tbuckley/cabot-search huggingface dataset:
Exploring the conditional coregulation of yeast gene expression through fuzzy k-means clustering
Authors: Audrey P Gasch, Michael B Eisen
Journal: Genome biology (2002)

Organisms simplify the orchestration of gene expression by coregulating genes whose products function together in the cell. Many proteins serve different roles depending on the demands of the organism, and therefore the corresponding genes are often coexpressed with different groups of genes under different situations. This poses a challenge in analyzing whole-genome expression data, because many genes will be similarly expressed to multiple, distinct groups of genes. Because most commonly used analytical methods cannot appropriately represent these relationships, the connections between conditionally coregulated genes are often missed. We used a heuristically modified version of fuzzy k-means clustering to identify overlapping clusters of yeast genes based on published gene-expression data following the response of yeast cells to environmental changes. We have validated the method by identifying groups of functionally related and coregulated genes, and in the process we have uncovered new correlations between yeast genes and between the experimental conditions based on similarities in gene-expression patterns. To investigate the regulation of gene expression, we correlated the clusters with known transcription factor binding sites present in the genes' promoters. These results give insights into the mechanism of the regulation of gene expression in yeast cells responding to environmental changes. Fuzzy k-means clustering is a useful analytical tool for extracting biological insights from gene-expression data. Our analysis presented here suggests that a prevalent theme in the regulation of yeast gene expression is the condition-specific coregulation of overlapping sets of genes.
Mixed Dementia
Authors: Kenneth M. Langa, Norman L. Foster, Eric B. Larson
Journal: JAMA (2004)

ContextThe prevalence of mixed dementia, defined as the coexistence of Alzheimer disease (AD) and vascular dementia (VaD), is likely to increase as the population ages.ObjectivesTo provide an overview of the diagnosis, pathophysiology, and interaction of AD and VaD in mixed dementia, and to provide a systematic literature review of the current evidence for the pharmacologic therapy of mixed dementia.Data Sources, Study Selection, and Data ExtractionThe Cochrane Database of Systematic Reviews was searched using the keyword dementia. MEDLINE was searched for English-language articles published within the last 10 years using the keywords mixed dementia, the combination of keywords Alzheimer disease, cerebrovascular disorders, and drug therapy, and the combination of keywords vascular dementia and drug therapy.Evidence SynthesisDementia is more likely to be present when vascular and AD lesions coexist, a situation that is especially common with increasing age. The measured benefits in clinical trials for the treatment of mixed dementia are best described as statistically significant differences in cognitive test scores and clinician and caregiver impressions of change. In these studies, the control groups’ scores typically decline while the treatment groups improve slightly or decline to a lesser degree over the study period. Nevertheless, even the patients who experience treatment benefits eventually decline. Cholinesterase inhibitor (ChI) therapy for mixed dementia shows modest clinical benefits that are similar to those found for ChI treatment of AD. The N-methyl-D-aspartate (NMDA) antagonist memantine also shows modest clinical benefits for the treatment of moderate to severe AD and mild to moderate VaD, but it has not been studied specifically in mixed dementia. The treatment of cardiovascular risk factors, especially hypertension, may be a more effective way to protect brain function as primary, secondary, and tertiary prevention for mixed dementia.ConclusionsCurrently available medications provide only modest clinical benefits once a patient has developed mixed dementia. Cardiovascular risk factor control, especially for hypertension and hyperlipidemia, as well as other interventions to prevent recurrent stroke, likely represent important strategies for preventing or slowing the progression of mixed dementia. Additional research is needed to define better what individuals and families hope to achieve from dementia treatment and to determine the most appropriate use of medication to achieve these goals.
Assessing performance of two lung age equations in an Australian population: Using data from the BOLD-Australia study
Authors: Michael Abramson, Marsha Ivey, David Johns, Graeme Maguire, Brett Toelle, Guy Marks, Richard Wood-Baker
Journal: European Respiratory Journal (2014)

Background:  Lung age is a simple concept for patients to grasp and frequently used as an aid in smoking cessation programmes. Lung age equations need to be reviewed for relevance to target populations.   Aim:  To assess how new lung age equations developed for Australian populations performed on BOLD-Australia dataset compared to previously used equations.   Methods:  Cross-sectional study of Australians aged ≥40yrs. Spirometry performed using the ndd EasyOne TM  in accordance with ERS/ATS guidelines; analysis restricted to Caucasians    Results:  2,793 participants with mean age of 57 (±SD 10) yrs; 52% ever smoked, 10.4% were current smokers and GOLD Stage I or higher COPD was 13.4% (95%CI: 12.2, 14.7). For both genders, recent Newbury equations estimated lung ages significantly older than actual age regardless of smoking status ( p  p  p    Conclusions:  Findings support use of updated equations suited to the population of interest. The Newbury equations performed well in BOLD-Australia dataset providing more meaningful lung age profile compared to chronological age, among smokers.   Support:  National Health and Medical Research Council.
Spatial Heterogeneity and Oxygen Dependence of Glucose Consumption in R3230Ac and Fibrosarcomas of the Fischer 344 Rat
Authors: Thies Schroeder, Hong Yuan, Benjamin L. Viglianti, Cathryn Peltz, Shubha Asopa, Zeljko Vujaskovic, Mark W. Dewhirst
Journal: Cancer Research (2005)

