tbuckley/cabot-search huggingface dataset:
Abstract 2784: Mitochondrial genomic backgrounds affect nuclear DNA methylation and gene expression
Authors: Carolyn J. Vivian, Amanda E. Brinker, Gerald C. Gooden, Christophe Legendre, Samuel Turpin, Devin C. Koestler, Bodour Salhia, Danny R. Welch
Journal: Cancer Research (2016)

Abstract Increasing evidence shows mitochondrial DNA (mtDNA) genetics contribute to complex diseases like cancer, but the mechanisms responsible are mostly unknown. A new genetically engineered mouse model was created that contains nuclear DNA from one mouse strain and mtDNA from different mouse strain(s), designated Mitochondrial Nuclear Exchange (MNX). We have demonstrated that specific mtDNA-nDNA combinations could modify metastasis efficiency. The underlying mechanism is hypothesized to be due to mtDNA-driven changes in nDNA expression, but how mtDNA regulates the coordinated gene expression is not yet known. Since DNA methylation is an important epigenetic modification that occurs in all vertebrate genomes and retrograde and anterograde cross-talk exists between the nuclear and mitochondrial genomes, we hypothesized that the nuclear epigenome, specifically methylation, changes as a result of mitochondrial haplotype. To test this hypothesis, we performed Meth-Seq using the Agilent Mouse SureSelectXT, RNA-Seq using Illumina HiSeq 2500®, and Affymetrix GeneChip® Mouse Transcriptome Array. Initial studies were performed using four male mouse brains (8 wk) that were pooled from different litters and cages of wild-type and MNX mice. Significant and selective differential DNA methylation and gene expression patterns were observed and indicate that there are some global, some subtle, but mostly reproducible, differences between these strains. Pathway analysis show clustering of changes involving cell adhesion, ion channels, cell surface receptors, metabolism and molecules involved in transport. Together these observations provide insights into how mtDNA could be altering epigenetic regulation and thereby contribute to cancer pathogenesis. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res, Steiner Family Fund for Metastasis Research, Kansas Bioscience Authority CA134981, P30-CA168524 Citation Format: Carolyn J. Vivian, Amanda E. Brinker, Gerald C. Gooden, Christophe Legendre, Samuel Turpin, Devin C. Koestler, Bodour Salhia, Danny R. Welch. Mitochondrial genomic backgrounds affect nuclear DNA methylation and gene expression. [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 2784.
Abstract 726: Involvement of proinflammatory chemokines in triple-negative breast cancer (TNBC)
Authors: Rosa Mistica C. Ignacio, Carla Gibbs, Eun-Sook Lee, Deok-Soo Son
Journal: Cancer Research (2016)

Abstract Objective: Triple-negative breast cancer (TNBC) accounts for 12-24% of total breast cancer, and contributes to the more aggressive, therapy-resistant and poorer outcomes. Our analysis based on The Cancer Genome Atlas (TCGA) indicated that basal-like BC subtype representing TNBC has enriched expression profiles for epidermal growth factor receptor 1 (EGFR) and transforming growth factor alpha (TGFá) compared to other subtypes. In addition, TNBC has a higher proinflammatory index compared to non-TNBC. Here we report that the proinflammatory chemokines such as CXCL1-3 and 8 are highly expressed in human TNBC cells and might be potentiated by TGFá-EGFR axis that contributes to cancer progression of TNBC. Methods: To gauge the role of TGFá-EGFR axis as a proinflammatory driver in TNBC cells, we first checked the expression profiles for EGFR family such as EGFR, HER2, ErbB3, and ErbB4 between TNBC (MCF10A, MB468, MB231, and BT549) and non-TNBC cells (MCF7, T47D). In addition, the expression levels of downstream signaling for EGFR (Akt/Erk) were measured by western blot. To dissect the role of TGFá-EGFR axis in enhancing proinflammatory index in TNBC cells, we utilized a more comprehensive study of the chemokines and chemokine receptors using human chemokine PCR array. Finally, to further confirm the role of TGFá-EGFR axis in inflammatory burden and cancer progression in TNBC, we used EGFR inhibitor and its downstream targets. Results: TNBC cells expressed more proinflammatory chemokines such as CXCL1-3 and 8 compared to non-TNBC cells. TNBC cells (MB468, MB231, and BT549) showed higher expression of EGFR which led to higher Akt activation as compared to non-TNBC cells. However, Erk is only activated in MB231. To dissect the involvement of Akt, expression of Akt isoforms in TNBC cells was accessed and Akt1 is the predominant isoform expressed in TNBC cells. To further assess the involvement of Akt1 in proinflammatory burden in TNBC cells, we used a commercial siRNA of Akt1 to knockdown Akt1. Knockdown of Akt1 significantly reduced the CXCL2 promoter activity. In addition, afatinib (an EGFR inhibitor) and MK2206 (an Akt inhibitor) significantly reduced the CXCL2 promoter activity. Conclusion: Thus, higher expression of proinflammatory chemokines CXCL1-3, and 8, via TGFá-EGFR axis-activated Akt, contributes to the inflammatory burden, probably promoting cancer progression, thereby followed by the overall high mortality in TNBC compared to non-TNBC. Citation Format: Rosa Mistica C. Ignacio, Carla Gibbs, Eun-Sook Lee, Deok-Soo Son. Involvement of proinflammatory chemokines in triple-negative breast cancer (TNBC). [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 726.
Medical Considerations before International Travel
Authors: David O. Freedman, Lin H. Chen, Phyllis E. Kozarsky
Journal: New England Journal of Medicine (2016)

