tbuckley/cabot-search huggingface dataset:
Weight Gain and Obesity in Infants and Young Children Exposed to Prolonged Antibiotic Prophylaxis
Authors: M. Bruce Edmonson, Jens C. Eickhoff
Journal: JAMA Pediatrics (2016)

An association between antibiotic use and excessive weight gain or obesity in healthy infants and young children has been reported, but evidence is inconsistent and based on observational studies of growth in relation to incidental antibiotic exposures.To evaluate whether prolonged antibiotic exposure is associated with weight gain in children participating in a clinical trial of antibiotic prophylaxis to prevent recurrent urinary tract infection.Secondary analysis of data from the Randomized Intervention for Children With Vesicoureteral Reflux Study, a 2-year randomized clinical trial that enrolled participants from 2007 to 2011. All 607 children who were randomized to receive antibiotic (n = 302) or placebo (n = 305) were included. Children with urinary tract anomalies, premature birth, or major comorbidities were excluded from participation.Trimethoprim-sulfamethoxazole or placebo taken orally, once daily, for 2 years.Weight gain as measured by change in weight-for-age z score from baseline to the end-of-study visit at 24 months. Secondary outcomes included weight gain at 6, 12, and 18 months and the prevalence of overweight or obesity at 24 months.Participants had a median age of 12 months (range, 2-71 months) and 558 of 607 (91.9%) were female. Anthropometric data were complete at the 24-month visit for 428 children (214 in the trimethoprim-sulfamethoxazole group and 214 in the placebo group). Weight gain in the trimethoprim-sulfamethoxazole group and the placebo group was similar (mean [SD] change in weight-for-age z score: +0.14 [0.83] and +0.18 [0.85], respectively; difference, -0.04 [95% CI, -0.19 to 0.12]; P = .65). There was no significant difference in weight gain at 6, 12, or 18 months or in the prevalence of overweight or obesity at 24 months (24.8% vs 25.7%; P = .82). Subgroup analyses showed no significant interaction between weight gain effect and age, sex, history of breastfeeding, prior antibiotic use, adherence to study medication, or development of urinary tract infection during the study.Based on a secondary analysis of data from a large clinical trial of trimethoprim-sulfamethoxazole prophylaxis, there was no evidence that prolonged exposure to this antibiotic has a concurrent effect on weight gain or the prevalence of overweight or obesity in healthy infants and young children.
Abstract 3287: Targeting GSK-3: a new approach for the treatment of neuroblastoma
Authors: Oleksii Dubrovskyi, Andrey Ugolkov, Irina Gaisina, Gennadiy Bondarenko, Luigi Strizzi, Naira Margaryan, Thomas O'Halloran, Alan Kozikowski, Mary Hendrix, Andrew Mazar
Journal: Cancer Research (2015)

Abstract Neuroblastoma is a devastating pediatric cancer and most patients older than 18 months present with multi-organ metastatic disease. High grade or recurrent disease is refractory to treatment with chemotherapy and almost uniformly fatal. Because GSK-3beta has been shown to be a positive regulator of NF-kappaB-mediated survival and chemoresistance in cancer cells, we hypothesize that the inhibition of GSK-3 may have potential therapeutic effects in neuroblastoma. To test this premise we used small molecule inhibitors, Western blotting, apoptotic and MTS assays to study the effect(s) of GSK-3 inactivation in neuroblastoma cell lines SK-N-DZ and SK-N-BE(2). Using chemically distinct GSK-3 inhibitors (AR-A014418, TDZD8 and 9-ING-41), we found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of neuroblastoma cells. We observed that inhibition of GSK-3 results in decreased expression of the anti-apoptotic molecules Bcl-XL and XIAP (NF-kappaB target genes) and a subsequent increase in neuroblastoma cell apoptosis. Moreover, we show that our novel GSK-3 inhibitor 9-ING-41 enhances the antitumor effects of irinotecan in neuroblastoma cells. Our results demonstrate that GSK-3 positively regulates neuroblastoma cell survival and proliferation and suggest that the inhibition of GSK-3 is a promising new approach for the treatment of neuroblastoma. Citation Format: Oleksii Dubrovskyi, Andrey Ugolkov, Irina Gaisina, Gennadiy Bondarenko, Luigi Strizzi, Naira Margaryan, Thomas O'Halloran, Alan Kozikowski, Mary Hendrix, Andrew Mazar. Targeting GSK-3: a new approach for the treatment of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3287. doi:10.1158/1538-7445.AM2015-3287
PTH-076 Establishing a<i>Clostridium difficile</i>management team: 1-year results post-implementation
Authors: S Gupta, S Mathew, M Twagira, S Vig, S Lim, S Watts, J Hawkes-reekes, D Nicholson, J Adisi, A Glasgow, J Graham, D Chaffer
Journal: Gut (2010)

