tbuckley/cabot-search huggingface dataset:
The American Academy of Dermatology (AAD) Ethics Pledge: I will put my patients' welfare above all other interests, provide care that adheres to professional standards of practice, provide care for those in need, and foster collegiality through interaction with the medical community
Authors: Benjamin K. Stoff, Karen Scully, Anne L. Housholder, Stephanie Fabbro, Jonathan Kantor
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 1047: Effect of 1,25-Dihydroxyvitamin D in regulating glutamic-oxaloacetic transaminase 1 (GOT1) and redox balance during breast cancer progression
Authors: Xuanzhu Zhou, Tomasz Wilmanski, Dorothy Teegarden
Journal: Cancer Research (2016)

Abstract Breast cancer is the second most common cancer among women in the US. The active form of vitamin D, 1α,25 dihydroxyvitamin D (1,25(OH)2D), is proposed to inhibit cellular processes that may prevent breast cancer. Possible pro-oxidative effects of 1,25(OH)2D in breast cancer cells which may selectively promote cell death have been proposed. Glutamic-oxaloacetic transaminase 1 (GOT1) is an essential transaminase in glutamine metabolism. GOT1 converts aspartate into oxaloacetate in the cytoplasm, which is then subsequently converted to malate and pyruvate. NADPH is produced during the last step of this process and increased NADPH/NADP+ ratio has the potential to maintain cellular redox balance. Therefore, it is of interest to study 1,25(OH)2D regulation of GOT1 during cancer progression to understand the role of vitamin D in regulating oxidative stress as a mechanism to prevent breast cancer. We employed untransformed MCF10A human breast epithelial cells (MCF10A), as well as Harvey ras-oncogene or ErbB2 (HER-2/neu) oncogene transformed cells (MCF10A-ras and MCF10A-ErbB2) as cell models for early cancer progression. Results showed that 1,25(OH)2D significantly decreased GOT1 mRNA expression at 48 hours in MCF10A-ras cells and MCF10A-ErbB2 cells by 35 ± 8.8% and 49 ± 10%, respectively, and GOT1 protein expression at 72 hours by 51 ± 4.9% and 51 ± 16%, respectively. The susceptibility of MCF10A-ras cells to hydrogen peroxide induced cell death was significantly increased by 1,25(OH)2D, as determined by measuring viable cell number using MTT assay. We further showed that 96-hour 1,25(OH)2D treatment significantly reduced cellular NADPH/NADP+ ratio by 30 ± 2.8% and GSH/GSSG ratio by 34 ± 2.7% in MCF10A-ras cells. Collectively, these results support that 1,25(OH)2D inhibits GOT1 expression and has pro-oxidative effects in oncogene transformed MCF10A cell lines, which may contribute to its role in preventing breast cancer development. Citation Format: Xuanzhu Zhou, Tomasz Wilmanski, Dorothy Teegarden. Effect of 1,25-Dihydroxyvitamin D in regulating glutamic-oxaloacetic transaminase 1 (GOT1) and redox balance during breast cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1047.
Abstract 4123: Thymoquinone inhibits bone metastasis in a breast cancer mouse model by modulating CXCR4/CXCL12 signaling axis
Authors: Muthu K. Shanmugam, Annie Hsu, Kam Man Hui, Benny K.H. Tan, Gautam Sethi
Journal: Cancer Research (2016)

Abstract Several lines of evidence(s) indicate that CXCR4 overexpression has been correlated with distant site metastasis and poor overall survival rate in patient with breast cancer. The tumor metastasis promoting molecule CXCR4 is considered as a potential therapeutic target for inhibiting breast cancer metastasis. Thus, novel agents that can down-regulate CXCR4 expression have potential against breast cancer metastasis. In the present report we investigated the effect of thymoquinone (TQ), derived from the seeds of medicinal plant Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. In addition, we evaluated the effect of TQ in a metastasis mouse model established by intracardiac injection of luciferase tagged MDA-MB-231 breast cancer cells that metastasize to the bones. We observed that TQ could inhibit the expression of CXCR4 in MCF-7 and MDA-MB-231 cells in a dose and time dependent manner. TQ (2 mg/kg or 4 mg/kg) treatment for four weeks significantly inhibited tumor growth and significantly reduced metastasis to multiple vital organs, including lungs, brain and bone. Immuno-histochemical analysis of the lung and brain tissue showed significant reduction in CXCR4, Ki67, MMP9, VEGFR2 and COX2 expression compared to control tissues. TQ treatment also reduced the overall bone tumor burden. Overall, our results show that TQ exerts its antitumor and anti-metastatic effects by downregulation of CXCR4 expression both in vitro and in vivo thus may have possible potential for the treatment of breast cancer. Acknowledgement: This work was supported by NUHS Basic Seed Research grant to Prof. Benny Tan. Citation Format: Muthu K. Shanmugam, Annie Hsu, Kam Man Hui, Benny K.H. Tan, Gautam Sethi. Thymoquinone inhibits bone metastasis in a breast cancer mouse model by modulating CXCR4/CXCL12 signaling axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4123.
Cost Analysis of Immunotherapy Using Dendritic Cells for Acute Myeloid Leukemia Patients
Authors: Ann L. Van de Velde, Sébastien Anguille, Philippe Beutels, Suzy Dom, Ingrid Cornille, Griet Nijs, Viggo F Van Tendeloo, Evelien L. Smits, Anke Verlinden, Alain P. Gadisseur, Wilfried A Schroyens, Zwi N Berneman
Journal: Blood (2014)
Abstract 4334: A novel linker to enable alcohol-containing payloads for the preparation of antibody-drug conjugates
Authors: Robert V. Kolakowski, Karl Haelsig, Scott Jeffrey, Peter Senter
Journal: Cancer Research (2016)

