tbuckley/cabot-search huggingface dataset:
Role of Cysteine-rich 61 Protein (CCN1) in Macrophage-mediated Oncolytic Herpes Simplex Virus Clearance
Authors: Amy Haseley Thorne, Walter H Meisen, Luke Russell, Ji Young Yoo, Chelsea M Bolyard, Justin D Lathia, Jeremy Rich, Vinay K Puduvalli, Hsiaoyin Mao, Jianhua Yu, Michael A Caligiuri, Susheela Tridandapani, Balveen Kaur
Journal: Molecular Therapy (2014)

Glioblastoma is a devastating disease, and there is an urgent need to develop novel therapies, such as oncolytic HSV1 (OV) to effectively target tumor cells. OV therapy depends on tumor-specific replication leading to destruction of neoplastic tissues. Host responses that curtail virus replication limit its efficacy in vivo. We have previously shown that cysteine-rich 61 protein (CCN1) activates a type 1 IFN antiviral defense response in glioblastoma cells. Incorporating TCGA data, we found CCN1 expression to be a negative prognostic factor for glioblastoma patients. Based on this, we used neutralizing antibodies against CCN1 to investigate its effect on OV therapy. Use of an anti-CCN1 antibody in mice bearing glioblastomas treated with OV led to enhanced virus expression along with reduced immune cell infiltration. OV-induced CCN1 increases macrophage migration toward infected glioblastoma cells by directly binding macrophages and also by enhancing the proinflammatory activation of macrophages inducing MCP-1 expression in glioblastoma cells. Activation of macrophages by CCN1 also increases viral clearance. Neutralization of integrin αMβ2 reversed CCN1-induced macrophage activation and migration, and reduced MCP-1 expression by glioblastoma cells. Our findings reveal that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors.
T1 Rev-erb , a novel anti-inflammatory target, modifies the circadian oscillation of pulmonary inflammation
Authors: J. Blaikley, L. Green, J. Gibbs, S. Farrow, A. Loudon, D. Singh, D. Ray
Journal: Thorax (2010)

<h3>Introduction</h3> Most inflammatory diseases demonstrate diurnal variation in severity, for example, chronic obstructive pulmonary disease (COPD) and asthma. We now show that the macrophage inflammatory response is regulated by the circadian cellular clock through Rev-erbα, a nuclear receptor. Additionally, a Rev-erbα ligand (GSK414112) regulates a distinct cytokine network in COPD alveolar macrophages. <h3>Results</h3> Circadian oscillation of core clock genes BMAL1, Per2 and Rev-erbα in human macrophages (mdms) demonstrates a functional cellular clock. For the first time we reveal that the inflammatory response is dependent on clock phase, exemplified by altered IL-6 LPS stimulated expression (p&lt;0.01). The critical function of Rev-erbα was confirmed through inhibition of the exaggerated IL-6 response by GSK414112 (p&lt;0.01). Lentiviral knockdown of Rev-erbα expression enhanced the IL-6 LPS response (p&lt;0.05) and attenuated GSK414112’s effect. It is known that GSK414112 recruits HDAC3 and NCOR onto Rev-erbα repressing transcription. To define whether Rev-erbα directly interacted with the IL-6 promoter, GSK414112’s effect on a series of IL-6 reporter genes was investigated. The full length IL6-luc reporter was repressed by GSK414112 (p&lt;0.01) but mutations to the closely related C/EBP (p&lt;0.01) or 3’AP-1 binding sites (p&lt;0.05) inhibited this effect. ChIP studies confirmed direct interaction of Rev-erbα with the IL-6 promoter. Reporter genes expressing consensus sites for C/EBP and AP-1 showed regulation of these transcription factors by Rev-erbα. Novel Rev-erbα actions were identified through transcriptome profiling of human mdms. SERPINE2, IL-6, PTX3 and MMP-12, all implicated in COPD, are regulated by GSK414112. The analysis also revealed a novel mechanism of action, reverse cholesterol transport, previously implicated in pulmonary inflammation. Luminex analysis on mdms from healthy volunteers and COPD alveolar macrophages revealed that GSK414112 significantly repressed secretion of certain cytokines including IL-6, eotaxin, IL-10, IP-10, G-CSF whilst other cytokines, for example, IL-8, TNFα, MIP 1α were unaffected. <h3>Conclusion</h3> Through Rev-erbα an autonomouscellular clock modifies the macrophage LPS response. Ligands for this nuclear receptor exert anti-inflammatory effects through suppression of target gene transcription and up regulation of the cholesterol efflux pathway, employing a novel transcription factor cross-talk mechanism. This mechanism is effective in suppressing glucocorticoid resistant targets as well as targeting the temporal aspects of inflammation.
Poisoning by a Large Dose of Tincture of Aconite: Remarkable Symptoms: Recovery
Authors: L. H. Jones
Journal: BMJ (1877)

