tbuckley/cabot-search huggingface dataset:
WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration
Authors: Wen Zhu, Gulnaz Begum, Kelli Pointer, Paul A. Clark, Sung Sen Yang, Shih Hua Lin, Kristopher T. Kahle, John S. Kuo, Dandan Sun
Journal: Molecular Cancer (2014)

The bumetanide (BMT)-sensitive Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) maintains cell volume homeostasis by increasing intracellular K+ and Cl- content via regulatory volume increase (RVI). Expression levels of NKCC1 positively correlate with the histological grade and severity of gliomas, the most common primary adult brain tumors, and up-regulated NKCC1 activity facilitates glioma cell migration and apoptotic resistance to the chemotherapeutic drug temozolomide (TMZ). However, the cellular mechanisms underlying NKCC1 functional up-regulation in glioma and in response to TMZ administration remain unknown. Expression of NKCC1 and its upstream kinases With-No-K (Lysine) kinase 1 (WNK1) and oxidative stress-responsive kinase-1 (OSR1) in different human glioma cell lines and glioma specimens were detected by western blotting and immunostaining. Live cell imaging and microchemotaxis assay were applied to record glioma cell movements under different treatment conditions. Fluorescence indicators were utilized to measure cell volume, intracellular K+ and Cl- content to reflect the activity of NKCC1 on ion transportation. Small interfering RNA (siRNA)-mediated knockdown of WNK1 or OSR1 was used to explore their roles in regulation of NKCC1 activity in glioma cells. Results of different treatment groups were compared by one-way ANOVA using the Bonferroni post-hoc test in the case of multiple comparisons. We show that compared to human neural stem cells and astrocytes, human glioma cells exhibit robust increases in the activation and phosphorylation of NKCC1 and its two upstream regulatory kinases, WNK1 and OSR1. siRNA-mediated knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content and RVI in glioma cells by abolishing NKCC1 regulatory phospho-activation. Unexpectedly, TMZ activates the WNK1/OSR1/NKCC1 signaling pathway and enhances glioma migration. Pharmacological inhibition of NKCC1 with its potent inhibitor BMT or siRNA knockdown of WNK1 or OSR1 significantly decreases glioma cell migration after TMZ treatment. Together, our data show a novel role for the WNK1/OSR1/NKCC1 pathway in basal and TMZ-induced glioma migration, and suggest that glioma treatment with TMZ might be improved by drugs that inhibit elements of the WNK1/OSR1/NKCC1 signaling pathway.
Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis
Authors: Anna De Benedetto, Mark K. Slifka, Nicholas M. Rafaels, I-Hsin Kuo, Steve N. Georas, Mark Boguniewicz, Tissa Hata, Lynda C. Schneider, Jon M. Hanifin, Richard L. Gallo, David C. Johnson, Kathleen C. Barnes, Donald Y.M. Leung, Lisa A. Beck
Journal: Journal of Allergy and Clinical Immunology (2011)
Phase II Study of Neoadjuvant Carboplatin and Paclitaxel Followed by Radiotherapy and Concurrent Cisplatin in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma: Therapeutic Monitoring With Plasma Epstein-Barr Virus DNA
Authors: Anthony T.C. Chan, Brigette B.Y. Ma, Y.M. Dennis Lo, S.F. Leung, W.H. Kwan, Edwin P. Hui, Tony S.K. Mok, Michael Kam, Lisa S. Chan, Samuel K.W. Chiu, K.H. Yu, K.Y. Cheung, Karen Lai, Maria Lai, Frankie Mo, Winnie Yeo, Ann King, Philip J. Johnson, Peter M.L. Teo, Benny Zee
Journal: Journal of Clinical Oncology (2004)

To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA.Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.
Pathogenesis of diffuse melanosis secondary to malignant melanoma*
Authors: K. KONRAD, K. WOLFF
Journal: British Journal of Dermatology (1974)

