tbuckley/cabot-search huggingface dataset:
Kupffer cell iron overload induces intercellular adhesion molecule-1 expression on hepatocytes in genetic hemochromatosis
Authors: Per Stå, Ulrika Broomé, Annika Scheynius, Ragnar Befrits, Rolf Hultcrantz
Journal: Hepatology (1995)

The mechanisms underlying iron-induced liver fibrogenesis in patients with genetic hemochromatosis are poorly understood. We studied signs of Kupffer cell activation and inflammatory responses in liver biopsy specimens obtained from 15 patients with untreated and six patients with treated hemochromatosis. Immunohisto-chemistry was performed on 11 of the untreated and all treated patients. Three of the untreated patients (20%) had cirrhosis and eight (53%) had fibrosis. None had chronic active hepatitis (CAH). Immunohistochemistry indicated that 55% of the untreated patients had sparse intercellular adhesion molecule-1 (ICAM-1) expression by hepatocytes, and all of these had Kupffer cell iron overload. No ICAM-1 expression was seen by hepatocytes in treated patients or healthy controls. ICAM-1 was strongly expressed by hepatocytes from control patients with inflammatory liver disease. HLA-DR reactivity was seen on sinusoidal cells in all groups, but not on hepatocytes except for two of the control patients with CAH. Twenty-seven percent of the untreated hemochromatosis patients displayed moderate infiltration by CD3-positive lymphocytes. Electron microscopy of samples from untreated hemochromatosis patients showed hypertrophic Kupffer cells containing iron-rich remnants of phagocytosed hepatocytes. Fat-storing cells close to iron-laden hepatocytes contained multiple lipid droplets and adjacent collagen fibril bundles. Thus, in patients with untreated genetic hemochromatosis and Kupffer cell iron overload, hepatocytes occasionally express ICAM-1. In regions with heavy iron overload, Kupffer cell hypertrophy and transition of fat-storing cells are seen. Our findings indicate that release of factors from iron-loaded, activated Kupffer cells is of importance for the transformation of fat-storing cells and increased collagen deposition seen in genetic hemochromatosis.
Novel therapeutic perspectives in pulmonary arterial hypertension
Authors: M. Humbert, O. Sitbon, G. Simonneau
Journal: European Respiratory Journal (2003)

Pulmonary arterial hypertension (PAH) refers to a disease spectrum of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance, right ventricular failure and, ultimately, death 1. It is usually accepted that a vasoconstrictive factor is involved in PAH 2. However, pure vasodilators, such as calcium channel blockers, have so far provided little or no beneficial effects on survival in the vast majority of patients, presumably because the pulmonary arteriopathy characteristic of PAH includes fibrotic and proliferative changes that predominate over vasoconstriction 3. Interestingly, novel therapeutic agents, such as prostacyclin and endothelin-receptor antagonists, have a better clinical efficacy than pure vasodilators in PAH, presumably because they have both vasodilator and antiproliferative properties 4–6.

Prostaglandin I2 (prostacyclin, epoprostenol) has been the most widely studied drug in PAH 5. Epoprostenol has a short half-life in the blood (3 min) and is inactivated at low pH 9. Therefore, epoprostenol can only be administered by continuous …
Vorinostat Inhibits Brain Metastatic Colonization in a Model of Triple-Negative Breast Cancer and Induces DNA Double-Strand Breaks
Authors: Diane Palmieri, Paul R. Lockman, Fancy C. Thomas, Emily Hua, Jeanne Herring, Elizabeth Hargrave, Matthew Johnson, Natasha Flores, Yongzhen Qian, Eleazar Vega-Valle, Kunal S. Taskar, Vinay Rudraraju, Rajendar K. Mittapalli, Julie A. Gaasch, Kaci A. Bohn, Helen R. Thorsheim, David J. Liewehr, Sean Davis, John F. Reilly, Robert Walker, Julie L. Bronder, Lionel Feigenbaum, Seth M. Steinberg, Kevin Camphausen, Paul S. Meltzer, Victoria M. Richon, Quentin R. Smith, Patricia S. Steeg
Journal: Clinical Cancer Research (2009)