Abstract To examine the oxygen-dependence of glucose consumption in solid tumors, we monitored gradients of glucose, lactate, and hypoxia in R3230Ac and FSA tumors growing in Fischer 344 rats. Bioluminescence imaging, detection of Hoechst 33342, and immunostaining of the hypoxia marker EF5 [2-8-N-(2,2,3,3,3-pentafluoropropyl)acetamide] were done in serial tumor slices. Glucose and lactate levels were also determined in liver and blood. Cells were further tested for glucose consumption and lactate production in vitro. In both tumor types, EF5 staining indicated similar maximum levels of hypoxia; the most intense staining occurred in perinecrotic regions. Glucose concentrations were highest in liver, declined from blood to tumor edge, further into vital tumor regions, and were lowest close to necrosis. Glucose was significantly lower in FSA than in R3230Ac tumors. Glucose concentrations in R3230Ac tumors were consistently higher in nonhypoxic than in hypoxic areas, with maximum values equal to systemic blood levels. Glucose in FSA tumors was close to zero, regardless of the presence or absence of hypoxia. Lactate did not differ significantly between the tumor types. FSA cells in culture showed a trend towards higher aerobic glucose consumption versus R3230Ac. Both cell lines increased their lactate production to similar levels under hypoxia. We conclude that both R3230Ac and FSA tumors retain the Pasteur effect, i.e., hypoxia triggers increased glycolysis. However, our results imply that increased aerobic glucose utilization leads to low glucose levels in FSA and a situation where supply limits uptake. This explains the repeatedly observed correlation between tumor blood flow and 18F-deoxyglucose uptake.
Fifteen-Year Survival Outcomes Following Primary Androgen-Deprivation Therapy for Localized Prostate Cancer
Authors: Grace L. Lu-Yao, Peter C. Albertsen, Dirk F. Moore, Weichung Shih, Yong Lin, Robert S. DiPaola, Siu-Long Yao
Journal: JAMA Internal Medicine (2014)

One in 6 American men will be diagnosed as having prostate cancer during their lifetime. Although there are no data to support the use of primary androgen-deprivation therapy (ADT) for early-stage prostate cancer, primary ADT has been widely used for localized prostate cancer, especially among older patients.To determine the long-term survival impact of primary ADT in older men with localized (T1/T2) prostate cancer.This was a population-based cohort study of 66,717 Medicare patients 66 years or older diagnosed from 1992 through 2009 who received no definitive local therapy within 180 days of prostate cancer diagnosis. The study was conducted in predefined US geographical areas covered by the Surveillance, Epidemiology, and End Results (SEER) Program. Instrumental variable analysis was used to assess the impact of primary ADT and control for potential biases associated with unmeasured confounding variables. The instrumental variable comprised combined health services areas with various usage rates of primary ADT. The analysis compared survival outcomes in the top tertile areas with those in the bottom tertile areas.Prostate cancer-specific survival and overall survival.With a median follow-up of 110 months, primary ADT was not associated with improved 15-year overall or prostate cancer-specific survival following the diagnosis of localized prostate cancer. Among patients with moderately differentiated cancers, the 15-year overall survival was 20.0% in areas with high primary ADT use vs 20.8% in areas with low use (difference: 95% CI, -2.2% to 0.4%), and the 15-year prostate cancer survival was 90.6% in both high- and low-use areas (difference: 95% CI, -1.1% to 1.2%). Among patients with poorly differentiated cancers, the 15-year cancer-specific survival was 78.6% in high-use areas vs 78.5%, in low-use areas (difference: 95% CI, -1.8% to 2.4%), and the 15-year overall survival was 8.6% in high-use areas vs 9.2% in low-use areas (difference: 95% CI, -1.5% to 0.4%).Primary ADT is not associated with improved long-term overall or disease-specific survival for men with localized prostate cancer. Primary ADT should be used only to palliate symptoms of disease or prevent imminent symptoms associated with disease progression.
Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison
Authors: Loren Laine, Sean P Curtis, Byron Cryer, Amarjot Kaur, Christopher P Cannon
Journal: The Lancet (2007)
Advance Care Planning in Patients With Cancer Referred to a Phase I Clinical Trials Program: The MD Anderson Cancer Center Experience
Authors: Siqing Fu, F. Diane Barber, Aung Naing, Jennifer Wheler, David Hong, Gerald Falchook, Sarina Piha-Paul, Apostolia Tsimberidou, Adrienne Howard, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

