tbuckley/cabot-search huggingface dataset:
Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force
Authors: Josef S Smolen, Jürgen Braun, Maxime Dougados, Paul Emery, Oliver FitzGerald, Philip Helliwell, Arthur Kavanaugh, Tore K Kvien, Robert Landewé, Thomas Luger, Philip Mease, Ignazio Olivieri, John Reveille, Christopher Ritchlin, Martin Rudwaleit, Monika Schoels, Joachim Sieper, Martinus de Wit, Xenofon Baraliakos, Neil Betteridge, Ruben Burgos-Vargas, Eduardo Collantes-Estevez, Atul Deodhar, Dirk Elewaut, Laure Gossec, Merryn Jongkees, Mara Maccarone, Kurt Redlich, Filip van den Bosch, James Cheng-Chung Wei, Kevin Winthrop, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). <h3>Objective</h3> To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. <h3>Methods</h3> Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. <h3>Results</h3> Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient9s status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9–10 (10: maximum agreement) for all recommendations. A research agenda was formulated. <h3>Conclusions</h3> The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.
Serum pepsinogens and risk of gastric and oesophageal cancers in the General Population Nutrition Intervention Trial cohort
Authors: J-S Ren, F Kamangar, Y-L Qiao, P R Taylor, H Liang, S M Dawsey, B Liu, J-H Fan, C C Abnet
Journal: Gut (2009)

<h3>Objective:</h3> Low serum pepsinogen I (PGI) and low pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy. We aimed to prospectively test the association between serum PGI/II ratio and risks of gastric non-cardia adenocarcinoma, gastric cardia adenocarcinoma, and oesophageal squamous cell carcinoma (OSCC). <h3>Design:</h3> Case–cohort study nested in a prospective cohort with over 15 years of follow-up. <h3>Setting:</h3> Rural region of the People's Republic of China. <h3>Subjects:</h3> Men and women aged 40–69 years at study baseline. <h3>Main outcome measures:</h3> Adjusted hazard ratios and 95% confidence intervals for the association between serum PGI/II ratio and cancer risk. <h3>Results:</h3> Compared to subjects with PGI/II ratio of &gt;4, those with ⩽4 had hazard ratios (HRs) (95% CIs) of 2.72 (1.77 to 4.20) and 2.12 (1.42 to 3.16) for non-cardia and cardia gastric adenocarcinomas, respectively. Risk of both cancers was also increased when we used other cut points ranging from 3 to 6, or quartile models, or nonlinear continuous models. Risk of OSCC was marginally increased in those with PGI/II ratio ⩽4, with HR (95% CI) of 1.56 (0.99 to 2.47), but quartile models and continuous models showed no increased risk. The nonlinear continuous models suggested that any single cut point collapsed subjects with dissimilar gastric adenocarcinoma risks, and that using cut points was not an efficient use of data in evaluating these associations. <h3>Conclusion:</h3> In this prospective study, we found similar and significantly increased risks of non-cardia and cardia gastric adenocarcinomas in subjects with low PGI/II ratio but little evidence for an association with the risk of OSCC.
Aspirin did not prevent vascular events or mortality in adults with a low ankle–brachial index
Authors: A.C. Felix Burden
Journal: Annals of Internal Medicine (2010)

Source Citation Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303:841-8. 20197530
Ethnic differences in use of hormone replacement therapy: community based survey
Authors: T. J Harris, D. G Cook, P. D Wicks, F. P Cappuccio
Journal: BMJ (1999)

Hormone replacement therapy is widely promoted to prevent cardiovascular disease and osteoporosis and relieve menopausal symptoms, although concern exists that much of the cardiovascular effect may be due to its selection by healthy women.1 Little is known about its use by women from different ethnic groups in the United Kingdom, particularly women of south Asian origin, who are at increased risk of coronary heart disease,2 osteoporosis,3 and diabetes4 compared with white women.

