tbuckley/cabot-search huggingface dataset:
Early infancy microbial and metabolic alterations affect risk of childhood asthma
Authors: Marie-Claire Arrieta, Leah T. Stiemsma, Pedro A. Dimitriu, Lisa Thorson, Shannon Russell, Sophie Yurist-Doutsch, Boris Kuzeljevic, Matthew J. Gold, Heidi M. Britton, Diana L. Lefebvre, Padmaja Subbarao, Piush Mandhane, Allan Becker, Kelly M. McNagny, Malcolm R. Sears, Tobias Kollmann, William W. Mohn, Stuart E. Turvey, B. Brett Finlay
Journal: Science Translational Medicine (2015)

Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.
Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study
Authors: Rochelle Bagatell, Kieran McHugh, Arlene Naranjo, Collin Van Ryn, Chaim Kirby, Penelope Brock, Karen A. Lyons, Lisa J. States, Yesenia Rojas, Alexandra Miller, Sam L. Volchenboum, Thorsten Simon, Barbara Krug, Sabine Sarnacki, Dominique Valteau-Couanet, Dietrich von Schweinitz, Birgit Kammer, Claudio Granata, Luca Pio, Julie R. Park, Jed Nuchtern
Journal: Journal of Clinical Oncology (2016)

The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC.Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as ≥ 30% reduction in longest dimension as per RECIST, ≥ 50% reduction in volume as per INRC, or ≥ 65% reduction in volume.Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection.None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension.
Spectrum of <i>KIT</i> and <i>PDGFRA</i> mutations in primary gastrointestinal stromal tumors: Polish Clinical GIST Registry experience
Authors: A. Wozniak, P. Rutkowski, M. Debiec-Rychter, J. Siedlecki, W. Michej, C. Osuch, M. Matlok, W. Ruka, J. Limon
Journal: Journal of Clinical Oncology (2009)

e21504 Background: KIT or PDGFRA gene mutations are found in 80–90% of gastrointestinal stromal tumors (GIST). The prognostic value of those mutations for the outcome in primary tumors is controversial. Objective: To assess the spectrum, frequency and prognostic significance of the KIT and PDGFRA gene mutations in Polish group of surgically treated primary GISTs. Methods: DNA isolated from paraffin blocks from 300 patients (pts) with histologically diagnosed primary GISTs included in clinical registry database, were analyzed using denaturing high performance liquid chromatography (DHPLC) and direct sequencing for KIT (exons 9, 11, 13, 17) and PDGFRA (exons 12, 14, 18) mutations. For primary GIST risk assessment the Miettinen stratification was used. Results: KIT/PDGFRA genes mutations were found in 82% tumors: KIT was mutated in 69% and PDGFRA in 13% of tumors. KIT exon 11 and 9 mutations were found in 61.5% and 7.5% respectively. Among KIT exon 11 mutants the most frequent were deletions (32.7%) followed by point mutations (15.3%), duplications (8.4%) and complex rearrangements (5.1%). KIT exon 11 mutations were found at the similar rates in tumors with gastric and non-gastric localization (53.9% vs. 46.1% respectively) while KIT exon 9 duplications were more often observed in non-gastric GISTs (86.4%, p=0.00036) and PDGFRA mutations were more frequently found in tumors originated from the stomach (86.8%; p=0.00017). In high risk tumors KIT exon 11 deletions were more frequently found than point mutations (p=0.017). On the other hand mutations in PDGFRA were more often observed in very low-/low- than high risk GISTs as compared to KIT exon 11 (p=0.0026). There was no statistically significant correlation between disease-free survival and the spectrum or frequency of mutations. Conclusions: Spectrum and frequency of KIT and PDGFRA mutations in Polish GIST population are similar to the previously described groups. No significance of mutations for disease outcome after surgery of primary tumors was found. [Table: see text]
AB0437 Does Body Mass Index Influence the Response to Abatacept in Rheumatoid Arthritis?
Authors: A. Gardette, S. Ottaviani, J. Sellam, F. Berenbaum, F. Lioté, B. Fautrel, E. Palazzo, A. Meyer, P. Dieudé
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Previous studies suggested that obesity could play a role in the outcome of rheumatoid arthritis (RA) and negatively affect the response to anti-TNFα agents. However, data are lacking on how it affects the response to abatacept (ABA). <h3>Objectives</h3> We aimed to determine whether body mass index (BMI) is involved in the response to ABA in RA. <h3>Methods</h3> In this multicenter retrospective study, we included 141 RA patients treated with ABA. BMI was calculated at the initiation of treatment. After six months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, tender and swollen joints, and consumption of corticosteroids were analyzed. The primary endpoint was decrease in DAS28 ≥1.2. Secondary outcomes were good EULAR response and EULAR remission. <h3>Results</h3> At baseline, the median [interquartile range] BMI was 26.0 [22.9-30.8] kg/m<sup>2</sup>. The number of patients with normal weight, overweight and obesity was 64, 38 and 39, respectively. Baseline characteristics (erosive status, sex, age, disease duration, and status FR anti-CCP) did not differ between the three subgroups of BMI. After six months, the number of RA patients with DAS28 decrease ≥1.2 and EULAR good response and remission was 57 (40.4%), 26 (18.4%) and 19 (13.5%), respectively. In univariate analysis, there was no difference in BMI between responders and non-responders for DAS28 decrease ≥1.2 (25.0 [23.4-31.3] <i>vs.</i> 26.3 [22.9-30.2], P=0.95), EULAR good response (26.4 [23.5-30.9] <i>vs.</i> 26.0 [22.9-30.6], P=0.96) and remission (26.7 [21.7-30.3] <i>vs.</i> 26.0 [23.0-30.1], P=0.83). <h3>Conclusions</h3> Contrary to anti-TNFα, BMI did not influence the response to ABA in RA. Prospective studies are needed to confirm these data. If confirmed, these results could be useful for the selection of biologic agent in obese RA patients. <h3>Disclosure of Interest</h3> None declared
Gene polimorphisms and biological factors as possible predictors for patients with pleural metastatic breast cancer
Authors: A. Montes-Worboys, A. Romero, A. M. Casas, E. Arellano, J. M. Juan, J. A. Moreno, F. Rodriguez Panadero
Journal: Journal of Clinical Oncology (2006)

