tbuckley/cabot-search huggingface dataset:
Neural Correlates of Irritability in Disruptive Mood Dysregulation and Bipolar Disorders
Authors: Jillian Lee Wiggins, Melissa A. Brotman, Nancy E. Adleman, Pilyoung Kim, Allison H. Oakes, Richard C. Reynolds, Gang Chen, Daniel S. Pine, Ellen Leibenluft
Journal: American Journal of Psychiatry (2016)

Objective: Bipolar disorder and disruptive mood dysregulation disorder (DMDD) are clinically and pathophysiologically distinct, yet irritability can be a clinical feature of both illnesses. The authors examine whether the neural mechanisms mediating irritability differ between bipolar disorder and DMDD, using a face emotion labeling paradigm because such labeling is deficient in both patient groups. The authors hypothesized that during face emotion labeling, irritability would be associated with dysfunctional activation in the amygdala and other temporal and prefrontal regions in both disorders, but that the nature of these associations would differ between DMDD and bipolar disorder. Method: During functional MRI acquisition, 71 youths (25 with DMDD, 24 with bipolar disorder, and 22 healthy youths) performed a labeling task with happy, fearful, and angry faces of varying emotional intensity. Results: Participants with DMDD and bipolar disorder showed similar levels of irritability and did not differ from each other or from healthy youths in face emotion labeling accuracy. Irritability correlated with amygdala activity across all intensities for all emotions in the DMDD group; such correlation was present in the bipolar disorder group only for fearful faces. In the ventral visual stream, associations between neural activity and irritability were found more consistently in the DMDD group than in the bipolar disorder group, especially in response to ambiguous angry faces. Conclusions: These results suggest diagnostic specificity in the neural correlates of irritability, a symptom of both DMDD and bipolar disorder. Such evidence of distinct neural correlates suggests the need to evaluate different approaches to treating irritability in the two disorders.
Met-Positive Advanced Hepatocellular Carcinoma and Child-Pugh Class a Liver Function in Asian Patients: a Randomized, Multicenter, Phase Ib/Ii Trial of the Oral C-Met Inhibitor Msc2156119J Vs Sorafenib
Authors: S. Qin, A. Cheng, H.Y. Lim, L. Xu, H. Zheng, F. Bladt
Journal: Annals of Oncology (2014)
Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial
Authors: Olivier Baud, Laure Maury, Florence Lebail, Duksha Ramful, Fatima El Moussawi, Claire Nicaise, Véronique Zupan-Simunek, Anne Coursol, Alain Beuchée, Pascal Bolot, Pierre Andrini, Damir Mohamed, Corinne Alberti
Journal: The Lancet (2016)
A novel RT-PCR approach to detecting EML4-ALK fusion genes in archival NSCLC tissue.
Authors: P. V. Danenberg, C. Stephens, J. Cooc, D. R. Gandara, P. C. Mack, P. P. Grimminger, K. D. Danenberg
Journal: Journal of Clinical Oncology (2010)

10535 Background: The echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) fusion gene can be detected in subsets of NSCLC, especially never-smoking patients with adenocarcinoma, and appears to be mutually exclusive of EGFR mutation. PF-1066, a potent and selective c-MET/ALK inhibitor, yields high response rates in ALK-positive patients, as detected by labor-intensive fluorescent in situ hybridization (FISH) methodology. Existing RT-PCR assays for these gene variants are designed to amplify large cDNA fragments (> 450 bases), while formalin-fixed paraffin-embedded (FFPE) specimens yield mostly RNA fragments of < 150 bases. Thus, our goal was to design a robust RT-PCR assay for EML4-ALK fusion gene transcripts suitable for use with commonly available FFPE tissues of limited size. Methods: Synthetic fragments representing the nine EML4-ALK fusion genes variants 1, 2, 3a, 3b, 4, 5a, 5b, 6 and 7 were generated by recursive PCR technology. The approach consisted of amplifying over-lapping fragments containing the fusion variant sequences with outside 5′ and 3′ primers. Primer probes were designed to detect specific EML4-ALK fusion gene fragments with a maximum amplicon of 170 bases by RT-PCR. Results: Functional RT-PCR assay were developed for each specific EML4-ALK variant, meeting criteria specified above for optimal clinical testing. Assays detecting multiple fusion variants without distinguishing specific variants were also designed. All nine known EML4-ALK variants can be detected using 6 RT-PCR assays. Screening of NSCLC cDNAs from the Response Genetics database is underway (molecular and clinical correlations to be presented). Conclusions: We developed RT-PCR assays capable of detecting EML4-ALK fusion gene variants from FFPE tissues. Two assays were successfully established: one that can detect and identify each individual variant, and one capable of detecting the presence of any variant as a single assay. We expect this methodology to provide a useful tool for large-scale screening of NSCLC or other FFPE tissues for the EML4-ALK fusion gene. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis Response Genetics DxS Abbott Laboratories, Bristol-Myers Squibb, Genentech, Lilly, Merck, Novartis, Pfizer
Phase II study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced non-small cell lung cancer (NSCLC)
Authors: A. I. Spira, N. O. Iannotti, M. A. Savin, M. Neubauer, N. Y. Gabrail, R. Yanagihara, K. K. Datta, E. A. Zang, S. Z. Fields, A. Das
Journal: Journal of Clinical Oncology (2007)

