tbuckley/cabot-search huggingface dataset:
Abstract 5564: The interplay between etiology-dependent genomic and epigenetic signatures: The paradigm of liver cancer
Authors: Izhak Haviv, Shira Perez, Anat Lavi-Itzkovitz, Antony Kaspi, Ana Tover, Assam El-Osta, Gur Yaari, Salomon Stemmer, Meital Gal-Tanamy
Journal: Cancer Research (2017)

Abstract The evolutionary theory assumes that occurrence of mutations in cancer is random. However, recent studies suggest that passenger mutations are not randomly scattered in cancer genomes and that chromatin organization dictate mutations profiles. Hepatocellular carcinoma (HCC) serves as a model of diverse spectrum of cancers, since it is induced by a number of well-known etiological agents, mainly Hepatitis C virus (HCV) and Hepatitis B virus (HBV). This provides a unique opportunity to test whether different etiological agents dictate distinct mutational landscapes across the genome through a unique epigenetic signature. The HCC-specific genomic mutations were studied in 80 HCC biopsies from three etiology groups - HBV, HCV, or other. To explore the mutational signature we performed target high-resolution sequencing that enables the detection of low-frequency passenger mutations. By using this strategy we identified novel distinct etiology-dependent regional mutations signature in specific genes and pathways in HCC that was not detected previously by exome sequencing of liver tumors. These observations suggest that viral infection modulate somatic mutations causing HCC. To explore the link between genomic signature and genome wide chromatin organization we studied the epigenetic changes occur following HCV infection. Epigenetic analysis unraveled known and novel pathways that are controlled by the virus such as Hepatic lipid metabolism, cell motility, cell cycle and immunity. Invers correlation between high mutation rate and enrichment of chromatin modifications associated with active transcription provides a link between etiology and cancer genome. Our novel approach offers a perspective into the mechanisms that shape mutational signature development in cancer. Note: This abstract was not presented at the meeting. Citation Format: Izhak Haviv, Shira Perez, Anat Lavi-Itzkovitz, Antony Kaspi, Ana Tover, Assam El-Osta, Gur Yaari, Salomon Stemmer, Meital Gal-Tanamy. The interplay between etiology-dependent genomic and epigenetic signatures: The paradigm of liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2017-5564
Abstract 2160: Novel sulfonamide derivative inhibits JAK2-STAT3 signaling and induces ROS-mediated apoptosis in colorectal cancer cells
Authors: Rehan Ahmad, Mansoor-Ali Vaali-Mohammed, Omar Al-Obeed, Maha Abdulla
Journal: Cancer Research (2017)

Abstract Colorectal cancer is a major worldwide health problem owing to its high prevalence and mortality rate. Developments in screening, prevention, biomarker, personalized therapies and chemotherapy have improved detection and treatment. However, despite these advances many patients with advanced metastatic tumors will still succumb to the disease. New anti-cancer agents are needed for treating advance stage colorectal cancer as most of the deaths occur due to cancer metastasis. A recently developed novel sulphonamide derivative, 4-((2-(4-(Dimethylamino)phenyl)quinazolin-4-yl)amino)benzenesulfonamide (3d) has shown to have potent antitumor effect; however the mechanism underlying the antitumor effect remains unknown. Our study revealed that 3d treatment significantly reduced the viability of human colorectal cancer cells HT-29 and SW620. This is further evidenced by the induction of p53 and Bax, release of cytochrome c, activation of caspase-9, caspase-7 and caspase-3 and cleavage of PARP in 3d treated cells. This compound was found to have significant effect on the inhibition of anti-apoptotic proteins, Bcl2, BclxL and XIAP. The results further demonstrate that 3d inhibited JAK2-STAT3 pathway by decreasing the constitutive and IL-6-induced phosphorylation of JAK2 and STAT3. 