Abstract Antibody-drug conjugates (ADCs) have emerged as important therapeutics for treating cancer as evidenced by the recent FDA approval of brentuximab vedotin Adcetris™ and trastuzumab emtansineKadcyla™, and the large number of ADCs (&amp;gt;35) currently in clinical trials. ADCs are composed of two core units: the targeting antibody and the drug-linker. The drug-linker typically consists of a cytotoxic payload, a moiety for covalent attachment to the antibody, and a conditionally cleavable linker that is stable in circulation but releases the cytotoxic payload upon internalization into a target cell. The released payload will possess a residual chemical functional group that is used for attachment of the drug to the cleavable linker. Functional groups that have been exploited within the ADC field for this purpose include amines (primary and secondary), thiols, and carboxylic acids. Unfortunately, many potential ADC payloads do not possess any of these functional group ‘handles’ that allow for stable conjugation and release of the drug in an unmodified form. Use of these payloads often requires modification of the drug structure to introduce a handle for conjugation. To avoid this, we have developed new linker chemistry, the methylene-alkoxy-carbamate (MAC), which enables direct conjugation of drugs through alcohol functional groups. Such groups are present on a diverse array of synthetic drugs and cytotoxic natural products, thus, expanding the potential chemical space available for payload selection. As proof-of-concept, we have linked Auristatin E through the secondary alcohol of the norephedrine residue and characterized the stability and in vivo activity of the resulting ADCs. To further define the potential applicability of the MAC unit, we have examined its stability and release properties with a series of model systems including primary, secondary, and tertiary alcohols as well as a phenol. We have also explored the effect of substitution of the MAC nitrogen on these properties. This novel linker chemistry is currently being applied to new payloads that were inaccessible with previous technology. Citation Format: Robert V. Kolakowski, Karl Haelsig, Scott Jeffrey, Peter Senter. A novel linker to enable alcohol-containing payloads for the preparation of antibody-drug conjugates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4334.
CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles
Authors: Yew Ann Leong, Yaping Chen, Hong Sheng Ong, Di Wu, Kevin Man, Claire Deleage, Martina Minnich, Benjamin J Meckiff, Yunbo Wei, Zhaohua Hou, Dimitra Zotos, Kevin A Fenix, Anurag Atnerkar, Simon Preston, Jeffrey G Chipman, Greg J Beilman, Cody C Allison, Lei Sun, Peng Wang, Jiawei Xu, Jesse G Toe, Hao K Lu, Yong Tao, Umaimainthan Palendira, Alexander L Dent, Alan L Landay, Marc Pellegrini, Iain Comerford, Shaun R McColl, Timothy W Schacker, Heather M Long, Jacob D Estes, Meinrad Busslinger, Gabrielle T Belz, Sharon R Lewin, Axel Kallies, Di Yu
Journal: Nature Immunology (2016)
CMV-Specific CD8+ T-CELL Function Is NOT Impaired In CLL
Authors: Doreen te Raa, Fernanda Pascutti, Juan J Garcia-Vallejo, Emilie Reinen, Ester B.M. Remmerswaal, René A.W. Van Lier, Eric Eldering, Marinus H.J. Van Oers, Sanne H. Tonino, Arnon P. Kater
Journal: Blood (2013)
Abstract 2295: GDNF family receptor alpha 4 (GFRa4)-targeted adoptive T-cell immunotherapy for medullary thyroid carcinoma
Authors: Vijay G. Bhoj, Selene Nunez-Cruz, Kenneth Zhou, Dimitrios Arhontoulis, Michael Feldman, Keith Mansfield, Haiyong Peng, Christoph Rader, Don L. Siegel, Michael C. Milone
Journal: Cancer Research (2016)