<h3>Introduction</h3> A <i>Clostridium difficile</i> Management Team was created at Mayday University Hospital in October 2008 in accordance with HPA (Health Protection Agency) guidance.1 It consists of a Consultant Gastroenterologist, as well as three other Consultants (Elderly Care, Surgical and Microbiology), four Clinical Nurse Specialists, an Antibiotic Pharmacist and a Dietician, working across the directorates. The Team reviews all patients with C.difficile infection and also implements infection control measures. We report our progress at 1-year post initiation. <h3>Methods</h3> All patients diagnosed with <i>C difficile</i> infection from October 2007 to October 2009 were included. These were classified as either Hospital Acquired Infections (HAIs) or Community Acquired Infections (CAIs). Information on deaths due to <i>C difficile</i> (either directly linked, or as a contributory factor) were extracted from the infection control surveillance system over the same period. <h3>Results</h3> A total of 540 <i>C difficile</i> cases were identified from January 2007 to October 2009. 330 HAIs occurred in the 21 months before intervention, averaging 16 cases/month. This fell to 5 cases/month in the intervention year from October 2008 to Oct 909 (a 69% reduction). CAI rates averaged 6/month in 2007, and 3/month in 2008, and remained unchanged at 3/month in the intervention year. Mortality figures showed 24 deaths in the 21 months pre-introduction, and 6 deaths in the intervention year (a 57% reduction compared to the preceding October 2007 to Oct 908). <h3>Conclusion</h3> Utilising a multidisciplinary team in the management of <i>Clostridium difficile</i> infection is recommended by the HPA.1 Our dedicated team focuses on optimising care, as well as ensuring the isolation and prompt clinical and laboratory diagnosis of suspected cases. The team also provides education to hospital staff and General Practitioners. This, together with other existing measures1<sup>3</sup> such as restrictive antibiotic prescribing, chlorine-based environmental cleaning and effective hand hygiene promotion has had a significant effect in reducing the burden of <i>C difficile</i> in our Trust.
Abstract 2133: Investigating the molecular interaction between KRAS mRNA and RNA binding protein CRD-BP
Authors: Sebastian J. Mackedenski, Chow H. Lee
Journal: Cancer Research (2015)

