: BMJ (1999)

To identify whether psychiatric disturbance in parentally bereaved children and surviving parents is related to service provision.Prospective case-control study.Two adjacent outer London health authorities.45 bereaved families with children aged 2 to 16 years.Psychological disturbance in parentally bereaved children and surviving parents, and statistical associations between sample characteristics and service provision.Parentally bereaved children and surviving parents showed higher than expected levels of psychiatric difficulties. Boys were more affected than girls, and bereaved mothers had more mental health difficulties than bereaved fathers. Levels of psychiatric disturbance in children were higher when parents showed probable psychiatric disorder. Service provision related to the age of the children and the manner of parental death. Children under 5 years of age were less likely to be offered services than older children even though their parents desired it. Children were significantly more likely to be offered services when the parent had committed suicide or when the death was expected. Children least likely to receive service support were those who were not in touch with services before parental death.Service provision was not significantly related to parental wishes or to level of psychiatric disturbance in parents or children. There is a role for general practitioners and primary care workers in identifying psychologically distressed surviving parents whose children may be psychiatrically disturbed, and referring them to appropriate services.
Release of decay-accelerating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). Selective modification of a complement regulatory protein.
Authors: M A Davitz, M G Low, V Nussenzweig
Journal: The Journal of Experimental Medicine (1986)

Decay-accelerating factor (DAF) is a 70,000 Mr membrane protein that inhibits amplification of the complement cascade on the cell surface, and protects cells from damage. Purified DAF can be reincorporated into the membrane of red cells and is functional. DAF is deficient in paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by increased sensitivity of erythrocytes to complement lysis. We show here that DAF is part of a newly described family of membrane proteins anchored to the lipid bilayer by means of phosphatidylinositol (PI). Treatment with PI-specific phospholipase C (PIPLC) releases 70-80, 60, and 10% of cell surface DAF from mononuclear cells, neutrophils, and erythrocytes, respectively. The PIPLC-released DAF (DAF-S) is slightly smaller (67,000 Mr) than the membrane form. DAF and DAF-S cannot be distinguished antigenically. Furthermore, DAF-S has lost its ability to significantly inhibit the C3-convertase, as well as its ability to incorporate into cell membranes. Since DAF can only inhibit C3-convertase endogenously, i.e., within the membrane of the same cell, it is likely that the loss of activity of DAF-S is causally related to its inability to reincorporate in the lipid bilayer. As shown by others, the complement-sensitive red cells from PNH patients lack acetylcholinesterase, which is also anchored to the membrane by PI (9). Thus it is possible that the molecular defect in PNH lies in the biosynthetic pathways leading to the attachment of PI to the polypeptide chains, in the transport of these proteins to the surface, or in their release by the action of endogenous phospholipases. From a practical standpoint the specific release of DAF by PIPLC could facilitate killing of tumor cells by amplifying the effects of the complement cascade on the surface of antibody-sensitized cells.
Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?
Authors: Z. Wang, C. Chen, S. N. Finger, S. d/o Kwajah M.M, M. Jung, H. Schwarz, N. Swanson, R. R. Lareu, M. Raghunath
Journal: European Respiratory Journal (2009)

Pulmonary fibrosis represents a fatal stage of interstitial lung diseases of known and idiopathic aetiology. No effective therapy is currently available. Based on an indication-discovery approach we present novel in vitro evidence that the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA), an FDA approved anti-cancer drug, has antifibrotic and anti-inflammatory potential. Human lung fibroblasts (fetal, adult and idiopathic adult pulmonary fibrosis) were treated with transforming growth factor (TGF)-beta 1 with or without SAHA. Collagen deposition, alpha-smooth muscle actin (alpha-SMA) expression, matrix metalloproteinase (MMP)1 activity, tissue inhibitor of MMP (TIMP)1 production, apoptosis and cell proliferation were assessed. Pro-inflammatory cytokines relevant to pulmonary fibrosis were assayed in SAHA-treated human peripheral blood mononuclear cells (PBMC) and its subpopulations. SAHA abrogated TGF-beta 1 effects on all the fibroblast lines by preventing their transdifferentiation into alpha-SMA positive myofibroblasts and increased collagen deposition without inducing apoptosis. However, MMP1 activity and TIMP1 production was modulated without a clear fibrolytic effect. SAHA also inhibited serum-induced proliferation of the fibroblast lines and caused hyperacetylation of alpha-tubulin and histone. Cytokine secretion was inhibited from PBMC and lymphocytes at nonapoptotic concentrations. Taken together, these data demonstrate combined antifibrotic and anti-inflammatory properties of SAHA, suggesting its therapeutic potential for pulmonary fibrosis.
Functional affinity of IgM rheumatoid factor in patients with rheumatoid arthritis and other autoimmune diseases.
Authors: S Rath, D N Hogben, M E Devey
Journal: Annals of the Rheumatic Diseases (1988)