Journal Article Pathogenesis of diffuse melanosis secondary to malignant melanoma Get access K. KONRAD, K. KONRAD Division of Experimental Dermatology, Department of Dermatology I., University of Vienna, Alserstrasse 4, A‐1097 Vienna, Austria Search for other works by this author on: Oxford Academic Google Scholar K. WOLFF K. WOLFF Division of Experimental Dermatology, Department of Dermatology I., University of Vienna, Alserstrasse 4, A‐1097 Vienna, Austria Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue 6, 1 December 1974, Pages 635–655, https://doi.org/10.1111/j.1365-2133.1974.tb12451.x Published: 01 December 1974 Article history Accepted: 03 June 1974 Published: 01 December 1974
Genetic Diversity in the Paramecium aurelia Species Complex
Authors: F. Catania, F. Wurmser, A. A. Potekhin, E. Przybos, M. Lynch
Journal: Molecular Biology and Evolution (2008)

Current understanding of the population genetics of free-living unicellular eukaryotes is limited, and the amount of genetic variability in these organisms is still a matter of debate. We characterized-reproductively and genetically-worldwide samples of multiple Paramecium species belonging to a cryptic species complex, Paramecium aurelia, whose species have been shown to be reproductively isolated. We found that levels of genetic diversity both in the nucleus and in the mitochondrion are substantial within groups of reproductively compatible P. aurelia strains but drop considerably when strains are partitioned according to their phylogenetic groupings. Our study reveals the existence of discrepancies between the mating behavior of a number of P. aurelia strains and their multilocus genetic profile, a controversial finding that has major consequences for both the current methods of species assignment and the species problem in the P. aurelia complex.
Increased Body Mass Index Is Associated With Improved Survival in United States Veterans With Diffuse Large B-Cell Lymphoma
Authors: Kenneth R. Carson, Nancy L. Bartlett, Jay R. McDonald, Suhong Luo, Angelique Zeringue, Jingxia Liu, Qiang Fu, Su-Hsin Chang, Graham A. Colditz
Journal: Journal of Clinical Oncology (2012)

Obesity increases the risk of death from many malignancies, including non-Hodgkin's lymphoma (NHL). In diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, the association between body mass index (BMI) at diagnosis and survival is unclear.We evaluated the association between BMI at diagnosis and overall survival in a retrospective cohort of 2,534 United States veterans diagnosed with DLBCL between October 1, 1998 and December 31, 2008. Cox modeling was used to control for patient- and disease-related prognostic variables.Mean age at diagnosis was 68 years (range, 20 to 100 years); 64% of patients were overweight (BMI, 25 to < 30) or obese (BMI, ≥ 30). Obese patients were significantly younger, had significantly fewer B symptoms, and trended toward lower-stage disease, compared with other BMI groups. Cox analysis showed reduced mortality in overweight and obese patients (overweight: hazard ratio [HR], 0.73; 95% CI, 0.65 to 0.83; obese: HR, 0.68; 95% CI, 0.58 to 0.80), compared with normal-weight patients (BMI, 18.5 to < 25). Treatment during the rituximab era reduced the risk of death without affecting the association between BMI and survival. Disease-related weight loss occurred in 29% of patients with weight data 1 year before diagnosis. Cox analysis based on BMI 1 year before diagnosis continued to demonstrate reduced risk of death in overweight and obese patients.Being overweight or obese at the time of DLBCL diagnosis is associated with improved overall survival. Understanding the mechanisms responsible for this association will require further study.
P80: a tumor-related protein found in many lymphomas of mice.
Authors: D J Grunwald, K Miller, R Risser
Journal: The Journal of Experimental Medicine (1982)

