tbuckley/cabot-search huggingface dataset:
Abstract 1185: Regulation of neutral amino acid transporters gene expression profile in non-small cell lung cancer
Authors: Pierre P. Massion, Maria Senosain, Mohamed Hassanein, Xiangming Ji, Jun Qian, Megan hoeksema
Journal: Cancer Research (2015)

Abstract INTRODUCTION: In a recent study, we showed that SLC1A5, a key glutamine (Gln) transporter, regulates tumor growth and survival in NSCLC. Here we sought to characterize the expression of other Gln transporters in lung cancer and to test whether the inhibition of SLC1A5 activity induced a change in expression of other amino acid transporters in NSCLC. METHODS: Neutral amino acid transporters reported in the cancer literature were evaluated in publically available lung cancer gene expression datasets. Among those, SLC38A1, SLC1A4, SLC1A5, SLC7A5, SLC7A11, SLC7A8 were selected for the in vitro validation. The expression of these genes was evaluated in two lung squamous carcinoma cell lines (HCC15, H226) and one adenocarcinoma cell line (A549) by RT-PCR and then quantified by qPCR, using SYBR® Green Supermix protocol. The expression of the same genes was assessed in response to transient SLC1A5 knockdown in HCC15 and A549 cell lines by qPCR. RESULTS: Amino acid transporters SLC38A1, SLC1A5, SLC7A5 and SLC7A11 are expressed in NSCLCs, a finding that was confirmed in the three cell lines studied. SLC1A4 was found to have the lowest expression and SLC7A8 no expression in any of cell lines. In response to SLC1A5 transient knockdown in A549, SLC38A1, SLC1A4 and SLC7A5 were significantly up-regulated (p&amp;lt;0.02); in contrast, in HCC15, SLC38A1, SLC1A4 and SLC7A5 were significantly down-regulated (p&amp;lt;0.02) and SLC7A11 was up-regulated (p&amp;lt;0.13). CONCLUSION: Our results show that SLC38A1, SLC1A5, SLC7A5 and SLC7A11 have the highest level of gene expression in NSCLC. We identified a possible compensatory mechanism to satisfy Gln transport and cellular function upon SLC1A5 silencing involving different transporters in a cell-specific manner. Compensatory mechanisms in response to SLC1A5 knockdown deserve further investigation as it may have implications in strategies aiming at inhibiting its activity. Further expression, localization and functional studies will follow to better understand changes occurring in lung cancer progression. Key words: Non-small cell lung cancer, SLC1A5, expression, amino acid, transporters Citation Format: Pierre P. Massion, Maria Senosain, Mohamed Hassanein, Xiangming Ji, Jun Qian, Megan hoeksema. Regulation of neutral amino acid transporters gene expression profile in non-small cell lung cancer. [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 1185. doi:10.1158/1538-7445.AM2015-1185
Abstract 2693: Overcoming MITF-conferred resistance through dual AURKA/MAPK-axis targeting
Authors: Gaurav Pathria, Bhavuk Garg, Kanika Garg, Viola Borgdorff, Christine Wagner, Giulio Superti-Furga, Stephan N. Wagner
Journal: Cancer Research (2015)

Abstract MITF is a frequently amplified lineage-specific oncogene in human melanoma. Current drug discovery effort has, however, paradoxically ignored its criticality in melanoma cell biology and has failed to address MITF-associated intrinsic and acquired drug resistance. Here, to search the kinase targets able to circumvent the MITF-conferred intrinsic drug resistance, we used a multi-kinase inhibitor-directed chemical proteomics-based differential target affinity screen in immortalized human melanocytes carrying ectopic MITF overexpression. Through a subsequent methodical ‘gene expression-disease stage’ associations and a detailed functional interrogation in molecular-genetically diverse melanoma cellular systems, we identify a mitotic Ser/Thr kinase, Aurora Kinase A (AURKA) as a potential drug target in human melanoma that successfully overcomes MITF-engendered drug resistance phenotype. Critically, assessing the long-term efficacy of the phase II clinical trial approved highly specific AURKA-inhibitor MLN-8237, we pre-emptively witness a robust MAPK signalling-mediated immediate acquired resistance program involving MITF and Cyclin D1 induction through activity and expression changes in CREB and c-Jun respectively in both the BRAF- and NRAS-mut cells. Notably, identification of these ERK-directed acquired resistance mechanisms informed combinatorial AURKA/BRAF or AURKA/MEK targeting as an intelligent therapeutic strategy in BRAF- and NRAS-mut melanomas respectively. Citation Format: Gaurav Pathria, Bhavuk Garg, Kanika Garg, Viola Borgdorff, Christine Wagner, Giulio Superti-Furga, Stephan N. Wagner. Overcoming MITF-conferred resistance through dual AURKA/MAPK-axis targeting. [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 2693. doi:10.1158/1538-7445.AM2015-2693
Molecular Pathways: Mucins and Drug Delivery in Cancer
Authors: Chinthalapally V. Rao, Naveena B. Janakiram, Altaf Mohammed
Journal: Clinical Cancer Research (2016)