3d further decreased JAK2- STAT3 target genes like Cyclin D1 and Survivin. Furthermore 3d treatment induced the generation of reactive oxygen species (ROS) in human colorectal cancer cells. Confirming our observation, NAC significantly inhibited ROS production, induction of apoptosis, cytochrome c release and PARP cleavage. Additionally, treatment with 3d resulted in decreased glutathione (GSH) levels. The results further demonstrate that 3d inhibited cell migration by modulating EMT markers and inhibiting TGFβ-induced phosphorylation of Smad2 and Samd3. Collectively these findings indicate that 3d inhibited JAK2-STAT3 signaling; induced apoptosis via generation of reactive oxygen species and inhibition of cell migration by altering EMT markers and TGFβ-Smad pathway. Note: This abstract was not presented at the meeting. Citation Format: Rehan Ahmad, Mansoor-Ali Vaali-Mohammed, Omar Al-Obeed, Maha Abdulla. Novel sulfonamide derivative inhibits JAK2-STAT3 signaling and induces ROS-mediated apoptosis in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2160. doi:10.1158/1538-7445.AM2017-2160
Abstract 5360: DNA repair increases sequencing accuracy without altering actual mutation frequency in clinical samples
Authors: Pingfang Liu, Lixin Chen, Laurence Ettwiller, Eileen Dimalanta, Theodore B. Davis, Thomas C. Evans
Journal: Cancer Research (2017)

Abstract Targeted cancer therapy based on genomic alterations can be remarkably effective. Currently, cancer genome profiling using next generation sequencing (NGS) is routinely applied in cancer care to guide personalized treatment. The accuracy of this profiling directly impacts therapeutic choices and the outcomes of patient care. We previously showed that false positive variants are abundant and can account for a major fraction of identified somatic variations in publicly available datasets (doi: http://dx.doi.org/10.1101/070334). These false positive variants show signs of mutagenic DNA damage. We further demonstrated that enzymatic DNA repair increases sequencing quality by lowering damage-induced background noise. Therefore, enzymatic DNA repair has the potential to improve sequencing accuracy, avoiding incorrect somatic variant calls and consequently reducing incorrect diagnostic conclusions. In this study, we investigated whether enzymatic DNA repair introduces any bias to NGS libraries using analysis by droplet digital PCR (ddPCR) and deep sequencing. DNA Reference Standards containing multiple common cancer mutations (Horizon Discovery, Inc.) were spiked into formalin-fixed paraffin-embedded (FFPE) DNA isolated from tumor samples from different tissue types at defined frequencies (0.5-10% quantified by ddPCR). Genotyping of the FFPE DNA ensured that they were free of any of the spiked-in mutations. After DNA repair and library preparation, mutation frequencies were quantified by ddPCR, and compared to the mutation levels in input DNA and control libraries without repair. Deep sequencing of 151 cancer genes including these spike-ins showed no difference in mutation frequency for the spiked-in mutations between the control and repair groups. However, the number of false positive variant calls was reduced in the repair group. Our data demonstrates that DNA repair significantly increases sequencing accuracy without altering the frequency of actual mutations in tumor samples. Citation Format: Pingfang Liu, Lixin Chen, Laurence Ettwiller, Eileen Dimalanta, Theodore B. Davis, Thomas C. Evans. DNA repair increases sequencing accuracy without altering actual mutation frequency in clinical samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5360. doi:10.1158/1538-7445.AM2017-5360
Abstract 2271:DNMT1expression is peripheral mononuclear cells is associated with increased breast cancer risk
Authors: Lissette Delgado-Cruzata, Xinran Ma, Yuyan Liao, Maya Kappil, Regina M. Santella, Mary Beth Terry
Journal: Cancer Research (2017)

