tbuckley/cabot-search huggingface dataset:
Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus
Authors: Ben Parker, Awal Al-Husain, Philip Pemberton, Allen P Yates, Pauline Ho, Rachel Gorodkin, Lee Suan Teh, M Yvonne Alexander, Ian N Bruce
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In a prospective observational study, we investigated whether patients with active systemic lupus erythematosus (SLE) had higher indices of endothelial damage and dysfunction than healthy controls and whether improved disease control was associated with improvement in these indices. <h3>Methods</h3> Twenty-seven patients with active SLE (four or more American College of Rheumatology (ACR) criteria) and 22 age-matched controls were assessed. Endothelial microparticles (EMPs; CD31+/annexin V+/CD42b−) were quantified using flow cytometry. Brachial artery flow-mediated dilatation (FMD) was measured using automated edge-tracking software. Twenty-two patients had a second assessment at a median (IQR) of 20 (16, 22) weeks after initiating new immunosuppressive therapy. <h3>Results</h3> SLE patients had a median (IQR) baseline global British Isles Lupus Assessment Group Disease Activity Index (BILAG-2004) score of 14 (12, 22). CD31+/annexin V+/CD42b− EMPs were higher (157 548/ml (59 906, 272 643) vs 41 025(30 179, 98 082); p=0.003) and endothelial-dependent FMD was lower (1.63% (−1.22, 5.32) vs 5.40% (3.02, 8.57); p=0.05) in SLE patients than controls. CD31+/annexin V+/CD42b− EMPs correlated inversely with FMD (%) (r<sup>2</sup> −0.40; p=0.006). At follow-up, the median (IQR) change in global BILAG-2004 score was −11 (−18, −3). CD31+/annexin V+/CD42b− EMP levels were reduced (166 982/ml (59 906, 278 775 vs 55 655(29 475, 188 659; p=0.02) and FMD had improved (0.33% (−2.31, 4.1) vs 3.19% (0.98, 5.09); p=0.1) at the second visit. <h3>Conclusions</h3> Active SLE is associated with evidence of increased endothelial damage and endothelial dysfunction, which improved with suppression of inflammation. Better control of active inflammatory disease may contribute to improved cardiovascular risk in patients with SLE.
Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an <i>In Vivo</i> Model of Childhood Astrocytoma
Authors: Hemant K. Bid, Aaron Kibler, Doris A. Phelps, Sagymbek Manap, Linlin Xiao, Jiayuh Lin, David Capper, Duane Oswald, Brian Geier, Mariko DeWire, Paul D. Smith, Raushan T. Kurmasheva, Xiaokui Mo, Soledad Fernandez, Peter J. Houghton
Journal: Clinical Cancer Research (2013)

The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAF(V600E) and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.BT-40 xenografts were selected in vivo for selumetinib resistance. Resistant tumors were obtained and characterized, as were tumors that reverted to sensitivity. Characterization included expression profiling, assessment of MEK signature and compensatory pathways, MEK inhibition, BRAF expression, and cytokine levels. Combination treatment of BT-40/AZD-resistant tumors with the MEK inhibitor and a STAT3 inhibitor (LLL12) was assessed.Resistance was unstable, tumors reverting to selumetinib sensitivity when passaged in untreated mice, and MEK was equally inhibited in sensitive and resistant tumors by selumetinib. Drug resistance was associated with an enhanced MEK signature and increased interleukin (IL)-6 and IL-8 expression. Selumetinib treatment induced phosphorylation of STAT3 (Y705) only in resistant xenografts, and similar results were observed in BRAF(V600E) astrocytic cell lines intrinsically resistant to selumetinib. Treatment of BT-40-resistant tumors with selumetinib or LLL12 had no significant effect, whereas combined treatment induced complete regressions of BT-40/AZD-resistant xenografts.Resistance to selumetinib selected in vivo in BT-40 tumor xenografts was unstable. In resistant tumors, selumetinib activated STAT3, and combined treatment with selumetinib and LLL12 induced complete responses in resistant BT-40 tumors. These results suggest dual targeting BRAF (V600E) signaling and STAT3 signaling may be effective in selumetinib-resistant tumors or may retard or prevent onset of resistance.
Bosentan therapy for patients with severe Raynaud's phenomenon in systemic sclerosis
Authors: M E Hettema, D Zhang, H Bootsma, C G M Kallenberg
Journal: Annals of the Rheumatic Diseases (2007)

Raynaud’s phenomenon (RP) is present in more than 95% of patients with systemic sclerosis (SSc). Its frequency and severity in combination with the presence of digital ulcers affect the quality of life of patients.1 Although the aetiology of RP is multifactorial, endothelin-1 has been suggested to play a role in its pathogenesis.2 Bosentan, an endothelin-1 receptor antagonist, has been shown to be effective in preventing the occurrence of new digital ulcers when compared with placebo.3