Examination of syngeneic tumor regressor sera prepared by immunization of mice with several different lymphomas revealed a common pattern of reactivity to proteins expressed in these tumors. Antibodies present in these sera immunoprecipitate a triplet of proteins of 115,000 mol wt (p115), 80,000 mol wt (p80), and 32,000 mol wt (p32) from many but not all T cell lymphomas of mice. P80, the predominant molecular species immunoprecipitated with these sera, is a nonglycosylated, phosphoprotein that does not appear to be expressed at the cell surface. Comparison of the tryptic peptides of p32 and p80 indicated that the peptides found in p32 are a subset of those found in p80. Comparison of the tryptic peptides of p80 with those of the p120 gag-fusion protein of Abelson murine leukemia virus demonstrated that p80 and p120 did not share tryptic peptides. Comparison of the partial proteolytic products generated by treatment of p80 molecules from different tumors with V8 protease did not reveal heterogeneity in p80 among tumors of different strains of mice. Direct labeling and competition blocking experiments with lysates from normal cells failed to provide evidence of p80 synthesis in normal thymus, spleen, or bone marrow. Thus, p80 is a biochemically identified tumor-related antigen of mouse lymphomas.
Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial
Authors: J S Smolen, P Emery, G F Ferraccioli, W Samborski, F Berenbaum, O R Davies, W Koetse, O Purcaru, B Bennett, H Burkhardt
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission. <h3>Methods</h3> Patients were randomised 1:1 to CZP (400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks) or placebo (every 2 weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52. <h3>Results</h3> Of 194 patients (CZP=96; placebo=98), &gt;90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p≤0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p&lt;0.001) achieved LDA. Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo (19.8% vs 3.1%; p≤0.01 and 14.6% vs 4.1%; p≤0.05). CZP patients reported improvements in physical function versus placebo (mean Health Assessment Questionnaire-Disability-Index change from baseline: CZP, −0.25 vs placebo, −0.03; p≤0.01). During the period following withdrawal of CZP or placebo, only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52, but CZP reinstitution allowed renewed improvement. Adverse and serious adverse event rates were comparable between CZP and placebo groups. <h3>Conclusions</h3> Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity, allowing low-disease activity or remission to be reached in a majority of the patients. However, the data suggest that CZP cannot be withdrawn in patients achieving remission. <h3>Trial registration number</h3> NCT00674362.
Exome Sequencing Reveals <i>AMER1</i> as a Frequently Mutated Gene in Colorectal Cancer
Authors: Rebeca Sanz-Pamplona, Adriana Lopez-Doriga, Laia Paré-Brunet, Kira Lázaro, Fernando Bellido, M. Henar Alonso, Susanna Aussó, Elisabet Guinó, Sergi Beltrán, Francesc Castro-Giner, Marta Gut, Xavier Sanjuan, Adria Closa, David Cordero, Francisco D. Morón-Duran, Antonio Soriano, Ramón Salazar, Laura Valle, Victor Moreno
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in colorectal cancer tumorigenesis. Experimental Design: The exomic DNA of 42 stage II, microsatellite-stable colon tumors and their paired mucosae were sequenced. Other molecular data available in the discovery dataset [gene expression, methylation, and copy number variations (CNV)] were used to further characterize these tumors. Additional datasets comprising 553 colorectal cancer samples were used to validate the discovered mutations. Results: As a result, 4,886 somatic single-nucleotide variants (SNV) were found. Almost all SNVs were private changes, with few mutations shared by more than one tumor, thus revealing tumor-specific mutational landscapes. Nevertheless, these diverse mutations converged into common cellular pathways, such as cell cycle or apoptosis. Among this mutational heterogeneity, variants resulting in early stop codons in the AMER1 (also known as FAM123B or WTX) gene emerged as recurrent mutations in colorectal cancer. Losses of AMER1 by other mechanisms apart from mutations such as methylation and copy number aberrations were also found. Tumors lacking this tumor suppressor gene exhibited a mesenchymal phenotype characterized by inhibition of the canonical Wnt pathway. Conclusions: In silico and experimental validation in independent datasets confirmed the existence of functional mutations in AMER1 in approximately 10% of analyzed colorectal cancer tumors. Moreover, these tumors exhibited a characteristic phenotype. Clin Cancer Res; 21(20); 4709–18. ©2015 AACR.
Angiotensin II–Inducible Smooth Muscle Cell Apoptosis Involves the Angiotensin II Type 2 Receptor, GATA-6 Activation, and FasL-Fas Engagement
Authors: Nicole Y. Tan, Jian-Mei Li, Roland Stocker, Levon M. Khachigian
Journal: Circulation Research (2009)