Over the past few decades, clinical and preclinical studies have clearly demonstrated the role of mucins in tumor development. It is well established that mucins form a barrier impeding drug access to target sites, leading to cancer chemoresistance. Recently gained knowledge regarding core enzyme synthesis has opened avenues to explore the possibility of disrupting mucin synthesis to improve drug efficacy. Cancer cells exploit aberrant mucin synthesis to efficiently mask the epithelial cells and ensure survival under hostile tumor microenvironment conditions. However, O-glycan synthesis enzyme core 2 beta 1,6 N-acetylglucosaminyltransferase (GCNT3/C2GnT-2) is overexpressed in Kras-driven mouse and human cancer, and inhibition of GCNT3 has been shown to disrupt mucin synthesis. This previously unrecognized developmental pathway might be responsible for aberrant mucin biosynthesis and chemoresistance. In this
Abstract 625: The frequency of gene amplifications in cancer revealed by a droplet digital PCR (ddPCR) based pan-cancer gene panel test
Authors: Austin P. So, Amy Wong, Jennifer Pecson, Girish Putcha, Gregory Jensen, Michael Lucero, Gary Stone, Jason Gillman, Pravin Mishra, David Loughmiller, Derrick S. Haslem, Lincoln Nadauld
Journal: Cancer Research (2015)

Abstract The development of molecular assays designed to detect gene amplifications has largely been hampered by technical challenges such as limited DNA quantity and tumor heterogeneity, which demand methods of very high precision and sensitivity. The recent introduction of affordable digital PCR platforms, such as droplet digital PCR (ddPCR), that are capable of providing single molecule resolution of target abundances thus provides a unique opportunity to address this gap in molecular diagnostics. A ddPCR-based test was therefore developed under CLIA-CAP guidelines to determine the amplification status of 12 commonly amplified genes targeted by FDA approved drugs. Termed the Amplinome Test, this test was applied to 49 clinical samples received over a period of 6 months and compared to the results obtained from a commercially available clinical sequencing test applied that also reports copy number alterations (CNAs). An overall concordance rate of 90% (532/588 calls) was observed between the two tests across the entire gene set, 5 of which were identified as amplified. There were 56 discordant copy number amplifications between the two testing modalities. The vast majority (55/56) of discordant calls arose from gene amplifications identified by the Amplinome test, but not detected by sequencing, indicating an 11-fold increase in sensitivity in detecting amplifications. One discordant call (HER3) was identified as amplified via sequencing, but confirmed to be unamplified via FISH. At the patient level, the Amplinome test identified 5-fold more patients as having actionable amplifications in at least one of the 12 assayed genes versus clinical sequencing (29 vs. 6). Clinical management was altered in 14 of the 29 patients with an actionable CNA identified on the Amplinome test; those patients received targeted therapy directed against the amplified gene. The ddPCR-based Amplinome test thus provides a highly sensitive method for measuring gene amplifications in cancer that alters patient management, and suggests that the prevalence of actionable amplifications may be significantly underestimated by standard clinical next-generation sequencing tests. Citation Format: Austin P. So, Amy Wong, Jennifer Pecson, Girish Putcha, Gregory Jensen, Michael Lucero, Gary Stone, Jason Gillman, Pravin Mishra, David Loughmiller, Derrick S. Haslem, Lincoln Nadauld. The frequency of gene amplifications in cancer revealed by a droplet digital PCR (ddPCR) based pan-cancer gene panel test. [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 625. doi:10.1158/1538-7445.AM2015-625
Extensively hydrolyzed casein formula containing Lactobacillus rhamnosus GG reduces the occurrence of other allergic manifestations in children with cow's milk allergy: 3-year randomized controlled trial
Authors: Roberto Berni Canani, Margherita Di Costanzo, Giorgio Bedogni, Antonio Amoroso, Linda Cosenza, Carmen Di Scala, Viviana Granata, Rita Nocerino
Journal: Journal of Allergy and Clinical Immunology (2016)

