tbuckley/cabot-search huggingface dataset:
Exercise, alone and in combination with an anti-CEA vaccine, reduces pancreatic tumor cell growth and enhances survival in mice.
Authors: Connie Rogers, Kenneth Hance, David Zaharoff, Susan Perkins, Stephen Hursting, Jeffrey Schlom, John Greiner
Journal: Cancer Research (2008)

2096  Regular exercise is strongly associated with reduced risk of colon, breast, and endometrial cancer, and possibly pancreatic and lung cancer. Furthermore, regular exercise is associated with a reduced risk of recurrence and death from colorectal and breast cancer. One mechanism that may mediate the protective effect of exercise on tumor incidence and/or recurrence is an enhancement of anti-tumor immunity. We have previously demonstrated that exercise significantly enhances NK cell function and vaccine responses in normal mice. Our laboratory has also demonstrated in both preclinical and clinical studies that therapeutic cancer vaccines targeted against the tumor antigen, carcinoembryonic antigen (CEA), enhance anti-tumor immunity and increase survival. The goal of this study was to explore the effects of exercise, alone and combined with a therapeutic cancer vaccine, on in vivo tumor growth and survival. The murine Panc02.CEA pancreatic tumor cell line was chosen because it shares many characteristics with human pancreatic tumors and because in vivo anti-tumor immunity against the parental cell line is mediated by NK and CD8+ T cells. CEA.Tg mice were randomized to 1 of 4 treatment groups (n=16/group): vehicle (HBSS), vaccine (V), exercise (EX), or vaccine + exercise (V+EX). Mice in the EX and V+EX groups had access to voluntary running wheels for 8 weeks prior to tumor implantation (10^6 cells) and throughout the vaccination protocol (17 wks) and ran 3.5 ± 0.4 and 3.0 ± 0.3 mi/day, respectively. Mice in the V and V + EX groups received a primary vaccination with 10^8 pfu recombinant vaccinia (rV)-CEA/TRICOM + 10^7 pfu recombinant fowlpox (rF)-GMCSF when mean tumor volume reached 30 mm3, followed by booster vaccinations with 10^8 pfu rF-CEA/TRICOM + 10^7 pfu rF-GMCSF at 2-wk intervals for 15 wks. At day 41 post tumor implantation, the mean tumor volumes in the HBSS, V, EX and V+EX groups were significantly different, 655 ± 138, 381 ± 105, 156 ± 61, 100 ± 46, respectively (P
Use of VEGF expression to predict for first-line treatment chemotherapy regimen in metastatic colorectal cancer.
Authors: Metin Ozkan, Veli Berk, Kemal Deniz, Halit Karaca, Mevlude Inanc, Oktay Bozkurt, Ayse Ocak Duran
Journal: Journal of Clinical Oncology (2013)

e14695 Background: In metastatic colorectal cancer treatment more successful results are achieved by adding anti-angiogenic therapy to the chemotherapy. Over expression of VEGF in colorectal cancer is known to be a poor prognosis factor but its effects on designating the therapy is not clear. In this study, results of the patients receiving FOLFIRI + Bevacizumab or XELOX + Bevacizumab were compared for VEGF expression. Methods: VEGF was assessed immunohistochemically in primary tumors of the 53 metastatic colorectal cancers. Severity and conformity of VEGF expression was evaluated. Results were used to assess the association with the therapy response, progression free survival (PFS) and overall survival (OS). Results: The median age of the patients was 55 (range, 32-79). In combination with bevacizumab 38 patients received FOLFIRI and 15 patients received XELOX. In 30 patients (57%) there was a strong expression of VEGF and in 23 patients (23%) the expression was weak. In the high VEGF expression group, PFS was 11 months in FOLFIRI receiving patients and 8 months in XELOX receiving ones but in low expression group PFS was 8 months in patients receiving either one of the two treatment protocols. In high expression group, PFS in FOLFIRI-bevacizumab combination receiving patients was different and this difference was statistically significant (p=0.009). Overall survival in FOLFIRI receiving patients with high VEGF expression was 26 months and with low VEGF expression it was 16 months (p=0.04). Median OS was not reached in the XELOX receiving patient group. FOLFIRI regime clinical benefit was 58% in high VEGF expression group whilst it was 34% in low expression group. This difference was not statistically significant but it was close to the significance threshold (p=0.06). There was no association between the therapy responses and VEGF expression of the 15 patients who received XELOX. Conclusions: There is no difference in efficacy between the first line chemotherapy regimens of the metastatic colorectal cancer. In this study, in metastatic colorectal patients with over expressed VEGF first line FOLFIRI-bevacizumab combination led to better response and survival rates.
Organophosphate Pesticide Exposure in Pregnancy in Association with Ultrasound and Delivery Measures of Fetal Growth
Authors: Kelly K. Ferguson, Michiel A. van den Dries, Romy Gaillard, Anjoeka Pronk, Suzanne Spaan, Henning Tiemeier, Vincent W. V. Jaddoe
Journal: Environmental Health Perspectives (2019)

