tbuckley/cabot-search huggingface dataset:
Abstract 4641: Bone marrow stromal cells frustrate temozolomide treatment of glioblastoma
Authors: Mark Katakowski, Elizabeth Pikula, Steven Kalkanis, Michael Chopp
Journal: Cancer Research (2016)

Abstract Temozolomide (TMZ) is the most widely used for the treatment of glioblastoma. However, despite the effectiveness of TMZ, progression and recurrence are observed in nearly all patients. Here, we report a heretofore unknown mechanism of TMZ chemo-resistance mediated by circulating exosomes. Exosomes are small microvesicles released by cells that efficiently transfer their molecular cargo to other cells, including tumor. We recently found that in response to TMZ treatment, human bone marrow stromal cells (MSCs) release exosomes that confer TMZ chemo-resistance upon glioblastoma cells. MSCs produce exosomes which can be found in circulating blood. TMZ is distributed systemically, thus we tested the effect of TMZ upon MSC-produced exosomes, and the profile of miRNAs within the exosomes. In addition, we tested if MSC exosomes altered the response of glioblastoma cells to TMZ. To test our hypotheses, we treated MSCs with TMZ, and performed miRNA PCR arrays upon exosomes produced by the MSCs (tMSC-exo). Furthermore, we exposed glioblastoma cells to tMSC-exo, and measured the effect upon tumor cell viability, and growth in the presence of TMZ. Finally, we collected serum exosomes from patients with glioblastoma upon resection, and after TMZ treatment. We tested if exosomes from these patients before and after TMZ treatment exhibit different chemo-resistive effects, and if TMZ treatment altered the miRNA profile in circulating exosomes. We report that tMSC-exo elicit a protective effect upon glioblastoma cells treated with TMZ. The miRNA profile of MSC exosomes was also significantly altered by TMZ. Like MSC exosomes, TMZ treatment altered the miRNA profile of circulating exosomes in glioblastoma patients, and resulted in increased chemo-resistance conferred by the exosomes upon tumor cells. Investigations of TMZ chemo-resistance have largely focused upon characteristics of the tumor cells the agent is intended to kill. Here, we elucidate a novel mechanism of resistance to TMZ which does not arise from the tumor itself. Our findings suggest that circulating exosomes may diminish the efficacy of TMZ treatment of glioblastoma. Citation Format: Mark Katakowski, Elizabeth Pikula, Steven Kalkanis, Michael Chopp. Bone marrow stromal cells frustrate temozolomide treatment of glioblastoma. [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 4641.
The role of epidermal growth factor receptor mutations (EGFRm) in NSCLC with leptomeningeal metastasis: A prospective observational study.
Authors: Yan Xu, Wei Zhong, Xin Ye, Yu Bai, Jessie Xu, Lucy Yin, Jing Zhao, Minjiang Chen, Xiaotong Zhang, Xiaoyan Si, Hanping Wang, Li Zhang, Longyun Li, Yi Xiao, Zhenfan Yang, Mengzhao Wang
Journal: Journal of Clinical Oncology (2015)

e19070 Background: Leptomeningeal metastasis (LM) is one of the disastrous events when managing advanced NSCLC due to a grave prognosis with median survival less than 12 weeks. However, little is known about the mechanism of metastasis. We conducted a prospective observational study to evaluate the correlation of EGFR status between primary tumors and CSF samples from NSCLC patients with LM, and followed up the clinical outcome of these patients undergoing EGFR TKI based treatment. Methods: From November 1st, 2013 to November 30th, 2014, 17 cases of NSCLC with LM were hospitalized in PUMCH. LM was confirmed by CSF cytology. 16 patients underwent EGFR-TKIs based comprehensive treatment (EGFR-TKIs±intrathecal (IT) chemotherapy±Whole brain irradiation (WBRT)), 1 patient underwent IT chemotherapy only. The primary end point was overall survival after the diagnosis of LM. EGFR mutation detection was performed in primary tumor and CSF samples. pEGFR expression in circulating tumor cells from CSF samples was evaluated by IHC assay. Ex vivo study was conducted by adding AZD3759, an EGFR TKI, into the CSF samples and incubating for 5 min at room temperature. Results: EGFR sensitive mutations and wild type EGFR were detected in 16 and 1 patients’ primary tumors, respectively, while all 16 collected CSF samples were found EGFR-sensitive mutation positive. pEGFR expression ranged from 25% to 90% by IHC assay and H scoring. 15 primary tumors responded to EGFR TKI treatment. After EGFR-TKI based comprehensive treatment, 16 patients had some improvement in CNS symptoms and CSF opening pressures, but not CSF cytology. 5 patients died with OS ranged from 1.5 to 18.7 months. Other 11 patients are still alive with follow-up period from 2.4 to 10.8 months. The median OS was not reached. pEGFR modulation was detected in 7 out of 10 CSF samples with AZD3759 ex vivotreatment. Conclusions: EGFR mutations might play an important role in the development of LM in NSCLC patients. EGFR-TKI based comprehensive treatment might confer a clinical benefit for NSCLC with LM, while more effective treatment is still needed.
Erratum: Corrigendum: Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin
Authors: Donghyun Kim, Yun-Gi Kim, Sang-Uk Seo, Dong-Jae Kim, Nobuhiko Kamada, Dave Prescott, Dana J Philpott, Philip Rosenstiel, Naohiro Inohara, Gabriel Núñez
Journal: Nature Medicine (2016)
Abstract 4088: Adipocytes-mediated autophagy activation and metabolic reprogramming promotes colon cancer survival
Authors: Yang-an Wen, Xiaopeng Xiong, Jennifer Harris, Yekaterina Zaytseva1, Tianyan Gao
Journal: Cancer Research (2016)