Patients with advanced malignancies referred for early clinical trials have a short life expectancy. We designed this survey to ascertain the status of advance care planning in this population.Patients who were seen in a phase I clinic were asked to anonymously complete an investigator-designed survey.Of 435 individuals approached, 215 (49%) returned completed or partially completed surveys, whereas many others stated that they wanted to avoid the topic, because they had come to the phase I clinic for cancer therapy. Most patients (n = 149; 69%) were still hopeful about their future. Approximately 42% of patients (n = 90) reported having a living will, 46% had a medical power of attorney (n = 98), and 19% had a do-not-resuscitate (DNR) order (n = 40). Approximately 20% of participants (n = 43) had not discussed advance care planning. Fifty-nine percent of patients wanted to discuss advance care planning with their physician. Having a DNR order in place was significantly more common in individuals who had a living will and/or a medical power of attorney.Although most patients referred to a phase I clinic remained optimistic, many had discussed a living will, medical power of attorney, and/or DNR order with their physician, family, and/or attorney. However, a significant minority had not addressed this issue with anyone, and many refused to take a survey on the topic. More than half of the patients wanted to discuss these matters with their physician. These observations suggest that extra effort to address advance care planning is needed for these patients.
Lithium-Induced Folliculitis
Authors: ARTHUR RIFKIN, STEPHEN B. KURTIN, FREDERIC QUITKIN, DONALD F. KLEIN
Journal: American Journal of Psychiatry (1973)

Twelve patients receiving long-term treatment with lithium developed folliculitis on their extremities and/or trunks. The rash disappeared in three patients who discontinued lithium therapy, and in one patient it reappeared when she again received lithium. The authors concluded that folliculitis is a common, but not serious, side effect of lithium treatment.
Heterogenous graft rejection pathways in class I major histocompatibility complex-disparate combinations and their differential susceptibility to immunomodulation induced by intravenous presensitization with relevant alloantigens.
Authors: S Kitagawa, H Iwata, S Sato, J Shimizu, T Hamaoka, H Fujiwara
Journal: The Journal of Experimental Medicine (1991)

The present study investigates the heterogeneity of graft rejection pathways in class I major histocompatibility complex (MHC)-disparate combinations and the susceptibility of each pathway to immunomodulation induced by intravenous presensitization with alloantigens. Depletion of CD8+ T cells was induced by repeated administration of anti-CD8 monoclonal antibody. CD8+ T cell-depleted mice failed to generate anti-allo class I MHC cytotoxic T cell (CTL) responses but exhibited anti-allo class I MHC T cell responses, such as mixed lymphocyte reaction (MLR)/IL-2 production, that were induced by CD4+ T cells. In contrast, donor-specific intravenous presensitization (DSP), as a model of donor-specific transfusion, induced almost complete elimination of CD4+ and CD8+ T cell-mediated MLR/IL-2 production, whereas this regimen did not affect the generation of CTL responses induced by DSP-resistant elements (CD8+ CTL precursors and CD4+ CTL helpers). Prolongation of skin graft survival was not induced by either of the above two regimens alone, but by the combination of these. Prolonged graft survival was obtained irrespective of whether the administration of anti-CD8 antibody capable of eliminating CTL was started before or after DSP. The combination of DSP with injection of anti-CD4 antibody also effectively prolonged graft survival. However, this was the case only when the injection of antibody was started before DSP, because such antibody administration was capable of inhibiting the generation of CTL responses by eliminating DSP-resistant CD4+ CTL helpers. These results indicate that (a) the graft rejection in class I-disparate combinations is induced by CD8+ CTL-involved and -independent pathways that are resistant and susceptible to DSP, respectively; (b) DSP contributes to, but is not sufficient for, the prolongation of graft survival; and (c) the suppression of graft rejection requires an additional treatment for reducing DSP-resistant CTL responses. The results are discussed in the context of potential clinical application in attempts to inhibit the generation of DSP-resistant CTL responses upon the prospective DSP.
Eosinophilic pneumonia and respiratory failure associated with venlafaxine treatment
Authors: M.C. Fleisch, F. Blauer, J.G.H. Gubler, M. Kuhn, T.A. Scherer
Journal: European Respiratory Journal (2000)