The scope of illnesses that may befall international travelers is broad. A guide to preparing for the preventable causes of illness is provided. Physicians may find it useful in counseling their patients who travel internationally. QUICK TAKE VIDEO SUMMARYTravel Health and Safety 01:58
Abstract 4242: Rhodamine esters as fluorescent tumor painting agents for glioblastoma
Authors: Yu-Hsi Lin, Steven Millward, Seth Gammon, Nikunj Satani, Naima Hammoudi, Joshua Philip Gray, Lindsay E. Kelderhouse, Argentina Ornelas, Haley Schroeder, Florian L. Muller
Journal: Cancer Research (2016)

Abstract GBM remains one of the most difficult cancers to treat. Despite surgery, radiation and chemotherapy, tumors invariably recur. There is a strong correlation between extend of resection and subsequent time to recurrence and ultimate patient survival. A key challenge for the neurosurgeon is to minimize removal normal brain tissue whilst being as aggressive as possible with regards of removal of tumor tissue. Defining tumor boundary during surgery remains challenging. Fluorescent dyes such as 5- Aminolevulinic acid, have been studied as aids for tumor delineation but have failed to gain widespread acceptance in clinical practice. It has long been known that a substantial number of cancers, including Glioblastoma, exhibit a hyperpolarization of the plasma and mitochondrial membrane potential. This hyperpolarization is manifest by increased retention of lipophilic cationic dyes (Nernstian probes), such as the SPECT-CT probes 99Tc-Sestamibi and 99Tc-Tetrofosmin in both glioma cells in culture and primary tumors. We synthesized a series of ester derivatives of Rhodamine B with high fluorescence quantum yield in the red spectrum and a very favorable biological safety profile. Utilizing a series of intracranial xenografted glioblastoma pre-clinical mouse models, we show that a single I.V. injection of 1 mg/kg fluoroethylrhodamine ester (RhoFe) results in dramatic selective fluorescence in tumor but not surrounding normal brain tissue. This was observed even in tumors with minimal breakdown of the blood brain barrier, as determined by T1-contrast enhancing agents. RhoFe-tumor-selective fluorescence can remain visible up to 72 hours after injection. Similar results were obtained with Tetramethylrhodamine ester (TMRE) and rhodamine 123 (Rho123), but unlike RhoFe, TMRE proved highly toxic, while Rho123 fluorescence was both weaker and in the green spectrum, accompanied by higher endogenous auto-fluorescence. While well tolerated in vivo, RhoFe shows strong photoxicity in cell culture, suggesting potential as a photodynamic therapy agent. Taken together, these data suggest that RhoFe may be a promising tumor painting agent, with potential utility in fluorescence guided surgery as well as photodynamic therapy. Citation Format: Yu-Hsi Lin, Steven Millward, Seth Gammon, Nikunj Satani, Naima Hammoudi, Joshua Philip Gray, Lindsay E. Kelderhouse, Argentina Ornelas, Haley Schroeder, Florian L. Muller. Rhodamine esters as fluorescent tumor painting agents for 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 4242.
Abstract 1957: MicroRNA analysis paired with a novel live cell viability assay: a complete epigenetic workflow in human cancer cell lines
Authors: Samantha Lewis, Brad Hook, Don Smith, Douglas Horejsh, Trista Schagat
Journal: Cancer Research (2016)

