tbuckley/cabot-search huggingface dataset:
p62 Links β-adrenergic input to mitochondrial function and thermogenesis
Authors: Timo D. Müller, Sang Jun Lee, Martin Jastroch, Dhiraj Kabra, Kerstin Stemmer, Michaela Aichler, Bill Abplanalp, Gayathri Ananthakrishnan, Nakul Bhardwaj, Sheila Collins, Senad Divanovic, Max Endele, Brian Finan, Yuanqing Gao, Kirk M. Habegger, Jazzmin Hembree, Kristy M. Heppner, Susanna Hofmann, Jenna Holland, Daniela Küchler, Maria Kutschke, Radha Krishna, Maarit Lehti, Rebecca Oelkrug, Nickki Ottaway, Diego Perez-Tilve, Christine Raver, Axel K. Walch, Sonja C. Schriever, John Speakman, Yu-Hua Tseng, Maria Diaz-Meco, Paul T. Pfluger, Jorge Moscat, Matthias H. Tschöp
Journal: Journal of Clinical Investigation (2012)

The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to β-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5β, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.
Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial
Authors: Mila Donker, Geertjan van Tienhoven, Marieke E Straver, Philip Meijnen, Cornelis J H van de Velde, Robert E Mansel, Luigi Cataliotti, A Helen Westenberg, Jean H G Klinkenbijl, Lorenzo Orzalesi, Willem H Bouma, Huub C J van der Mijle, Grard A P Nieuwenhuijzen, Sanne C Veltkamp, Leen Slaets, Nicole J Duez, Peter W de Graaf, Thijs van Dalen, Andreas Marinelli, Herman Rijna, Marko Snoj, Nigel J Bundred, Jos W S Merkus, Yazid Belkacemi, Patrick Petignat, Dominic A X Schinagl, Corneel Coens, Carlo G M Messina, Jan Bogaerts, Emiel J T Rutgers
Journal: The Lancet Oncology (2014)
Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations
Authors: H. Chen, J.E.A. Common, R.L. Haines, A. Balakrishnan, S.J. Brown, C.S.M. Goh, H.J. Cordell, A. Sandilands, L.E. Campbell, K. Kroboth, A.D. Irvine, D.L.M. Goh, M.B.Y. Tang, H.P. van Bever, Y.C. Giam, W.H.I. McLean, E.B. Lane
Journal: British Journal of Dermatology (2011)

Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD.To investigate further the spectrum of FLG-null mutations in Chinese patients and to compare it with that in other populations.We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate-to-severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results In total, 22 FLG-null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher's exact test; P = 5·3 × 10⁻⁹; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher's exact test; P = 9·0 × 10⁻¹⁵; OR 5·8), keratosis pilaris (Fisher's exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063).This study emphasizes the wider genetic landscape of FLG-null mutations in Asia that is slowly emerging.
Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells
Authors: Ayelet Dar, Polina Goichberg, Vera Shinder, Alexander Kalinkovich, Orit Kollet, Neta Netzer, Raanan Margalit, Marion Zsak, Arnon Nagler, Izhar Hardan, Igor Resnick, Antal Rot, Tsvee Lapidot
Journal: Nature Immunology (2005)
Somatic Mutations of the <i>HER2</i> Kinase Domain in Lung Adenocarcinomas
Authors: Hisayuki Shigematsu, Takao Takahashi, Masaharu Nomura, Kuntal Majmudar, Makoto Suzuki, Huei Lee, Ignacio I. Wistuba, Kwun M. Fong, Shinichi Toyooka, Nobuyoshi Shimizu, Takehiko Fujisawa, John D. Minna, Adi F. Gazdar
Journal: Cancer Research (2005)

Abstract Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non–small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394; P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.
Comment on ‘Cancer genetic counselling’ by P. Mandich et al. (Ann Oncol 2005; 16: 171)
Authors: A. Contegiacomo, M. Pensabene, I. Capuano, L. Tauchmanova, M. Federico, D. Turchetti, L. Cortesi, P. Marchetti, E. Ricevuto, G. Cianci, V. Barbieri, S. Venuta, V. Silingardi
Journal: Annals of Oncology (2005)
Inflammatory Markers and Development of Symptom Burden in Patients with Multiple Myeloma during Autologous Stem Cell Transplantation
Authors: Xin Shelley Wang, Qiuling Shi, Nina D. Shah, Cobi J. Heijnen, Evan N. Cohen, James M. Reuben, Robert Z. Orlowski, Muzaffar H. Qazilbash, Valen E. Johnson, Loretta A. Williams, Tito R. Mendoza, Charles S. Cleeland
Journal: Clinical Cancer Research (2014)