Fas ligand (FasL)-mediated smooth muscle cell (SMC) apoptosis within the vulnerable plaque may lead to plaque instability and rupture, events that underlie myocardial infarction and stroke.The molecular mechanisms underlying FasL transcription and FasL-dependent SMC apoptosis were investigated in this study in vitro and in vivo.We demonstrate that GATA-6, the predominant GATA family member expressed in SMCs, stimulates SMC apoptosis in an extracellular FasL-dependent manner. Both GATA-6 and FasL were inducibly and transiently expressed following balloon injury to rat carotid arteries. We identified two potential GATA binding in the FasL promoter and demonstrated using DNA binding and chromatin immunoprecipitation assays that GATA-6 regulates FasL through one ((-298)TTATCA(-303)) but not both these elements. Angiotensin II (Ang II) stimulated expression of both GATA-6 and FasL. Ang II increased SMC apoptosis in an Ang II type 2 receptor-, caspase 8-, and FasL-dependent fashion. GATA-6 activation was MEK-ERK1/2- and JNK-dependent, and GATA-6 small interfering RNA blocked Ang II-inducible FasL expression and SMC apoptosis. Administration of Ang II to rats increased FasL expression and apoptosis in carotid artery SMCs in an Ang II type 2 receptor- and GATA-6-dependent manner.This study provides new insights into the transcriptional events underpinning FasL-dependent SMC apoptosis after exposure to Ang II.
CCT241533 Is a Potent and Selective Inhibitor of CHK2 that Potentiates the Cytotoxicity of PARP Inhibitors
Authors: Victoria E. Anderson, Michael I. Walton, Paul D. Eve, Katherine J. Boxall, Laurent Antoni, John J. Caldwell, Wynne Aherne, Laurence H. Pearl, Antony W. Oliver, Ian Collins, Michelle D. Garrett
Journal: Cancer Research (2011)

Abstract CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC50 of 3 nmol/L and shows minimal cross-reactivity against a panel of kinases at 1 μmol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone, and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors. Cancer Res; 71(2); 463–72. ©2011 AACR.
Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress
Authors: A. R. Bachar, L. Scheffer, A. S. Schroeder, H. K. Nakamura, L. J. Cobb, Y. K. Oh, L. O. Lerman, R. E. Pagano, P. Cohen, A. Lerman
Journal: Cardiovascular Research (2010)

Humanin (HN) is a 24-amino acid peptide that has been shown to have an anti-apoptotic function against neuronal cell death caused by Alzheimer's disease. Increased oxidative stress, one of the major factors contributing to this cell death, also plays an important role in the inflammatory process of atherosclerosis. The current study was designed to test the hypothesis that HN is expressed in the human vascular wall and may protect against oxidative stress. HN expression in the vascular wall was detected by immunostaining in the endothelial cell layer of human internal mammary arteries (n = 5), atherosclerotic coronary arteries (n = 17), and sections of the greater saphenous vein (n = 3). HN mRNA was expressed in the human aortic endothelial cells (HAECs). Cytoprotective effects of HN against oxidative stress were tested in vitro in HAECs. Pre-treatment with 0.1 µM HN reduced oxidized LDL (Ox-LDL)-induced (i) formation of reactive oxygen species by 50%, (ii) apoptosis by ∼50% as determined by TUNEL staining, and (iii) formation of ceramide, a lipid second messenger involved in the apoptosis signalling cascade, by ∼20%. The current study demonstrates for the first time the expression of HN in the endothelial cell layer of human blood vessels. Exogenous addition of HN to endothelial cell cultures was shown to be effective against Ox-LDL-induced apoptosis. These findings suggest that HN may play a role and may have a protective effect in early atherosclerosis in humans.
Novel Molecular Subtypes of Serous and Endometrioid Ovarian Cancer Linked to Clinical Outcome
Authors: Richard W. Tothill, Anna V. Tinker, Joshy George, Robert Brown, Stephen B. Fox, Stephen Lade, Daryl S. Johnson, Melanie K. Trivett, Dariush Etemadmoghadam, Bianca Locandro, Nadia Traficante, Sian Fereday, Jillian A. Hung, Yoke-Eng Chiew, Izhak Haviv, Dorota Gertig, Anna deFazio, David D.L. Bowtell
Journal: Clinical Cancer Research (2008)

The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.