7546 Background: Eribulin is a structurally-simplified, fully synthetic analog of the marine sponge natural product halichondrin B. Eribulin inhibits microtubule dynamics via a mechanistically novel mode of action. Methods: An open-label, single-arm, Phase II study of eribulin was conducted in patients with advanced NSCLC (ECOG of 0 or 1) who were treated with platinum-based doublet chemotherapy and stratified by prior taxane exposure. A total of 103 patients (83 with prior taxanes and 20 taxane naïve) were treated with eribulin (1.4 mg/m 2 ), administered as a bolus infusion over 2 –5 minutes on Days 1, 8, and 15 of a 28-day cycle (N=77). Due to delays or skipped doses secondary to myelosuppression at Day 15 with recovery by Day 21, the protocol was amended to a schedule of Days 1 and 8 of a 21-day cycle (N=26). The primary efficacy endpoint was objective response rate. Independent radiologic review was used to confirm responses. Results: Of 106 enrolled patients, 103 received eribulin. Median age was 65 years and median number of prior therapies was 2, including taxanes (81%), gemcitabine (40%), pemetrexed (23%), and EGFR inhibitors (34%). Median number of cycles administered was 3 (range 1–15). Drug related toxicities included neutropenia grade 3 (23%) and 4 (26%), febrile neutropenia (4%), grade 3 fatigue (11%), grade 3 nausea (2%), and peripheral neuropathy grade 1/2 (37%) and 3 (2%). Based on RECIST criteria, the overall response rate (all partial responses) was 9.7% (95% CI: 4.0–15.4 %), with 10.8% PR in taxane pre-treated, and 5% PR in taxane naïve patients. Overall disease control rate (PR + SD) was 55.3%. 12-week progression free survival (PFS) rate was 53.0% (95% CI: 42.6–63.3%) and median PFS was 102 days (range 1–408+). Median duration of response was 176 days (range 50–291+), and median overall survival was 287 days (range 16–423+). The one year survival rate was 46.4% (95% CI: 34.9–58.0%). Conclusions: In this group of NSCLC patients who were treated with a median of two prior therapies, consisting in the majority of cases of two cytotoxic regimens, eribulin demonstrated an overall PR rate of 9.7% (10.8% in the taxane pre-treated) and 9.6 months median survival. No significant financial relationships to disclose.
Benefits of exercise in combination with epoetin alfa for multiple myeloma
Authors: E. A. Coleman, S. K. Coon, R. Kennedy, K. Lockhart, E. J. Anaissie, B. Barlogie
Journal: Journal of Clinical Oncology (2006)

8605 Background: Epoetin alfa increases hemoglobin levels and reduces the need for RBC transfusions in diverse groups of patients with cancer-related anemia. Interest in other potential benefits led to this study comparing outcomes relative to the duration of epoetin alfa therapy and exercise for patients receiving intensive therapy for multiple myeloma while enrolled in a randomized, controlled trial of a home-based individualized exercise program. Outcomes of interest included the number of attempts at and days of stem cell collection relative to exercise and the time to recovery post transplant, response to treatment, as well as RBC and platelet transfusions relative to the duration of epoetin alfa and exercise. Methods: The patients were enrolled in a treatment protocol consisting of high dose chemotherapy and tandem stem cell transplants. Participants were randomized to exercise (n = 54) or usual care (n = 57) groups as they enrolled in the treatment protocol. Participants in both groups received epoetin alfa according to an algorithm. All participants were in the study for approximately 15 weeks through stem cell collection. Sixty-nine (69) of 70 consecutive eligible patients continued in the study for approximately 15 weeks more through their first transplant. Results: All groups of patients were equivalent for age, gender and race and the exercise and usual care groups were equivalent for duration of epotein alfa. There were non significant findings for post transplant recovery and response to treatment relative to the duration of epoetin alfa therapy and exercise program. Patients who received epoetin alfa for the longer duration had significantly (p &lt; .01) higher mean hemoglobin levels during the transplant period but there was no significant difference at discharge from transplant. Patients in the exercise group had significantly (p &lt; .05) fewer RBC and platelet transfusions and significantly (p &lt; .05) fewer attempts at stem cell collection and total days of collection. Conclusions: These findings suggest that exercise in combination with prophylactic epoetin alfa therapy benefits patients by reducing the number of RBC and platelet transfusions and the number of attempts at and number of days of stem cell collection. [Table: see text]
Mismatch repair proficiency as a predictor of response to the PARP inhibitor AZD2281.
Authors: R. A. Redman, S. J. York
Journal: Journal of Clinical Oncology (2010)