Abstract Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism underlying the functional interaction between obesity and cancer remains elusive. Here, we demonstrated that adipocytes isolated from adipose tissues of colon cancer patients play an important role in promoting tumor cell survival and progression by altering cellular metabolism. In stage IV colon cancer cases, abundant adipocytes were found in close association with invasive colon cancer cells. Co-culture of adipocytes with colon cancer cells led to direct transfer of free fatty acids (FAs) released by the adipocytes to colon cancer cells. Uptake of FAs allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation, suggesting that FAs from adipocytes were used as an energy source by the cancer cells. In addition, we found that co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize FAs and blocked the growth promoting effect of adipocytes. Furthermore, we found that adipocytes induced dedifferentiation of tumor cells in primary colon cancer cells and mouse tumor organoids. Taken together, these results identify adipocytes as active contributors to the tumor microenvironment that promote tumor growth and survival by serving as an energy provider and a metabolic regulator for the embedded colon cancer cells. Citation Format: Yang-an Wen, Xiaopeng Xiong, Jennifer Harris, Yekaterina Zaytseva1, Tianyan Gao. Adipocytes-mediated autophagy activation and metabolic reprogramming promotes colon cancer survival. [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 4088.
A point mutation in the GYPC gene results in the expression of the blood group Ana antigen on glycophorin D but not on glycophorin C: further evidence that glycophorin D is a product of the GYPC gene
Authors: G Daniels, MJ King, ND Avent, G Khalid, M Reid, G Mallinson, J Symthe, B Cedergren
Journal: Blood (1993)
Associations of fibroblast growth factor 23 with urate metabolism in patients with chronic kidney disease
Authors: Teppei Sakoh, Masaru Nakayama, Takuya Tsuchihashi, Ryota Yoshitomi, Shigeru Tanaka, Eisuke Katafuchi, Akiko Fukui, Yui Shikuwa, Naohiko Anzai, Takanari Kitazono, Kazuhiko Tsuruya
Journal: Metabolism (2016)
Abstract 1248: Ibrutinib inhibits platelet aggregation through inhibition of mitochondrial respiratory chain function and suppression of Syk activation
Authors: Jie Huang, Helen Pelicano, Feng Li, Michael J. Keating, Peng Huang
Journal: Cancer Research (2016)