Abstract The requirements for nucleic acid purification for use in RNA profiling have expanded with the growing interest in the role of microRNAs (miRNAs) and other small non-coding RNAs in cancer cell growth and metastasis. This evolution of expression analysis has highlighted the need for more sophisticated tools for total RNA isolation from cancer cells and tissues, beyond traditional translated messenger RNAs (mRNA). To address this need, we describe tools to isolate total RNA, for mRNA and miRNA analyses, in the context of an epigenetic workflow with cancer cell lines. In these experiments, histone deacetylase (HDAC) inhibitor treatment of different cancer cell lines was performed and expression of miRNA and mRNAs measured in parallel with assays for cell viability, cytotoxicity, and HDAC activity. This workflow multiplexes RNA and miRNA expression profiling with assays for viability and cytotoxicity to efficiently capture a more complete understanding of expression results. With this improved cell viability workflow, one experiment from the same well can yield information about cell health, cytotoxicity, HDAC activity, and mRNA plus miRNA expression profiling. Our workflow incorporates monitoring of cell health in real-time during experimental treatments, simple and effective total RNA purification, and robust quantitative PCR reagents for a comprehensive experimental design. Citation Format: Samantha Lewis, Brad Hook, Don Smith, Douglas Horejsh, Trista Schagat. MicroRNA analysis paired with a novel live cell viability assay: a complete epigenetic workflow in human cancer cell lines. [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 1957.
Abstract 2850: Role of shelterin proteins for telomere shortening in chronic lymphocytic leukemia
Authors: Ganchimeg Ishdorj, Sara EF Kost, Yunli Zang, Spencer B. Gibson, James B. Johnston
Journal: Cancer Research (2016)

Abstract Telomeres are important in maintaining the integrity of the chromosomes. A series of shelterin proteins (TRF1, TRF2, RAP1, POT1a and b, TIPP1 and TIN2), are involved in the maintenance of telomeres. In chronic lymphocytic leukemia (CLL), the telomeres are shorter than in normal B cells, with very short telomeres being associated with poor survival. In the present study, we demonstrate that the leukemia cell telomere length shortens over time were CLL are followed over year, indicating that telomere shortening in these cells is an ongoing process. When CLL cell metaphases were examined by Q-FISH, telomere length shortening was found to affect all chromosomes equally. To determine whether these telomere changes were related to alterations in the shelterin complex, protein levels of the six shelterins were determined in CLL cells and normal pooled B cells. In general, apart from TIN2, the shelterin protein levels were increased in CLL cells and TRF2 levels were higher in IgVH unmutated cells than in mutated cells. TIN2 protein levels were dramatically reduced in CLL cells as compared to normal B cells and an alternative isoform of TIN2 was observed, both in IgVH mutated and unmuted cases. TIN2 targeted RT-PCR followed by sequencing revealed a deletion of the entire exon 2, totaling 105 bp. This abnormality appeared in monoclonal B-cell lymphocytosis (MBL) indicating that this was an early event. In addition, a subgroup of patients showed an increase in the spliced form of TIN2, when followed over time, suggesting that this might provide the cell with a survival advantage. A protein translated from the spliced variant RNA is expected to be deleted for 35 amino acids at the N-terminus, which is the binding site for TRF2. As TIN2 maintains telomere structure by forming a complex of TRF1 and TRF2 with the telomere, this should not occur with the splice variant. Indicating a pathological role of spliced TIN2 in CLL, TRF2 was localized in both the nuclei and cytoplasm in CLL cells compared to localization only to the nucleus in normal B cells. To confirm the function of the spliced TIN2, we have overexpressed the both full length and spliced clones of TIN2 in HEK293 cells and are presently determining the localization of TRF2 and the ability to form a TRF2/TIN2 complex. Thus, these studies demonstrate a unique splice variant of TIN2 in CLL, which potentially may influence the formation of the shelterin complex and contribute to telomere shortening in this disease. Citation Format: Ganchimeg Ishdorj, Sara EF Kost, Yunli Zang, Spencer B. Gibson, James B. Johnston. Role of shelterin proteins for telomere shortening in chronic lymphocytic leukemia. [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 2850.
Ten-year trends in direct costs of asthma: a population-based study
Authors: H. Tavakoli, J. M. FitzGerald, W. Chen, L. Lynd, T. Kendzerska, S. Aaron, A. Gershon, C. Marra, M. Sadatsafavi
Journal: Allergy (2016)

