tbuckley/cabot-search huggingface dataset:
Abstract 4398: Identification of bile duct cancer specific fusion genes in patient tissues
Authors: Kahee Kim, Dawoon Esther Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song
Journal: Cancer Research (2017)

Abstract Gene fusion occurs when a part of one gene fuses with or attaches to a part of another gene by genome rearrangement and the result in gene fusion may possess oncogenic properties; fused gene may be translated into a unique protein that may promotes cancer properties. Bile duct cancer are one of the most lethal cancer types with low 5-year survival rates, but lack of proper diagnostic or prognostic markers. Our aim was to investigate bile duct cancer specific fusion genes found in patient’s specimens. We extracted total RNA from five bile duct cancer tissues and normal tissues from the same patients. We performed RNA sequencing and the result data was analyzed using ChimeraScan, Jaffa or Fusionchacher softwares to detect gene fusion. To identify the cancer somatic fusion gene, the fusion occurred in normal tissues and previously reported fusion genes found in normal tissues were excluded and the fusion occurred in coding region was included. As a result, we found 52 bile duct cancer tissue specific- fusion genes. We analyzed the expression of selected fusion genes in 30 bile duct cancer patients and cancer cell lines by qRT-PCR. As a result we observed two novel bile duct cancer specific fusion genes. We cloned one of the fusion genes and transfected into the bile duct cancer cell lines SNU-1196 to assess, and increase in cell motility was observed in vitro. These findings indicate the presence of novel fusion genes as well as its possible application for the early diagnosis or prognosis of bile duct cancer. Citation Format: Kahee Kim, Dawoon Esther Jung, Mi-kyoung Seo, Sang Woo Kim, Si Young Song. Identification of bile duct cancer specific fusion genes in patient tissues [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 4398. doi:10.1158/1538-7445.AM2017-4398
H1N1 vaccination in Sjögren’s syndrome triggers polyclonal B cell activation and promotes autoantibody production
Authors: Susanna Brauner, Lasse Folkersen, Marika Kvarnström, Sabrina Meisgen, Sven Petersen, Michaela Franzén-Malmros, Johannes Mofors, Karl A Brokstad, Lars Klareskog, Roland Jonsson, Lisa S Westerberg, Christina Trollmo, Vivianne Malmström, Aurelie Ambrosi, Vijay K Kuchroo, Gunnel Nordmark, Marie Wahren-Herlenius
Journal: Annals of the Rheumatic Diseases (2017)

Vaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naïve patients diagnosed with primary Sjögren's syndrome (pSS) to an H1N1 influenza vaccine.Patients with Sjögren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naïve B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology.Surprisingly, treatment-naïve patients with Sjögren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naïve B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naïve B cells to chloroquine.This comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjögren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients.
Abstract 1556: Algorithms for discovery of somatic single nucleotide mutation display specific artifacts and different detection capabilities under the effect of read coverage and sample heterogeneity
Authors: Wenming Xiao, Leihong Wu, Gokhan Yavas, Huixiao Hong, Baitang Ning, Weida Tong, Eric F. Donaldson, Zivana Tezak, Reena Philip, Howard Jacob, Louis M. Staudt
Journal: Cancer Research (2017)

