tbuckley/cabot-search huggingface dataset:
Correlation of vascular endothelial growth factor receptor 2 (VEGFR-2) with platelet-derived growth factor receptor α (PDGFR-α) on circulating epithelial tumor cells (CETCs) in breast cancer patients.
Authors: Monika Pizon, Dorothea Schott, Ulrich A. Pachmann, Katharina Pachmann
Journal: Journal of Clinical Oncology (2016)

e14010 Background: CETC analysis is a promising diagnostic field for estimating the risk for metastatic relapse and progression in patients with malignant disease. CETCs characterization can be used as a liquid biopsy for prognostic and predictive purposes in breast and other cancers. VEGFR-2 and PDGFR-α play an important role in tumor growth and the progression of cancer disease. The purpose of the current study was therefore to investigate their expression on CETCs. Methods: Double antibody staining was used to determine VEGFR-2 and PDGFR-α positive CETCs from non-metastatic and metastatic breast cancer patients. Results: VEGFR-2 and PDGFR-α positive CETCs were detected in 100% of breast cancer patients. A statistically high correlation was found between VEGFR-2 and PDGFR-α positive CETCs (r = 0.754 and p < 0.001). We observed no statistically significant correlations between the number of CETCs and frequency of VEGFR-2 and PDGFR-α positive CETCs. The number of VEGFR-2 and PDGFR-α positive CETCs was not associated with tumor stage, hormone receptor status or nodal/distant metastasis. Conclusions: Our results show that CETCs in breast cancer patients are frequently positive for VEGFR-2 and PDGFR-α. PDGFR-α besides VEGFR-2 could be a potential target in personalized cancer treatment.
A distinct immunophenotype identifies a subset of <i>NPM1</i>‐mutated AML with <i>TET2</i> or <i>IDH1/2</i> mutations and improved outcome
Authors: Emily F. Mason, Frank C. Kuo, Robert P. Hasserjian, Adam C. Seegmiller, Olga Pozdnyakova
Journal: American Journal of Hematology (2017)

Abstract Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in AML. NPM1 mutations often co‐occur with FLT3‐ITDs and mutations in genes regulating DNA methylation, such as DNMT3A , TET2 , and IDH1/2 . It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1 ‐mutated AML and correlated sequencing data with immunophenotypic and clinical findings. Of 84 cases (63%) that lacked monocytic differentiation (“myeloid AML”), 40 (48%) demonstrated an acute promyelocytic leukemia‐like (APL‐like) immunophenotype by flow cytometry, with absence of CD34 and HLA‐DR and strong myeloperoxidase expression, in the absence of a PML‐RARA translocation. Pathologic variants in TET2 , IDH1, or IDH2 were identified in 39/40 APL‐like cases. This subset of NPM1 ‐mutated AML was associated with longer relapse‐free and overall survival, when compared with cases that were positive for CD34 and/or HLA‐DR. The combination of NPM1 and TET2 or IDH1/2 mutations along with an APL‐like immunophenotype identifies a distinct subtype of AML. Further studies addressing its biology and clinical significance may be especially relevant in the era of IDH inhibitors and recent work showing efficacy of ATRA therapy in NPM1 and IDH1 ‐mutated AML.
Rapid and sensitive liquid chromatography–tandem mass spectrometric method for the quantitative determination of potentially harmful substance 5,5′-oxydimethylenebis (2-furfural) in traditional Chinese medicine injections
Authors: Qingce Zang, Yang Gao, Luojiao Huang, Jiuming He, Sheng Lin, Hongtao Jin, Ruiping Zhang, Zeper Abliz
Journal: Acta Pharmaceutica Sinica B (2017)