Abstract Loss of global DNA methylation in peripheral tissue has been identified as a biomarker of breast cancer susceptibility in several studies. DNA methyl-transferases or DNMTs are the enzymes in charge of catalyzing the addition of the methyl group to the DNA molecule. Of the different DNMTs described in humans, only DNMT1 has been found to be in charge of adding methyl groups to the newly synthesized DNA strand. Therefore, compromised levels of this enzyme might lead to a loss of global DNA methylation and concomitantly an increase in breast cancer risk. However, to date no study has examined the association between peripheral levels of DNMT1 and breast cancer. To investigate this relation, we conducted a case-control study including sisters in the New York site of the Breast Cancer Family Registry. We extracted mRNA from peripheral mononuclear cells (PMNC) in 196 sister sets, a total of 479 female participants, and assayed DNMT1 gene expression levels using Taqman expression assays. The results were analyzed using generalized estimating equations (GEE). We found that there were no large differences between the mean levels of DNMT1 expression levels of women with breast cancer and controls; mean level in cases was 0.46 ± 0.71 versus 0.63 ± 1.42 in controls (p=0.10). When examining expression levels as a continuous variable, there also were no associations in GEE regression models adjusting for age at blood drawn and smoking status Odds Ratio (OR) = 1.17 (95% confidence interval (CI) = 0.97 - 1.40 per one unit increase in expression levels), p=0.11). However, when results were analyzed by categorizing DNMT1 expression in tertiles, lower DNMT1 expression (≤ 0.17%) was associated with statistically significantly higher odds of breast cancer (OR = 1.47 (95%CI = 1.02 - 2.10), p=0.04). If replicated in other studies, these findings suggest that low DNMT1 expression in PBMC has the potential to be used as a biomarker of breast cancer risk in women at high risk of the disease. Citation Format: Lissette Delgado-Cruzata, Xinran Ma, Yuyan Liao, Maya Kappil, Regina M. Santella, Mary Beth Terry. DNMT1 expression is peripheral mononuclear cells is associated with increased breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2017-2271
Abstract 4770: Novel CXCR3 allosteric modulators inhibit breast cancer stem cells and metastasis
Authors: Namita Kundu, Regine Brox, Xinrong Ma, Jocelyn Reader, Nuska Tschammer, Amy M. Fulton
Journal: Cancer Research (2017)

Abstract There is an urgent need to identify molecular targets that are relevant to metastatic and/or stem-like cancer cells (CSC). Theoretically, surface-expressed G-protein coupled receptors on CSC are attractive therapeutic targets. There is considerable evidence that the inflammatory milieu of the tumor microenvironment drives CSC and we now show that two isoforms of the chemokine receptor CXCR3 play important but distinct roles in cancer behavior. In the bulk tumor cell population, CXCR3, isoform A is highly expressed relative to CXCR3B. CXCR3A is critical to metastatic success. CXCR3, isoform B, is highly upregulated in breast cancer CSC. When CXCR3B is gene-silenced in a model of basal-type, metastatic breast cancer, tumorsphere-forming capacity is reduced and the aldehyde dehydrogenase-positive (ALDH1+) population is correspondingly decreased. Conversely, overexpression of CXCR3B enhances these CSC properties. Thus, CXCR3B is critical to maintenance of the phenotype and function of breast CSC. CXCR3 ligands CXCL9, CXCL10 and CXCL11 all bind with high affinity to CXCR3, however, each ligand is coupled to different intracellular signaling pathways. For example, others have reported that, in HEK cells, CXCL10 strongly induces ERK activation, but CXCL11 does not. In our hands, CXCL11 more potently induces an ALDH1+ population in MDA-MB-231 cells compared to CXCL10. We have developed novel allosteric modulators of CXCR3 that demonstrate probe (ligand)-dependence. BD64 preferentially inhibits CXCL11-mediated β-arrestin 2 recruitment relative to inhibition of GPCR signaling; BD103 is significantly more effective at blocking CXCL11 versus CXCL10-mediated GPCR signaling. Neither BD64 nor BD103 affects the proliferation of non-CSC, however both compounds inhibit the ability of CSC