e13644 Background: Microsatellite instability (MSI), the result of defective DNA mismatch repair (MMR), is observed in approximately 15% of colorectal cancers. It can either occur sporadically through epigenetic silencing of genes responsible for MMR or through autosomal dominant inheritance of Lynch syndrome. Inhibition of poly(ADP-ribose) polymerase (PARP) has recently been demonstrated to have antitumor activity in cancers associated with defective double strand break repair. The effect of PARP inhibition on unselected MSI tumors, as compared to those with intact MMR conferring microsatellite stability (MSS), is currently unknown. Methods: The mlh1−/− human colon cancer cell line HCT116 was stably transfected with pTRE-MLH1, restoring functional MMR. Expression of MLH1 is constitutive in the absence of drug, but with addition of doxycycline, the Tet-repressor silences MLH1 expression and restores the original MSI phenotype. This system constitutes two isogenic cell “lines” differing only in their capacity for MMR. HCT116-pTRE-MLH1 cells were seeded in a 96-well plate ± doxycycline, and 48 hours later were treated with the PARP inhibitor, AZD2281, in serial dilutions ranging from 1 nM to 100 μM. Viability was measured after three days of AZD2281 treatment by MTT assay. In a parallel experiment, cells were treated with serial dilutions of oxaliplatin ± AZD2281 at a dose of 10 μM (IC35 for MSS cells). Viability was measured by MTT assay after three days of exposure to oxaliplatin/AZD2281. Results: MSS cells are more sensitive to PARP inhibition with AZD2281 as a single agent than are MSI cells. The IC50 in the presence of MLH1 (MSS) was 35 μM, whereas the IC50 in the absence of MLH1 was not reached in this assay. The IC25 was 11-fold higher in the presence of doxycycline (43 μM versus 3.9 μM in absence of doxycycline). The addition of AZD2281 did not potentiate the cytotoxicity of oxaliplatin either in the presence or absence of MLH1. Conclusions: Cells proficient in MMR are more sensitive to PARP inhibition with AZD2281 as a single agent than are MSI cells. The addition of PARP inhibitor to the traditional cytotoxic agent oxaliplatin did not potentiate cell death in either MSI or MSS cells. No significant financial relationships to disclose.
Modelling the impact of deferring HCV treatment on liver-related complications in HIV coinfected men who have sex with men
Authors: Cindy Zahnd, Luisa Salazar-Vizcaya, Jean-François Dufour, Beat Müllhaupt, Gilles Wandeler, Roger Kouyos, Janne Estill, Barbara Bertisch, Andri Rauch, Olivia Keiser
Journal: Journal of Hepatology (2016)

Hepatitis C (HCV) is a leading cause of morbidity and mortality in people who live with HIV. In many countries, access to direct acting antiviral agents to treat HCV is restricted to individuals with advanced liver disease (METAVIR stage F3 or F4). Our goal was to estimate the long term impact of deferring HCV treatment for men who have sex with men (MSM) who are coinfected with HIV and often have multiple risk factors for liver disease progression.We developed an individual-based model of liver disease progression in HIV/HCV coinfected MSM. We estimated liver-related morbidity and mortality as well as the median time spent with replicating HCV infection when individuals were treated in liver fibrosis stages F0, F1, F2, F3 or F4 on the METAVIR scale.The percentage of individuals who died of liver-related complications was 2% if treatment was initiated in F0 or F1. It increased to 3% if treatment was deferred until F2, 7% if it was deferred until F3 and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5years if treatment was initiated in F2 to almost 15years if it was deferred until F4.Deferring HCV therapy until advanced liver fibrosis is established could increase liver-related morbidity and mortality in HIV/HCV coinfected individuals, and substantially prolong the time individuals spend with a replicating HCV infection.
The Antitumor Efficacy of IL2/IL21-Cultured Polyfunctional Neu-Specific T Cells Is TNFα/IL17 Dependent
Authors: Vy Phan-Lai, Yushe Dang, Ekram Gad, Jennifer Childs, Mary L. Disis
Journal: Clinical Cancer Research (2015)