With the rapid development and wide application of traditional Chinese medicine injection (TCMI), a number of adverse events of some TCMIs have incessantly been reported and have drawn broad attention in recent years. Establishing effective and practical analytical methods for safety evaluation and quality control of TCMI can help to improve the safety of TCMIs in clinical applications. In this study, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and validated for the quantitative determination of potentially harmful substance 5,5'-oxydimethylenebis (2-furfural, OMBF) in TCMI samples. Chromatographic separation was performed on a C18 reversed-phase column (150 mm × 2.1 mm, 5 µm) by gradient elution, using methanol-water containing 0.1% formic acid as mobile phase at the flow rate of 0.3 mL/min. MS/MS detection was performed on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction-monitoring mode. The method was sensitive with a limit of quantification of 0.3 ng/mL and linear over the range of 0.3-30 ng/mL (r=0.9998). Intra- and inter-day precision for analyte was <9.52% RSD with recoveries in the range 88.0-109.67% at three concentration levels. The validated method was successfully applied to quantitatively determine the compound OMBF in TCMIs and glucose injections. Our study indicates that this method is simple, sensitive, practicable and reliable, and could be applied for safety evaluation and quality control of TCMIs and glucose injections.
Abstract 15515: Adverse Cardiovascular Effects of the Mood and Anxiety Disorders and Their Treatments on Heart Rate Variability. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): A Cross-Sectional Analysis of Baseline Characteristics
Authors: Andrew H Kemp, Andre R Brunoni, Maria-Angelica Nunes, Jose-Geraldo Mill, Antonio L Ribeiro, Alexandre C Pereira, Isabela M Bensenor, Paulo A Lotufo
Journal: Circulation (2013)

Background:  The effects of the mood and anxiety disorders, and their treatments on vagally-mediated cardiovascular function remain unclear. Resting-state heart rate (HR) and its variability (HRV) are psychophysiological markers of the cholinergic anti-inflammatory pathway, mediated by the vagus nerve, which plays a major role in the regulation of cytokine activity. We hypothesised that HR will be increased and HRV, decreased in these disorders. We also sought to determine the impact of antidepressant treatments. We further examined the impact of additional confounding variables including age, sex, physical activity, metabolic syndrome and coronary heart disease on findings.   Methods:  The ELSA-BRASIL cohort includes a total of 15,105 participants. The Clinical Interview Schedule - Revised was used to obtain diagnoses of mood and anxiety disorders. HR as well as the square root of the mean squared difference of successive NNs (RMSSD) and high frequency HRV - commonly employed and stable measures of HRV - were extracted from a 10-minute supine electrocardiogram recording for analysis.   Results:  Patients with mood and anxiety disorders displayed elevated HR, although effect sizes were small (p
In an Anniversary Year, <i>Diabetes Care</i> Takes a Selfie
Authors: Matthew C. Riddle
Journal: Diabetes Care (2017)

This issue marks Diabetes Care ’s 40th anniversary. The journal’s first issue appeared in January 1978, with Jay Skyler as the cofounding Editor in Chief (EIC). Five of the 14 contributions to the issue concerned urine testing for glucose (1), and we were all much younger. To commemorate this historic event we will present in an upcoming issue, as a “Profile in Progress,” the story of this no-longer-young journal and how, over time, it has evolved into a life of its own, transcending the many individuals who have worked for and contributed to it.