There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011.A retrospective cohort of individuals aged 5-55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups.A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7-$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year.A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma.
Abstract 4941: Overexpression of Reg proteins in human pancreatic ductal adenocarcinoma and acinar-to-ductal metaplasia
Authors: Qing Li, Hao Wang, George Zogopoulos, Qin Shao, Jun-Li Liu, Zu-Hua Gao
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types, with a 5-year survival rate &amp;lt;5%. Tumor specific biomarkers that can aid in early detection and treatment monitoring are urgently needed in order to improve the outcomes. Human Reg family proteins (Reg1A, Reg1B, Reg3A, Reg3G and Reg4) are a group of calcium-dependent (C-type) lectins that promote cell growth and respond to inflammatory stimulants. We examined their associations with pancreatic ductal adenocarcinoma (PDAC). In patients with PDAC, the serum levels of Reg1A and 1B were significantly elevated (p = 0.0003 and 0.0018), which correlated with TNM stages of the patients. By using immunohistochemistry (IHC), the expression of Reg1A, Reg1B and Reg4 was observed in the malignant glandular epithelium of pancreatic intraepithelial neoplasia (PanIN) and invasive PDAC. The intensity of Reg1A and Reg1B staining positively correlated with the histological grades of PanIN. The serum levels and tissue expression of Reg1A and Reg1B were negatively correlated with the differentiation grades of invasive PDAC. Additionally, patchy expression of Reg1A andReg3A/G was also observed in areas with acinar-to-ductal metaplasia (ADM) adjacent to cancer cells. Our data suggests that the changes in Reg proteins were closely associated with the carcinogenesis of PDAC. Reg1A and 1B proteins showed specificity for pancreatic ductal differentiation and could be used as clinical markers for early detection of PDAC, monitoring therapeutic response and predicting tumor recurrence after therapy and tumor metastasis. The expression of Reg family proteins in both ADM and PanIN cells supports the notion that ADM could be an alternative mechanism of PDAC carcinogenesis. Citation Format: Qing Li, Hao Wang, George Zogopoulos, Qin Shao, Jun-Li Liu, Zu-Hua Gao. Overexpression of Reg proteins in human pancreatic ductal adenocarcinoma and acinar-to-ductal metaplasia. [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 4941.
Abstract 1597: Claudin-1 expression promote TNF-a-induced epithelial-mesenchymal transition and growth in colorectal adenocarcinoma cells
Authors: Ajaz Ahmad Bhat, Rizwan Ahmad, Amar B. Singh, Punita Dhawan
Journal: Cancer Research (2016)

Abstract Epithelial-mesenchymal transition (EMT) is an important mechanism in colorectal cancer progression and malignancy. Importantly, inflammatory mediators are critical constituents of the local tumor environment and an intimate link between colon cancer progression and inflammation in now validated. Notably, we and others have previously reported key role of the deregulated claudin-1, a tight junction protein, in colon carcinogenesis including colitis-associated colon cancer (CAC). Of interest, the increase in claudin-1 expression in CAC was found to be associated with the inflammatory epithelium. We have further demonstrated that inflammation induced by DSS (Dextran Sodium Sulfate) administration promotes colon cancer in APCmin/Claudin-1 transgenic mice. However, what role claudin-1 plays in inflammation-induced colon cancer remains unclear. In current study, we tested the causal significance of claudin-1 expression in inflammation-associated colon cancer using colon cancer cells subjected to TNF-αα, a pro-inflammatory cytokine, treatment. HT29 colon adenocarcinoma cells cultured in the presence of TNF-α (10ng/ml), demonstrated a sharp decrease in E-cadherin expression and an increase in Vimentin expression versus control cells suggesting TNF-αα treatment induced EMT. Also, significant increase in cell proliferation and wound healing was observed in TNF-α treated cells at 24 and 48 hours of TNF-αα treatment (versus control cells). Interestingly, TNF-αα treatment also upregulated (and delocalized) claudin-1 expression in a time-dependent manner. An increase in the phosphorylation of Erk1/2 and Src, signaling associated with colon cancer survival and transformation, in TNF-αα treated cells further correlated with our published observations that claudin-1 expression promotes these signaling pathways in colon cancer cells. In support, shRNA-mediated inhibition of claudin-1 expression in HT-29 cells largely abrogated the effects of TNF-αα treatment including proliferation, p-erk and p-Src expression. Also, TNF-αα induced EMT was largely suppressed in the absence of claudin-1 expression. Taken together, our data confirm the previously described key role of claudin-1 in regulating tumorigenic abilities of colon cancer cells and further highlights a key role of claudin-1 in inflammation-induced colorectal cancer growth and progression. We predict claudin-1 expression can serve as a biomarker to predict CAC progression and malignancy. Citation Format: Ajaz Ahmad Bhat, Rizwan Ahmad, Amar B. Singh, Punita Dhawan. Claudin-1 expression promote TNF-a-induced epithelial-mesenchymal transition and growth in colorectal adenocarcinoma cells. [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 1597.