BackgroundChildren with cow's milk allergy (CMA) have an increased risk of other allergic manifestations (AMs).ObjectiveWe performed a parallel-arm randomized controlled trial to test whether administration of an extensively hydrolyzed casein formula (EHCF) containing the probiotic Lactobacillus rhamnosus GG (LGG) can reduce the occurrence of other AMs in children with CMA.MethodsChildren with IgE-mediated CMA were randomly allocated to the EHCF or EHCF+LGG groups and followed for 36 months. The main outcome was occurrence of at least 1 AM (eczema, urticaria, asthma, and rhinoconjunctivitis). The secondary outcome was tolerance acquisition, which was defined as the negativization of a double-blind food challenge results at 12, 24, and 36 months. AMs were diagnosed according to standardized criteria. Tolerance acquisition was evaluated every 12 months.ResultsA total of 220 children (147 boys [67%]) with a median age of 5.0 months (interquartile range, 3.0-8.0 months) were randomized; 110 children were placed in the EHCF group, and 110 children were placed in the EHCF+LGG group. In the complete case analysis the absolute risk difference for the occurrence of at least 1 AM over 36 months was −0.23 (95% CI, −0.36 to −0.10; P < .001), and the absolute risk difference for the acquisition of cow's milk tolerance was 0.20 (95% CI, 0.05-0.35; P < .01) at 12 months, 0.24 (95% CI, 0.08-0.41; P < .01) at 24 months, and 0.27 (95% CI, 0.11-0.43; P < .001) at 36 months. In the sensitivity analysis the effect size of the main outcome was virtually unchanged when the occurrence of AMs was assigned to all 27 missing children.ConclusionsEHCF+LGG reduces the incidence of other AMs and hastens the development of oral tolerance in children with IgE-mediated CMA.
Abstract 3678: Imaging AZD1152HQPA Accurin™ nanoparticle accumulation in preclinical tumors
Authors: Richard Goodwin, John Swales, Anna Nilsson, Per Andren, Nicola Strittmatter, Zoltan Takats, Colin Howes, Paula Taylor, Susan Ashton, Philip Jewsbury, Simon T. Barry
Journal: Cancer Research (2015)

Abstract AZD1152HQPA Accurin is a passively targeted nanoparticle containing the active metabolite of the Aurora B kinase prodrug AZD1152. In preclinical studies, AZD1152HQPA Accurin displays reduced bone marrow toxicity associated with AZD1152 together with increases in anti-tumour activity. Nanoparticles are proposed to enable delivery and retention of drug to the tumour thereby increasing efficacy and modifying therapeutic index. While it is possible to demonstrate increased duration of modulation of pharmacodynamic biomarkers and drug exposure by nanoparticle delivery, directly demonstrating that nanoparticles accumulate in the tumour is challenging. To investigate the intra tumoural distribution of AZD1152HQPA Accurin nanoparticles we have employed mass spectrometry techniques to image samples derived from human colorectal cancer SW620 studies in rats. We have separately identified the nanoparticle itself, drug encapsulated in nanoparticle, and drug released from nanoparticle; the latter by detecting a metabolite that is only generated from released drug. First MALDI (matrix assisted laser desorption ionization) which offers 20 μm spatial resolution, was used to detect AZD1152-hQPA (released and encapsulated). Second LESA (liquid extraction surface analysis), which offers 1000 μm spatial resolution, was used to detect drug and metabolite, enabling co-distribution to be demonstrated. Finally DESI (desorption electrospray ionization) which offers 100 μm spatial resolution was used to detect drug, metabolite and nanoparticle constituent showing the co-distribution in more detail. Using this combination of approaches it is possible to demonstrate the presence of nanoparticle-delivered AZD1152HQPA metabolite in the tumour at extended timepoints; co-located with nanoparticle and unchanged (encapsulated) drug. At these time points no drug remains if delivered as a simple IV infusion. Collectively this imaging mass spectrometry analysis demonstrates AZD1152HQPA Accurin accumulation in pre-clinical tumours and confirms that the Accurin accesses the tumour and achieves sustained drug release within the tumour. Citation Format: Richard Goodwin, John Swales, Anna Nilsson, Per Andren, Nicola Strittmatter, Zoltan Takats, Colin Howes, Paula Taylor, Susan Ashton, Philip Jewsbury, Simon T. Barry. Imaging AZD1152HQPA Accurin™ nanoparticle accumulation in preclinical tumors. [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 3678. doi:10.1158/1538-7445.AM2015-3678
Rise of multidrug-resistant non-vaccine serotype 15A Streptococcus pneumoniae in the United Kingdom, 2001 to 2014
Authors: Carmen Sheppard, Norman K. Fry, Shazad Mushtaq, Neil Woodford, Rosy Reynolds, Regina Janes, Rachel Pike, Robert Hill, Maimuna Kimuli, Peter Staves, Michel Doumith, Timothy Harrison, David M Livermore
Journal: Eurosurveillance (2016)