Abstract Ibrutinib represents a therapeutic improvement in hematologic cancers, but it is associated with bleeding-related adverse events. To minimize such adverse events and improve the therapeutic utility of this drug, it is important to understand the underlying mechanisms responsible for the adverse events. In this study, we observed that platelets isolate from the blood samples of chronic lymphocytic leukemia (CLL) treated with Ibrutinib exhibited deficiencies in collagen-mediated aggregation. Mechanistic studies identified the mitochondrial respiratory chain as a potential mediator of ibrutinib-induced impairment of platelet function. A short-term treatment of platelets isolated from human blood with ibrutinib for less than one hour led to reactive oxygen species (ROS) generation associated with inhibition of mitochondrial respiration, as evident by a reduction in oxygen consumption rate measured by a Seahorse metabolic analyser. Long-term incubation of megakaryocytes with ibrutinib markedly suppressed the expression of mitochondrial electron transport chain components in platelets and a reduction in mitochondrial respiration. Interference with the respiratory chain by rotenone also resulted in similar reduction in collagen-induced platelet aggregation. Interestingly, ROS generation upon collagen stimulation induced tyrosine phosphorylation of Syk (spleen tyrosine kinase) to activate platelet, while impairment of respiratory chain induced by ibrutinib diminished collagen-evoked activation of the Syk pathway. These data suggest that ibrutinib suppresses mitochondrial respiration, leading to defects in collagen-induced platelet aggregation, potentially through inhibiting the activation of the Syk pathway. Citation Format: Jie Huang, Helen Pelicano, Feng Li, Michael J. Keating, Peng Huang. Ibrutinib inhibits platelet aggregation through inhibition of mitochondrial respiratory chain function and suppression of Syk activation. [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 1248.
Abstract 3299: Bacterial DNA integrations in the genomes of gastric tumor and adjacent samples
Authors: Kelly Robinson, Nikhil Kumar, Javier Torres, Julie C. Dunning Hotopp
Journal: Cancer Research (2016)

Abstract There are 10 times more bacterial cells in the human body than human cells, and various bacteria are known to influence carcinogenesis. While viral DNA integrations in the human genome have been shown to promote carcinogenesis, bacterial DNA integrations (BDI) into the human genome are rarely investigated. Our previous analysis of publicly available sequencing data from the Cancer Genome Atlas showed BDIs from Pseudomonas spp. rRNA into the 5’-UTR of four proto-oncogenes as well as in Ig (the immunoglobulin gene) of gastric cancer samples. However, we were left with many unanswered questions when we were unable to obtain the materials required to validate our findings. Therefore, we sought to sequence a different cohort of gastric cancer patients in order to identify BDIs. Whole exome sequencing was completed on seven tumor samples and six adjacent gastric samples, as well as one intestinal metaplasia sample and one non-atrophic gastritis sample. Four of those samples were also investigated with transcriptomics and whole genome sequencing. Using our previously published BWA-based pipeline, we identified putative BDIs from Helicobacter pylori rRNA into numerous genes in one tumor sample as well as in its adjacent matched sample, including BDIs in the Ig locus. Helicobacter pylori is considered a carcinogen by the World Health Organization due to its ability to promote carcinogenesis in gastric tissue, causing us to speculate that these integrations could be carcinogenic. Similarly to our analysis of the Cancer Genome Atlas data, we also identified a few samples with BDIs from Pseudomonas spp. and about half of the samples possessed BDIs from other bacteria. We identified at least one BDI in each sample regardless of the sequencing data type. Validation of these results is ongoing and will be presented. Given these results, more consideration should be given to BDIs into the human genome when bacterial associations with diseases are suspected. Citation Format: Kelly Robinson, Nikhil Kumar, Javier Torres, Julie C. Dunning Hotopp. Bacterial DNA integrations in the genomes of gastric tumor and adjacent samples. [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 3299.
PTH-209 Patient experiences of parenteral nutrition in an acute teaching hospital: Abstract PTH-209 Table 1
Authors: NJ Wyer, C Carpenter
Journal: Gut (2015)