Against this background, we hypothesized that bosentan can be a useful and effective strategy in SSc patients with RP. Therefore we assessed the effects of bosentan …
Antioxidants and Cancer. IV. Initiating Activity of Malonaldehyde as a Carcinogen
Authors: R J Shamberger, T L Andreone, C E Willis
Journal: JNCI Journal of the National Cancer Institute (1974)

Malonaldehyde was applied once to the shaved backs of mice. After daily treatment with 0.1% croton oil, 52% of the mice had tumors at 30 weeks. In the same experiment, other mice were treated once with β-propiolactone, glycidaldehyde, or 7,12-dimethylbenz- [a]anthracene (DMBA), and then daily with croton oil. These animals had 44, 40, and 95% tumors, respectively, at 30 weeks. Twelve mg malonaldehyde applied daily proved toxic, sometimes fatally so. Five animals also had carcinomas of their internal organs. After daily treatment with 0.36 mg malonaldehyde, no animals died of carcinoma. The predicted reactivity of malonaldehyde was confirmed; after 1 hour, only 1.9% of the applied malonaldehyde was detectable. All skin treated with DMBA, benzo[a]pyrene, and 3-methylcholanthrene had increased malonaldehyde levels.
CMV Seropositivity Determines Epoetin Dose and Hemoglobin Levels in Patients with CKD
Authors: Michiel G.H. Betjes, Willem Weimar, Nicolle H.R. Litjens
Journal: Journal of the American Society of Nephrology (2009)

Cytomegalovirus (CMV)-seropositive patients with ESRD may have more CD4+ T cells lacking the co-stimulatory molecule CD28 (CD4+CD28null) than CMV-seronegative patients. Increased numbers of CD28null T cells associates with epoetin nonresponsiveness in patients with ESRD, but whether expansion of CD4+CD28null T cells in CMV-seropositive patients associates with demand for epoetin is unknown. In a cohort of 129 stable patients with ESRD, CMV seropositivity significantly associated with a lower hemoglobin level in predialysis patients (12.5 versus 11.5 g/dl; P < 0.02). CMV seropositivity did not associate with average hemoglobin level in hemodialysis patients, but CMV-seropositive patients required significantly more epoetin (median 12,000 versus 6300 U/wk; P = 0.02). Multivariate linear regression analysis identified CMV seropositivity as the only variable significantly associated with hemoglobin levels in predialysis patients and epoetin dosages in hemodialysis patients. In CMV-seropositive hemodialysis patients, the number of circulating CD4+CD28null T cells positively correlated with epoetin dosage. These CD4+CD28null T cells were proinflammatory; they were capable of producing large amounts of IFN-γ and TNF-α. In conclusion, expansion of CD4+CD28null T cells in CMV-seropositive patients with ESRD associates with increased demand for epoetin.
Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome
Authors: Guillermo Garcia-Manero, Francesco Paolo Tambaro, Nebiyou B. Bekele, Hui Yang, Farhad Ravandi, Elias Jabbour, Gautam Borthakur, Tapan M. Kadia, Marina Y. Konopleva, Stefan Faderl, Jorge E. Cortes, Mark Brandt, Yumin Hu, Deborah McCue, Willie Mae Newsome, Sherry R. Pierce, Marcos de Lima, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2012)

To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely.After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival.The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.
Increased NOS2 predicts poor survival in estrogen receptor–negative breast cancer patients
Authors: Sharon A. Glynn, Brenda J. Boersma, Tiffany H. Dorsey, Ming Yi, Harris G. Yfantis, Lisa A. Ridnour, Damali N. Martin, Christopher H. Switzer, Robert S. Hudson, David A. Wink, Dong H. Lee, Robert M. Stephens, Stefan Ambs
Journal: Journal of Clinical Investigation (2010)

Inducible nitric oxide synthase (NOS2) is involved in wound healing, angiogenesis, and carcinogenesis. NOS2 upregulation and increased nitric oxide (NO) production affect the redox state of cells and can induce protein, lipid, and DNA modifications. To investigate whether NOS2 levels influence survival of breast cancer patients, we examined NOS2 expression and its association with tumor markers and survival in 248 breast tumors. In multivariable survival analysis, increased NOS2 predicted inferior survival in women with estrogen receptor α-negative (ER-negative) tumors. Microdissected tumor epithelium from ER-negative tumors with high NOS2 had increased IL-8 and a gene expression signature characteristic of basal-like breast cancer with poor prognosis. In cell culture, NO only induced selected signature genes in ER-negative breast cancer cells. ER transgene expression in ER-negative cells inhibited NO-induced upregulation of the stem cell marker CD44 and other proteins encoded by signature genes, but not of IL-8. Exposure to NO also enhanced cell motility and invasion of ER-negative cells. Last, pathway analysis linked the tumor NOS2 gene signature to c-Myc activation. Thus, NOS2 is associated with a basal-like transcription pattern and poor survival of ER-negative patients.
Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease
Authors: Madeleine Zetterberg, Annica Sjölander, Malin von Otter, Mona Palmér, Sara Landgren, Lennart Minthon, Anders Wallin, Niels Andreasen, Kaj Blennow, Henrik Zetterberg
Journal: Molecular Neurodegeneration (2010)

Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE epsilon4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD.
Respiratory disease in 2010: looking to the past will prepare us for the future
Authors: D. M. Mannino
Journal: Thorax (2010)

Hanging on the wall in my office are two obituaries, one of Dr Charles Fletcher who died in 19951 and the other of Dr Benjamin Burrows who died in 2002.2 Their pictures look over the desk where I do a great deal of my work and provide inspiration and, through their collective body of work, guidance. I would like to think that the work that I do continues in a very small way the work that these giants in our field started. Dr Fletcher was responsible for, among other accomplishments, defining the natural history of chronic obstructive pulmonary disease in his landmark study of British men.3–5 Dr Burrows founded the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD)6 that has added greatly to our knowledge of respiratory disease. Drs Fletcher and Burrows trained and mentored many of our current leaders in respiratory health and coauthored several publications.7 8 An ongoing legacy of Dr Burrows is the TESAOD, which continues to provide valuable and important information relevant to today.

The publication by Guerra et al in this issue of Thorax ( see page 499 ) provides an example of Dr Burrows' ongoing legacy and the convergence of his work with that of …
Brain Atrophy in Type 2 Diabetes
Authors: Chris Moran, Thanh G. Phan, Jian Chen, Leigh Blizzard, Richard Beare, Alison Venn, Gerald Münch, Amanda G. Wood, Josephine Forbes, Timothy M. Greenaway, Susan Pearson, Velandai Srikanth
Journal: Diabetes Care (2013)

Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function.This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures.T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume.Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.
Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells.
Authors: N Hama, F Paliogianni, B J Fessler, D T Boumpas
Journal: The Journal of Experimental Medicine (1995)

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers
Authors: Laura Baglietto, Noralane M. Lindor, James G. Dowty, Darren M. White, Anja Wagner, Encarna B. Gomez Garcia, Annette H. J. T. Vriends, Nicola R. Cartwright, Rebecca A. Barnetson, Susan M. Farrington, Albert Tenesa, Heather Hampel, Daniel Buchanan, Sven Arnold, Joanne Young, Michael D. Walsh, Jeremy Jass, Finlay Macrae, Yoland Antill, Ingrid M. Winship, Graham G. Giles, Jack Goldblatt, Susan Parry, Graeme Suthers, Barbara Leggett, Malinda Butz, Melyssa Aronson, Jenny N. Poynter, John A. Baron, Loic Le Marchand, Robert Haile, Steve Gallinger, John L. Hopper, John Potter, Albert de la Chapelle, Hans F. Vasen, Malcolm G. Dunlop, Stephen N. Thibodeau, Mark A. Jenkins
Journal: JNCI Journal of the National Cancer Institute (2009)

Germline mutations in MSH6 account for 10%–20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.
Gas and dust exposure in underground construction is associated with signs of airway inflammation
Authors: B. Ulvestad, M.B. Lund, B. Bakke, P.G. Djupesland, J. Kongerud, J. Boe
Journal: European Respiratory Journal (2001)

Exposure to gases and dust may induce airway inflammation. It was hypothesized that heavy construction workers who had been exposed to dust and gases in underground construction work for 1 yr, would have early signs of upper and lower airway inflammation, as compared to outdoor workers. A study group comprising 29 nonsmoking underground concrete workers (mean± sd age 44±12 yrs), and a reference group of 26 outdoor concrete workers (39±12 yrs) were examined by acoustic rhinometry, nasal and exhaled nitric oxide spirometry and a questionnaire on respiratory symptoms. Exposure measurements were carried out. The underground workers had higher exposure to total and respirable dust, α‐quartz and nitrogen dioxide than the references (p&lt;0.001). The occurrence of respiratory symptoms was higher in the underground workers than in the references (p&lt;0.05). Exhaled nitric oxide (NO) (geometric mean±sem) was higher in the underground workers than in the references (8.4±1.09 versus 5.6±1.07 parts per billion (ppb), p=0.001), whereas spirometric values were comparable. The underground workers had smaller nasal cross-sectional area and volume than the references, and more pronounced increases after decongestion (p&lt;0.001). To conclude the exposure in underground construction may cause nasal mucosal swelling and increased levels of exhaled nitric oxide, indicating signs of upper and lower airway inflammation.