The functional affinity of IgM rheumatoid factors (RF) was measured in 31 patients with rheumatoid arthritis (RA), 24 with systemic lupus erythematosus (SLE), 13 with Sjögren's syndrome (SS), and in 13 seropositive healthy individuals. The functional affinity of IgM RF from patients with RA was significantly lower than in the other clinical groups studied. In addition, there was a significant inverse correlation between functional affinity and titre of IgM RF in all the groups. These results suggest that the usual mechanisms of affinity based selective pressure (somatic diversification and antigen selection) may operate differently for autoantibodies to serum antigens such as IgG.
Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown
Authors: Fan-Ru Lin, Hui-Kai Kuo, Hsia-Yuan Ying, Fu-Hung Yang, Kuo-I Lin
Journal: Cancer Research (2007)

B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1-dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells.
Hospital Characteristics Associated with Timeliness of Care in Veterans with Lung Cancer
Authors: Ellen M. Schultz, Adam A. Powell, Alex McMillan, Julie K. Olsson, Mark A. Enderle, Barry A. Graham, Diana L. Ordin, Michael K. Gould
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Timeliness is one of six important dimensions of health care quality recognized by the Institute of Medicine.To evaluate timeliness of lung cancer care and identify institutional characteristics associated with timely care within the Veterans Affairs (VA) health care system.We used data from a VA nation-wide retrospective chart review and an independent audit of VA cancer programs to examine the association between time to first treatment and potentially explanatory institutional characteristics (e.g., volume of lung cancer patients) for 2,372 veterans diagnosed with lung cancer between 1 January 2002 and 1 September 2005 at 127 VA medical centers. We developed linear mixed effects models to control for clustering of patients within hospitals and we stratified analyses by stage.Median time to treatment varied widely between (23 to 182 d) and within facilities. Median time to treatment was 90 days in patients with stage I or II cancer and 52 days in those with more advanced disease (P < 0.0001). Factors associated with shorter times to treatment included a nonacademic setting and the existence of a specialized diagnostic clinic (in patients with limited-stage disease), performing a patient flow analysis (in patients with advanced disease), and leadership beliefs about providing timely care (in both groups). However, institutional characteristics explained less than 1% of the observed variation in treatment times.Time to lung cancer treatment in U.S. veterans is highly variable. The numerous institutional characteristics we examined explained relatively little of this variability, suggesting that patient, clinician, and/or unmeasured institutional characteristics may be more important determinants of timely care.
Renal function impairment induced by change in posture in patients with cirrhosis and ascites.
Authors: M Bernardi, C Santini, F Trevisani, M Baraldini, A Ligabue, G Gasbarrini
Journal: Gut (1985)

The assumption of upright posture by patients with liver cirrhosis leads to striking activation of adrenergic and renin-angiotensin systems. The tilting-induced modifications in renal function of eight healthy controls and 14 untreated patients with liver cirrhosis and ascites were related to plasma concentrations of noradrenaline, renin activity and aldosterone. All patients had preserved renal blood perfusion. All parameters were evaluated during bed rest for two hours and in the sitting posture for one hour. Basal plasma renin activity (0.1 greater than p greater than 0.05), aldosterone and noradrenaline concentrations (p less than or equal to 0.01) were raised in cirrhotics. The renal function tests (creatinine clearance, filtered sodium, tubular rejection fraction, urinary sodium excretion) were significantly reduced in cirrhosis. Under basal conditions, in cirrhotic patients tubular rejection fraction and urinary sodium excretion were inversely related to both noradrenaline and aldosterone concentrations. After tilting, the noradrenaline and aldosterone integrated outputs (sigma delta) were significantly greater in cirrhosis. All renal function tests significantly decreased in cirrhotics, whereas creatinine clearance only significantly decreased in controls. Patient's tubular rejection fraction of sodium and sodium excretion were related to sigma delta aldosteronaemia (r = -0.72; p less than 0.01), but no longer to sigma delta plasma noradrenaline.