Increasing research suggests that inflammation mediates symptom development. In this longitudinal study, we examined inflammatory factors related to the development of high symptom burden during autologous hematopoietic stem cell transplant (AuSCT) for multiple myeloma. Patients (n = 63) repeatedly reported symptom severity on the MD Anderson Symptom Inventory multiple myeloma module (MDASI-MM) and contributed blood samples periodically for up to 100 days after AuSCT for inflammatory marker assays. The temporal associations between serum inflammatory marker concentrations and symptom severity outcomes were examined by nonlinear mixed-effect modeling. Fatigue, pain, disturbed sleep, lack of appetite, and drowsiness were consistently the most severe MDASI-MM symptoms during the study. Peak symptom severity occurred on day 8 after AuSCT, during white blood cell count nadir. Patterns of serum interleukin (IL)-6 (peak on day 9) and soluble IL-6 receptor (sIL-6R; nadir on day 8) expression paralleled symptom development over time (both P < 0.0001). By univariate analysis, serum IL-6, sIL-6R, IL-10, C-reactive protein, macrophage inflammatory protein (MIP)-1α, sIL-1R2, sIL-1RA, and soluble tumor necrosis factor receptor 1 were significantly related to the most severe symptoms during the first 30 days after AuSCT (all P < 0.05). By multivariate analysis, IL-6 (estimate = 0.170; P = 0.004) and MIP-1α (estimate = -0.172; P = 0.006) were temporally associated with the severity of the component symptom score. Systemic inflammatory response was associated with high symptom burden during the acute phase of AuSCT. Additional research is needed to understand how the inflammatory response is mechanistically associated with symptom expression and whether suppression of this response can reduce symptoms without compromising tumor control.
Better see to better agree: phosphohistone H3 increases interobserver agreement in mitotic count for meningioma grading and imposes new specific thresholds
Authors: Eleonora Duregon, Adele Cassenti, Alessandra Pittaro, Laura Ventura, Rebecca Senetta, Roberta Rudà, Paola Cassoni
Journal: Neuro-Oncology (2015)

Mitotic count on hematoxylin and eosin (H&E)–stained slides is a crucial diagnostic criterion in meningioma grading. However, mitosis assessment on H&E slides can be impaired by technical factors and by pathologist's experience. Phosphohistone H3 (PHH3) serine-10 is a mitosis-specific antibody that has proven to facilitate mitotic count in various tumors. A series of 70 meningiomas (15 grade I, 40 grade II, 15 grade III) was used to validate PHH3 intra- and interobserver reproducibility and to identify PHH3-specific mitotic thresholds. Four pathologists with different experience in neuropathology counted mitoses on both H&E- and PHH3-stained slides. H&E and PHH3 mitotic rates were highly correlated (Pearson's r = 0.92, P < .0001). PHH3 mitotic counts had both a good mean interobserver correlation (Rm = 0.83) and a good intraclass correlation (0.78), higher than H&E mitotic indices (Rm = 0.77, intraclass correlation = 0.71). After further stratification of meningiomas according to World Health Organization grade, PHH3 performed better in terms of interobserver concordance (Kendall's W = 0.761) compared with H&E (Kendall's W = 0.697). Referring to the same meningioma groups identified by World Health Organization grade as the gold standard, the volume under the receiver operator characteristic surface was 0.91, indicating a very good diagnostic ability of PHH3 scores in discriminating the 3 meningioma groups. The 2 optimal PHH3-specific cutoff values were 6.61 and 22.02. PHH3 staining is a useful diagnostic complementary tool to standard H&E mitotic count, optimizing intra- and interobserver reproducibility. PHH3-specific mitotic thresholds should be adopted to avoid overgrading of meningioma when ancillary methods are employed.
Late-breaking abstract: Late-breaking abstract: E-cigarette exposure induces pathological responses that result in lung tissue destruction and airway hyper reactivity in mice
Authors: Patrick Geraghty, Jules Dabo, Itsaso Garcia-Arcos, Neville Cummins, Robert Foronjy
Journal: European Respiratory Journal (2014)

