tbuckley/cabot-search huggingface dataset:
Autoimmune disorders increase the risk of developing pulmonary embolism
Authors: Helen Umpleby
Journal: Thorax (2012)

Autoimmune disorders increase the risk of developing pulmonary embolismThis large retrospective study analysed the effect of 33 autoimmune disorders on the risk of developing pulmonary emboli (PE).Five hundred and fifteen thousand one hundred and thirty-seven patients in Sweden with an autoimmune disorder initially diagnosed on hospital admission were identified and retrospectively analysed for PE, between 1964 and 2008.Risk of PE increased across all age groups in the first year post admission.Risk gradually decreased after hospitalisation but remained above the control group at 10 years post admission.Length of stay did not affect the risk.The thrombotic risk may have been related to active inflammation, side effects of the autoimmune treatment and/or immobilisation.The study postulated that the fall in risk over time was attributable to the inflammatory activity of autoimmune conditions decreasing with effective treatment.Overall risk of PE was lower during 1989e2008 than during 1964e1988.Interestingly, no difference was seen after the introduction of low molecular weight heparin in the 1990s.This was a large study, comparing autoimmune disorders to the general population.However, acute hospital data was used, potentially skewing the study population towards severer cases.There was also no data on thrombo-prophylaxis or treatment.The study suggests that autoimmune disorders are associated with a particularly high risk of PE and should be considered hypercoagulable disorders; this risk decreases but persists over time.Thrombo-prophylaxis should be considered in these patients, potentially for some time post discharge.However, further studies to assess its effectiveness are warranted.
Treating patients with documented atherosclerosis to national cholesterol education program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin
Authors: Alan S Brown, Rebecca G Bakker-Arkema, Laurence Yellen, Robert W Henley, Richard Guthrie, Cam F Campbell, Michael Koren, William Woo, Richard McLain, Donald M Black
Journal: Journal of the American College of Cardiology (1998)
Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice.
Authors: H Tighe, P P Chen, R Tucker, T J Kipps, J Roudier, F R Jirik, D A Carson
Journal: The Journal of Experimental Medicine (1993)

We have generated transgenic mice that express the immunoglobulin (Ig)M heavy chain and kappa light chain genes coding for a human IgM rheumatoid factor (RF), Les. Transgenic B cells expressing human IgM RF show striking similarities to their counterparts in normal humans. They comprise a significant proportion of the adult B cell population, but secrete only low levels of RF into the serum. The RF transgene-expressing B cells localize to primary B cell follicles and the mantle zone regions of secondary follicles in the spleen. Using these mice we have been able to show that one of the central functions of normal RF-expressing B cells may be to act as highly efficient antigen-presenting cells for low concentrations of immune-complexed antigen. High levels of secretion of IgM RF can not be induced under normal circumstances, although RF-expressing B cells proliferate well in vitro to both aggregated human IgG and anti-human IgM antibodies. However, these mice are not intrinsically secretion deficient. By crossing the RF transgenic mice with the autoimmune MRL/lpr background, we find a dramatic increase, &amp;gt; 200-fold, in levels of serum RF. The results strongly suggest that a major function of normal resting RF B cells is unrelated to antibody secretion. Rather, the RF B cells in the follicles may play a role in antigen presentation and regulation of immune responses to antibody-bound nonself-, and possibly self-antigens. This physiologic role of RF B cells may be disrupted in RF-associated autoimmune disease.
Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2–IIB cervical cancer patients
Authors: L. Cetina, A. González-Enciso, D. Cantú, J. Coronel, D. Pérez-Montiel, J. Hinojosa, A. Serrano, L. Rivera, A. Poitevin, A. Mota, E. Trejo, G. Montalvo, D. Muñoz, J. Robles-Flores, J. de la Garza, J. Chanona, R. Jiménez-Lima, T. Wegman, A. Dueñas-González
Journal: Annals of Oncology (2013)
High levels of activation-induced cytidine deaminase expression in adult T-cell leukaemia/lymphoma
Authors: M. Nakamura, K. Sugita, Y. Sawada, R. Yoshiki, R. Hino, Y. Tokura
Journal: British Journal of Dermatology (2011)