to form tumorspheres. Furthermore, both CXCR3 antagonists reverse ligand-mediated induction of the ALDH1+ fraction. Most interesting is that both BD64 and BD103 effectively inhibit tumor cell colonization of the lung. These data suggest that optimal tumor control will be achieved when both metastatic, CXCR3Ahigh as well as CXCR3Bhigh CSC populations are inhibited by highly specific CXCR3 modulators. Note: This abstract was not presented at the meeting. Citation Format: Namita Kundu, Regine Brox, Xinrong Ma, Jocelyn Reader, Nuska Tschammer, Amy M. Fulton. Novel CXCR3 allosteric modulators inhibit breast cancer stem cells and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4770. doi:10.1158/1538-7445.AM2017-4770
Abstract 3323: Anticancer activity of medicinal plant and neuroglioma
Authors: Michael Quincy Shivers
Journal: Cancer Research (2017)

Abstract Neuroglioma, also called gliocytoma, is one of the common malignant tumors in central nervous system at present. Neuroglioma can make aggressive growth around brain tissue, so complete radical treatment can be realized by single excision. Nutritional and botanical treatments have been found useful in treating neuroglioma and other types of cancers. Vernonia amygdalina (VA) is a valuable medicinal plant that is widespread in East and West Africa. It has been reported to have not only diverse therapeutic effects for many tropical diseases, but has recently been shown to possess anti-cancer properties. Therefore, the goal of this research was to determine the therapeutic mechanisms of VA leaf extracts in the management of brain tumor. To achieve this goal, Human H4 neuroglioma cells were treated with different concentrations of Vernonia Amygdalina for 24 hr. Cell survival was determined by MTs assay. The extent of oxidative cell/tissue damage was determined by measuring malondialdehyde (lipid peroxidation biomarker) concentrations by spectrophotometry. Cell apoptosis was measured by flow cytometry assessment (Annexin V/PI assay). Data obtained from the MTS assay indicated that VA significantly (p &amp;lt; 0.05) reduced the viability of in H4 cells in a concentration-dependent manner. We detected a significant (p &amp;lt; 0.05) increase in malondialdehyde (MDA) concentrations in VA-treated glioblastoma cells compared to the control. Flow cytometry data showed a strong concentration-response relationship between VA exposure annexin V/PI positive cells. Taken together, our finding indicates that VA induced cytotoxicity and apoptosis in H4 cells is associated with the formation of MDA, a by-product of lipid peroxidation and biomarker of oxidative stress. At therapeutic concentrations, VA-induced cytotoxic and apoptotic effects in H4 cells is mediated by oxidative stress. Note: This abstract was not presented at the meeting. Citation Format: Michael Quincy Shivers. Anticancer activity of medicinal plant and neuroglioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3323. doi:10.1158/1538-7445.AM2017-3323
Abstract 1768: A practical tool for probing protein glycosylation in clinical samples: Application to characterizing subtypes of MUC5AC glycosylation in distinct subsets of pancreatic cancer patients
Authors: Peter Y. Hsueh
Journal: Cancer Research (2017)

Abstract Glycans are critical to protein biology and are useful as disease biomarkers. Many studies of glycans rely on clinical specimens, but the low amount of sample available for some specimens limits the experimental options. We have a method to obtain information about protein glycosylation using a minimal amount of protein, and we applied it to the study of biomarkers in the blood plasma of pancreatic cancer patients. The method works by treating proteins that were captured by antibody microarrays (2.2 x 2.2 mm) with exoglycosidases to successively expose underlying features, and then probing the native or exposed features using a panel of lectins or glycan-binding antibodies. We use an algorithm to interpret the data and provide predictions about the glycan motifs that are present in the sample. We applied the method