10671 Background: Pronosis of breast cancer varies widely in patients with similar clinical features. Therefore, we investigated other factors with possible prognostic value. The CYP17 gene has a polimorphism related to a increased susceptibility to breast cancer (single T; A1 allele to C; A2 allele). ( Mitrunen et al. Cancer Epidemiol Biomarkers Prev 2000,9;12;1343–8). On the other hand, it has been found in the MTHFR gene a common C-T substitution at nucleotide 677 that is associated with reduced enzyme activity and increased risk of breast cancer (Capmbell et al., Breast Cancer Research 2002;4,6:R14). Other genes such as GSTT1 and GSTM1 variant genotypes have a controversial association to breast cancer. We have analyzed the genotype and biological factors in a group of patients with pleural metastatic cancer of the breast and compared it to a control group of women with no cancer. Methods: Forty-six patients with breast cancer and forty women as controls were includes in the study. Age at diagnosis of the primary tumor, TNM staging, interval free of disease, estrogen and progesteron receptors, Ki67, p53 and Her-2neu expression were recorded, as well as survival from the time of diagnosis and polimorphism of CYP17, MTHFR, GSTT1 and GSTM1 genes. Results: Mean survival differed significantly between patients having pleural effusion as the first site of relapse as compared to those with other sites of relapse (28’9 vs 11’9 months, p = 0’004). A high Ki67 expression correlated best with longer survival after talc pleurodesis. We detected a high frequency in the CYP17 A2 variant genotype in patients with metastatic breast cancer compared to the control group. As for MTFHR gene, we found a high frequency for the T/T genotypes variant in breast cancer group. No significant differences between control and cancer group were found in either GSTT1 and GSTM1 gene variations. Conclusions: Genotype and biological factors, such as factors investigated in this study, play an important role as predictors for patients with pleural metastatic breast cancer. No significant financial relationships to disclose.
PACIFICレジストリ(虚血性冠動脈疾患後のアテローム血栓疾患予防):日本の冠不全症候群の初期入院患者2年間試験の基本データ
Authors: Kimura Kazuo, Daida Hiroyuki, Tsutsui Hiroyuki, Isshiki Takaaki, Ikari Yuji, Matsubara Tetsuo, Kimura Takeshi, Kitakaze Masafumi, Matsumoto Masayasu, Ogawa Hisao, Yokoi Hiroyoshi
Journal: Circulation (2010)
The New CD95 Ligand Inhibitor APG101 Leads To Decreased Apoptosis and Improved Erythroid Differentiation In Primary CD34+ Cells From Patients With Low Risk Myelodysplastic Syndrome (MDS)
Authors: Florian Nolte, Claudia Kunz, Stephanie Fey, Julia Obländer, Susanne Brendel, Marion Klaumünzer, Maximilian Mossner, Johann-Christoph Jann, Stefanie Uhlig, Daniel Nowak, Harald Fricke, Wolf-Karsten Hofmann
Journal: Blood (2013)
RB200, a pan-HER ligand trap, is a novel inhibitor of tumor growth and metastasis
Authors: Pei Jin, H. Michael Shepard
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