E-cigarettes emit less particulates and toxins than standard cigarettes but they still expose users to a multitude of potentially harmful compounds. Given their growing use, there is a strong public health need to assess the safety and lung effects of e-cigarettes. This study developed an in vivo model of e-cigarette exposure in A/J mice using a small animal nebulizer. Cohorts of mice (n=8 per group) were exposed for 1 hour/day, 5 days a week for 4 months to either nebulized PBS, vehicle (50% propylene glycol/50% vegetable glycerin), e-cigarette liquid (American eLiquid Store) containing 18 mg/ml nicotine in 50%PG/50% VG or e-cigarette liquid containing 36 mg/ml nicotine in 50% PG/50% VG. Exposure to e-cigarette vapor with nicotine increased lung cytokine and protease expression, mucin staining in the airways, caspase 3/7 activity in the tissue and TUNEL staining in the lung parenchyma.  In addition, e-cigarettes induced emphysema and airway hyperreactivity while the vehicle had no effect.  Thus, this study shows for the first time that e-cigarette exposure causes asthma and emphysema in vivo.
Phase II Study of Dose-Adjusted EPOCH and Rituximab in Untreated Diffuse Large B-Cell Lymphoma With Analysis of Germinal Center and Post-Germinal Center Biomarkers
Authors: Wyndham H. Wilson, Kieron Dunleavy, Stefania Pittaluga, Upendra Hegde, Nicole Grant, Seth M. Steinberg, Mark Raffeld, Martin Gutierrez, Bruce A. Chabner, Louis Staudt, Elaine S. Jaffe, John E. Janik
Journal: Journal of Clinical Oncology (2008)

Purpose To assess the clinical outcome and the influence of biomarkers associated with apoptosis inhibition (Bcl-2), tumor proliferation (MIB-1), and cellular differentiation on the outcome with dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab (R) infusional therapy in diffuse large B-cell lymphoma (DLBCL) with analysis of germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry. Patients and Methods Phase II study of 72 patients with untreated de novo DLBCL who were at least 18 years of age and stage II or higher. Radiation consolidation was not permitted. Results Patients had a median age of 50 years (range, 19 to 85) and 40% had a high-intermediate or high International Prognostic Index (IPI). At 5 years, progression-free survival (PFS) and overall survival (OS) were 79% and 80%, respectively, with a median potential follow-up of 54 months. PFS was 91%, 90%, 67%, and 47%, and OS was 100%, 90%, 74%, and 37%, for 0 to 1, 2, 3, and 4 to 5 IPI factors, respectively, at 5 years. The Bcl-2 and MIB-1 biomarkers were not associated with PFS or OS. Based on DA-EPOCH historical controls, rituximab only benefited Bcl-2 positive tumors. Bcl-6 expression was associated with higher PFS whereas GCB exhibited a marginally significant higher PFS compared with post-GCB DLBCL. Conclusion DA-EPOCH-R outcome was not affected by tumor proliferation and rituximab appeared to overcome the adverse effect of Bcl-2. Bcl-6 may identify a biologic program associated with a superior outcome. Overall, DA-EPOCH-R shows promising outcome in low and intermediate IPI groups. A molecular model of treatment outcome with rituximab and chemotherapy is presented.
Comparing Oxazaphosphorines for Treating Ewing Sarcoma: Is the Answer Important Two Decades Later?
Authors: William H. Meyer, Holcombe E. Grier
Journal: Journal of Clinical Oncology (2014)

In the article that accompanies this editorial, Le Deley et al 1 present the results of the Euro-EWING99-R1 study (European Ewing Tumour Working Initiative of National Groups Ewing Tumour Studies 1999) that compared cyclophosphamide with ifosfamide in consolidation therapy for standard-risk patients with Ewing sarcoma.Ifosfamide was used as part of induction therapy for both groups.This international collaboration required 10 years of accrual, capturing the vast majority of European patients.The authors found that, in combination with vincristine and dactinomycin, cyclophosphamide (VAC arm) may be a suitable replacement for ifosfamide (VAI arm) in the consolidation phase of treatment for this group of patients.The trial followed a previous study (the Ewing Intergroup Cooperative Ewing's Sarcoma Study [EICESS-92]) that began enrollment in July 1992 and compared these two oxazaphosphorines in similar standard-risk patients with Ewing sarcoma. 2 The EICESS-92 was not sufficiently powered to detect a treatment difference smaller than 15%.The study by Le Deley et al was designed to definitively answer this question concerning cyclophosphamide versus ifosfamide.Oxazaphosphorines are an essential part of curative multiagent chemotherapy for Ewing sarcoma.Cyclophosphamide has been included in studies since the inception of chemotherapy approaches for this malignancy.In the 1980s, ifosfamide was shown to be active in recurrent Ewing sarcoma, with data that suggested it might be more active than cyclophosphamide.Single-arm studies aimed at improving outcomes replaced cyclophosphamide with ifosfamide. 3,4These efforts attempted to leverage the antitumor activity of ifosfamide and differences in toxicity profiles of these two agents, clearly important concerns.Intensive therapy with cyclophosphamide results in severe dose-related marrow suppression and often causes sterility at higher cumulative doses, particularly in males.This noninferiority study initially set the maximal allowable difference at 10%, requiring enrollment of 548 patients.During study conduct, overall better outcome than predicted by the initial statistical design was noted, decreasing the power of the study.At the planned third interim analysis (with 75% of events observed), the sample size was re-estimated, and the independent data monitoring committee recommended an increase in the sample size to 806 patients.At study completion, 856 patients were included in the random assignment.
PartitionFinder: Combined Selection of Partitioning Schemes and Substitution Models for Phylogenetic Analyses
Authors: R. Lanfear, B. Calcott, S. Y. W. Ho, S. Guindon
Journal: Molecular Biology and Evolution (2012)