In recent January issues of Diabetes Care it has been customary for the EIC to comment on the state of the journal (2). On this occasion, having completed my first year in this role, I propose to begin by celebrating the announcement made in July that Diabetes Care had earned the highest impact factor ever attained by an American Diabetes Association (ADA) journal. The journal’s score for this index of influence increased from 8.9 the prior year to 11.9 in 2017, higher than that of all other journals focused exclusively on diabetes. It is a remarkable increase, and if I were a crafty politician I would claim all credit because it was announced soon after my appointment as EIC. But, in truth, this achievement resulted from the work of William T. Cefalu, the outgoing EIC, and the outstanding associate editors (AEs) and editorial staff during the last 2 years. It is likely also related to the increase of interest in diabetes itself. The diabetes community is clearly looking to us to present the newest and best research and commentary. I believe that in 2017 we have been able to meet that expectation, with articles that match or exceed those in previous years. Moreover, circulation of the …
Simultaneous three-dimensional visualization of mineralized and soft skeletal tissues by a novel microCT contrast agent with polyoxometalate structure
Authors: Greet Kerckhofs, Steve Stegen, Nick van Gastel, Annelies Sap, Guillaume Falgayrac, Guillaume Penel, Marjorie Durand, Frank P. Luyten, Liesbet Geris, Katleen Vandamme, Tatjana Parac-Vogt, Geert Carmeliet
Journal: Biomaterials (2017)
RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions
Authors: Brandon Hogstad, Marie-Luise Berres, Rikhia Chakraborty, Jun Tang, Camille Bigenwald, Madhavika Serasinghe, Karen Phaik Har Lim, Howard Lin, Tsz-Kwong Man, Romain Remark, Samantha Baxter, Veronika Kana, Stefan Jordan, Zoi Karoulia, Wing-hong Kwan, Marylene Leboeuf, Elisa Brandt, Helene Salmon, Kenneth McClain, Poulikos Poulikakos, Jerry Chipuk, Willem J.M. Mulder, Carl E. Allen, Miriam Merad
Journal: The Journal of Experimental Medicine (2017)

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.
Crescendo Skin Sympathetic Nerve Activity and Ventricular Arrhythmia
Authors: Ryan A. Kabir, Anisiia Doytchinova, Xiao Liu, David Adams, Susan Straka, Lan S. Chen, Changyu Shen, Shien-Fong Lin, Thomas H. Everett, Peng-Sheng Chen
Journal: Journal of the American College of Cardiology (2017)
Guidelines for Statistical Analysis Plans
Authors: David L. DeMets, Thomas D. Cook, Kevin A. Buhr
Journal: JAMA (2017)

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Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression
Authors: Bernardo Sampaio-Junior, Gabriel Tortella, Lucas Borrione, Adriano H. Moffa, Rodrigo Machado-Vieira, Eric Cretaz, Adriano Fernandes da Silva, Renério Fraguas, Luana V. Aparício, Izio Klein, Beny Lafer, Stephan Goerigk, Isabela Martins Benseñor, Paulo Andrade Lotufo, Wagner F. Gattaz, André Russowsky Brunoni
Journal: JAMA Psychiatry (2017)

More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression.
Of mice, rats, and men: Small animal model of hepatitis C virus infection
Authors: Arash Grakoui, Christopher M. Walker
Journal: Hepatology (2017)

1Emory University School of Medicine, Division of Infectious Diseases, Yerkes National Primate Research Center, Division of Microbiology and Immunology, and Emory Vaccine CenterAtlantaGA 2Department of PediatricsNationwide Children's Hospital, and The Ohio State University School of MedicineColumbusOH
Effect of somatic mutations in the four genes of the HER family on occurrence in HER2-positive breast cancer, cell proliferation rates, and resistance to HER2-targeted therapies in vitro.
Authors: Naomi Elster, Alex J Eustace, Yue Fan, Jarushka Naidoo, Joanna Fay, Elaine Kay, Aoife Carr, Oscar S. Breathnach, Patrick G. Morris, William Grogan, Arnold D. Hill, Colm Power, Michael J Allen, Susan Kennedy, John Crown, William M. Gallagher, Sinead Toomey, Bryan Hennessy
Journal: Journal of Clinical Oncology (2015)