Abstract Purpose: As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer. Experimental Design: The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo. Results: Following systemic administration, uptake of [14C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P &amp;lt; 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52. Conclusions: We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation. (Clin Cancer Res 2009;15(19):6148–57)
Clinical sacroiliac tests in ankylosing spondylitis and other causes of low back pain--2 studies.
Authors: P W Blower, A J Griffin
Journal: Annals of the Rheumatic Diseases (1984)

Independent assessment by 2 observers of 4 tests for sacroiliac (SI) pain in patients with either mechanical/degenerative low back pain (M/D LBP) or ankylosing spondylitis (AS) showed all 4 to be reproducible, but only 2 of them, namely, pressure over the anterior superior iliac spines and pressure over the lower half of the sacrum, gave worthwhile discrimination. Positive results in these 2 tests were significantly associated with definite AS but also with the combination of low back pain, the HLA B27 antigen, and normal or near normal radiographs, a condition we have called presumptive ankylosing spondylitis.
Primary hip replacement prostheses and their evidence base: systematic review of literature
Authors: F Kynaston-Pearson, A M Ashmore, T T Malak, I Rombach, A Taylor, D Beard, N K Arden, A Price, D Prieto-Alhambra, A Judge, A J Carr, S Glyn-Jones
Journal: British Journal of Sports Medicine (2014)

STUDY QUESTION To what extent are prostheses with no readily available evidence to support their use being implanted in primary total hip arthroplasty? SUMMARY ANSWER A quarter of prostheses available to orthopaedic surgeons in England and Wales have no readily available evidence of clinical effectiveness to support their use. WHAT IS KNOWN AND WHAT THIS PAPER ADDS The high failure rate of some metal-on-metal hip replacements has highlighted the need for an adequate evidence base for orthopaedic implants. A considerable number of prostheses available to the surgeon for use in primary total hip arthroplasty in the UK have no available evidence of clinical effectiveness to support their use.
Expression of laminin and its receptor LBP-32 in human and rat hepatoma cells
Authors: Pierre-Yves Rescan, Bruno Clement, Yoshihiko Yamada, Denise Glaise, Bartolome Segui-Real, Christiane Guguen-Guillouzo, André Guillouzo
Journal: Hepatology (1991)

Dramatic cellular changes that occur during hepatocarcinogenesis are associated with major alterations in extracellular matrix formation and in the relationships between cells and their microenvironment. We have studied the expression of laminin, the major noncollagenous glycoprotein of basement membrane, and the laminin receptor 32 kD laminin-binding protein in two rat (Faza 967 and HTC) and two human (HepG2 and HBGC2) hepatoma cell lines that express a variety of liver-specific functions. Laminin was found in the rough endoplasmic reticulum of these cells when the indirect immunoperoxidase method and electron microscopic examination were used. Radiolabeled laminin, immunoprecipitated from both media and cell extracts, was resolved by electrophoresis on sodium dodecyl sulfate gel in two major polypeptides that comigrated with the A and B subunits from Engelbreth-Holm-Swarm tumor laminin. Immunoblot analysis showed that the Mr = 400,000 polypeptide did not correspond to the A subunit of laminin. Northern blot analyses demonstrated large amounts of B1 and B2 mRNAs but no A chain mRNA. We conclude that the tumor cells produce the laminin B chains only. In contrast, normal adult hepatocytes from either man or rat lacked laminin mRNAs, whereas in 1-day primary culture, B chain mRNAs became detectable. The steady-state level of 32 kD laminin-binding protein mRNA was 10-fold and threefold higher in rat hepatoma cells than in freshly isolated and 1-day cultured normal rat hepatocytes, respectively. In human hepatocytes, the steady-state levels of 32 kD laminin-binding protein mRNAs varied depending on the donor and never reached the level of the human hepatoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Functional normalization of 450k methylation array data improves replication in large cancer studies
Authors: Jean-Philippe Fortin, Aurélie Labbe, Mathieu Lemire, Brent W Zanke, Thomas J Hudson, Elana J Fertig, Celia MT Greenwood, Kasper D Hansen
Journal: Genome biology (2014)