Abstract Metastatic medullary thyroid cancer (MTC) is a rare, but often aggressive, thyroid malignancy with a 5-year survival rate of 28% and few effective therapeutic options. Adoptive T-cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CARTs) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4), which associates with the RET receptor tyrosine kinase, as a putative antigenic target for CAR-based therapy of MTC. Using RNA in situ hybridization (RNAscope) and quantitative RT-PCR, we show that GFRα4 is highly expressed in MTC. Normal tissue expression of GFRα4 mRNA is restricted to parafollicular cells (C-cells) within the thyroid, the normal cell type from which MTC originates, and normal thymus.Based upon the highly restricted expression, we generated two high affinity single chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by selecting a naïve rabbit antibody library by phage display. Second generation CARs bearing the CD137 costimulatory domain were constructed using these GFRα4-specific scFvs. GFRα4-specific CARTs trigger antigen-dependent cytotoxicity and cytokine production in vitro, and they are able to control pre-established TT cell tumors in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CARTs, and support this molecule as a promising target for adoptive T cell immunotherapy and other antibody-based therapy of MTC. Citation Format: Vijay G. Bhoj, Selene Nunez-Cruz, Kenneth Zhou, Dimitrios Arhontoulis, Michael Feldman, Keith Mansfield, Haiyong Peng, Christoph Rader, Don L. Siegel, Michael C. Milone. GDNF family receptor alpha 4 (GFRa4)-targeted adoptive T-cell immunotherapy for medullary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2295.
Survival and Surgical Interventions for Children With Trisomy 13 and 18
Authors: Katherine E. Nelson, Laura C. Rosella, Sanjay Mahant, Astrid Guttmann
Journal: JAMA (2016)

<h3>Importance</h3> Trisomy 13 and 18 are genetic diagnoses with characteristic physical features, organ anomalies, and neurodevelopmental disability. Most children with these disorders die shortly after birth, although limited data suggest some children survive longer. Surgeries are controversial, and little evidence is available about outcomes. <h3>Objective</h3> To describe survival and utilization of any type of surgery among children with trisomy 13 and 18 born over a 21-year period in Ontario, Canada. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used linked health administrative databases to identify children born in Ontario between April 1, 1991, and March 31, 2012, with a diagnosis code for trisomy 13 or 18 on a hospital record in the first year of life. Survival was calculated from birth and death dates; children living on March 31, 2013, were censored at their last clinical encounter. <h3>Exposures</h3> All procedures classified as occurring in an operating room through March 31, 2013, were categorized as<i>major</i>,<i>intermediate</i>, or<i>minor</i>surgeries. <h3>Main Outcomes and Measures</h3> Survival and surgical procedure utilization. <h3>Results</h3> The cohorts included 174 children with trisomy 13 (mean [SD] birth weight, 2.5 [0.7] kg; 98 [56.3%] female); and 254 children with trisomy 18 (mean birth weight, 1.8 [0.7] kg; 157 [61.8%] female), with follow-up times of 0 to more than 7000 days. Median (interquartile range [IQR]) survival times were 12.5 (2-195) days for trisomy 13 and 9 (2-92) days for trisomy 18. One-year survival for trisomy 13 was 19.8% (95% CI, 14.2%-26.1%) and 12.6% (95% CI, 8.9%-17.1%) for trisomy 18. Ten-year survival for trisomy 13 was 12.9% (95% CI, 8.4%-18.5%) and 9.8% (95% CI, 6.4%-14.0%) for trisomy 18. Survival did not change over the study period. Forty-one children (23.6%) with trisomy 13 and 35 children (13.8%) with trisomy 18 underwent surgeries, ranging from myringotomy to complex cardiac repair. Median age at first surgery for trisomy 13 was 92 (IQR, 30.5-384.5) days and for trisomy 18, it was 205.5 (IQR, 20.0-518.0) days. Kaplan-Meier curves showed 1-year survival after first surgery of 70.7% (95% CI, 54.3%-82.2%; n = 23) for trisomy 13 and 68.6% (95% CI, 50.5%-81.2%; n = 29) for trisomy 18. <h3>Conclusions and Relevance</h3> Among children born with trisomy 13 or 18 in Ontario, early mortality was the most common outcome, but 10% to 13% survived for 10 years. Among children who underwent surgical interventions, 1-year survival was high.
Pretreatment of the Esophagus with Manganese Superoxide Dismutase Plasmid/Liposome Complex (MnSOD-PL) before Irradiation Results in Increased Migration and Proliferation of Marrow-Derived Stem Cell Progenitors in the Esophageal Squamous Epithelium.
Authors: Michael W. Epperly, Yunyun Niu, Hongmei Shen, Joel S. Greenberger
Journal: Blood (2006)
£60m scheme will cover GPs’ rising indemnity costs
Authors: Abi Rimmer
Journal: BMJ (2016)

NHS England has announced new funding designed to offset the rising cost of GP indemnity.