In phylogenetic analyses of molecular sequence data, partitioning involves estimating independent models of molecular evolution for different sets of sites in a sequence alignment. Choosing an appropriate partitioning scheme is an important step in most analyses because it can affect the accuracy of phylogenetic reconstruction. Despite this, partitioning schemes are often chosen without explicit statistical justification. Here, we describe two new objective methods for the combined selection of best-fit partitioning schemes and nucleotide substitution models. These methods allow millions of partitioning schemes to be compared in realistic time frames and so permit the objective selection of partitioning schemes even for large multilocus DNA data sets. We demonstrate that these methods significantly outperform previous approaches, including both the ad hoc selection of partitioning schemes (e.g., partitioning by gene or codon position) and a recently proposed hierarchical clustering method. We have implemented these methods in an open-source program, PartitionFinder. This program allows users to select partitioning schemes and substitution models using a range of information-theoretic metrics (e.g., the Bayesian information criterion, akaike information criterion [AIC], and corrected AIC). We hope that PartitionFinder will encourage the objective selection of partitioning schemes and thus lead to improvements in phylogenetic analyses. PartitionFinder is written in Python and runs under Mac OSX 10.4 and above. The program, source code, and a detailed manual are freely available from www.robertlanfear.com/partitionfinder.
Haloperidol in Emotionally Disturbed Mentally Retarded Individuals
Authors: H. WARREN BURK, FRANK J. MENOLASCINO
Journal: American Journal of Psychiatry (1968)

The authors report a clinical study of the efficacy of a butyrophenone derivative (haloperidol) in a sample of mentally retarded children with associated emotional disturbances. The drug was noted to significantly alter the major target symptoms of such emotional disturbances. It appears that haloperidol is a welcome addition to the slowly growing armamentarium of effective psychopharmacological agents for the emotionally disturbed mentally retarded.
Barriers to Eye Care Among People Aged 40 Years and Older With Diagnosed Diabetes, 2006–2010
Authors: Chiu-Fang Chou, Cheryl E. Sherrod, Xinzhi Zhang, Lawrence E. Barker, Kai McKeever Bullard, John E. Crews, Jinan B. Saaddine
Journal: Diabetes Care (2013)

OBJECTIVE We examine barriers to receiving recommended eye care among people aged ≥40 years with diagnosed diabetes. RESEARCH DESIGN AND METHODS We analyzed 2006-2010 Behavioral Risk Factor Surveillance System data from 22 states (n = 27,699). Respondents who had not sought eye care in the preceding 12 months were asked the main reason why. We categorized the reasons as cost/lack of insurance, no need, no eye doctor/travel/appointment, and other (meaning everything else). We used multinomial logistic regression to control for race/ethnicity, education, income, and other selected covariates. RESULTS Among adults with diagnosed diabetes, nonadherence to the recommended annual eye examinations was 23.5%. The most commonly reported reasons for not receiving eye care in the preceding 12 months were "no need" and "cost or lack of insurance" (39.7 and 32.3%, respectively). Other reasons were "no eye doctor," "no transportation" or "could not get appointment" (6.4%), and "other" (21.5%). After controlling for covariates, adults aged 40-64 years were more likely than those aged ≥65 years (relative risk ratio [RRR] = 2.79; 95% CI 2.01-3.89) and women were more likely than men (RRR = 2.33; 95% CI 1.75-3.14) to report "cost or lack of insurance" as their main reason. However, people aged 40-64 years were less likely than those aged ≥65 years to report "no need" (RRR = 0.51; 95% CI 0.39-0.67) as their main reason. CONCLUSIONS Addressing concerns about "cost or lack of insurance" for adults under 65 years and "no perceived need" among those 65 years and older could help improve eye care service utilization among people with diabetes.