Abstract The Coding Region Determinant-Binding Protein (CRD-BP) is an RNA-binding protein which, among other functions, provides a protective effect for select target mRNA transcripts against degradation, effectively increasing their half-life leading to elevated level of gene expression. CRD-BP was first identified due to its inherent ability to bind to a specific coding region of c-myc mRNA. It has further been demonstrated to convey a protective effect to target transcripts, including GLI1, MITF, CD44, and KRAS as well as a host of other mRNAs. CRD-BP is normally under strict spatiotemporal regulation; expressed only during early developmental stages where rapid growth is necessary. However, CRD-BP re-expression has been reported to occur in a number of human cancers, suggesting its roles as an onco-protein. Abnormal expression or function of KRAS, a CRD-BP target, is implicated in some cancers; roughly 90% of pancreatic cancers, 60% of colorectal, and 50% of lung cancers, making KRAS an attractive target for cancer therapies and highlighting the significance of understanding the CRD-BP-KRAS mRNA interaction. To help understand the CRD-BP-RNA interaction, we have previously mutated the first glycine of the G-X-X-G motif in the KH domains of CRD-BP to an aspartate. Using electrophoretic mobility shift assay, we showed that mutation at any two KH domains, except the KH3 and KH4 di-domains, completely abrogated CRD-BP-c-myc and CD44 RNAs interactions. To understand the CRD-BP-KRAS RNA interaction, we used the identical site-directed KH mutants of CRD-BP to assess their binding profiles to a 185-nt KRAS RNA corresponding to a specific coding region of KRAS mRNA. Using EMSA, additional binding assessments were carried out in a systematic fashion to determine the smallest region of KRAS mRNA bound by CRD-BP. In addition, plasmids carrying these variants of FLAG-CRD-BP were transfected into HeLa cells. Immuno-precipitation (IP) using anti-FLAG was performed, followed by RT-qPCR to measure the relative amounts of KRAS mRNA associated with each of the variants as compared to the controls. The in vitro EMSA and IP cell data were all consistent with the notion that all KH domain(s) are critical for CRD-BP-KRAS RNA interaction. These experiments and their results will be discussed in further detail upon presentation. Citation Format: Sebastian J. Mackedenski, Chow H. Lee. Investigating the molecular interaction between KRAS mRNA and RNA binding protein CRD-BP. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2015-2133
A Novel Evidence That PNH Affected Cells Residing in Bone Marrow (BM) Due to Impaired Incorporation of CXCR4 and VLA-4 Into Membrane Lipid Rafts Show Defective SDF-1- and VCAM-1-Mediated Retention in BM What Leads to Their Increased Motility and Impaired Interaction with the BM Stem Cell Niches
Authors: Kasia Mierzejewska, Cesar Rodriguez, Vivek R. Sharma, Magdalena Kucia, Jaroslaw P. Maciejewski, Janina Ratajczak, Mariusz Z Ratajczak
Journal: Blood (2012)
Tigecycline Was a Promising Candidate for Febrile Neutropenic and Carbapenem-Resistant Patients with Hematologic Malignancy
Authors: Bing Xu, Lingli He, Pengcheng Shi, Xutao Guo, Jie Li, Yan Wang, Manman Deng, Yong Zhou, Yin Li, Jiabao Liang
Journal: Blood (2015)
In vitro and in vivo antitumor efficacy of the sequentially combined vinorelbine and gefitinib in Non-Small Cell Lung Cancer cell lines
Authors: G. Barletta, C. Genova, E. Rijavec, F. Biello, C. Maggioni, M.G. Dal Bello, A. Alama, S. Coco, I. Vanni, A. Truini, G. Sambuceti, F. Grossi
Journal: Annals of Oncology (2015)
Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease
Authors: Daisy Bougard, Jean-Philippe Brandel, Maxime Bélondrade, Vincent Béringue, Christiane Segarra, Hervé Fleury, Jean-Louis Laplanche, Charly Mayran, Simon Nicot, Alison Green, Arlette Welaratne, David Narbey, Chantal Fournier-Wirth, Richard Knight, Robert Will, Pierre Tiberghien, Stéphane Haïk, Joliette Coste
Journal: Science Translational Medicine (2016)

A sensitive blood diagnostic assay can identify patients with variant Creutzfeldt-Jakob disease before symptoms appear and during the clinical phase.
Incidence and Prognostic Relevance of ASXL2 Mutations in Adult CBF-AML with t(8;21)(q22;q22): A Study of the German-Austrian AML Study Group (AMLSG)
Authors: Nikolaus Jahn, Mridul Agrawal, Lars Bullinger, Daniela Weber, Andrea Corbacioglu, Verena I. Gaidzik, Felicitas Thol, Michael Heuser, Juergen Krauter, Gudrun Göhring, Andrea Kuendgen, Walter Fiedler, Mohammad Amen Wattad, Gerhard Held, Doris Kraemer, Heinz A. Horst, Michael Lübbert, Arnold Ganser, Richard F. Schlenk, Hartmut Dohner, Konstanze Dohner, Peter Paschka
Journal: Blood (2015)
Dose-Escalation with BEACOPP Escalated Is Superior to ABVD In the Combined-Modality Treatment of Early Unfavorable Hodgkin Lymphoma: Final Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial
Authors: Andreas Engert, Peter Borchmann, Annette Pluetschow, Bastian von Tresckow, Jana Markova, Felicitas Hitz, Zdenek Kral, Richard Greil, Max S Topp, Matthias Villalobos, Josee M. Zijlstra, Martin Soekler, Harald Stein, Hans-Theodor Eich, Rolf-Peter Mueller, Michael Fuchs, Volker Diehl
Journal: Blood (2010)
433. DNA Monoclonal Antibodies Target Influenza Virus In Vivo
Authors: Sarah T.C. Elliott, Ami Patel, Megan C. Wise, Seleeke Flingai, Amelia Keaton, Jian Yan, Kate E. Broderick, Trevor Smith, Niranjan Y. Sardesai, Karrupiah Muthumani, David B. Weiner
Journal: Molecular Therapy (2016)