to the analysis of the glycosylation of a biomarker, MUC5AC, found in the plasma of patients with pancreatic cancer. An O-linked glycan on MUC5AC that is elevated in the plasma of about 75% of patient had mostly 2,3 linked sialic acid on type-1 N-acetyl-lactosamine (LacNAc), whereas other glycans on MUC5AC had a 2,6 linkage of sialic acid on type-2 LacNAc. Another glycan, fucosylated and sialylated/sulfated type-2 LacNAc, which is elevated in distinct subset of patients, was on N-linked glycans, representing an unusual finding of N-linked glycans on mucins associated with cancer. Further developments are enabling the testing for consistent structural features associating with subtypes of cancer, which could improve our ability to detect and target the subtypes. The on-chip glycan modification and probing (on-chip GMAP) method provides a platform for analyzing protein glycosylation in clinical specimens and could facilitate the characterization and discovery of glycan biomarkers. Citation Format: Peter Y. Hsueh. A practical tool for probing protein glycosylation in clinical samples: Application to characterizing subtypes of MUC5AC glycosylation in distinct subsets of pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1768. doi:10.1158/1538-7445.AM2017-1768
Abstract 902: Cancer-stem-cell (CSC) marker, DCLK1-S, enhances invasive potential of cancer cells by phosphorylating/activating NFATc2: role of COL3A1 and SPARC in mediating metastatic effects of DCLK1-S/NFATc2
Authors: Malaney O. Connell, Shubhashish Sarkar, Heidi Spratt, Steven Widen, Thomas G. Wood, Pomila Singh
Journal: Cancer Research (2017)

Abstract DCLK1 expression is critically required for colon carcinogenesis in mice, and for maintaining tumorogenic potential of human colon cancer cells (hCCCs) (Singh et al, 2016). Down-regulation of DCLK1, combined with chemoprevention, eliminates CSCs, and avoids colon cancer relapse (Kantara et al, 2014). We recently discovered that long (L) and Short (S) isoforms of DCLK1 (DCLK1-L/DCLK1-S) are transcribed by two separate promoters (5’(α)/IntronV(β)) in the hDCLK1-gene (O’Connell et al, 2015). During adenoma-carcinoma sequence of colon-tumorigeneses, L-isoform becomes silenced by DNA-methylation while S-isoform gets upregulated by many fold (O’Connell et al, 2015). S-isoform specifically imparts invasive potential to cancer cells, unlike L-isoform (Singh et al, 2016); others have similarly reported metastatic potential of DCLK1 expressing cancer cells (Ito et al, 2016). Thus the goal of our studies was to evaluate molecular/genetic pathways mediating invasive effects of DCLK1-S in cancer cells. Isogenic clones of HCT116-cells, wild-type or down-regulated for DCLK1-S (HCT-C/HCT-D), were subjected to next generation sequencing and pathways analysis. SPARC and COL3A1 emerged as two candidate genes/proteins, which were decreased/increased by several fold in response to loss/overexpression of DCLK1-S, respectively. We present data confirming a critical role of COL3A1 and SPARC in mediating metastatic effects of DCLK1-S expression in hCCCs. We additionally discovered that DCLK1-S functions as a specific kinase for the transcriptional factor, NFATc2, and phosphorylates 53SPPS56 motif of NFATc2, resulting in activation of NFATc2 and increased expression of COL3A1. Conclusions. Our novel findings, suggest for the first time, that DCLK1-S expression by colonic tumors in humans, mediates invasive potential of colon cancer cells by phosphorylation/activation of NFATc2, resulting in up-regulation of COL3A1/SPARC; the latter proteins re-model extracellular matrix, assisting unhindered invasion of colon cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Malaney O. Connell, Shubhashish Sarkar, Heidi Spratt, Steven Widen, Thomas G. Wood, Pomila Singh. Cancer-stem-cell (CSC) marker, DCLK1-S, enhances invasive potential of cancer cells by phosphorylating/activating NFATc2: role of COL3A1 and SPARC in mediating metastatic effects of DCLK1-S/NFATc2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 902. doi:10.1158/1538-7445.AM2017-902