Infusion of HER2-specific T cells, derived from vaccine-primed patients and expanded with IL2/IL12, has induced tumor regression in a minority of patients with metastatic treatment-refractory HER2(+) breast cancer. We questioned whether alteration of cytokine growth factors used to culture vaccine-primed T cells could improve antitumor activity.Using the TgMMTV-neu murine mammary tumor model, we cultured T cells derived from mice immunized with a previously defined neu class II peptide, p98-114 (neu p98), and evaluated different cytokine combinations for expansion.Infusion of neu p98-specific T-cell lines derived from all cytokine conditions evaluated resulted in significant antitumor activity compared with infused naïve splenocytes (P < 0.05). T cells cultured with IL2/IL21 could uniquely mediate complete regression of spontaneous mammary tumors. IL2/IL21 cultured neu-specific T cells demonstrated a different cytokine secretion pattern as compared with other cultured T cells; secreting high levels of TNFα and IL17 (P < 0.05). Moreover, tumor-infiltrating CD8(+) cells were significantly increased after the infusion of IL2/IL21 cultured T cells as compared with tumors treated with T cells expanded under other cytokine conditions (P < 0.001). The antitumor effect of the infusion of IL2/IL21 cultured cells was mediated by CD8 T cells. Depletion of TNFα or IL17, but not IFNγ, abrogated the tumor growth inhibition induced by the IL2/IL21 T cells and markedly decreased the influx of CD8 into tumors. Finally, IL2/IL21-cultured human antigen specific T cells also displayed a similar polyfunctional Th1/Th17 phenotype.Expansion of HER2 vaccine-primed T cells with IL2/IL21 may have the potential to effectively mediate tumor regression when used in adoptive transfer. Clin Cancer Res; 22(9); 2207-16. ©2015 AACR.
Mammary Tumor Formation Within Outgrowths of Transplanted Hyperplastic Nodules From Carcinogen-Treated Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Leonard J. Beuving
Journal: JNCI Journal of the National Cancer Institute (1968)

Hyperplastic alveolar nodules and ducts from the mammary glands of carcinogen-treated Lewis rats were transplanted into gland-free mammary fat pads of isologous animals. Eight of the 37 resulting hyperplastic outgrowths gave rise to mammary tumors within 11–52 weeks, whereas no tumors appeared in the normal outgrowths. Thus, hyperplastic alveolar nodules in carcinogen-treated rats may be designated as preneo-plastic in the same sense as the term is applied to preneoplastic hyperplastic alveolar nodules in mice.
TH2 specific biomarker profile determines steroid responsiveness in severe asthma
Authors: Anna James, Maciek Kupczyk, Junya Ono, Stoichiro Ohta, Kenji Izuhara, Sven-Erik Dahlén
Journal: European Respiratory Journal (2013)

Biomarkers able to determine responsiveness to therapy in severe asthma (SA) are needed. Our goal was to examine the usefulness of periostin, eosinophils and exhaled NO as potential T H 2 specific markers of glucocorticoid responsiveness in SA.  Following a 4 week treatment optimization period, patients with SA (n=85) and mild-to-moderate asthma (MA) (n=66) underwent a 2 wk double-blind placebo controlled oral prednisolone (0.5 mg/kg BW daily) intervention (OPI). Serum periostin levels were measured by ELISA using 2 rat anti-human periostin mAbs (clones SS18A & SS17B), (Okamoto et al. ERJ 2011;37:1119).  The OPI improved lung function in SA (FEV 1 : 2.28±0.13 L post vs 2.04±0.12 L pre, p  Our findings confirm associations between serum periostin levels, eosinophilic inflammation and responsiveness to corticosteroid treatment. Furthermore, we demonstrate that levels of serum periostin are sensitive to oral steroid treatment.
Role of endobronchial ultasound-guided transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma
Authors: Füsun Alatas, Emine Dundar, Hüseyin Yildirim, Muzaffer Metintas, Güntülü Ak
Journal: European Respiratory Journal (2011)

Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is technique used for the diagnosis of peribronchial/peritracheal mass lesion and the staging of bronchogenic carcinoma.  The aim of this study is to determine the role of EBUS-TBNA in patients with peribronchial/peritracheal mass without endobronchial lesion suspected for bronchogenic carcinoma and patients with a diameter of mediastinal/hilar lympadenopathy bigger than 1 cm in CT, prediagnosed as bronchogenic carcinoma.  Between April 2010 and January 2011, 56 patients with mean age 60,8 years (47 M/9 F) were admitted to study. EBUS-TBNA was performed to only lymph node in 47 patients, both lymph node and mass in 5 patients and only mass 4 patients. The definite diagnosis was done in twenty five patients without endobronchial lesion. Ninety six out of ninety seven lymph node aspiration was positive (70 mediastinal/27 hilar). One patient diagnosed with mediastinoscopy. (Sensitivity 98,9%, specificity 100%, PPV 100%, NPV 67% and accuracy 98,9%)  Twelve N3 lymph node were positive for malignancy.Seven out of nine mass biopsy were diagnosed as malignant. Two patients were diagnosed with other diagnostic procedures. No complication was observed during EBUS-TBNA.  In conclusion, EBUS-TBNA seemed a safe and effective technique in making bronchogenic carsinoma diagnosis for mediastinal/hilar lymph nodes and intrapulmonary masses.
Airway surface dehydration is a novel risk factor for allergic airway inflammation
Authors: Benedikt Fritzsching, Lu Dai, Charlotte Van Bodegom, Jolanthe Schatterny, Stephanie Hirtz, Zhe Zhou-Suckow, Matthias Hagner, Sandra Christochowitz, Marcus A. Mall
Journal: European Respiratory Journal (2014)

Introduction:  Our recent evidence from mice lacking the epithelial Cl -  channel SLC26A9 and mice with airway specific overexpression of the amiloride-sensitive epithelial Na +  channel (βENaC-Tg) suggests that dysregulated epithelial ion transport and airway surface dehydration may be implicated in the pathogenesis of allergic airway disease (Anagnostopoulou et al., JCI 2012 and Mall et al., AmJRespirCritCare Med 2008). We hypothesized that airway surface dehydration and reduced mucociliary clearance may increase the susceptibility for allergic airway inflammation due to reduced allergen clearance.   Methods:  Aspergillus fumigatus extract (Af) was applied by repeated intratracheal instillations into βENaC-Tg mice (C57BL/6) and BAL cell counts, airway morphology, airway hyperresponsiveness (AHR, by Flexivent lung function) and allergen clearance were compared to wild-type mice. IL-13 expressing cell types in the lung were identified by 11-color flow cytometry.   Results:  Airway eosinophils, pulmonary IL-13 expression and AHR were significantly increased in Af-challenged compared to vehicle-treated βENaC-Tg mice. 11-color flow cytometry of lung tissue detected IL-13 secretion from Th2 cells, but also from ILC-2 and airway epithelial cells. IL-13 effector functions were further highlighted by STAT6 deletion, a critical molecule for IL-13 signaling. These bENaC-Tg/STAT6 -/-  mice were protected from Af-induced airway eosinophilia, mucus obstruction and elevated IL-13 expression.   Conclusion:  Collectively, our results indicate that airway surface dehydration and impaired mucus and allergen clearance constitute risk factors for key pathologies in allergic airway disease.   Acknowledgements:  DFG (DFG MA 2081/3-2).
Abstract 19721: Circulating miR-146a Shows Positive Correlation with Arterial Stiffness and Negative Correlation with Aerobic Exercise Capacity Among Healthy Adults
Authors: Amir Rezvan, Kimberly Rooney, Ibhar Al Mheid, Nima Ghasemzadeh, Hanjoong Jo, Arshed A Quyyumi, Charles D Searles
Journal: Circulation (2014)

Background: miR-146a is a micro-RNA expressed in many cell types, with increased expression in response to inflammation via TLR activation, leading to negative feedback regulation of inflammatory pathways. miR-146a has been associated with atherosclerosis, abdominal aortic aneurysm and ischemic stroke. Circulating miR-146a (c-miR-146a) levels are higher in hyperglycemia, hyperlipidemia and acute coronary syndrome. c-miR-146a levels may change variably in response to exercise in healthy individuals. We hypothesized that c-miR-146a will be associated with sub-clinical vascular disease and explored its relationship with measures of arterial stiffness and cardiopulmonary fitness. Methods: In 39 healthy (no medications, screened for absence of hypertension, hyperlipidemia, diabetes and obesity) non-smoking volunteers, 56% male, aged 46.53 ± 11years, enrolled in Emory’s preventive health initiative study, we performed qPCR (TaqMan) for serum miR-146a levels and normalized to miR-346 (shown to have stable levels...