A population based survey was carried out in Wandsworth, south London, where roughly 12% of residents are from the Caribbean or west Africa (that is, of African descent) and 6% are of Indian, Pakistani, or Bangladeshi origin (that is, south Asian). Women aged 40-59 were invited from nine general practices as part of a cardiovascular screening study.4 The response rate was 66% (941/1429). Of the 941 women screened, 882 were from one of the ethnic groups being studied.

Ethnic group was recorded at interview on the basis of answers to several questions, including questions on country of …
Cancer Cell Dormancy in Novel Mouse Models for Reversible Pancreatic Cancer: A Lingering Challenge in the Development of Targeted Therapies
Authors: Wan-Chi Lin, Nirakar Rajbhandari, Kay-Uwe Wagner
Journal: Cancer Research (2014)

Significant advances have been made in the identification of key molecular pathways that play pivotal roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Among the common genetic and epigenetic changes, oncogenic mutations in Kras and upregulation of the c-Myc oncogene are frequent events in PDAC. Using genetically defined in vivo models, several studies have recently demonstrated that expression of mutant Kras and c-Myc is equally important for the initiation and maintenance of pancreatic cancer. The targeted downregulation of a single oncogene resulted in cancer cell death at primary and metastatic sites. These findings are very encouraging and provide a strong rationale for the development of targeted therapies against these oncogenic drivers. Despite what seemed to be a complete response to the ablation of the oncogene, a few dormant cancer cells remained present, and it was demonstrated that they are a cellular reservoir for a swift relapse of pancreatic cancer following oncogene reactivation. This review summarizes the basic principles of cancer dormancy and the applicability of the novel genetic models for reversible metastatic PDAC to elucidate the role of cancer stem cells as well as biologic and molecular mechanisms that mediate the survival of dormant tumor cells.
"Crack lung" caused by an impure preparation.
Authors: O. M. Kon, J. B. Redhead, D. Gillen, J. Fothergill, J. A. Henry, D. M. Mitchell
Journal: Thorax (1996)

Pulmonary complications of crack cocaine have been reported mainly from American centres. Crack usage is now on the increase in the UK. Three cases of "crack lung" are reported in patients who acquired the drug from the same source. The pulmonary syndrome they developed was due to an impure form of crack.
Nonmyeloablative Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus
Authors: Richard K. Burt
Journal: JAMA (2006)

ContextManifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease.ObjectiveTo assess the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment-refractory SLE.Design, Setting, and ParticipantsA single-arm trial of 50 patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through January 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center.InterventionsPeripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (5 μg/kg per day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg).Main Outcome MeasuresThe primary end point was survival, both overall and disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), serology (antinuclear antibody [ANA] and anti–double-stranded (ds) DNA), complement C3 and C4, and changes in renal and pulmonary organ function assessed before treatment and at 6 months, 12 months, and then yearly for 5 years.ResultsFifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). By intention to treat, treatment-related mortality was 4% (2/50). With a mean follow-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal function and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin.ConclusionsIn treatment-refractory SLE, autologous nonmyeloablative HSCT results in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial.Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT00271934
MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice
Authors: Weiguo Zou, Matthew B. Greenblatt, Jae-Hyuck Shim, Shashi Kant, Bo Zhai, Sutada Lotinun, Nicholas Brady, Dorothy Zhang Hu, Steven P. Gygi, Roland Baron, Roger J. Davis, Dallas Jones, Laurie H. Glimcher
Journal: Journal of Clinical Investigation (2011)

Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients.
Modulation of canine myocardial sarcolemmal membrane fluidity by amphiphilic compounds.
Authors: K L Fink, R W Gross
Journal: Circulation Research (1984)