615 Background: Somatic mutations in the 4 HER family genes (EGFR, HER2, 3, 4) occur in HER2-positive breast cancer (HER2+ BC). (Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumors. Nature 2012;490(7418): 61-70.) We investigated their frequency in a large set of HER2+ BCs and their therapeutic relevance. Methods: Tumors from 246 HER2+ BC patients who received adjuvant trastuzumab-based therapy after surgery were reviewed by a pathologist for tumor content. DNA from 48 matched normal and cancerous samples was sequenced using the Agilent kinome library and a MiSeq. Somatic HER gene mutations identified in this way had their frequency determined by Sequenom MassArray (n=246). HER gene mutations were correlated with patient outcomes. Constructs of 2 hotspot HER3/4 mutations were created and transfected into BT474, HCC1569 and HCC1954 cells. Doubling time, proliferation, Boyden chamber assays and RPPA were used to determine effects of mutations on cell growth, invasion, signalling and response to HER2-targeted therapies. Results: 12 somatic deleterious mutually exclusive mutations in the kinase and furin like domains of the 4 HER genes (3 EGFR, 2 HER2, 2 HER3, 5 HER4 mutations) were identified in 6.5 % of HER2+ BCs including 2 hotspot mutations in HER3/4. HER gene mutations did not impact OS or RFS after adjuvant trastuzumab. HER3/4 hotspot mutations increased doubling rates in vitro and induced resistance to anti-HER2/EGFR TKIs (Table) but not trastuzumab. Transfected cells were sensitive to the PI3K inhibitor copanlisib and copanlisib also restored sensitivity to these TKIs in these cell lines. Conclusions: HER family mutations occur in 6.5% of HER2+BC and affect tumour growth and response to HER2-targeted therapies. Effects of 2 hotspot HER3/4 mutations on response to TKI's (nM) in vitro in transfected (MUT) vs. wild type (WT) cell lines. '*' indicates a p-value of < 0.05. HER3 MUT IC50 HER3 WT IC50 Lapatinib (BT474) 58.3 +/- 5.2 * 42.7 +/- 4.1 Afatinib (HCC1569) 129.8 +/- 8.8 * 38.4 +/- 3.9 Afatinib (HCC1954) 81.5 +/- 8.0 * 52.8 +/- 3.2 HER4 MUT IC50 HER4 WT IC50 Afatinib (HCC1569) 76.5 +/- 1.3* 44.1 +/- 4.1
A phase I, open label, two part, safety and tolerability study of U3-1784 in patients with advanced solid tumours.
Authors: Marika Ciprotti, Reimar Abraham, Mendel Jansen, Shinya Tokuhiro, Masaharu Hanai, Masataka Oitate, Dale Edward Shuster, Alberto Martinez
Journal: Journal of Clinical Oncology (2016)

TPS2593 Background: Fibroblast Growth Factor Receptor 4 (FGFR4) is the fourth member of a family of FGF tyrosine kinase receptors that regulate cellular pathways involved in proliferation, differentiation and survival. Fibroblast Growth Factor 19 (FGF19), a natural ligand of FGFR4, has unique specificity for its receptor and regulates bile acid synthesis and hepatocyte proliferation in the normal liver. Although FGF signalling has been found to be of importance in a number of tumour types, including prostate, breast, pancreatic, pituitary and gynaecological tumours, growing evidence suggests that FGF19/FGFR4 pathway is a key driver in the development of hepatocellular carcinoma (HCC). U3-1784 is a fully human IgG1 monoclonal antibody and antagonist to FGF19 ligand. It selectively targets FGFR4 without binding to FGFR 1, 2 and 3. Methods: The study is divided into 2 parts: in part 1 (Dose Escalation Phase) multiple ascending doses (3 + 3 design) of U3-1784 are given to patients with histologically or cytologically confirmed advanced solid tumours; part 2 (Dose Expansion Phase) is carried out in up to 27 patients with histologically or cytologically confirmed HCC. Patients ≥ 18 years of age, performance status ≤ 1 and whose malignancies are refractory to, intolerant of, or not eligible for standard treatment, or who decline standard therapy, or for whom no therapy with curative intent is available are eligible to enter this study. U3-1784 is administered intravenously every 2 weeks. Primary objectives are: safety and tolerability of U3-1784, maximum tolerated dose and/or safety of the maximum administered dose. Secondary objectives are: pharmacokinetic and pharmacodynamics (alpha-fetoprotein, bile acids, AST/ALT) of U3-1784, emergence of antidrug antibodies. Exploratory objectives are: tumour response by RECIST 1.1, overall response rate, disease control rate, time to progression, overall survival, duration of response/stable disease and additional biomarkers. Enrolment to cohort 1 began in January 2016. Clinical trial information: 2015-002670-20.
CD1a presentation of endogenous antigens by group 2 innate lymphoid cells
Authors: Clare S. Hardman, Yi-Ling Chen, Maryam Salimi, Rachael Jarrett, David Johnson, Valtteri J. Järvinen, Raymond J. Owens, Emmanouela Repapi, David J. Cousins, Jillian L. Barlow, Andrew N. J. McKenzie, Graham Ogg
Journal: Science Immunology (2017)