Abstract We propose an extension to quantile normalization that removes unwanted technical variation using control probes. We adapt our algorithm, functional normalization, to the Illumina 450k methylation array and address the open problem of normalizing methylation data with global epigenetic changes, such as human cancers. Using data sets from The Cancer Genome Atlas and a large case–control study, we show that our algorithm outperforms all existing normalization methods with respect to replication of results between experiments, and yields robust results even in the presence of batch effects. Functional normalization can be applied to any microarray platform, provided suitable control probes are available.
Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia
Authors: Yubin Ge, Alan A. Dombkowski, Katherine M. LaFiura, Dana Tatman, Ravikiran S. Yedidi, Mark L. Stout, Steven A. Buck, Gita Massey, David L. Becton, Howard J. Weinstein, Yaddanapudi Ravindranath, Larry H. Matherly, Jeffrey W. Taub
Journal: Blood (2005)
Antidepressant Use Before and After the Diagnosis of Type 2 Diabetes
Authors: Mika Kivimäki, Adam G. Tabák, Debbie A. Lawlor, G. David Batty, Archana Singh-Manoux, Markus Jokela, Marianna Virtanen, Paula Salo, Tuula Oksanen, Jaana Pentti, Daniel R. Witte, Jussi Vahtera
Journal: Diabetes Care (2010)

OBJECTIVE To examine antidepressant use before and after the diagnosis of diabetes. RESEARCH DESIGN AND METHODS This study was a longitudinal analysis of diabetic and nondiabetic groups selected from a prospective cohort study of 151,618 men and women in Finland (the Finnish Public Sector Study, 1995–2005). We analyzed the use of antidepressants in those 493 individuals who developed type 2 diabetes and their 2,450 matched nondiabetic control subjects for each year during a period covering 4 years before and 4 years after the diagnosis. For comparison, we undertook a corresponding analysis on 748 individuals who developed cancer and their 3,730 matched control subjects. RESULTS In multilevel longitudinal models, the odds ratio for antidepressant use in those who developed diabetes was 2.00 (95% CI 1.57–2.55) times greater than that in nondiabetic subjects. The relative difference in antidepressant use between these groups was similar before and after the diabetes diagnosis except for a temporary peak in antidepressant use at the year of the diagnosis (OR 2.66 [95% CI 1.94–3.65]). In incident cancer case subjects, antidepressant use substantially increased after the cancer diagnosis, demonstrating that our analysis was sensitive for detecting long-term changes in antidepressant trajectories when they existed. CONCLUSIONS Awareness of the diagnosis of type 2 diabetes may temporarily increase the risk of depressive symptoms. Further research is needed to determine whether more prevalent use of antidepressants noted before the diagnosis of diabetes relates to effects of depression, side effects of antidepressant use, or a common causal pathway for depression and diabetes.
Haplotype and isoform specific expression estimation using multi-mapping RNA-seq reads
Authors: Ernest Turro, Shu-Yi Su, Ângela Gonçalves, Lachlan JM Coin, Sylvia Richardson, Alex Lewin
Journal: Genome biology (2011)

Abstract We present a novel pipeline and methodology for simultaneously estimating isoform expression and allelic imbalance in diploid organisms using RNA-seq data. We achieve this by modeling the expression of haplotype-specific isoforms. If unknown, the two parental isoform sequences can be individually reconstructed. A new statistical method, MMSEQ, deconvolves the mapping of reads to multiple transcripts (isoforms or haplotype-specific isoforms). Our software can take into account non-uniform read generation and works with paired-end reads.
Targeting the α Receptor for Platelet-Derived Growth Factor as a Primary or Combination Therapy in a Preclinical Model of Prostate Cancer Skeletal Metastasis
Authors: Mike R. Russell, Qingxin Liu, Alessandro Fatatis
Journal: Clinical Cancer Research (2010)