Amphiphilic moieties such as lysophosphoglycerides and long-chain acyl carnitines accumulate in ischemic myocardium and potentially contribute to the sequelae of myocardial ischemia. To characterize alterations in membrane molecular dynamics produced by amphiphilic compounds, highly purified preparations of canine myocardial sarcolemma were spin-labeled with paramagnetic probes (5-, 12-, or 16-doxyl stearate), and alterations produced by amphiphilic compounds were quantified by electron spin resonance spectroscopy. Incorporation of 1.5, 3, or 6 mol % palmitoyl lysophosphatidylcholine resulted in a decrease of the order parameter of 16-doxyl stearate from 0.164 to 0.161, 0.155, and 0.145, respectively. Similar increases in membrane fluidity in the interior of the bilayer were present when palmitoyl lysophosphatidylethanolamine, L-palmitoyl carnitine, and platelet-activating factor were incorporated into sarcolemma. In contrast, incubation of sarcolemma with lysophosphatidylcholine did not result in significant change of the order parameter of 5-doxyl stearate, even at 6 mol %, demonstrating that lysophosphatidylcholine increases the transmembrane fluidity gradient. Sarcolemma treated with phospholipase A2 exhibited a time-dependent decrease in the rotational correlation time and order parameter when lysophospholipids constituted a small amount (6%) of sarcolemmal phospholipids. Furthermore, the effects of lysophosphatidylcholine were not dependent upon its physical state, since bilayers composed of gramicidin and lysophosphatidylcholine resulted in similar increases in membrane fluidity as micellar lysophosphatidylcholine. The results suggest that alterations in sarcolemmal molecular dynamics are one mechanism through which amphiphilic moieties mediate their multiple effects. Such alterations could contribute to the electrophysiological and biochemical sequelae of myocardial ischemia.
Ablation of Atrial Flutter in a Patient With Mustard Procedure Using Integration of Real-Time Electroanatomical Mapping With 3-Dimensional Computed Tomographic Imaging
Authors: Arash Aryana, Richard R. Liberthson, E. Kevin Heist, Andre d’Avila, Ravi Mandapati, Ricardo C. Cury, Jeremy N. Ruskin, Moussa C. Mansour
Journal: Circulation (2007)
Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease
Authors: Thomas Steinmüller, Daniel Seehofer, Nada Rayes, Andrea R. Müller, Utz Settmacher, Sven Jonas, Ruth Neuhaus, Thomas Berg, Uwe Hopf, Peter Neuhaus
Journal: Hepatology (2002)

Liver transplantation in patients with hepatitis B has been under discussion for 20 years because of inferior results without reinfection prophylaxis; therefore, we analyzed our overall experience with liver transplantation in hepatitis B patients with immunoprophylaxis, particularly the influence of the available antiviral treatment in different periods. From 1988 to 2000, 228 liver transplants in 206 hepatitis B patients were performed. Indications were acute liver failure (10%), hepatitis B virus (HBV) cirrhosis alone (67%) or with hepatitis D virus (HDV) (13%), or hepatitis C virus (HCV) coinfection (7%). All patients received long-term immunoprophylaxis (anti-HBs > 100 U/L). HBV DNA-positive patients were treated before and after surgery with famciclovir or lamivudine since 1993 and 1996, respectively. Since 1993, antivirals also were used for HBV reinfection. The 1-, 5-, and 10-year patient survival rates were 91%, 81%, and 73%. In patients with hepatocellular carcinoma (HCC) (60% 5-year survival, P <.01) or HBV reinfection (69% 5-year survival, P <.01) survival was significantly impaired. Those with HDV or HCV coinfection had a slightly better survival than with HBV monoinfection (P >.05, not significant). Preoperative positive HBV DNA (hybridization-assay) test results were associated with a slightly impaired patient survival (78% 5-year survival, P >.05, not significant versus DNA-negative). Preoperative positive hepatitis B e antigen (HBeAg) predicted significantly worse survival (P <.05 versus negative HBeAg). Graft loss caused by reinfection was most frequent before the availability of antiviral drugs. Two-year patient survival increased from 85% in era I (1988-1993) to 94% in era III (1997-2000, P <.05). The 2-year recurrence rates in these 2 periods were 42% and 8% (P <.05). In conclusion, excellent long-term results can be achieved in hepatitis B patients after liver transplantation with modern strategies, and survival rates are similar to other indications. Based on our experience, hepatitis B patients, including those with active viral replication, should not be excluded from liver transplantation.
Impaired Fasting Glucose in Cystic Fibrosis
Authors: Brigitte I. Frohnert, Katie Larson Ode, Antoinette Moran, Brandon M. Nathan, Theresa Laguna, Bonnie Holme, William Thomas
Journal: Diabetes Care (2010)