B17 

RB200 is an Fc-mediated heterodimer of native HER1 and HER3 ligand binding domains. RB200 can sequester most growth factors that activate the human EGF receptor family members. It inhibits cancer cell proliferation in vitro, and suppresses tumor growth and metastases in mouse xenograft models. Thus, RB200 becomes the first pan-specific therapeutic protein that downregulates EGF receptor family.
Whole brain radiotherapy for brain metastases from non-small lung cancer: Quality of life (QoL) and overall survival (OS) results from the UK Medical Research Council QUARTZ randomised clinical trial (ISRCTN 3826061).
Authors: Paula Mary Mulvenna, Matthew Guy Nankivell, Rachael Barton, Corinne Faivre-Finn, Paula Wilson, Barbara Moore, Elaine McColl, Iona Brisbane, David Ardron, Benjamin Sydes, Cheryl Pugh, Tanya Holt, Neil Bayman, Sally Morgan, Caroline Lee, Kathryn Waite, Richard Stephens, Mahesh M K Parmar, Ruth E Langley
Journal: Journal of Clinical Oncology (2015)

8005 Background: Brain metastases affect up to 40% of patients with non-small cell lung cancer (NSCLC), and for inoperable cases whole brain radiotherapy (WBRT) and dexamethasone is standard treatment. However there are no randomised clinical trials to show whether WBRT improves either QoL or survival. Methods: A phase III randomised non-inferiority trial with a primary outcome measure of quality adjusted life years (QALYs). Patients with brain metastases from NSCLC (not suitable for resection or stereotactic radiotherapy) were randomly allocated to either optimal supportive care, including dexamethasone, plus WBRT 20 Gy/5f (OSC+WBRT) or OSC alone. QALYs were generated from OS and patients' weekly completion of the EQ-5D questionnaire. OSC alone was considered non-inferior to OSC+WBRT if not greater than 7 QALY days worse (80% power and a 1-sided 5% significance level required 534 patients.) Secondary outcome measures include sub-group analyses to identify/validate predictive classifications. Results: From 2007-2014 538 patients were recruited from 69 UK and 3 Australian centres. Baseline characteristics were balanced between arms and reflect everyday clinical practice: male 58%, median age 66 years (range 38 – 85), Karnofsky performance status < 70 38%, 54% had extracranial metastases, 30% had a solitary brain metastasis and 59% diagnosed with brain metastases within 28 days of randomisation. By January 2015 522/538 patients had died. There was no significant difference in OS from randomisation (hazard ratio 1.05 (95% CI 0.89 – 1.26) median survival OSC+WBRT v OSC (65 v 57 days)), overall QoL or steroid use between the 2 groups. The difference between the mean QALYs was -1.9 days (OSC+WBRT 43.3 v OSC 41.4 QALY days), two-sided 90% confidence interval for difference -9.1 to +6.6 QALY days. Conclusions: This is the only large randomised trial evaluating the utility of WBRT in this disease. Although the results include the pre-specified non-inferiority margin, the estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients. Clinical trial information: 3826061.
Abstract 29: Virtual Small Groups for Weight Management: An innovative delivery mechanism for evidence-based lifestyle interventions
Authors: Kristen M Azar, Magi Aurora, Elsie J Wang, Amy Muzaffar, Alice Pressman, Latha P Palaniappan
Journal: Circulation (2014)