Conjugate vaccines have reduced pneumococcal disease in vaccinated children and unvaccinated adults, but non-vaccine serotypes are of concern, particularly if antibiotic resistant. We reviewed Streptococcus pneumoniae collected via: (i) the British Society for Antimicrobial Chemotherapy (BSAC) surveillances from 2001-2014; (ii) Public Health England's (PHE) invasive isolate surveillance from 2005-2014 and (iii) referral to PHE for resistance investigation from 2005-2014. Serotype 15A increased in all series, with many representatives showing triple resistance to macrolides, tetracyclines and penicillin. 15A was consistently among the 10 most prevalent serotypes from 2011 in PHE and BSAC invasive isolate/bacteraemia surveillance but never previously; 26-33% of these invasive 15A isolates had triple resistance. BSAC respiratory isolates were only serotyped in 2013/14 and 2014/15 (October to September); 15A was most prevalent serotype in both periods, comprising 9-11% of isolates, 38-48% of them with triple resistance. Serotype 15A represented 0-4% of S. pneumoniae referred to PHE for reference investigation annually until 2008 but rose to 29% (2013) and 32% (2014). Almost all multidrug-resistant 15A isolates were sequence type (ST) 63 variants, whereas susceptible 15A isolates were clonally diverse. The rise of serotype 15A suggests that pneumococcal conjugate vaccines will need ongoing adaptation.
Abstract 2911: Leptin Notch VEGFR-2 axis influences cancer stromal cell behavior
Authors: Viola Lanier, Merle Jeffers, Johannes Walterberger, Leonard Anderson, Ruben Gonzalez
Journal: Cancer Research (2015)