<h3>Introduction</h3> There is a lack of research investigating the experience of patients with intestinal failure (IF) who require parenteral nutrition (PN) in acute care. The NCEPOD national audit (Stewart <i><i>et al.</i></i>2010) demonstrated high levels of complications in patients receiving PN. Furthermore, gastrointestinal symptoms caused by IF require complex regimens of medication and the modification or restriction of fluid and diet. It is recommended that all acute hospitals should have a nutrition team (NICE 2006), however nutrition teams need to better understand how to best support patients receiving PN in hospital. The aim of this study was to explore the patient experiences of receiving PN in the acute healthcare setting. <h3>Method</h3> Descriptive phenomenology was the chosen methodology. Purposive sampling was used to recruit ten participants who had received PN for &gt;7 days in an acute teaching hospital. In-depth interviews were conducted, which were audio-recorded. The interviews were transcribed verbatim and qualitatively analysed, guided by Colaizzi’s (1978) approach. <h3>Results</h3> PN was universally considered positive by patients. It was ‘life saving’ and they felt it unlikely that they would have survived the hospital admission without it. Three core themes and seven subthemes were identified: <h3>Conclusion</h3> Patients who require PN wish to be heard and be involved in decisions about their nutritional care; however healthcare professionals in acute care frequently fail to operate in a patient centred manner. This is particularly evident when several clinical teams are involved and when enteral nutrition is being introduced. When conflicting nutritional advice is given to patients it affects their trust and confidence in the clinical teams. The patient experience whilst on PN could be improved by nutrition teams having greater autonomy regarding the provision of nutritional advice and by providing more support to patients on dealing with the altered relationship with eating. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Colaizzi, P. (1978) Psychological Research as a Phenomenologist Views it. In <i>Existential Phenomenological Alternatives for Psychology</i>. Ed. by Valle, R. and King, M. New York, NY: Oxford University Press, 48–71 NICE (2006) <i>Nutrition Support in Adults: </i>Oral Nutrition Support<i>, Enteral Tube Feeding and Parenteral Nutrition</i>: NICE Stewart JAD, Mason DG, Smith N, Protopapa K, Mason M. <i>A Mixed Bag</i>. An Enquiry into the Care of Hospital Patients Receiving Parenteral Nutrition: NCEPOD, 2010
Abstract 1113: Mir-194-3p suppresses tumorigenic potential of glioblastoma stem cells by targeting the canonical NF-kB pathway
Authors: Rajbir Singh, Kamalakannan Palanichamy, John R. Jacob, Arnab Chakravarti
Journal: Cancer Research (2016)

Abstract Glioblastoma (GBM) is the most common tumor of the central nervous system, with its deadly nature owing to high rates of invasion and angiogenesis. A key element in its pathogenesis is a small subpopulation of neoplastic cells called glioma stem cells (GSCs) that are responsible for tumor initiation, maintenance and relapse. Approaches to target GSCs have mostly proved futile due to their chemo- and radio-resistance potential. Given that microRNAs carry a potential to affect both normal and stem cells, we employed a microRNA-based targeted approach to identify the subset of microRNAs that could distinctively affect the stemness of GSCs. Our study tests the hypothesis that GSCs will show an altered miRNA expression upon their differentiation, and their profiling may lead to identification of specific microRNAs that regulate the process. Our initial efforts resulted in identification of hsa-miR-194-3p as one of the potential candidates, which was consistently downregulated in multiple GSCs that we investigated. Stable cell lines overexpressing hsa-miR-194-3p showed a decreased proliferation rate and reduced sphere-forming ability. In silico analysis revealed TAB2, an upstream activator of NF-κB pathway to be the potential target of hsa-miR-194-3p, which was confirmed by luciferase assay and knockdown approaches. The regulatory role of hsa-miR-194-3p was substantiated by its ability to inhibit the NF-κB pathway and the corresponding downstream targets including IL-6 and STAT3. In vivo studies revealed a reduced tumor forming ability when the cell lines overexpressing hsa-miR-194-3p were injected intracranially in NOD/SCID mice, compared with the non-target control. Our results indicate that hsa-miR-194-3p blocked the canonical NF-κB signaling and negatively affected tumor formation. We have carried out this study this in a unique model system expecting it to uncover another layer of complexity that may add a new facet to meet the challenge imposed by the cancer stem cell paradigm. In conclusion, we accentuate the anti-tumorigenic role of hsa-miR-194-3p as a connecting link to both stemness and NF-κB signaling. Funding sources: This work was supported by R01CA108633 (To AC), 1RC2CA148190 (To AC) U10CA180850-01 (To AC), 1R01CA169368 (To AC) from the National Cancer Institute (NCI), Brain Tumor Funders Collaborative Grant (To AC), Ohio State University Comprehensive Cancer Center Award (To AC). Citation Format: Rajbir Singh, Kamalakannan Palanichamy, John R. Jacob, Arnab Chakravarti. Mir-194-3p suppresses tumorigenic potential of glioblastoma stem cells by targeting the canonical NF-kB pathway. [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 1113.
Abstract 3035: Decrease Of Aortic Valve Area In A Hypercholesterolemic Rabbit Model Is Reversed By Short-term ApoAI-treatment
Authors: Walter S Speidl, Borja Ibanez, Carlos G Santos-Gallego, Mario J Garcia, Valentin Fuster, Martin E Goldman, Juan J Badimon
Journal: Circulation (2007)