Abstract Understanding the performance and capability of different bioinformatics algorithms used for the discovery of somatic variants is very important for helping scientists choose an appropriate tool for cancer research. In this study, we developed a comparison approach and created a series of data sets that could be used to provide such guidance. We mixed reads from two well characterized individuals, NA12878 and NA24385, and generated a series of data sets with different coverages and sample heterogeneity. We then used these data sets to evaluate five commonly utilized somatic mutation detection tools. Our results indicate that read coverage has a significant impact on the accuracy and capability of mutation calling by individual bioinformatics algorithms. The mutation caller that performs well with high read coverage may perform poorly with low read coverage. On the other hand, the tool that performed well in calling variants in a relatively higher homogeneity sample may not have the same power to detect rare variants with low mutation allele frequency. In addition, we demonstrated that different mutation calling algorithms are associated with specific artifacts that were sensitive to read coverage. Furthermore, there were large numbers of false positives and false negatives shared by five callers, indicating that other factors, such as read alignment, library preparation, and even the properties of the sequencing platform could be the sources of false discovery for somatic variants. We observed similar behavior of the five variant calling algorithms using the sequencing data of a pair of matched tumor/normal cell lines, confirming the findings from the comparative analyses on the mixture of reads from the two normal individuals. Our findings are expected to facilitate selection of bioinformatics pipelines that fit for specific purposes in cancer research based on sequencing data. Citation Format: Wenming Xiao, Leihong Wu, Gokhan Yavas, Huixiao Hong, Baitang Ning, Weida Tong, Eric F. Donaldson, Zivana Tezak, Reena Philip, Howard Jacob, Louis M. Staudt. Algorithms for discovery of somatic single nucleotide mutation display specific artifacts and different detection capabilities under the effect of read coverage and sample heterogeneity [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 1556. doi:10.1158/1538-7445.AM2017-1556
Abstract LB-181: Cutaneous SCC may escape immune surveillance by secreting complement factor H
Authors: Ellise Loomis, Christopher Pulford, Chandana Uppalapati, Agnes Pascual, McKale Montgomery, Kathryn J. Leyva, Elizabeth E. Hull
Journal: Cancer Research (2017)

Abstract Developing tumors evade elimination by the immune system using a variety of mechanisms. Evidence suggests that cutaneous squamous cell carcinomas (cSCCs) may evade immune system surveillance by secreting complement factor H (CFH), a regulatory protein of the complement system. As part of its normal function, CFH binds to glycosaminoglycans on the surface of host cells where it acts as a cofactor for Factor I mediated C3b cleavage and accelerates the decay of the C3-convertase C3bBb. This mechanism for protecting self-cells also involves shifting the immune response from a pro-inflammatory T-helper-1 cell to an anti-inflammatory regulatory T-cell response. Data presented here suggest that some cSCCs have the ability to upregulate expression of CFH and studies have shown that this could be in response to the pro-inflammatory cytokine interferon-γ. We suggest that, in our cSCC samples, a potential negative-feedback loop exists in which the initial immune response to the developing tumor triggers expression of an immunosuppressive molecule, allowing the cancer to create an environment conducive to evading immune surveillance mechanisms. Note: This abstract was not presented at the meeting. Citation Format: Ellise Loomis, Christopher Pulford, Chandana Uppalapati, Agnes Pascual, McKale Montgomery, Kathryn J. Leyva, Elizabeth E. Hull. Cutaneous SCC may escape immune surveillance by secreting complement factor H [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 LB-181. doi:10.1158/1538-7445.AM2017-LB-181
Abstract 2107: Tetra-arsenic hexoxide induces G2/M cell cycle arrest, apoptosis, and autophagy via p38 MAPK- and AKT-mediated pathways in SW620 human colon cancer cells
Authors: Won Sup Lee, Jeong Won Yun, Min Jeong Kim, Arulkumar Nagappan, Jing Nan Lu, Seong-Hwan Chang, Jae-Hoon Jeong, GonSup Kim, Jin-Myung Jung, Soon Chan Hong
Journal: Cancer Research (2017)