Abstract PURPOSE: Breast cancer cells induce changes in the stromal environment during malignancy. These changes promote growth, angiogenesis, invasion, and metastasis. The secretion of the adipokine, leptin, from adipose tissue has been shown to contribute to cell proliferation, migration and survival. We previously reported that leptin induces Notch, a pro-survival factor and contributor to the VEGF/VEGFR-2 pro-angiogenic system. We hypothesize that the leptin Notch axis induces activation of fibroblast cells and leads to endothelial cell proliferation, tubule formation, and survival. These effects could be related to leptin-induced Notch expression and VEGFR-2 transactivation, independent of VEGF. METHODS: Mouse Embryo Fibroblast cells (NIH/3T3), human umbilical vein endothelial cells (HUVEC) and porcine aorta endothelial cells (PAEC) were challenged with leptin (dose and time-response), and inhibitors of Notch (DAPT) and VEGFR-2 (SU5416 kinase inhibitor). Expression of Notch, VEGFR-2, Ob-R and phosphorylation of VEGFR-2 were determined. The impact of treatment on angiogenic features of endothelial cells was determined. To determine whether leptin-Notch axis activates fibroblast cells, leptin doses 0.6, 1.2, and 6.2 were used. RESULTS: Leptin induced phosphorylation of VEGFR-2 at intracellular site Y1175 and tubule formation in HUVEC. Leptin induced phosphorylation of VEGFR-2 at sites Y951, Y996, Y1059, and Y1175 in PAEC VEGFR2. Protein expression of Notch4 and Jagged1 was induced by leptin treatment in NIH/3t3 cells. CONCLUSION: Leptin secreted by fibroblast cells and/or adipose tissue may contribute to tumor angiogenesis by acting directly on stromal cells and inducing a VEGFR-2/Notch crosstalk. Novel therapies that target leptin signaling could be a new strategy for the prevention and treatment of breast cancer. These therapies could be more relevant for obese cancer patients with high circulating amounts of leptin. Citation Format: Viola Lanier, Merle Jeffers, Johannes Walterberger, Leonard Anderson, Ruben Gonzalez. Leptin Notch VEGFR-2 axis influences cancer stromal cell behavior. [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 2911. doi:10.1158/1538-7445.AM2015-2911
Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma
Authors: Naoshad Muhammad, Sourav Bhattacharya, Robert Steele, Nancy Phillips, Ratna B. Ray
Journal: Clinical Cancer Research (2016)

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSC) play a significant role in recurrence and chemoresistance. We previously observed that c-Fos was highly upregulated in the HNSCC sphere-forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.Experimental Design and Results: We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in nontumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Furthermore, subcutaneous transplantation of c-Fos-overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared with parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial-mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2, and Notch1). Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells.Conclusions: Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment. Clin Cancer Res; 23(12); 3120-8. ©2016 AACR.
Abstract 3953: HORMAD1 plays an important role in the HNSCC carcinogenesis
Authors: Viviane Carlin, Dorival Mendes Rodrigues-Junior, Thais Priscila Biassi, Bruno Heidi Nakano Nozima, Marcus Vinicius Buri, Andre Luiz Vettore
Journal: Cancer Research (2015)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide. Approximately one-third of patients present with early-stage disease and these patients are treated with either surgery or radiotherapy, with cure rates of 70-90%. The majority of patients, however, present with locally advanced stage disease. Radical treatment in this situation requires multimodality therapy with surgery, commonly followed by postoperative radiotherapy or chemotherapy. These treatments are intensive and associated with severe acute toxicity and long-term sequelae. Despite recent advances in both surgical and radiotherapy delivery techniques, up to 50% of locally advanced tumours relapse usually within the first 2 years after treatment. The development of novel therapeutic approaches and their integration into the current forms of treatment is of great interest to improve the therapeutic efficacy. Immunotherapy may provide an alternative for current treatment approach. Cancer/testis antigens (CTAs) are a family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues except for testis and placenta. This tumor-restricted pattern of expression, together with their strong in vivo immunogenicity, identified CTA as ideal targets for tumor-specific immunotherapeutic approaches. A screening for CTAs expressed in HNSCC detected HORMAD1 recurrently expressed in these tumors. Objectives: The aim of this study is better understand the role of HORMAD1 in HNSCC by evaluating its influence in different tumorigenic processes, such as apoptosis, cell cycle and migration. Methods: The HORMAD1 expression was evaluated in HNSCC cell lines by RT-PCR and the presence of HORMAD1 protein was confirmed by Western Blot. HORMAD1 expression was silenced by shRNA and assays were conducted to evaluate the impact of HORMAD1 absence in cell cycle regulation and apoptosis. Results: The HORMAD1 gene was knocked-down in a HNSCC cell line and functional assays revealed a reduction in the proportion of the cells in the G1 phase of cell cycle and an induction of the apoptosis when HORMAD1 is absent. Conclusions: Our results demonstrate that HORMAD1 is frequently expressed in HNSCC and our in vitro observations indicate that this CTA may play an important role in the HNSCC carcinogenesis. Citation Format: Viviane Carlin, Dorival Mendes Rodrigues-Junior, Thais Priscila Biassi, Bruno Heidi Nakano Nozima, Marcus Vinicius Buri, Andre Luiz Vettore. HORMAD1 plays an important role in the HNSCC carcinogenesis. [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 3953. doi:10.1158/1538-7445.AM2015-3953