Background. Aortic valve stenosis (AVS) is the second most common indication for heart surgery. Althoug recent observations linked AVS and atherosclerosis, medical treatment of AVS is limited. ApoAI-Milano (ApoAI-M) is a mutant form of ApoAI. We have recently shown that ApoAI-M rapidly regressed established atherosclerotic lesions in a hypercholesteremic rabbit model. The aim of this study was to test whether hypercholestermia decreases AVA in rabbits and whether this can be reversed by short-term ApoAI-M-treatment. Methods. We used transthoracic echocardiography (Philips HD 11 XE echograph with a 12-MHz phased-array probe) to compare AVA, as determined by continuity equation, of 14 white New Zeeland rabbits, fed with atherogenic diet (0.2 % of cholesterol) for nine month, with 6 healthy controls. The hypercholesterolemic animals were then randomized into ApoAI-M (ETC-216; Pfizer): 2 injections (75mg/Kg) in 4 days, or placebo. Six days after the last dose, we assessed aortic valve morphology by echocardiography and histopathology. Results. Hypercholesteremic diet resulted in a markedly reduced AVA compared to controls (0.17±0.02cm2 vs. 0.21±0.03cm2, p&lt;0.01). ApoAI-M treatment increased AVA by 27 % (p&lt;0.05) whereas placebo had no effect, resulting in significantly higher AVA in treated rabbits (0.22±0.03cm2 vs 0.16±0.02cm2, p&lt;0.005). Histopathologic cross-examination showed markedly reduced thickness of aortic valve leaflets in ApoAI-M-treated rabbits. Conclusion. We show that reduction of AVA can be induced experimentally in hypercholesterolemic rabbits and can be investigated by transthoracic echocardiography. In addition, this study provides for the first time evidence that AVA can be increased pharmacologically, namely by treatment with ApoAI-M.
Identification of novel EGFR ectodomain mutations based on a large database of clinical circulating cell-free DNA sequencing tests.
Authors: Christine Elaine Lee, Richard Burnham Lanman, Kimberly C. Banks, Rebecca J Nagy, Stefanie Mortimer, Daniel A. Simon, Darya Chudova, Helmy Eltoukhy, AmirAli Talasaz, Enrique Lastra, Scott Kopetz, John H. Strickler
Journal: Journal of Clinical Oncology (2016)

e23167 Identification of novel EGFR ectodomain (ECD) mutations based on a database of clinical circulating cell-free DNA sequencing testsBackground: The Cancer Genome Atlas primarily sequenced early stage, treatment-naïve cancers, whereas our laboratory primarily sequences treatment refractory metastatic solid tumors. Circulating cell-free DNA (cfDNA) next generation sequencing (NGS) has enhanced sensitivity, which may aid in the detection of emerging resistant clones. In patients with RAS wild-type metastatic colorectal cancer (mCRC) EGFRECD mutations are associated with acquired resistance to anti-EGFR therapies. Here we report the frequencies of ECD mutations in patients with mCRC. Methods: Guardant360 is a cfDNA NGS test targeting 70 genes with complete exon sequencing for single nucleotide variants (SNVs), including all 28 exons in EGFR. Analytical sensitivity ranges to 0.05% mutant allele fraction (MAF) with analytic specificity for SNVs > 99.9999%. The 25th, 50th and 75thpercentile MAF for all 13,987 patients tested from June 2014 through January 2016 were 0.2%, 0.4% and 2.5%. Results: From 2014-2016 1,347 tests were performed on 1,257 patients with mCRC. Exon 12 EGFR SNVs [median MAF(range)] with > 3 recurrences were: 8 S464X [0.9%(0.1-3.1)]; 18 G465X [0.5%(.1-3.1); 3 K467X [0.3%(.2-1.0)]; 4 I491X [0.9%(0.3-1.6)]; 11 S492X [2.1%(0.3-5.1)]. Two novel EGFR SNVs were: 20 V441X [1.3%(0.1-2.8)]; and 5 S442X [0.2%(.1-2.7)]. Range of EGFR SNVs per case was 1-6, with a single hypermutated case demonstrating many resistance sub-clones: 6 EGFR exon 12 SNVs, and 4 KRAS and 3 NRAS SNVs in codons 12 and 61, and an STRN-ALKfusion at 0.1% MAF. Conclusions: A database of cfDNA NGS results in patients with mCRC revealed EGFR ECD SNVs known to drive anti-EGFR therapy resistance. Two spatially co-located SNVs of unknown significance were discovered, and these occurred in some cases at the highest MAF of EGFR SNVs. This analysis suggests that these two novel SNVs may function as major drivers of clonal resistance.