in contact with the heart, " in which", says Dr. Balfour, " the pulsa- tion, though expansile from being communicated through fluid, is less forcible than that of the heart.'In this particular case, the pulsation was fully as forcible as the apex-beat; but the apex-pulsation was feeble.Dr. Balfour's proposition is not, therefore, invalidated, provided that the cardiac pulsation is of normal force.In spite of the great similarity to aneurism, the diagnosis of intra- thoracic tumour was arrived at for the following reasons.-.The extensive iiature of the dulness.An aneurism sufficiently large to cause such dulness would have produced more active pressure- symptoms-notably pain.There had been slight pain in this case at the commencement of the illness.2. The great emaciation.There was no obstruction of the (esophagus, no prolonged suffering-conditions which cause emaciation in aneurism.
Genome-Wide miRNA Expression Profiling Identifies <i>miR</i>-<i>9</i>-<i>3</i> and <i>miR</i>-<i>193a</i> as Targets for DNA Methylation in Non–Small Cell Lung Cancers
Authors: Gerwin Heller, Marlene Weinzierl, Christian Noll, Valerie Babinsky, Barbara Ziegler, Corinna Altenberger, Christoph Minichsdorfer, György Lang, Balazs Döme, Adelheid End-Pfützenreuter, Britt-Madeleine Arns, Yuliya Grin, Walter Klepetko, Christoph C. Zielinski, Sabine Zöchbauer-Müller
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non–small cell lung cancers (NSCLC). Experimental Design: We conducted microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. miRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding nonmalignant lung tissue samples of 101 patients with stage I–III NSCLC. Results: By comparing microarray data of untreated and drug-treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analyzed. Moreover, miR-9-3 and miR-193a were found to be tumor specifically methylated in patients with NSCLC. We observed a shorter disease-free survival of patients with miR-9-3 methylated lung squamous cell carcinoma (LSCC) than patients with miR-9-3 unmethylated LSCC by multivariate analysis [HR = 3.8; 95% confidence interval (CI), 1.3–11.2, P = 0.017] and a shorter overall survival of patients with miR-9-3 methylated LSCC than patients with miR-9-3 unmethylated LSCC by univariate analysis (P = 0.013). Conclusions: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in patients with LSCC. Clin Cancer Res; 18(6); 1619–29. ©2012 AACR.
Nav-igating through a complex landscape: SCN10A and cardiac conduction
Authors: David S. Park, Glenn I. Fishman
Journal: Journal of Clinical Investigation (2014)

Genome-wide association studies (GWAS) have implicated SCN10A, which encodes a nociceptor-associated voltage-gated sodium channel subunit, as a modulator of cardiac conduction; however, this role has traditionally been ascribed to SCN5A, which is highly expressed in cardiac muscle. SCN10A is believed to affect cardiac conduction either directly through cardiomyocytes or indirectly via intracardiac neurons. In this issue of the JCI, van den Boogaard and colleagues introduce a third possibility: that the SCN10A locus acts as an enhancer of SCN5A gene expression. The authors demonstrate that SCN10A expression is negligible within human and murine hearts, and that a T-box enhancer within the SCN10A locus drives SCN5A expression within cardiomyocytes. This work reasserts SCN5A as the key determinant of cardiac conduction and highlights the importance of deciphering the functionality of coding versus noncoding regions when interpreting GWAS data.
Anergic T cells are defective in both jun NH2-terminal kinase and mitogen-activated protein kinase signaling pathways.
Authors: D R DeSilva, W S Feeser, E J Tancula, P A Scherle
Journal: The Journal of Experimental Medicine (1996)

T helper type 1 cells (Th1) become anergic when stimulated through the antigen receptor in the absence of costimulation. They do not produce IL-2 or proliferate in response to subsequent stimulation. Previous studies have indicated that anergic T cells are defective in the trnsactivational activity of the transcription factor, AP-1, which is required for optimal IL-2 transcription. Using two murine Th1 cell clones, we demonstrate that anergic Th1 cells have defects in both jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activities. These kinases have been shown to be important for the upregulation of AP-1 activity. Furthermore, our data show that ERK and JNK activities are restored when anergy is induced in the presence of the protein synthesis inhibitor cycloheximide, or when anergic T cells are allowed to proliferate in response to exogenous IL-2. These treatments have previously been shown to prevent or reverse the anergic state. Our results suggest that defects in both JNK and ERK may result in the decreased AP-1 activity and the reduced IL-2 transcription observed in anergic T cells.
Should Intravenous Iron Be the Standard of Care in Oncology?
Authors: Michael Auerbach
Journal: Journal of Clinical Oncology (2008)

Before 1989, when epoetin was introduced for dialysisassociated anemia, the use of intravenous (IV) iron in the United States was typically avoided.Shortly thereafter, it was shown that responses to epoetin could be improved by IV iron supplementation.By 1998, IV iron had become standard of care in dialysis patients receiving epoetin, 1 and the use of erythropoiesis-stimulating agents (ESAs) in oncology patients was in its infancy.In the ensuing decade, we have witnessed improvements in quality of life and fewer transfusions among patients receiving ESAs for the anemia associated with cancer and cancer chemotherapy.Some studies have shown the maximum improvement in energy, activity, and quality of life occurs when the hemoglobin (Hb) increases from 11 to 13 g/dL. 2In August 2007, the Committee on Medicare and Medicaid Services issued a Decision Memo restricting ESA usage when patients' Hb levels are Ն10 g/dL.These new regulations were recommended on the basis of data suggesting harm with ESAs when used outside of established guidelines.To date, no study has shown a negative impact on cancer outcomes or survival in patients when ESAs were used in accordance with previously established American Society of Hematology, American Society of Clinical Oncology, or National Comprehensive Cancer Network guidelines.Recent data in the renal literature suggest that it is not the Hb level, but ESA exposure, that is associated with negative outcomes. 3he success of IV iron supplementation in improving responses to ESAs in the anemia of end-stage renal disease has yet to be realized by the oncology community.Oncologists spend three times more on ESAs than nephrologists.A 50% reduction in transfusions has been accomplished in oncology patients, whereas transfusions have been virtually eliminated in the dialysis population. 4Is it possible that it is the suboptimal use of these expensive drugs that played a role in the restrictions recently imposed?Two articles in this issue of the Journal of Clinical Oncology represent the fourth and fifth of five recent publications showing that administration of IV iron to oncology patients receiving ESAs results in significantly greater increments in Hb and hematopoietic response rates compared with ESAs alone or with oral iron 5-9 (Table 1).In all five studies, the benefit was independent of baseline iron parameters.These two studies add unique and useful information to a rapidly growing body of data supporting the routine use of IV iron as an adjunct to ESA therapy in appropriately selected oncology patients.Bastit et al 5 studied 396 patients with nonmyeloid malignancies receiving chemotherapy, with Hb less than 10.5 g/dL and ferritin more than 10 ng/mL or transferrin saturation (TSAT) more than 15%.
National Commissioning Board admits struggle to recruit staff
Authors: A. O'Dowd
Journal: BMJ (2012)

The National Commissioning Board is struggling to recruit enough experienced staff, it has emerged. The body will control a large proportion of the NHS budget from next year, and direct England’s general practitioner led clinical commissioning groups.