Platelet-derived growth factor α (PDGFRα) is highly expressed in primary prostate cancer and associated skeletal metastases. Here, we tested whether targeting this receptor could impair metastatic colonization and progression, as well as prolong survival, either as primary or as combination therapy.We used a preclinical animal model of metastasis in which PC3-ML human prostate cancer cells are inoculated directly in the blood circulation. First, the humanized, monoclonal antibody IMC-3G3 was administered to mice bearing established skeletal metastases. Second, we targeted the stromal PDGFRα with IMC-1E10, an antibody specific for the murine receptor. Third, IMC-3G3 and the bisphosphonate zoledronic acid (ZA), administered separately or in combination, were tested on the progression of skeletal lesions and overall survival. In addition, the ability of IMC-3G3 and ZA to impair initial colonization of the bone marrow by prostate cancer cells was investigated.The blockade of PDGFRα on prostate cancer cells by IMC-3G3 reduces the size of established skeletal metastases, whereas the IMC-1E10 antibody directed against the stromal PDGFRα fails to inhibit metastatic progression. IMC-3G3 and ZA, either separately or in combination, significantly slow tumor growth and seem to prolong survival. Lastly, the blockade of PDGFRα by IMC-3G3 inhibits the initial phase of bone colonization, whereas ZA is ineffective at this stage.This study presents compelling evidence that targeting PDGFRα with IMC-3G3 delays the progression of early metastatic foci and reduces the size of more established lesions. In addition, IMC-3G3, either alone or in combination with ZA, prolongs survival in animal models.
Pseudoseptic pseudogout in progressive pseudorheumatoid arthritis of childhood.
Authors: J D Bradley
Journal: Annals of the Rheumatic Diseases (1987)

Progressive pseudorheumatoid arthritis of childhood is an uncommon arthropathy of unknown aetiology, which is related to spondyloepiphyseal dysplasia tarda. Previous reports have noted the absence of joint inflammation in this disease. An adult is described here with this arthropathy, who developed episodic acute inflammatory arthritis that mimicked septic arthritis, but proved to be pseudogout. The relation between pseudogout and progressive pseudorheumatoid arthritis of childhood is discussed.
AMP-Activated Protein Kinase Activates p38 Mitogen-Activated Protein Kinase by Increasing Recruitment of p38 MAPK to TAB1 in the Ischemic Heart
Authors: Ji Li, Edward J. Miller, Jun Ninomiya-Tsuji, Raymond R. Russell, Lawrence H. Young
Journal: Circulation Research (2005)

AMP-activated protein kinase (AMPK) promotes glucose transport, maintains ATP stores, and prevents injury and apoptosis during ischemia. AMPK has several direct molecular targets in the heart but also may interact with other stress-signaling pathways. This study examined the role of AMPK in the activation of the p38 mitogen-activated protein kinase (MAPK). In isolated heart muscles, the AMPK activator 5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside (AICAR) increased p38 MAPK activation. In AMPK-deficient mouse hearts, expressing a kinase-dead (KD) alpha2 catalytic subunit, p38 MAPK activation was markedly reduced during low-flow ischemia (2.3- versus 7-fold in wild-type hearts, P<0.01) and was similarly reduced during severe no-flow ischemia in KD hearts (P<0.01 versus ischemic wild type). Knockout of the p38 MAPK upstream kinase, MAPK kinase 3 (MKK3), did not affect ischemic activation of either AMPK or p38 MAPK in transgenic mkk3(-/-) mouse hearts. Ischemia increased p38 MAPK recruitment to transforming growth factor-beta-activated protein kinase 1-binding protein 1 (TAB1), a scaffold protein that promotes p38 MAPK autophosphorylation. Moreover, TAB1 was associated with the alpha2 catalytic subunit of AMPK. p38 MAPK recruitment to TAB1/AMPK complexes required AMPK activation and was reduced in ischemic AMPK-deficient transgenic mouse hearts. The potential role of p38 MAPK in mediating the downstream action of AMPK to promote glucose transport was also assessed. The p38 MAPK inhibitor SB203580 partially inhibited both AICAR- and hypoxia-stimulated glucose uptake and GLUT4 translocation. Activation of p38 MAPK by anisomycin also increased glucose transport in heart muscles. Thus, AMPK has an important role in promoting p38 MAPK activation in the ischemic heart by inducing p38 MAPK autophosphorylation through interaction with the scaffold protein TAB1.
Emergency contraception in post-conflict Somalia: assessing awareness and perceptions of need
Authors: F Gure, M Koshin Dahir, M Yusuf, A M Foster
Journal: The Lancet Global Health (2015)