BACKGROUND: Perturbations in fetal growth may have adverse consequences for childhood and later life health.Organophosphate pesticide (OP) exposure has been associated with reduced birth weight at delivery but results are not consistent.We investigated this question by utilizing ultrasound measures of size in utero in combination with measures from delivery.METHODS: Within Generation R, a population-based prospective cohort conducted between 2002 and 2006 in Rotterdam, Netherlands, we measured dialkyl phosphates (DAPs), OP metabolites, in urine samples from early, middle, and late pregnancy and created a subject-specific average to estimate OP exposure (n = 784).Ultrasound measures of head circumference, femur length, and estimated fetal weight from middle and late pregnancy and delivery measures were converted to standard deviation scores (SDS).Associations with DAP average were examined in linear mixed effects models that included an interaction term between gestational age at measurement and DAP average to investigate whether the relationship differed over time.Windows of vulnerability to exposure were assessed by modeling urinary DAPs from each visit in relation to growth measurements.RESULTS: A 10-fold increase in average DAPs was associated with a -0:53 SDS decrease in fetal length (95% CI = -0:83, -0:23) and a -0:32 SDS decrease in estimated fetal weight (95% CI = -0:59, -0:04) at 20 weeks of gestation.These differences corresponded to 5% and 6% decreases relative to the mean.Effect estimates were greatest in magnitude for DAP concentrations measured early in pregnancy.Associations between average DAPs and growth measures at delivery were positive but not significant for head circumference and length and were null for weight.
Pulmonary Aptamer Signatures in Children’s Interstitial and Diffuse Lung Disease
Authors: Robin R. Deterding, Brandie D. Wagner, J. Kirk Harris, Emily M. DeBoer
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Biomarker signatures are needed in children with children's interstitial and diffuse lung disease (chILD) to improve diagnostic approaches, increase our understanding of disease pathogenesis, monitor disease progression, and develop new treatment strategies. Proteomic technology using SOMAmer (Slow Off-rate Modified Aptamer) nucleic acid-based protein-binding reagents allows for biomarker discovery.
Quantification of K-RAS codon 12 GAT and GTT mutation in colon tumor and non-tumor tissue by allele-specific competitive blocker PCR
Authors: Barbara Parsons, Kathyrn Marchant-Miros, Tracie Verkler, Page McKinzie, Robert Delongchamp, Patterson Tucker, Ralph Broadwater, Lamps Laura, Lawrence Kim
Journal: Cancer Research (2007)

5245  Because K-RAS mutation has been implicated in the etiology of many human cancers, including colon cancer, it is important to understand how accumulation of K-RAS mutation relates to carcinogenic progression. The purpose of this study was to quantify K-RAS mutation in tissues that correspond to the various stages of sporadic colon cancer development. Levels of K-RAS mutation were measured in human colonic mucosa, tumor adjacent mucosa, adenomas, and adenocarcinomas. A novel technique, allele-specific competitive blocker-PCR (ACB-PCR), was employed to determine the K-RAS mutant fraction (MF, ratio of mutant to wild-type sequence) in DNA isolated from the colon tissues of men between the ages of 50 and 79. The ACB-PCR assay is sensitive enough to quantify K-RAS codon 12 GAT (aspartate) and GTT (valine) MFs down to a frequency of 10-5, i.e. in up to a 100,000-fold excess of wild-type DNA. Study results are summarized below.  Based upon the ACB-PCR measurements and anatomical information collected from the literature, it is estimated that the colonic mucosa contains ~60,000 K-RAS mutations, with codon 12 GAT mutation present at higher frequency in the colonic mucosa than the GTT mutation. Additionally, the K-RAS codon 12 GTT mutation was found to decrease significantly during adenoma to adenocarcinoma progression (chi square, P
Using political sanctions to discourage intergroup attacks: Social identity and authority legitimacy
Authors: Karolina Urbanska, Sam Pehrson
Journal: Behavioral and Brain Sciences (2019)