Funding sources: This work was supported by Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Conflicts of interest: none declared. Madam, Adult T‐cell leukaemia/lymphoma (ATLL) is a malignancy of mature CD4+ T cells caused by a human T‐cell leukaemia virus type I (HTLV‐1).1 This endemic haematological neoplasm is prevalent in southern Japan and develops in 1–5% of individuals infected with HTLV‐1 after more than two decades of viral persistence. ATLL malignant T cells are usually positive for CD4 and CD25. Cutaneous involvement is seen in up to 50% of patients with ATLL, and various skin eruptions, such as erythroderma, tumours, nodules and papules, are observed. Recently, we showed that the type of skin eruptions is an independent and important prognostic indicator for ATLL.2 Activation‐induced cytidine deaminase (AICDA) is a member of the cytidine deaminase family that acts as an editor of DNA and RNA, and is essential for somatic hypermutation and class‐switch recombination in immunoglobulin genes.3 Several lines of evidence have revealed that inappropriate expression of AICDA acts as a genomic mutator that contributes to tumorigenesis.4 AICDA is highly expressed in malignant cancers, such as gastric cancer and hepatocellular carcinoma, after Helicobacter pylori or hepatitis virus infection.5 In a patient with ATLL, we found that peripheral CD4+ CD25+ cells highly expressed AICDA and contained a mutation of the tumour suppressor gene, TP53. This finding led us to investigate the AICDA expression in peripheral blood and skin‐infiltrating ATLL cells in 18 patients with ATLL.
PI3K Pathway Dependencies in Endometrioid Endometrial Cancer Cell Lines
Authors: Britta Weigelt, Patricia H. Warne, Maryou B. Lambros, Jorge S. Reis-Filho, Julian Downward
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110β signaling for survival. Experimental Design: Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110α, and p110β isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal–regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. Results: EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110β inhibitors GSK2636771 and AZD6482, and only in combination with the p110α selective inhibitor A66 was a decrease in cell viability observed. Conclusions: Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110β alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. Clin Cancer Res; 19(13); 3533–44. ©2013 AACR.
A saturable high affinity binding site for transcobalamin II-vitamin B12 complexes in human placental membrane preparations.
Authors: P A Friedman, M A Shia, J K Wallace
Journal: Journal of Clinical Investigation (1977)

Studies were designed to evaluate the binding of binding of vitamin B12 to cell membrane preparations from human placenta. The transcobalamin II-vitamin B12 complex (TCII-B12), which has a much greater affinity for the membranes than vitamin B12 alone, binds to a single saturable binding site with an approximate Ka = 7.2 mM-1. The binding requires a divalent cation and is temperature-dependent. Free TCII can compete with TCII-B12 for the binding site but has somewhat less affinity than does TCII-B12. Rat TCII-B12 has an affinity constant that is less than one-fifth that of human TCII-B12; human TCI-B12, bovine TCII-B12, hog intrinsic factor-B12 (IF-B12), and human IF-B12 do not bind to the membranes. Pretreating the membranes with trypsin causes a marked decrease in subsequent binding; this suggests the binding site includes a relatively exposed membrane protein. These data suggest that a specific cell surface receptor for the TCII-B12 complex exists in placenta. This TCII-B12 receptor can be solubilized with Triton X-100.
Systematic Review of Psychological Approaches to the Management of Neuropsychiatric Symptoms of Dementia
Authors: Gill Livingston, Kate Johnston, Cornelius Katona, Joni Paton, Constantine G. Lyketsos
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors systematically reviewed the literature on psychological approaches to treating the neuropsychiatric symptoms of dementia. METHOD: Reports of studies that examined effects of any therapy derived from a psychological approach that satisfied prespecified criteria were reviewed. Data were extracted, the quality of each study was rated, and an overall rating was given to each study by using the Oxford Centre for Evidence-Based Medicine criteria. RESULTS: A total of 1,632 studies were identified, and 162 satisfied the inclusion criteria for the review. Specific types of psychoeducation for caregivers about managing neuropsychiatric symptoms were effective treatments whose benefits lasted for months, but other caregiver interventions were not. Behavioral management techniques that are centered on individual patients' behavior or on caregiver behavior had similar benefits, as did cognitive stimulation. Music therapy and Snoezelen, and possibly sensory stimulation, were useful during the treatment session but had no longer-term effects; interventions that changed the visual environment looked promising, but more research is needed. CONCLUSIONS: Only behavior management therapies, specific types of caregiver and residential care staff education, and possibly cognitive stimulation appear to have lasting effectiveness for the management of dementia-associated neuropsychiatric symptoms. Lack of evidence regarding other therapies is not evidence of lack of efficacy. Conclusions are limited because of the paucity of high-quality research (only nine level-1 studies were identified). More high-quality investigation is needed.
Performance of alternative strategies for primary cervical cancer screening in sub-Saharan Africa: systematic review and meta-analysis of diagnostic test accuracy studies
Authors: Joël Fokom-Domgue, Christophe Combescure, Victoire Fokom-Defo, Pierre Marie Tebeu, Pierre Vassilakos, André Pascal Kengne, Patrick Petignat
Journal: BMJ (2015)