Background: Innovative, feasible and effective treatment strategies are urgently needed to address the obesity epidemic. While group interventions for weight loss have been shown to be efficacious, adherence is often low due to participant burden in attending in-person weekly meetings. Technology offers the potential for highly scalable intervention strategies that can be disseminated in diverse settings, and may improve access and adherence. This study assessed the feasibility and effectiveness of using virtual small groups for weight loss treatment. Methods: Obese men (BMI ≥30kg/m 2 ) age 21-60 years, were recruited within a primary care clinic. We delivered an adapted Group Lifestyle Balance curriculum , based on the Diabetes Prevention Program lifestyle intervention, for 3-months using synchronous, encrypted, web-based video conferencing. Each session allowed for 8 participants and 1 facilitator, all attending from their own personal computer. Body weight was remotely monitored weekly using wireless scales. Participants (n= 48) were randomized to receive the intervention immediately following the baseline assessment, or 3-months later, as a delayed intervention control group. The main outcome of mean change in body weight was compared between intervention and control groups using student’s t-test. Results: Baseline characteristics did not differ between the intervention (n = 25) and delayed intervention control groups (n = 23). Intervention participants lost more weight than those in the delayed intervention control group, losing on average 4.3% (95% CI: -5.9%, -2.6%, P = 0.0004) of their initial body weight. The decrease in body weight was greater among men in the intervention group than in the delayed control group, with a mean difference of -3.9 kg (-5.9kg, -1.9kg, P = 0.0003) and mean difference for BMI of-1.2 kg/m 2 (-1.9 kg/m 2 ,-0.4 kg/m 2 , P = 0.0021). On average, of the 12 weeks of the intervention, participants transmitted weekly weights 10.2 times (9.1,11.3) and attended 9.0 sessions (7.9, 10.0), or 74.7% (9 of 12) of total sessions offered. Conclusion: This pilot study is the first attempt to our knowledge to evaluate the delivery of a group behavior weight loss intervention via video conferencing in a primary care setting. Virtual small groups may be an effective means of healthcare service delivery and allow for face-to-face group interaction, while overcoming some barriers to access that a participant of an in-person program may face.
Quantitative and Qualtitative Evaluation Of Circulating Cell-Free DNA As a Prognostic Biomarker In Hodgkin Lymphoma
Authors: Stefan Hohaus, Manuela Giachelia, Elisa Cupelli, Annarosa Cuccaro, Giuseppina Massini, Francesca Bartolomei, Francesco D'Alò, Maria Teresa Voso, Giuseppe Leone
Journal: Blood (2013)
Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis
Authors: Jieru E. Lin, Francheska Colon-Gonzalez, Erik Blomain, Gilbert W. Kim, Amanda Aing, Brian Stoecker, Justin Rock, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Michal Tomczak, Richard S. Blumberg, Scott A. Waldman
Journal: Cancer Research (2016)

Abstract Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin–GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. Cancer Res; 76(2); 339–46. ©2016 AACR.
Abstract 16198: Inhibition of PCSK9 Transcription by Berberine Involves Down-regulation of HNF1 Protein Cellular Levels Through Ubiquitin-proteasome Pathway
Authors: Bin Dong, Hai Li, Jingwen Liu
Journal: Circulation (2012)

PCSK9 plays an important role in control of plasma LDL cholesterol metabolism by modulating the degradation of hepatic LDL receptor (LDLR). Our previously studies have demonstrated that PCSK9 gene transcription in liver cells is regulated by the hepatocyte nuclear factor 1α (HNF1α) through a highly conserved HNF1 binding site located 28 bp upstream of the SRE-1 site of the PCSK9 gene promoter. Importantly, we have shown that the natural cholesterol lowering compound berberine (BBR) inhibits PCSK9 transcription via this regulatory element. The aim of this current study was to further investigate the inhibitory mechanisms of BBR on PCSK9 transcription involving HNF1α. Here we report that BBR had no effects on HNF1α mRNA expressions but it greatly reduced HNF1α protein levels in HepG2 cells and in liver of hamsters in vivo, suggesting that BBR might affect HNF1α protein stability. Since the ubiquitin-proteasome pathway (UPP) and the autophagy-lysosomal pathway are two major cellular proteolytic systems for intracellular protein degradation in eukaryotic cells, we used specific inhibitors to block individual pathways to examine their possible roles in regulation of HNF1α protein degradation. Treating HepG2 cells with autophagy/lysosomes inhibitor bafilomycin A1 markedly increased cellular levels of LDLR and PCSK9, which confirmed their known intracellular degradations by lysosomes. In contrast, HNF1α protein amount was not affected by bafilomycin A1 treatment but it was dose-dependently increased by UPP inhibitors bortezomib and MG132, thereby suggesting that HNF1α protein degradation is regulated by UPP. Through conducting immunoprecipitation and immunoblotting we further detected multi-ubiquitination ladder pattern of HNF1α in cells overexpressing ubiquitin. Finally, we show that the BBR reducing effect on HNF1α protein abundance can be blocked by concurrent treatment with proteasome inhibitors. Altogether, our studies suggest a functional role of the ubiquitin-proteasome pathway in the regulation of PCSK9 gene transcription through modifying the protein stability of HNF1α upon BBR treatment. This study shed new light on cellular mechanisms that control PCSK9 expression, thereby influencing blood LDL-cholesterol levels.
Abstract 13768: Pim-1 Preserves Mitochondrial Morphology by Inhibiting Drp1 Translocation
Authors: Shabana Din, Matt Mason, Mirko Volkers, Mathias Konstandin, Bevan Johnson, Jodi Nunnari, Mark A Sussman
Journal: Circulation (2012)

Rationale: Mitochondrial morphologic dynamics affect cardiac ischemic injury. Dynamin Related Protein 1 (Drp1) mediates mitochondrial fission with mitochondrial localization during pathological cha...