De Dreu and Gross offer novel solutions to discouraging attackers via political sanctions. We offer insights from social psychological and criminological research on when such sanctions would work and when they could backfire. We argue that the influence of such sanctioning ultimately rests upon the extent to which such authorities can claim to represent the society that they serve.
Nuclear Sensor Interferon‐Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression
Authors: Yuanyuan Yang, Xinzhuan Zhao, Ziyu Wang, Wangqin Shu, Lijie Li, Yuqi Li, Zhiwei Guo, Bo Gao, Sidong Xiong
Journal: Hepatology (2019)

Nuclear-located covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a determining factor for HBV persistence and the key obstacle for a cure of chronic hepatitis B. However, it remains unclear whether and how the host immune system senses HBV cccDNA and its biological consequences.Here, we demonstrated that interferon-inducible protein 16 (IFI16) could serve as a unique innate sensor to recognize and bind to HBV cccDNA in hepatic nuclei, leading to the inhibition of cccDNA transcription and HBV replication. Mechanistically, our data showed that IFI16 promoted the epigenetic suppression of HBV cccDNA by targeting an interferon-stimulated response element (ISRE) present in cccDNA. It is of interest that this ISRE was also revealed to play an important role in IFI16-activated type I interferon responses. Furthermore, our data revealed that HBV could down-regulate the expression level of IFI16 in hepatocytes, and there was a negative correlation between IFI16 and HBV transcripts in liver biopsies, suggesting the possible role of IFI16 in suppressing cccDNA function under physiological conditions.The nuclear sensor IFI16 suppresses cccDNA function by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA, and IFI16 may present as a therapeutic target against HBV infection.
Association of Genetic and Environmental Risks for Attention-Deficit/Hyperactivity Disorder With Hypomanic Symptoms in Youths
Authors: Georgina M. Hosang, Paul Lichtenstein, Angelica Ronald, Sebastian Lundström, Mark J. Taylor
Journal: JAMA Psychiatry (2019)

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder are highly comorbid, with significantly associated symptoms. The mechanisms that account for their co-occurrence are not known.To examine the degree to which genetic and environmental risk factors for ADHD traits, across childhood and adolescence, are associated with adolescent hypomanic symptoms.This study used data on 13 532 twin pairs from the Child and Adolescent Twin Study in Sweden, a prospective, longitudinal twin study. Their parents provided ADHD data when children were 9 or 12 years of age. Of those who reached 15 years of age, 3784 participated. Of those who reached 18 years of age, 3013 participated. The study was performed from December 20, 2017, to December 5, 2018. Data analysis was performed at the Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden, from March 1, 2018, to October 31, 2018.Attention-deficit/hyperactivity disorder traits and hypomanic symptoms were assessed using parent-rated instruments. Associations between ADHD and adolescent hypomanic symptoms across childhood and adolescence were investigated using generalized estimating equations. Multivariate twin models were used to examine the extent to which genetic and environmental risk factors for ADHD were associated with hypomania.Among 3784 15-year-old twin pairs and 3013 18-year-old twin pairs, ADHD and hypomanic symptoms were significantly associated (age 15 years: β = 0.30; 95% CI, 0.24-0.34; P < .001; age 18 years: β = 0.19; 95% CI, 0.16-0.22; P < .001), especially for the hyperactivity-impulsivity ADHD symptom domain (age 15 years: β = 0.53; 95% CI, 0.46-0.60; P < .001; age 18 years: β = 0.36; 95% CI, 0.30-0.42; P < .001) compared with the inattention domain (age 15 years: β = 0.40; 95% CI, 0.34-0.47; P < .001; age 18 years: β = 0.24; 95% CI, 0.19-0.29; P < .001). Between 13% and 29% of the genetic risk factors for hypomania were also associated with ADHD, with higher estimates detected for symptoms of hyperactivity-impulsivity (10%-25%) compared with inattention (6%-16%). Environmental factors played a negligible role in the associations. Genetic factors unique to adolescent hypomania were associated with 25% to 42% of its variance, suggesting some etiologic distinction between these forms of psychopathology.More than a quarter of the genetic risk factors for adolescent hypomanic traits were also associated with ADHD symptoms in childhood and adolescence, with hypomania-specific genetic risk factors detected. These findings suggest that ADHD and hypomanic symptoms are associated with shared genetic factors, which should be the focus of further research.
Abstract #4808: Met activation sustains a metastatic phenotype in non-small cell lung cancer patients and is associated with KRAS mutation
Authors: Elisa Benedettini, Natalie Vena, Dyane Bailey, Michelangelo Fiorentino, Alessandro Fornari, Silvano Bosari, Lucian Chirieac, Bart Lutterbach, Massimo Loda
Journal: Cancer Research (2009)

Background> The Met (Hepatocyte Growth Factor Receptor, HGFR) tyrosine kinase can stimulate cancer cell migration and invasion as well as proliferation and survival: these biological functions are consistent with a role for Met in the metastatic process. Methods> We investigated the role of Met in a lymph node-derived lung cancer cell line (H1993) and a line derived from the primary lung tumor of the same patient (H2073), as well as in tissue samples from 18 primary NSCLCs and their paired brain metastases and from primary 22 NSCLCs without metastases. The two groups of patients had matched clinical-pathological features, were never treated with epidermal growth factor receptor (EGFR) inhibitors and were followed-up for an average of 35 months. Met was investigated by immunohistochemistry (IHC) and FISH. IHC for EGFR and Erbb2 and wide screen mutation analysis by Oncomap were also performed in all the cases. Results> While Met was found to be active and amplified in the metastatic line H1993, the H2073 line did not harbor Met activation or amplification. The inhibition of Met by shRNA as well as by specific small molecule inhibitors resulted in the arrest of both migration and growth of H1993 but had not effect on H2073. In contrast, EGFR was activated in primary tumor-derived H2073 cells and not in H1993 cells, and EGFR inhibition severely limited the proliferation only of H2073 cells. The analysis of the metastatic NSCLCs and their paired brain metastases showed that both phosphorylation and expression of Met were heterogeneous and focal in primary tumors but were markedly enriched in the brain metastases (p=0.031, p=0.002 respectively). In contrast, neither EGFR not Erbb2 expression were up-regulated in the metastases. Met activation and expression were significantly associated with shorter metastasis-free survival (p=0.041 and p=0.011 respectively). High Met copy number gain was detected in a subset of brain metastases (27%) and paired primary lung tumors (13%), but bona fide Met amplification as well as Met mutations were never observed. Finally we observed that 70% of the samples with activated Met also carried KRAS mutations. Conclusions>(1) Met activation in metastatic NSCLC never treated with EGFR inhibitors is not driven by genetic mutations and/or amplification of Met; (2) treatment with Met inhibitors of NSCLC patients harboring activated Met may prevent metastatic spread; (3) the presence of RAS mutations in a significant number of Met-activated cases may affect the strategy of pathway inhibition.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4808.
The political complexity of attack and defense
Authors: Talbot M Andrews, Leonie Huddy, Reuben Kline, H Hannah Nam, Katherine Sawyer
Journal: Behavioral and Brain Sciences (2019)

Abstract De Dreu and Gross's distinction between attack and defense is complicated in real-world conflicts because competing leaders construe their position as one of defense, and power imbalances place status quo challengers in a defensive position. Their account of defense as vigilant avoidance is incomplete because it avoids a reference to anger which transforms anxious avoidance into collective and unified action.
Abstract 15458: Isoproterenol Fails to Activate Cardiac SK Currents in Mice Heterozygous for the N98S Calmodulin Mutation
Authors: Adonis Z Wu, Wen-Chin Tsai, Dechun Yin, Thomas H Everett, Zhenhui Chen, Shien-Fong Lin, Peng-Sheng Chen, Michael Rubart-von der Lohe
Journal: Circulation (2017)

Introduction: The human N98S calmodulin (CaM) mutation is associated with catecholaminergic ventricular tachycardia (CPVT). We generated knock-in mice heterozygous for the N98S-CaM mutation in the ...
Omega-3 polyunsaturated fatty acids impinge on CD4+ T cell motility and adipose tissue distribution via direct and lipid mediator-dependent effects
Authors: Danilo Cucchi, Dolores Camacho-Muñoz, Michelangelo Certo, Jennifer Niven, Joanne Smith, Anna Nicolaou, Claudio Mauro
Journal: Cardiovascular Research (2019)

Adaptive immunity contributes to the pathogenesis of cardiovascular metabolic disorders (CVMD). The omega-3 polyunsaturated fatty acids (n-3PUFA) are beneficial for cardiovascular health, with potential to improve the dysregulated adaptive immune responses associated with metabolic imbalance. We aimed to explore the mechanisms through which n-3PUFA may alter T cell motility and tissue distribution to promote a less inflammatory environment and improve lymphocyte function in CVMD.
Clinical Response and Tolerability of Selinexor in Acute Myeloid Leukemia and Other Hematologic Malignancies - a Systematic Review
Authors: Muhammad Junaid Tariq, Muhammad Yasir, Amna Khalid, Saher Nasir Amin, Sharoon Samuel, Muhammad Jahanzeb Khalil, Shehroz Aslam, Malik Qistas Ahmad, Muhammad Asad Fraz, Muhammad Usman, Awais Ijaz, Arafat Ali Farooqui, Seren Durer, Ceren Durer, Faiz Anwer
Journal: Blood (2018)
Single nucleotide polymorphisms to predict for neoadjuvant chemotherapy in breast cancer according to estrogen receptor (ER) status.
Authors: Diane Pannier, Aurelie Dumont, Emmanuelle Tresch, Jinying Chen, Agnes Ducoulombier, Francoise Revillion, Jacques Bonneterre, Jean-Philippe Peyrat
Journal: Journal of Clinical Oncology (2013)

544 Background: Neoadjuvant chemotherapy (NCT) using anthracyclines and taxanes is a standard treatment for locally advanced breast cancer and pathologic complete response (pCR) is a major prognostic factor for survival. Gene polymorphisms have been identified as modulators of chemotherapy response. Our study investigated constitutional variants of genes associated with a change in the response to neoadjuvant chemotherapy using taxanes and/or anthracyclines in patients with breast adenocarcinoma. Methods: From November 2007 to January 2012, 118 women with breast adenocarcinoma histologically proven, with no Her2 surexpression, receiving or having received a neoadjuvant chemotherapy with taxanes and/or anthracyclines were included in the study. NCT associated 3 FEC100 then 3 Docetaxel every 21 days. Genotyping of 46 SNPs was performed on germline DNA using real time PCR. pCR was correlated to clinical characteristics and genotypes using univariate logistic regression. Results: 21.2% had a pCR according to Sataloff classification. pCR is increased in SBRIII (p=0.009), estrogen receptor negative (p=0.005) and triple negative (p=0.006) tumors. 7 SNP are significantly associated with pCR in ER+ breast tumors (pCR=13.5%). Among these SNP, pCR is increased for patients carrying almost one G allele for SLCO1B3-rs11045585 (pCR=28.6%; p=0.032), for homozygotes GG for SHTM1-rs1979277 (pCR=24.3%, p=0.006) and for homozygotes CC for CYP1B1-rs1056836 (pCR=25.7%; p=0.003). Moreover, 4 SNPs are significantly associated with pCR in ER- breast tumors: ERCC1-rs11615 (carriers of almost one C allele: pCR=50%; p=0.030), CD24-rs52812045 (Homozygotes CC pCR=56.3%, p=0.033), CYP2B6-rs2279343(carriers of one or two G allele: pCR=52.6%; p=0.046) and GSTP1-rs1695 (carriers of one or two G allele: pCR=48%; p=0.050). Conclusions: Besides ER status, polymorphisms could be useful markers to predict response to anthracyclines/taxanes NCT in breast cancer. Furthermore, this work is the first describing ERCC1-rs11615, SLCO1B3-rs11045585 and SHTM1-rs1979277 as new potential genetic markers for NCT in breast cancer. (The first 3 authors contributed equally to this work.)
Dengue: Philippines declares national epidemic as cases surge across South East Asia
Authors: Owen Dyer
Journal: BMJ (2019)

The government of the Philippines has declared a national epidemic of dengue fever for the first time this century, as the number of infections surged to twice last year’s toll, killing 622 people, many of them young children.

The country recorded 146 062 dengue cases from January to 20 July this year, 98% more than in the same period in 2018.

The health secretary, Francisco Duque, told a press conference on 7 August that his ministry was now recording more than 5000 new cases a week. “This is really staggering,” he said. “This is going to be a record number.”

Two years ago the Philippines banned Sanofi Pasteur’s Dengvaxia,1 the …
Leadership: clinical directors need more support, says GMC report
Authors: Abi Rimmer
Journal: BMJ (2019)

Consultants taking their first steps into leadership as clinical directors are often left to “sink or swim” and need more support, research commissioned by the General Medical Council (GMC) has found.

Suzanne Shale, a medical ethics consultant, was commissioned by the GMC to study how doctors in senior leadership roles created positive workplace cultures.1 The research was informed by 27 in-depth interviews with participants in senior leadership positions throughout the NHS.

It found that the job of clinical director was one of the most demanding …