BackgroundThe national health system in Somalia has been seriously undermined by almost two decades of civil war and conflict. Somalia's high total fertility rate, high maternal mortality ratio, and low contraceptive prevalence rate coupled with restrictive abortion laws make addressing the lack of family planning services an important priority. In crisis and conflict or post-conflict settings such as Somalia, emergency contraception can be important for pregnancy prevention, yet Somalia remains one of the few countries in the world without a registered progestin-only emergency contraceptive pill. In 2014, we conducted fieldwork in Somalia to explore awareness of and attitudes to emergency contraception.MethodsWe conducted a qualitative, multi-methods study comprised of ten formal, semi-structured interviews with key informants (ie, physicians, non-governmental officials, and government officials) in Mogadishu, structured, in-person interviews with 20 Somali pharmacists in a range of neighbourhoods, and four focus group discussions with 21 married and unmarried Somali women. Most key informants and pharmacists were purposively sampled, with additional participants recruited through snowball sampling. Focus group participants were recruited through our study's partner non-governmental organisations in Mogadishu. Findings from this study will be disseminated to stakeholders in the form of a summarised report and will inform future projects and policies about the potential expansion of emergency contraception in Somalia.FindingsResponses from most participants showed little knowledge of existing family planning methods or emergency contraception. However, once emergency contraception was described, all participants expressed tremendous enthusiasm for expanding access to post-coital contraceptive methods in Somalia. They believed that the provision of emergency contraception would fill a major gap in reproductive health service delivery. All stakeholders involved in the study identified ways that emergency contraception could be incorporated into the health system.InterpretationAlthough importation and use of pharmaceuticals in Somalia is severely unregulated, and measures for formal registration of medications in Somalia do not exist, results from our study highlight mechanisms that could be explored to expand access to emergency contraception in Somalia. This study sheds much needed light on why Somalia continues to be a global exception with respect to a dedicated product and suggests that there are possible avenues for overcoming existing barriers.FundingThis study has received funding from the Society of Family Planning's Research Fund, as well as the Faculty of Graduate and Post-doctoral Studies at the University of Ottawa.
Parkinson's Disease: Genetics and Pathogenesis
Authors: Joshua M. Shulman, Philip L. De Jager, Mel B. Feany
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Recent investigation into the mechanisms of Parkinson's disease (PD) has generated remarkable insight while simultaneously challenging traditional conceptual frameworks. Although the disease remains defined clinically by its cardinal motor manifestations and pathologically by midbrain dopaminergic cell loss in association with Lewy bodies, it is now recognized that PD has substantially more widespread impact, causing a host of nonmotor symptoms and associated pathology in multiple regions throughout the nervous system. Further, the discovery and validation of PD-susceptibility genes contradict the historical view that environmental factors predominate, and blur distinctions between familial and sporadic disease. Genetic advances have also promoted the development of improved animal models, highlighted responsible molecular pathways, and revealed mechanistic overlap with other neurodegenerative disorders. In this review, we synthesize emerging lessons on PD pathogenesis from clinical, pathological, and genetic studies toward a unified concept of the disorder that may accelerate the design and testing of the next generation of PD therapies.