Human skin–derived ILC2 express CD1a and present endogenous PLA2G4A-dependent antigens to T cells.
Biological effect of IL-33R/ST2 in atopic asthmatic children; serum IL-33 changes by administration of omalizumab
Authors: Yosuke Baba, Hiromichi Yamada, Toshiyuki Yoneyama, Tomoaki Yokokura, Susumu Yamazaki, Eisuke Inage, Mari Mori, Yoshikazu Ohtsuka, Masato Kantake, Toshiaoki Shimizu, MP
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 17991: Differential Acetylation Mediates Import of Cytosolic SOD2 Into Mitochondria and SOD2 Aggregation Associated With Physiological Hypertrophy in the Heart of SOD2-tg Mice
Authors: Yeong-Renn Chen, Chwen-Lih Chen, Patrick Kang, Zhicheng Jin
Journal: Circulation (2016)

Cardiac-specific overexpression of SOD2 (mitochondrial manganese superoxide dismutase, mouse model of SOD2-tg) induces supernormal and physiologically hypertrophic phenotypes in mouse heart. However, the reductive stress imposed by SOD2 overexpression also results in protein aggregation of SOD2 pentamer and differential hyperacetylation of SOD2 in the compartments of mitochondrial matrix, mitochondrial inner membrane, and cytosol. We studied SOD2 acetylation in matrix, in submitochondrial particle (SMP), and in cytosol from SOD2-tg mouse heart. LC/MS/MS analysis revealed that K68, K75, K89, K114, K122, K130, K132, K134, and K154 residues of the cytosolic SOD2 were acetylated. LC/MS/MS analysis further indicated that K68, K122, and K130 of SOD2 in SMP and K68, K122, K 130, K202 of matrix SOD2 were acetylated. The results suggested that import of cytosolic SOD2 precursor into mitochondria resulted in specific deacetylation of K75, K89, K114, K132, K134, K154 residues, and site-specific acetylation of K202 residue in the matrix. In vitro acetylation of matrix SOD2 with acetic anhydride de-aggregated pentameric SOD2, restored the profile of hyperacetylation observed in cytosolic SOD2, and decreased the enzymatic activity of matrix SOD2 as measured by EPR. As indicated by the 3D structure of SOD2, specific acetylation of K89, K134, and K154 detected in cytosolic SOD2 induces unfolding tertiary structure and breaking salt bridges for stabilizing the quaternary structure. Stable isotope labeling of both wild type and SOD2-tg matrix proteins followed by LC/MS analysis indicated significant up-regulation of stress-induced mitochondrial hsp70 (GRP75) and down-regulation of presequence protease (PREP), thus supporting increased reductive stress, compromised mitochondrial localization, and weakening correct folding of the nascent SOD2. Stable isotope labeling further revealed down-regulation in the metabolic enzymes of the fatty acid oxidation pathway, thus promoting cardiac remodeling of hypertrophy. In conclusion, hyperacetylation maintains the unfolded cytosolic SOD2 and mediates import of SOD2 across the mitochondrial membrane. Activation and misfolding of the matrix SOD2 is subsequently initiated via deacetylation in matrix.