Drugs are well known causes of eosinophilic lung disease. In many patients, symptoms increase slowly, pulmonary infiltrates and eosinophilia progress over weeks, and resolve upon withdrawal of the offending agent. Rarely, the disease presents like acute eosinophilic pneumonia with acute onset of symptoms and rapidly progressing infiltrates which may be associated with respiratory failure. This report describe a case of venlafaxine-induced acute eosinophilic pneumonia causing respiratory insufficiency that rapidly resolved upon institution of corticosteroid treatment. This 5-hydroxytryptamine and noradrenaline reuptake inhibitor was previously not known to cause lung or peripheral blood eosinophilia. Considering the increasing use of this class of medication physicians have to be aware of this life-threatening and fully reversible complication.
Bendamustine Is Effective in p53-Deficient B-Cell Neoplasms and Requires Oxidative Stress and Caspase-Independent Signaling
Authors: Gaël Roué, Mónica López-Guerra, Pierre Milpied, Patricia Pérez-Galán, Neus Villamor, Emili Montserrat, Elias Campo, Dolors Colomer
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are two incurable B-cell lymphoid neoplasms characterized by distinct clinical presentation and evolution. Bendamustine hydrochloride is a multifunctional, alkylating agent with a purine-like ring system that exhibits activity in multiple cancer models, including CLL and MCL, but whose mechanism is only partially described. Our aim was to analyze the apoptotic pathways activated by bendamustine in CLL and MCL together with the relevance of p53 mutation in determining the response to this drug. Experimental Design: Thirteen CLL/MCL cell lines and primary tumor cells from 8 MCL and 25 CLL patients were cultured for up to 24 h with bendamustine followed by cytotoxic assays, flow cytometry, immunofluorescence, and Western blot analysis of p53 response pathway and apoptosis-related factors. Results: Bendamustine displayed cytotoxic activity on most CLL and MCL primary cells and cell lines irrespective of ZAP-70 expression and p53 status. Bendamustine was found to act synergistically with nucleoside analogues in both CLL and MCL, this combination being effective in p53 mutated cases resistant to standard chemotherapy. Bendamustine cytotoxicity was mediated by the generation of reactive oxygen species and triggering of the intrinsic apoptotic pathway involving up-regulation of PUMA and NOXA, conformational activation of BAX and BAK, and cytosolic release of caspase-related and caspase-unrelated mitochondrial apoptogenic proteins. Conclusions: Our findings support the use of bendamustine as a therapeutic agent, alone or in combination, for CLL and MCL with p53 alterations and describe the molecular basis of its activity in these entities.
Decrease in orthopaedic operations, including total joint replacements, in patients with rheumatoid arthritis between 2001 and 2007: data from Japanese outpatients in a single institute-based large observational cohort (IORRA): Figure 1
Authors: S Momohara, E Inoue, K Ikari, K Kawamura, S Tsukahara, T Iwamoto, M Hara, A Taniguchi, H Yamanaka
Journal: Annals of the Rheumatic Diseases (2009)

MHC class II deficiency or bare lymphocyte syndrome is a severe combined immunodeficiency caused by defects in MHC-specific regulatory factors. Fibroblasts derived from two recently identified bare lymphocyte syndrome patients, EBA and FZA, were found to contain novel mutations in the RFX-B gene. RFX-B encodes a component of the RFX transcription factor that functions in the assembly of multiple transcription factors on MHC class II promoters. Unlike RFX5- and RFXAP-deficient cells, transfection of exogenous class II transactivator (CIITA) into these RFX-B-deficient fibroblasts resulted in the induction of HLA-DR and HLA-DP and, to a lesser extent, HLA-DQ. Similarly, CIITA-mediated induction of MHC class I, β<sub>2</sub>-microglobulin, and invariant chain genes was also found in these RFX-B-deficient fibroblasts. Expression of wild-type RFX-B completely reverted the noted deficiencies in these cells. Transfection of CIITA into Ramia cells, a B cell line that does not produce a stable RFX-B mRNA, resulted in induction of an MHC class II reporter, suggesting that CIITA overexpression may partially override the RFX-B defect.
Ireland sets up fund for patients who cannot get insurance
Authors: Doug Payne
Journal: BMJ (2001)

The Irish government is setting up an insurance fund to reduce some of the problems faced by people infected by contaminated blood products in getting insurance.

The idea for the fund—of one million Irish pounds (£820 000; $1.2m)—arose after a report commissioned by the Irish health department showed that people infected with hepatitis C through being given anti-D immunoglobulin and patients with haemophilia who contracted HIV from factor VIII …
The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis
Authors: Armelle Luscan, Ghjuvan'Ghjacumu Shackleford, Julien Masliah-Planchon, Ingrid Laurendeau, Nicolas Ortonne, Jennifer Varin, François Lallemand, Karen Leroy, Valérie Dumaine, Mikael Hivelin, Didier Borderie, Thomas De Raedt, Laurence Valeyrie-Allanore, Frédérique Larousserie, Benoît Terris, Laurent Lantieri, Michel Vidaud, Dominique Vidaud, Pierre Wolkenstein, Béatrice Parfait, Ivan Bièche, Charbel Massaad, Eric Pasmant
Journal: Clinical Cancer Research (2013)

The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies.The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial-mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines.The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active β-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann-mesenchymal transition.We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis.