tbuckley/cabot-search huggingface dataset:
MB-27 * PATHWAY ANALYSIS OF A HUMAN NEURAL STEM CELL MODEL OF AGGRESSIVE MEDULLOBLASTOMA REVEALS CKD INBHIBITION AS A POTENTIAL THERAPEUTIC MODALITY
Authors: A. Hanaford, T. Archer, P. Tamayo, S. Pomeroy, C. Eberhart, E. Raabe
Journal: Neuro-Oncology (2015)

Medulloblastoma, the most common malignant brain tumor in children, is divided into multiple subgroups with different associated mutations and clinical prognoses. To facilitate studying the biology and developing new therapeutic options, we created a model of aggressive medulloblastoma using human neural stem cells. Neural stem cells were obtained from the cerebellar anlage of first trimester fetal autopsy specimens and transfected using lentiviral vectors with different combinations of oncogenes associated with poor prognosis medulloblastoma: dominant-negative p53, hTERT, c-MYC, and constitutively active AKT. Cerebellar derived stem cells transformed with all four oncogenes formed fast growing, aggressive tumors that were histologically similar to primary anaplastic medulloblastoma tumors. We compared the expression profile of primary medulloblastoma tumors to our model, and confirmed that our model most closely matches the most aggressive and clinically devastating subgroup of medulloblastoma. The expression profile of our model was compared with a drug sensitivity database to identify therapeutic agents that could target our model. One class of drugs identified was cyclin-dependent kinase inhibitors. Because MYC also regulates the expression of CDKs 4/6, we hypothesized that flavopiridol (alvocidib), a cyclin dependent kinase inhibitor currently in clinical trials for a variety of tumor types would be effective against MYC-driven medulloblastoma. Our model and the medulloblastoma cell lines D425Med and D283Med were sensitive to treatment with flavopiridol. The IC50 of flavopiridol was less than 50nM for all cell lines tested. Flavopiridol decreased the growth and proliferation of both cell lines and our neurosphere model as measured by MTS assay and BrdU incorporation (p < 0.001)). Flavopiridol also included apoptosis as determined by staining for cleaved caspase-3 and flow cytometry (p < 0.01). The data shown here demonstrate that our human neurosphere model of medulloblastoma can facilitate the identification of agents with therapeutic efficacy against aggressive medulloblastoma.
Differential diagnosis and management of focal pulmonary ground-glass opacities
Authors: J-J. Hung, W-J. Jeng, J-S. Liu, W-H. Hsu
Journal: European Respiratory Journal (2009)

To the Editors: 

In a recent article printed in the European Respiratory Journal , Infante et al. 1 validated a stepwise approach including oral antibiotics, follow-up computed tomography and computed tomography-guided biopsy for the differential diagnosis and management of focal pulmonary ground-glass opacities (GGOs). Although a retrospective study, their work provides critical information on discrimination and management of focal GGOs. However, some of the results in the article did not fully support their conclusions.

One of the major conclusions in the study by Infante et al. 1 was that the stepwise approach increased the diagnostic specificity and reduced time to definitive diagnosis. They recommended response to antibiotic trial as the first management step. After a course of oral antibiotics, five (12.5%) patients with inflammatory lesions were ruled out. However, six patients in their study were evaluated with lesions retrospectively visible in earlier computed tomography scans and oral antibiotics were not given. Since the patients …
Pak1 as a Novel Therapeutic Target for Antihypertrophic Treatment in the Heart
Authors: Wei Liu, Min Zi, Ronald Naumann, Susanne Ulm, Jiawei Jin, Domenico M. Taglieri, Sukhpal Prehar, Junhong Gui, Hoyee Tsui, Rui-Ping Xiao, Ludwig Neyses, R. John Solaro, Yunbo Ke, Elizabeth J. Cartwright, Ming Lei, Xin Wang
Journal: Circulation (2011)

Background— Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy. Methods and Results— Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1 cko ). When subjected to 2 weeks of pressure overload, Pak1 cko mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1 cko mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1 cko mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation. Conclusions— These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.
A Diabetes Outcome Progression Trial (ADOPT)
Authors: Giancarlo Viberti, Steven E. Kahn, Douglas A. Greene, William H. Herman, Bernard Zinman, Rury R. Holman, Steven M. Haffner, Daniel Levy, John M. Lachin, Rhona A. Berry, Mark A. Heise, Nigel P. Jones, Martin I. Freed
Journal: Diabetes Care (2002)

Therapies with metformin, sulfonylureas, or insulin improve glycemic control in the short term but do not prevent progressive islet beta-cell failure or long-term deterioration in glycemia. Our goal was to evaluate, in patients recently diagnosed with type 2 diabetes (<3 years), the long-term efficacy of monotherapy with rosiglitazone on glycemic control and on the progression of pathophysiological abnormalities associated with type 2 diabetes as compared with metformin or glyburide monotherapy.A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind, parallel-group study consisting of a screening visit, a 4-week placebo run-in, a 4-year treatment period, and an observational follow-up of approximately 3,600 drug-naïve patients with type 2 diabetes diagnosed within the previous 3 years. After run-in, patients will be randomized to rosiglitazone, glyburide, or metformin titrated to the maximum effective daily doses (8 mg rosiglitazone, 15 mg glyburide, or 2 g metformin). The primary outcome is time to monotherapy failure, defined as the time following titration to the maximal effective or tolerated dose when fasting plasma glucose exceeds 180 mg/dl (10 mmol/l). Secondary outcomes include measures of islet beta-cell function, insulin sensitivity, dyslipidemia, changes in urinary albumin excretion, plasminogen activator inhibitor-1 antigen, fibrinogen, and C-reactive protein. Safety and tolerability will also be evaluated. Patient-reported outcomes and resource utilization data will be collected and analyzed.ADOPT will provide data on the effect of mechanistically differing treatment options on metabolic control, beta-cell function, and markers of macrovascular disease risk in type 2 diabetes.
Tropical enteropathy in Rhodesia.
Authors: G Thomas, D J Clain, A C Wicks
Journal: Gut (1976)

Tropical enteropathy, which may be related to tropical sprue, has been described in many developing countries including parts of Africa. The jejunal changes of enteropathy are seen in Rhodesians of all social and racial categories. Xylose excretion, however, is related to socioeconomic status, but not race. Upper socioeconomic Africans and Europeans excrete significantly more xylose than lower socioeconomic Africans. Vitamin B12 and fat absorption are normal, suggesting predominant involvement of the proximal small intestine. Tropical enteropathy in Rhodesia is similar to that seen in Nigeria but is associated with less malabsorption than is found in the Caribbean, the Indian subcontinent, and South East Asia. The possible aetiological factors are discussed. It is postulated that the lighter exposure of upper class Africans and Europeans to repeated gastrointestinal infections may accound for their superior xylose absorption compared with Africans of low socioeconomic circumstances. It is further suggested that the milder enteropathy seen in Africa may be explained by a lower prevalence of acute gastroenteritis than in experienced elsewhere in the tropics.
Blue Skies for the Best People
Authors: Ruth Williams
Journal: Circulation Research (2014)

Many argue that the freedom to pursue so-called blue-sky research is essential in science.Indeed, in the field of cardiology itself, many major discoveries have been made thanks to curiosity-driven, blue-sky science. 3Thus, unshackling scientists from the pressure to hit specific research targets in short time frames-3 aims in a maximum of 5 years, in the case of the NIH's traditional RO1 scheme-could enable them to be a little more risky
Inactivation and dissociation ofs-adenosylmethionine synthetase by modification of sulfhydryl groups and its possile occurrence in cirrhosis
Authors: Fernando Corrales, Carmen Cabrero, Maria A. Pajares, Pablo Ortiz, Antonio Martin-Duce, Jose M. Mato
Journal: Hepatology (1990)

Catalytically active human and rat liver S-adenosylmethionine synthetase exists mainly in tetramer and dimer form. In liver biopsy samples from cirrhotic patients a marked reduction in total S-adenosylmethionine synthetase activity and a specific loss of the tetrameric form of the enzyme exist. We have investigated the possible role of sulfhydryl groups in maintaining the structure and activity of S-adenosylmethionine synthetase. Both forms of S-adenosylmethionine synthetase are rapidly inactivated by N-ethylmaleimide, and the loss of enzyme activity correlates with the incorporation of approximately 2 moles N-ethylmaleimide per mole of subunit. In addition, reaction with N-ethylmaleimide resulted in displacement of the tetramer-dimer equilibrium of the enzyme toward the dimer, but no monomer was detected under these conditions. A catalytically active monomeric S-adenosylmethionine synthetase was detected in the cytosolic extract from a liver biopsy sample from a cirrhotic patient, supporting our model for the structure of S-adenosylmethionine synthetase. Because treatment of S-adenosylmethionine synthetase with N-ethylmaleimide resembles the situation of this enzyme in cirrhotic patients, it is proposed that impaired protection of the enzyme from oxidizing agents caused by a decreased synthesis of glutathione can explain the diminished synthesis of S-adenosylmethionine in liver cirrhosis.
Role of HMGB1 in apoptosis-mediated sepsis lethality
Authors: Shixin Qin, Haichao Wang, Renqi Yuan, Hui Li, Mahendar Ochani, Kanta Ochani, Mauricio Rosas-Ballina, Chris J. Czura, Jared M. Huston, Ed Miller, Xinchun Lin, Barbara Sherry, Anjali Kumar, Greg LaRosa, Walter Newman, Kevin J. Tracey, Huan Yang
Journal: The Journal of Experimental Medicine (2006)

Severe sepsis, a lethal syndrome after infection or injury, is the third leading cause of mortality in the United States. The pathogenesis of severe sepsis is characterized by organ damage and accumulation of apoptotic lymphocytes in the spleen, thymus, and other organs. To examine the potential causal relationships of apoptosis to organ damage, we administered Z-VAD-FMK, a broad-spectrum caspase inhibitor, to mice with sepsis. We found that Z-VAD-FMK–treated septic mice had decreased levels of high mobility group box 1 (HMGB1), a critical cytokine mediator of organ damage in severe sepsis, and suppressed apoptosis in the spleen and thymus. In vitro, apoptotic cells activate macrophages to release HMGB1. Monoclonal antibodies against HMGB1 conferred protection against organ damage but did not prevent the accumulation of apoptotic cells in the spleen. Thus, our data indicate that HMGB1 production is downstream of apoptosis on the final common pathway to organ damage in severe sepsis.
Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis
Authors: R. A H M van den Oord, A. Sheikh
Journal: BMJ (2009)

<b>Objective</b> To investigate whether filaggrin gene defects, present in up to one in 10 western Europeans and North Americans, increase the risk of developing allergic sensitisation and allergic disorders. <b>Design</b> Systematic review and meta-analysis. <b>Data sources</b> Medline, Embase, ISI Science Citation Index, BIOSIS, ISI Web of Knowledge, UK National Research Register, clinical trials.gov, the Index to Theses and Digital dissertations, and grey literature using OpenSIGLE. <b>Study selection</b> Genetic epidemiological studies (family, case-control) of the association between filaggrin gene defects and allergic sensitisation or allergic disorders. <b>Data extraction</b> Atopic eczema or dermatitis, food allergy, asthma, allergic rhinitis, and anaphylaxis, along with relevant immunological variables relating to the risk of allergic sensitisation as assessed by either positive skin prick testing or increased levels of allergen specific IgE. <b>Data synthesis</b> 24 studies were included. The odds of developing allergic sensitisation was 1.91 (95% confidence interval 1.44 to 2.54) in the family studies and 1.57 (1.20 to 2.07) in the case-control studies. The odds of developing atopic eczema was 1.99 (1.72 to 2.31) in the family studies and 4.78 (3.31 to 6.92) in the case-control studies. Three studies investigated the association between filaggrin gene mutations and allergic rhinitis in people without atopic eczema: overall odds ratio 1.78 (1.16 to 2.73). The four studies that investigated the association between filaggrin gene mutations and allergic rhinitis in people with atopic eczema reported a significant association: pooled odds ratio from case-control studies 2.84 (2.08 to 3.88). An overall odds ratio for the association between filaggrin gene mutations and asthma in people with atopic eczema was 2.79 (1.77 to 4.41) in case-control studies and 2.30 (1.66 to 3.18) in family studies. None of the studies that investigated filaggrin gene mutations and asthma in people without atopic eczema reported a significant association; overall odds ratio was 1.30 (0.7 to 2.30) in the case-control studies. The funnel plots suggested that publication bias was unlikely to be an explanation for these findings. No studies investigated the association between filaggrin gene mutations and food allergy or anaphylaxis. <b>Conclusions</b> Filaggrin gene defects increase the risk of developing allergic sensitisation, atopic eczema, and allergic rhinitis. Evidence of the relation between filaggrin gene mutations and atopic eczema was strong, with people manifesting increased severity and persistence of disease. Filaggrin gene mutations also increased the risk of asthma in people with atopic eczema. Restoring skin barrier function in filaggrin deficient people in early life may help prevent the development of sensitisation and halt the development and progression of allergic disease.
Induction of Higher-Avidity Human CTLs by Vector-Mediated Enhanced Costimulation of Antigen-Presenting Cells
Authors: Sixun Yang, Kwong-Yok Tsang, Jeffrey Schlom
Journal: Clinical Cancer Research (2005)

Abstract The efficacy of antigen-specific CD8+ CTLs depends not only on the quantity of CTLs generated but also perhaps, more importantly, on the avidity of the CTLs. To date, however, no strategy has been shown to preferentially induce higher-avidity human CTLs. In the present study, antigen-presenting cells (APC) generated from human peripheral blood mononuclear cells were infected with a recombinant avipox vector (rF-) containing the transgenes for a triad of costimulatory molecules (human B7.1, intercellular adhesion molecule-1, and LFA-3, designated as rF-TRICOM) and then used to elicit peptide-specific CTLs from autologous T cells. Compared with peptide-pulsed noninfected APCs or peptide-pulsed APCs infected with wild-type vector, peptide-pulsed APCs infected with rF-TRICOM induced not only more CTLs but also higher-avidity CTLs; this was shown by tetramer staining, tetramer dissociation, IFN-γ production, and cytolytic assays. Peptide-pulsed rF-TRICOM-infected dendritic cells were also shown to induce CTLs with a &amp;gt;10-fold higher avidity than CTLs induced using CD40L-matured dendritic cells; the use of peptide-pulsed CD40L-matured dendritic cells infected with rF-TRICOM as APCs induced CTLs of even greater avidity. To our knowledge, these studies are the first to show a methodology to induce higher-avidity human CTLs and have implications for the development of more efficient vaccines for a range of human cancers.
Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits
Authors: E CHAN, S DATLA, R DILLEY, H HICKEY, G DRUMMOND, G DUSTING
Journal: Cardiovascular Research (2007)

Reactive oxygen species including superoxide have been shown to promote atherogenesis. We previously showed that a major source of superoxide, the NADPH oxidase system, is upregulated in the intima and adventitia during remodelling induced by periarterial collars in rabbits. We have now examined the action of the NADPH oxidase inhibitor apocynin, given via the adventitia, on the neointima formation and endothelial function in this model.Perivascular collars were implanted around the common carotid arteries of male NZW rabbits for 14 days to induce intimal thickening. The periarterial space of one collar was filled with apocynin (1 mM) while the contralateral collar with the vehicle (0.1% DMSO).After 14 days, local treatment with apocynin via the adventitia, reduced superoxide generation. In addition, apocynin significantly reduced neointima formation and proliferation of cells in both the neointima and adventitia. Moreover, NO-dependent vasorelaxation to acetylcholine, which is normally impaired in collared arteries, was improved, and apocynin suppressed the endothelial expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1.NADPH oxidase is implicated in vascular remodelling and superoxide-stimulated cell proliferation in the neointima contributes to intimal hyperplasia in this collar model. Targeting NADPH oxidase via adventitial drug delivery not only reduces superoxide generation, but also normalises endothelial cell function. Targeting the primary source of NADPH oxidase-derived superoxide is an effective approach to prevent deleterious arterial remodelling, providing a rationale for designing more efficacious and selective inhibitors of vascular NADPH oxidase as potential therapeutics for human vascular disease.
Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases
Authors: Michael C. Heinrich, Heikki Joensuu, George D. Demetri, Christopher L. Corless, Jane Apperley, Jonathan A. Fletcher, Denis Soulieres, Stephan Dirnhofer, Amy Harlow, Ajia Town, Arin McKinley, Shane G. Supple, John Seymour, Lilla Di Scala, Allan van Oosterom, Richard Herrmann, Zariana Nikolova, and Grant McArthur
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases. Experimental Design: This was a phase II, open-label, single arm study. Patients ≥15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point. Results: One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response. Conclusion: Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment.
Serum miR-1290 as a Marker of Pancreatic Cancer—Response
Authors: Ang Li, Jun Yu, Haeryoung Kim, Christopher L. Wolfgang, Marcia Irene Canto, Ralph H. Hruban, Michael Goggins
Journal: Clinical Cancer Research (2013)

The authors thank Frampton and colleagues for their interest in our study. They commented on our use of miR-16, stating that because studies have reported that red blood cells are a major source of miR-16 and serum levels are elevated in hemolyzed blood samples, there is debate about whether it is a