<b>Objective</b> To assess and compare the accuracy of visual inspection with acetic acid (VIA), visual inspection with Lugol's iodine (VILI), and human papillomavirus (HPV) testing as alternative standalone methods for primary cervical cancer screening in sub-Saharan Africa. <b>Design</b> Systematic review and meta-analysis of diagnostic test accuracy studies. <b>Data sources</b> Systematic searches of multiple databases including Medline, Embase, and Scopus for studies published between January 1994 and June 2014. <b>Review methods</b> Inclusion criteria for studies were: alternative methods to cytology used as a standalone test for primary screening; study population not at particular risk of cervical cancer (excluding studies focusing on HIV positive women or women with gynaecological symptoms); women screened by nurses; reference test (colposcopy and directed biopsies) performed at least in women with positive screening results. Two reviewers independently screened studies for eligibility and extracted data for inclusion, and evaluated study quality using the quality assessment of diagnostic accuracy studies 2 (QUADAS-2) checklist. Primary outcomes were absolute accuracy measures (sensitivity and specificity) of screening tests to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+). <b>Results</b> 15 studies of moderate quality were included (n=61 381 for VIA, n=46 435 for VILI, n=11 322 for HPV testing). Prevalence of CIN2+ did not vary by screening test and ranged from 2.3% (95% confidence interval 1.5% to 3.3%) in VILI studies to 4.9% (2.7% to 7.8%) in HPV testing studies. Positivity rates of VILI, VIA, and HPV testing were 16.5% (9.8% to 24.7%), 16.8% (11.0% to 23.6%), and 25.8% (17.4% to 35.3%), respectively. Pooled sensitivity was higher for VILI (95.1%; 90.1% to 97.7%) than VIA (82.4%; 76.3% to 87.3%) in studies where the reference test was performed in all women (P&lt;0.001). Pooled specificity of VILI and VIA were similar (87.2% (78.1% to 92.8%) <i>v</i> 87.4% (77.1% to 93.4%); P=0.85). Pooled sensitivity and specificity were similar for HPV testing versus VIA (both P≥0.23) and versus VILI (both P≥0.16). Accuracy of VIA and VILI increased with sample size and time period. <b>Conclusions</b> For primary screening of cervical cancer in sub-Saharan Africa, VILI is a simple and affordable alternative to cytology that demonstrates higher sensitivity than VIA. Implementation studies are needed to assess the effect of these screening strategies on the incidence and outcomes of cervical cancer in the region.
Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Hypoxia-Inducible Factor 1α Protein Accumulation and Vascular Endothelial Growth Factor Expression in Human Cervical Carcinoma Cells
Authors: Xudong Tang, Qunzhou Zhang, Junko Nishitani, Jimmy Brown, Shihong Shi, Anh D. Le
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression. Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated. Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK 1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol. Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α–dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α–mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.
Tumor Control and Regrowth Probability After a Single Radiation of Experimental Animal Tumors 2
Authors: M. Urano, N. Fukuda, K. Ando, S. Koike, N. Tanaka
Journal: JNCI Journal of the National Cancer Institute (1974)

Single radiation dose to yield 50% tumor control (TCD50) of various sizes of C3H mouse mammary carcinoma was examined. Tumor cell sensitivity to single radiation by X-ray or neutrons was determined by endpoint dilution, and the number of tumor cells in the tumor was determined by a count of tumor cell nuclei. A mathematical analysis of tumor control probability was made from these results; a formula was proposed which accounted for cell population kinetics or division probability model, cell sensitivity to radiation, and number of tumor cells. Analysis of regrowth probability of tumors irradiated with a single X-ray indicated that tumors recurring after TCD50 might develop rapid regrowth after a long growth lag or a long period of slow growth, but the probability of cell division was reduced.
Blockade of individual Notch ligands and receptors controls graft-versus-host disease
Authors: Ivy T. Tran, Ashley R. Sandy, Alexis J. Carulli, Christen Ebens, Jooho Chung, Gloria T. Shan, Vedran Radojcic, Ann Friedman, Thomas Gridley, Amy Shelton, Pavan Reddy, Linda C. Samuelson, Minhong Yan, Christian W. Siebel, Ivan Maillard
Journal: Journal of Clinical Investigation (2013)

Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These strategies are incompletely effective and decrease the anticancer activity of the allogeneic graft. We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived T cells showed markedly decreased production of inflammatory cytokines, but normal in vivo proliferation, increased accumulation of regulatory T cells, and preserved anticancer effects. Here, we report that γ-secretase inhibitors can block all Notch signals in alloreactive T cells, but lead to severe on-target intestinal toxicity. Using newly developed humanized antibodies and conditional genetic models, we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during GVHD, with dominant roles for Notch1 and Delta-like4. Notch1 inhibition controlled GVHD, but led to treatment-limiting toxicity. In contrast, Delta-like1/4 inhibition blocked GVHD without limiting adverse effects while preserving substantial anticancer activity. Transient blockade in the peritransplant period provided durable protection. These findings open new perspectives for selective and safe targeting of individual Notch pathway components in GVHD and other T cell–mediated human disorders.
Insights into sick sinus syndrome from an inducible mouse model
Authors: Stefan Herrmann, Larissa Fabritz, Beate Layh, Paulus Kirchhof, Andreas Ludwig
Journal: Cardiovascular Research (2010)

Sick sinus syndrome is a generalized abnormality of cardiac impulse formation and is responsible for a large proportion of pacemaker implantations. Although the exact aetiology is not known, it is widely accepted that age-dependent degenerative fibrosis of nodal tissue is the most common cause. Despite its importance, an animal model for sick sinus syndrome is lacking. We attempted to generate a mouse model phenocopying the pathohistological changes as well as the characteristic arrhythmic manifestations of this syndrome. We crossed two genetically engineered mouse lines, ROSA-eGFP-DTA and HCN4-KiT-Cre, to achieve an inducible deletion of cells specifically in the cardiac pacemaking and conduction system. This deletion resulted in a degenerative fibrosis of nodal tissue, which accurately reflects the pathohistological findings in human sick sinus syndrome. The extent of the sino-atrial fibrosis could be controlled by varying the dosage of the inducing substance, tamoxifen. A high-dose protocol resulted in the complete ablation of all sino-atrial cells as demonstrated by histochemical analysis and quantitative reverse transcriptase–polymerase chain reaction. The animals developed a variety of arrhythmias, including progressive bradycardia, sinus pauses, supraventricular and ventricular tachycardia and chronotropic incompetence. Remarkably, the complete destruction of the primary pacemaker centre resulted in only a small increase in mortality. This study describes the generation and analysis of an inducible mouse model which closely reflects the pathophysiological characteristics of sick sinus syndrome. The model, with the ability to control the extent of nodal cell ablation and fibrosis, offers new insights into sick sinus syndrome and other cardiac conduction diseases.
Mechanism of Action for Combined CDK4/6 and Er Inhibition in ER Positive Breast Cancer
Authors: M. Koehler, T.L. VanArsdale, D. Shields, K. Arndt, J. Yuan, N. Lee, K. Eisele, J. Chionis, J. Cao, C.L. Painter
Journal: Annals of Oncology (2014)
Combined Deficiency in Glutathione Peroxidase 4 and Vitamin E Causes Multiorgan Thrombus Formation and Early Death in Mice
Authors: Markus Wortmann, Manuela Schneider, Joachim Pircher, Juliane Hellfritsch, Michaela Aichler, Naidu Vegi, Pirkko Kölle, Peter Kuhlencordt, Axel Walch, Ulrich Pohl, Georg W. Bornkamm, Marcus Conrad, Heike Beck
Journal: Circulation Research (2013)

Rationale: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. Objective: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. Methods and Results: Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E–depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, ≈80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia. Conclusions: Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.
RGS/Gi2α interactions modulate platelet accumulation and thrombus formation at sites of vascular injury
Authors: Rachel S. Signarvic, Aleksandra Cierniewska, Timothy J. Stalker, Karen P. Fong, Manash S. Chatterjee, Paul R. Hess, Peisong Ma, Scott L. Diamond, Richard R. Neubig, Lawrence F. Brass
Journal: Blood (2010)