Despite promising innovations, influenza vaccines and antiviral drugs fail to provide full protection from seasonal infection, and provide little defense against novel and potentially pandemic viral strains. Broadly cross-protective monoclonal antibodies have been developed with the aim of providing protection against highly divergent influenza viruses. However, the utility of delivering purified protein antibody as therapy or prophylaxis against influenza is limited, especially in pandemic settings. Use of gene therapy to generate monoclonal antibodies in vivo provides a simplified, flexible, and relatively inexpensive alternative to protein antibody treatment. In this study, we used intramuscular electroporation of plasmid DNA encoding immunoglobulin to express DNA monoclonal antibodies (DMAb) against influenza hemagglutinin (HA) surface protein in mice. Multiple aspects of plasmid construction, antibody design, and delivery were optimized to enhance expression of DMAb from muscle cells in vivo. We investigated multiple antibody clones, including the broadly-neutralizing anti-influenza-H1 antibody 5J8. The 5J8 DMAb was expressed at µg/mL levels in serum of both nude and immune-competent mice. Serum DMAb produced from muscle in vivo were functional in vitro - with the ability to bind influenza HA, block hemagglutination of red blood cells, and neutralize influenza virus. Serum DMAb expression levels approximate those required for protection. Influenza challenge studies of mice treated with 5J8 DMAb are underway. DMAb provide an important new approach to immune therapy. DNA has an excellent safety profile and averts challenges of pre-existing serology associated with many viral vectors. Here, we demonstrate that DNA can be used to deliver consistently high levels of potent monoclonal antibodies for protection against a viral pathogen.
Results from a phase I safety lead-in study investigating the combination of erlotinib and the histone deacetylase inhibitor entinostat in patients with advanced NSCLC
Authors: K. Konduri, A. I. Spira, R. M. Jotte, T. Boyd, T. Boyd, Y. A. Gaffar, C. Reynolds, S. E. Witta
Journal: Journal of Clinical Oncology (2009)

e14545 Background: Preclinical studies showed the synergistic effect of entinostat with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in NSCLC cell lines. Entinostat (SNDX-275, Syndax Pharmaceuticals) is an oral, class 1 isoform selective HDACi that restores the expression of e-cadherin and sensitivity to EGFR-TKI in NSCLC cell lines. The aim of this study was to determine the safety and feasibility of combining entinostat with erlotinib in advanced NSCLC patients in order to determine the recommended Phase 2 dose. Methods: Patients with recurrent or metastatic NSCLC whose tumors progressed on prior chemotherapy were treated with either 5 or 10mg orally of entinostat once every two weeks and erlotinib 150mg daily. Results: A total of 9 patients were enrolled (3 at entinostat 5mg; 6 at 10mg). Characteristics: Sex: M/F: 6/3; Age range: 46–84 yrs; ECOG PS: 0–1; Smoking status: 1/8 (never/current or prior smokers); Number of prior treatments: 1–2. There was one DLT of grade 3 asthenia. This occurred in one of the six patients in the 10mg dose cohort. The most common adverse events were anorexia, and asthenia. This was more often noted in elderly patients. Of the 9 evaluable patients, one patient had a confirmed partial response and remains on study (&gt;5 cycles) and another patient had stable disease for 8 months. Pharmacokinetic analysis has been completed with both drugs exhibiting levels comparable to historical data. No drug:drug interaction was observed. EGFR FISH, EGFR mutation, and epithelial-to-mesenchymal marker analysis is in progress. Conclusions: This study has established the safety and a recommended phase 2 dose of 10 mg of entinostat once every other week in combination with 150 mg daily of erlotinib in a 28-day cycle in advanced NSCLC patients. A randomized, double blinded phase 2 study has been initiated with 43 patients enrolled to date. [Table: see text]
Abstract 861: Survivin-mediated adaptive response: a risk factor for IGRT
Authors: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Gayle E. Woloschak, Jian Jian Li, Ralph R. Weichselbaum
Journal: Cancer Research (2014)