OBJECTIVE While glucose tolerance abnormalities are common in cystic fibrosis (CF), impaired fasting glucose (IFG) has scarcely been explored. No studies have examined the relation between IFG and clinical status. RESEARCH DESIGN AND METHODS Data were retrieved from the University of Minnesota CF database on oral glucose tolerance tests (OGTTs) performed in 1996–2005. Subjects were identified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CF–related diabetes without fasting hyperglycemia (CFRD FH−). Patients with fasting hyperglycemia were excluded. The presence of IFG was assessed within each category. In a separate case-control cohort study, subjects with IFG were matched to CF control subjects by age, sex, and OGTT class to explore outcomes. RESULTS For the total population (n = 310), the prevalence of IFG was 22%, and by OGTT class was NGT 14%, IGT 31%, CFRD FH− 53%. Within the cohort study, mortality was significantly reduced in IFG (two vs. nine deaths, odds ratio [OR] = 0.2 [95% CI 0.04–0.9]). IFG did not confer increased risk of progression to diabetes (OR 0.66 [0.29–1.48]). Lung function was better in pediatric IFG subjects with IGT and not significantly worse in adults with IGT or adults and children with NGT and CFRD FH−. BMI was not significantly different in IFG subjects versus control subjects. CONCLUSIONS Contrary to expectations in patients with CF, IFG appeared to be associated with improved survival and was not associated with worse nutritional or pulmonary status or increased progression to fasting hyperglycemia.
Antitumor Activity of BRAF Inhibitor Vemurafenib in Preclinical Models of BRAF-Mutant Colorectal Cancer
Authors: Hong Yang, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, William D. Bradley, Richard J. Lee, Kathleen Schostack, Mary Ellen Simcox, Scott Kopetz, David Heimbrook, Brian Lestini, Gideon Bollag, Fei Su
Journal: Cancer Research (2011)

The protein kinase BRAF is a key component of the RAS-RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAF(V600)-expressing cell lines and inhibiting tumor growth in BRAF(V600E) bearing xenograft models. Because vemurafenib has shown limited single-agent clinical activity in BRAF(V600E)-mutant metastatic CRC, we therefore explored a range of combination therapies, with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor (MK-2206). The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.
Smooth Muscle Cell Phenotypic Transition Associated With Calcification
Authors: Susie A. Steitz, Mei Y. Speer, Gabrielle Curinga, Hsueh-Ying Yang, Paul Haynes, Ruedi Aebersold, Thorsten Schinke, Gerard Karsenty, Cecilia M. Giachelli
Journal: Circulation Research (2001)

Bovine aortic smooth muscle cell (BASMC) cultures undergo mineralization on addition of the organic phosphate donor, beta-glycerophosphate (betaGP). Mineralization is characterized by apatite deposition on collagen fibrils and the presence of matrix vesicles, as has been described in calcified vascular lesions in vivo as well as in bone and teeth. In the present study, we used this model to investigate the molecular mechanisms driving vascular calcification. We found that BASMCs lost their lineage markers, SM22alpha and smooth muscle alpha-actin, within 10 days of being placed under calcifying conditions. Conversely, the cells gained an osteogenic phenotype as indicated by an increase in expression and DNA-binding activity of the transcription factor, core binding factor alpha1 (Cbfa1). Moreover, genes containing the Cbfa1 binding site, OSE2, including osteopontin, osteocalcin, and alkaline phosphatase were elevated. The relevance of these in vitro findings to vascular calcification in vivo was further studied in matrix GLA protein null (MGP(-/-)) mice whose arteries spontaneously calcify. We found that arterial calcification was associated with a similar loss in smooth muscle markers and a gain of osteopontin and Cbfa1 expression. These data demonstrate a novel association of vascular calcification with smooth muscle cell phenotypic transition, in which several osteogenic proteins including osteopontin, osteocalcin, and the bone determining factor Cbfa1 are gained. The findings suggest a positive role for SMCs in promoting vascular calcification.