The new two year indemnity support scheme for GPs, worth £30m a year, will launch in April 2017. NHS England said that the funding would be paid to GPs as a lump sum in arrears, so that payments made to account for inflation in indemnity fees in 2016-17 would be paid in April 2017.

The news comes after NHS England published a review on GP indemnity,1 which found that the cost of indemnity was likely …
Postzygotic mosaicism in basal cell naevus syndrome
Authors: M.G.H.C. Reinders, H.J. Boersma, E.M. Leter, M. Vreeburg, A.D.C. Paulussen, A.H.M.M. Arits, G.M.J.M. Roemen, E.J.M. Speel, P.M. Steijlen, M. van Geel, K. Mosterd
Journal: British Journal of Dermatology (2016)

Basal cell naevus syndrome (BCNS) is an autosomal dominant disorder most commonly caused by a germline mutation in the Drosophila homologue of patched‐1 gene (PTCH1). Here we describe a patient with clinical signs of BCNS, caused by postzygotic mosaicism of a PTCH1 mutation. We performed restriction fragment length polymorphism analysis and Droplet Digital polymerase chain reaction to determine the degree of mosaicism in different tissues of this patient. Our case shows that a relatively low‐grade mosaicism can lead to clinical signs reminiscent of those caused by a germline mutation. This finding has important implications for genetic counselling and therefore is pivotal to recognize for dermatologists, as well as for clinical geneticists and clinical laboratory geneticists.
Abstract 1503: Discovery of new breast cancer relevant genes using the cancer genomics public database
Authors: Ritika R. Samant, Rajeev S. Samant
Journal: Cancer Research (2016)

Abstract We used the cBio portal to query the importance of key players in breast cancer. Telomerase (TERT) is an important protein that ensures successful immortalization of cancer cells. Immortalization is a key step to establish uncontrolled cell division. MYC is an oncogene that is very relevant in breast cancer. Our searches showed that both genes (TERT and MYC) are amplified in a high percent of patients. We wanted to explore if there are genetic events that co-occur with telomerase amplification. We found that NONO gene mutation had a high tendency of co-occurrence with telomerase amplification. We wanted to understand if this subset of tumors with mutation of NONO reveals any additional correlations. Our query revealed that PDE4DIP (Phosphodiesterase 4D interacting protein) is amplified concurrent with the NONO mutation. There is no notable cancer related data on PDE4DIP in publicly available peer-reviewed publication records (PubMed). However, when we queried PDE4DIP, we discovered that it is amplified in a large majority of the breast cancer cases. Thus, it is surprisingly more common than TERT or MYC amplification. We propose that it is very important to understand the relevance of PDE4DIP and NONO to breast cancer. Citation Format: Ritika R. Samant, Rajeev S. Samant. Discovery of new breast cancer relevant genes using the cancer genomics public database. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1503.
Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts
Authors: M J McDonnell, S Aliberti, P C Goeminne, K Dimakou, S C Zucchetti, J Davidson, C Ward, J G Laffey, S Finch, A Pesci, L J Dupont, T C Fardon, D Skrbic, D Obradovic, S Cowman, M R Loebinger, R M Rutherford, A De Soyza, J D Chalmers
Journal: Thorax (2016)

<h3>Introduction</h3> Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. <h3>Methods</h3> We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. <h3>Results</h3> The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p&lt;0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. <h3>Conclusion</h3> The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.
Abstract 5185: Development of patient-derived xenograft (PDX) models for pancreatic carcinoma as a preclinical platform for drug development
Authors: Jill Ricono, Jayant Thatte, Colleen Scott, Thomas B. Broudy
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors in humans. A notable feature of PDA is its innate resistance to many chemotherapies. In preclinical studies, Abraxane showed antitumor activity as a single agent and synergistic activity in combination with gemcitabine in murine models of pancreatic cancer. In this study, we have developed and characterized multiple models of patient derived xenograft (PDX) pancreatic models. These models recapitulate major structural and genetic features noted in patient populations. Developed PDX models are from both prior treated and non prior treated patients with varying levels of resistance to Gemcitibine. Here we have investigated efficacy of standard of care agents in these pancreatic models and demonstrate the potential utility of the pancreatic models in drug discovery efforts in oncology for the treatment of pancreatic cancer. Citation Format: Jill Ricono, Jayant Thatte, Colleen Scott, Thomas B. Broudy. Development of patient-derived xenograft (PDX) models for pancreatic carcinoma as a preclinical platform for drug development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5185.
Safety and immunogenicity of a booster dose of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults: A randomized phase 1 study
Authors: Helen Marshall, Michael Nissen, Peter Richmond, Sepehr Shakib, Qin Jiang, David Cooper, Denise Rill, James Baber, Joseph Eiden, William C. Gruber, Kathrin U. Jansen, Annaliesa S. Anderson, Edward T. Zito, Douglas Girgenti
Journal: Journal of Infection (2016)