Abstract Exposure of cells to very low doses of ionizing radiation can induce an enhanced resistance or adaptive response to a subsequent larger radiation dose as demonstrated by an increase in cell survival. Expression of a radio-adaptive response has been attributed to pro-survival signaling processes induced by very low radiation doses in the range of 5 to 100 mGy. The radiation-induced adaptive response is gaining considerable attention due in part to the expanding use of imaging technologies such as computerized axial tomography and portal imaging to monitor tumor response and positioning during multi-dose standard radiation therapy protocols. The focus of this study was to investigate whether this process could occur when the very small imaging radiation dose was administered prior to or following the administration of the first of two typically used radiation therapy level doses. SA-NH mouse sarcoma cells and SA-NH cells stably transfected with mutated IκBα (SA-NH+mIκBα1) to inhibit the activation of NFκB were grown to confluence in vitro or as tumors in the right hind leg of C3H mice. Percentage of cell survival, apoptosis frequencies and survivin protein levels were determined as a function of radiation conditions and transfection of cells with survivin siRNA. A significant radio-adaptive response was observed in cells exposed to 5 mGy - 100 mGy 15 min to 6 h prior to or after irradiation with the first of two 2 Gy therapeutic radiation doses and was associated with a concomitant reduction in apoptosis frequencies and a rapid elevation in survivin protein levels. The very low dose radiation-induced elevation in survivin levels, the reduction in apoptosis frequencies and enhanced cell survival were not observed in SA-NH+mIκBα1 cells or SA-NH cells transfected with survivin siRNA. We have identified a very low radiation dose-induced survivin-mediated adaptive response that could compromise therapeutic outcomes associated with the increased usage of imaging procedures in radiation therapy. This work was supported by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.) Citation Format: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Gayle E. Woloschak, Jian Jian Li, Ralph R. Weichselbaum. Survivin-mediated adaptive response: a risk factor for IGRT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2014-861
Novel Findings for the Role of Microenvironment and Heat Shock Proteins (HSP) in B -Cell Recptor (BCR) Activation, Disease Progression and Transformation of Follicular Non-Hodgkin Lymphoma (FL): Gene Expression Profiling (GEP) and Immuno-Histochemical (IH) Studies Reveal New Pathways for Potential Targeted Therapies
Authors: Saad M B Rassam, John Schofield, Farooq Malik, Azim M Mohamedali, Bartlomiej Przychodzen, Gabrielle Elstein, Ghulam J Mufti
Journal: Blood (2015)
A Rapid Approach for the Integrated Central Review of Acute Myeloid Leukemia Diagnosis In a Nationwide Clinical Trial for Children
Authors: Akitoshi Kinoshita, Hayato Miyachi, Hiromichi Matsushita, Tomohiko Taki, Miharu Yabe, Nobutaka Kiyokawa, Kiminori Terui, Hideaki Ohta, Takao Deguchi, Hiroyuki Takahashi, Takashi Taga, Yasuhide Hayashi, Akio Tawa, Souichi Adachi, Masahito Tsurusawa, Keizo Horibe
Journal: Blood (2010)
Abstract 1267: The senescence-associated secretory phenotype requires the histone variant macroH2A1 and is antagonized by ATM in a novel ER stress response
Authors: Hongshan Chen, Penelope D. Ruiz, Wendy McKimpson, Leonid Novikov, Richard N. Kitsis, Matthew J. Gamble
Journal: Cancer Research (2015)

Abstract Oncogene induced senescence (OIS) is an important tumor suppressive mechanism typified by permanent proliferative arrest, a persistent DNA damage response and the senescent-associated secretory phenotype (SASP). MacroH2A1, a histone variant that plays tumor suppressive roles in a several cancer types is upregulated during OIS. Our ChIP-seq data demonstrate that SASP genes are found in macroH2A1-containing chromatin. Additionally, we found that macroH2A1 is a critical positive regulator of both the transcriptional upregulation of SASP genes and the persistent ATM activation seen during senescence. SASP factors participate in a positive feedback loop to maintain senescence through autocrine signaling and can also induce paracrine senescence in bystander cells. Strikingly, we find that cells depleted of macroH2A1 are immune to paracrine senescence triggered by SASP factors, indicating that macroH2A1 is a critical regulator of SASP positive feedback. Additionally, ectopic expression of macroH2A1.1, the macroH2A1 splice variant that is typically lost in cancer cells, is sufficient to trigger senescence in normal cells complete with a robust SASP response and persistent activation of ATM. Due to the increased expression of secreted factors, endoplasmic reticulum (ER) stress is a feature of OIS. ER stress has been shown to lead to the generation of reactive oxygen species which can cause DNA damage and ATM activation. We determined that ER stress, as assayed by the activation of the unfolded protein response, is reduced during OIS in cells depleted of macroH2A1. Furthermore, activated ATM participates in a novel negative feedback loop reducing SASP expression in response to ER stress by triggering the removal of macroH2A1 from SASP genes. Overall, our results demonstrate that SASP gene expression is regulated by the combined actions of a positive feedback loop that requires macroH2A1 and a negative feedback loop where ER stress leads to ATM activation critical for the removal of macroH2A1 from SASP genes and consequently their repression. Citation Format: Hongshan Chen, Penelope D. Ruiz, Wendy McKimpson, Leonid Novikov, Richard N. Kitsis, Matthew J. Gamble. The senescence-associated secretory phenotype requires the histone variant macroH2A1 and is antagonized by ATM in a novel ER stress response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2015-1267