Around 4000 staff are needed for the National Commissioning Board, which is based in Leeds, but apart from the national director and non-executive roles, the vast majority of posts are still to be filled before the board becomes fully operational in April next year.

In the board’s most recent assurance framework document1 for July—its own risk register—in the category of “very high risk” it says: “There is a risk that the …
Hormone replacement therapy in postmenopausal women with rheumatoid arthritis stabilises bone mineral density by digital x-ray radiogrammetry in a randomised controlled trial
Authors: Helena Forsblad-d'Elia, Hans Carlsten
Journal: Annals of the Rheumatic Diseases (2010)

Rheumatoid arthritis (RA) is characterised by synovitis, cartilage destruction in the joints, erosions in the subchondral bone at the joint margins and by periarticular osteopenia1 and also by generalised osteoporosis affecting the axial and appendicular bones.2 Conventional radiographs are the standard method for detection and quantification of joint destruction in RA, but its sensitivity is limited. Bone loss less than around 30% cannot be detected on plain radiographs.3 Radiogrammetry assessing cortical bone width as a measure of bone strength and bone loss was proposed in 1960.4 In RA localised bone involvement in the hands can be measured by digital x-ray radiogrammetry (DXR), which gives an estimate of cortical hand bone mineral density (BMD) in the metacarpal joints two …
Effect of addition of rituximab to salvage chemotherapy on outcome of patients with diffuse large B-cell lymphoma relapsing after an autologous stem-cell transplantation
Authors: J.M. Calvo-Villas, A. Martín, E. Conde, A. Pascual, I. Heras, R. Varela, J. de la Rubia, M.J. Ramirez, J.L. Díez-Martín, C. Panizo, M.J. Rodríguez-Salazar, M.J. Pascual, E.M. Donato, E. González-Barca, M.D. Caballero
Journal: Annals of Oncology (2010)
Expression of PGD2 receptor CRTH2 (DP2) on human lung fibroblasts
Authors: T. Nakajima, K. Asano, Y. Shiraishi, K. Niimi, M. Wakaki, Y. Suzuki, T. Shiomi, T. Oguma, A. Ishizaka
Journal: Journal of Allergy and Clinical Immunology (2005)
Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration
Authors: Christine D. Pozniak, Arundhati Sengupta Ghosh, Alvin Gogineni, Jesse E. Hanson, Seung-Hye Lee, Jessica L. Larson, Hilda Solanoy, Daisy Bustos, Hong Li, Hai Ngu, Adrian M. Jubb, Gai Ayalon, Jiansheng Wu, Kimberly Scearce-Levie, Qiang Zhou, Robby M. Weimer, Donald S. Kirkpatrick, Joseph W. Lewcock
Journal: The Journal of Experimental Medicine (2013)

Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid–induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.
The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats
Authors: Shimon Reif, Boaz Weis, Hussein Aeed, Mali Gana-Weis, Liliana Zaidel, Yona Avni, Roberto G Romanelli, Massimo Pinzani, Yoel Kloog, Rafael Bruck
Journal: Journal of Hepatology (1999)
Natural History of Venous Thromboembolism
Authors: Clive Kearon
Journal: Circulation (2003)

Most deep vein thromboses (DVTs) start in the calf, and most probably resolve spontaneously. Thrombi that remain confined to the calf rarely cause leg symptoms or symptomatic pulmonary embolism (PE). The probability that calf DVT will extend to involve the proximal veins and subsequently cause PE increases with the severity of the initiating prothrombotic stimulus. Although acute venous thromboembolism (VTE) usually presents with either leg or pulmonary symptoms, most patients have thrombosis at both sites at the time of diagnosis. Proximal DVTs resolve slowly during treatment with anticoagulants, and thrombi remain detectable in half of the patients after a year. Resolution of DVT is less likely in patients with a large initial thrombus or cancer. About 10% of patients with symptomatic DVTs develop severe post-thrombotic syndrome within 5 years, and recurrent ipsilateral DVT increases this risk. About 10% of PEs are rapidly fatal, and an additional 5% cause death later, despite diagnosis and treatment. About 50% of diagnosed PEs are associated with right ventricular dysfunction, which is associated with a ≈5-fold greater in-hospital mortality. There is ≈50% resolution of PE after 1 month of treatment, and perfusion eventually returns to normal in two thirds of patients. About 5% of treated patients with PE develop pulmonary hypertension as a result of poor resolution. After a course of treatment, the risk of recurrent thrombosis is higher (ie, ≈10% per patient-year) in patients without reversible risk factors, in those with cancer, and in those with prothrombotic biochemical abnormalities such as antiphospholipid antibodies and homozygous factor V Leiden.
Cognitive impairment and the associated risk factors among the elderly in the Shanghai urban area: a pilot study from China
Authors: Jun-Peng Zhuang, Gang Wang, Qi Cheng, Li-Ling Wang, Rong Fang, Li-Hua Liu, Ran Xiong, Yu Zhang, Ya-Xing Gui, Wen-Yan Kang, Hui-Dong Tang, Sheng-Di Chen
Journal: Translational Neurodegeneration (2012)

Abstract Objectives Our study aimed to investigate the prevalence of cognitive impairment(CI) and the associated risk factors among elderly people in Shanghai urban area, China. Methods A population-based survey was conducted among people aged 55 years or older in urban areas of Shanghai. Face-to-face interviews were carried out to collect information including demographic characteristics, medical history, and medication use, etc. The validated Chinese version of the Mini-Mental State Examination(MMSE) was used to screen subjects with CI, and the criteria of CI were adjusted for education levels. Results A total of 3,176 home-living residents (≥55 years old) were included in the study. Among them, 266 people (102 men and 164 women) were identified as cognition impaired, with a prevalence of 8.38% (266/3,176, 95% CI: (8.26, 8.49)) for both genders, 9.21% (102/1,107,95% CI: (9.18, 9.33)) for men and 7.93% (164/2,069, 95% CI: (7.80, 8.09)) for women, respectively. Furthermore, we found that several significant risk factors, including social factors(education, number of children, marriage status, and family structure), physiological factors (age, blood glucose level, and obesity), factors on living styles(physical exercise, diet &amp; chronic diseases), and genetic factor(ApoE), associated with CI onset. Conclusions This study confirms the high prevalence of CI among the elderly population in the Shanghai urban in China, similar to previous epidemiologic studies in Western countries. The putative risk factors associated with CI merit further investigated.
Lenalidomide and Rituximab in Waldenstrom's Macroglobulinemia
Authors: Steven P. Treon, Jacob D. Soumerai, Andrew R. Branagan, Zachary R. Hunter, Christopher J. Patterson, Leukothea Ioakimidis, Luis Chu, Paul Musto, Ari D. Baron, Johannes C. Nunnink, Joseph J. Kash, Terenig O. Terjanian, Paul M. Hyman, Elena L. Nawfel, David J. Sharon, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated lenalidomide and rituximab in symptomatic Waldenstrom's macroglobulinemia (WM) patients naive to either agent. Experimental Design: Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m2/wk) dosed on weeks 2 to 5 and 13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated. Results: Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients (median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias. The overall response and major response (&amp;lt;50% decrease in serum IgM) rates were 50% and 25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of 8 responding patients have progressed with a median time to progression of 18.9 months. Conclusion: Lenalidomide produces unexpected but clinically significant acute anemia in patients with WM. In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable.
The planning–control model and spatio-motor deficits following brain damage
Authors: H. Branch Coslett, Laurel J. Buxbaum
Journal: Behavioral and Brain Sciences (2004)

Glover's planning–control model accommodates a substantial number of findings from subjects who have motor deficits as a consequence of brain lesions. A number of consistently observed and robust findings are not, however, explained by Glover's theory; additionally, the claim that the IPL supports planning whereas the SPL supports control is not consistently supported in the literature.