Abstract Tetraarsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980’s. Evidence suggests that As4O6 show anti-cancer effects, whose mechanisms are different from those for As2O3. However, the detailed anticancer mechanism is still unclear. Here, we investigated the anticancer effects of As4O6 on SW620 human colon cancer cells. As4O6 induced cell death in a dose-dependent manner. Flow cytometry analysis revealed that As4O6 increased the sub-G1 (apoptotic cell population) and G2/M phase population in a dose-dependent manner. Further, nuclear condensation and cleaved nuclei were also observed upon staining with Hoechst 33342 in As4O6-treated SW620 cells. Western blot revealed that As4O6 significantly down-regulated the cyclin B1, cdc 2, pro-caspases -3, -8 and -9, and up-regulated p21 and cleavage of PARP in SW620 cells. In addition, As4O6 increased the expression of death receptor 5 (DR5), suppressed Bcl-2 and XIAP family proteins, and promoted the conversion of LC3-I to LC3-II in a Beclin-1 independent manner. Interestingly, As4O6 dephosphorylated Akt and JNK and phosphorylated p38 MAPK, and the cell death was inhibited by p38 MAPK inhibitor; whereas Akt inhibitor augmented the As4O6 induced cell death, suggesting p38 MAPK and AKT were associated with As4O6-induced cell death. Taken together, these findings suggest that As4O6 induced G2/M arrest, apoptosis and autophagic cell death at least in part through p38 MAPK and AKT pathways in SW620 human colon cancer cells. This study may explain the anecdotal anticancer effects showing central necrosis with dormant status of cancers when treated by As4O6 as folk remedy. Citation Format: Won Sup Lee, Jeong Won Yun, Min Jeong Kim, Arulkumar Nagappan, Jing Nan Lu, Seong-Hwan Chang, Jae-Hoon Jeong, GonSup Kim, Jin-Myung Jung, Soon Chan Hong. Tetra-arsenic hexoxide induces G2/M cell cycle arrest, apoptosis, and autophagy via p38 MAPK- and AKT-mediated pathways in SW620 human colon 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 2107. doi:10.1158/1538-7445.AM2017-2107
Abstract 971: Genome directed diagnosis informs clinical cancer care
Authors: Alexander Penson, Niedzica Camacho, Anna M. Varghese, Adam Abeshouse, Pedram Razavi, Aijazuddin Syed, Ahmet Zehir, Nikolaus Schultz, David B. Solit, David Hyman, Barry S. Taylor, Michael F. Berger
Journal: Cancer Research (2017)

Abstract Cancer treatment is primarily guided by the organ of origin, which despite extensive histopathological and clinical evaluation, remains ambiguous in many cases and may be inaccurate in cases of occult primary. We determine the extent to which routine prospective tumour sequencing, combined with conventional histopathology, can be used to infer the tumor type and thereby direct clinical decisions. Characteristic patterns of somatic mutations, broad and focal copy number alterations, structural rearrangements, mutational signatures, and other facets acquired from prospective tumor sequencing can inform the tissue of origin classification of patient disease. Such prospective sequencing of active cancer patients presents an opportunity to guide diagnosis and therapy beyond the identification of individual biomarkers of treatment response. Probabilistic classification allows for systematic combination of genome-directed diagnosis with conventional histopathology and clinical history in the course of disease management. Using more than 10,000 tumors collected from advanced cancer patients at our institution and sequenced using a comprehensive cancer panel (MSK-IMPACT) encompassing 341 genes, we have developed a probabilistic classifier that infers the tumor type from nine broad categories of genomic aberrations. Scores from a RandomForest classifier are calibrated to correspond to the probability for each of the 22 interrogated tumor types. In 18% of all cases, a prediction is made with very high confidence (greater than 99%), of which just over 99% agree with the existing diagnosis. The classifier has been used to guide clinical decision making, including re-diagnoses that distinguish between a recurrence and a new primary, spare or encourage surgery, facilitate access to FDA-approved molecularly targeted drugs and prompt germline genetic testing. We demonstrate that genome-directed diagnosis, based on alterations routinely identified from prospective sequencing, can inform clinical cancer care with the potential to improve patient outcomes. Citation Format: Alexander Penson, Niedzica Camacho, Anna M. Varghese, Adam Abeshouse, Pedram Razavi, Aijazuddin Syed, Ahmet Zehir, Nikolaus Schultz, David B. Solit, David Hyman, Barry S. Taylor, Michael F. Berger. Genome directed diagnosis informs clinical cancer care [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 971. doi:10.1158/1538-7445.AM2017-971
Abstract 4768: A SHARP /Xist complex regulates breast cancer stem cells
Authors: Yongyou Zhu, Li Shang, Justin Colacino, Michael Brooks, Ramdane Harouaka, Chang-Ching Lin, Ming Luo, Max S. Wicha
Journal: Cancer Research (2017)

Abstract Many cancers including breast cancer display hieratical organization and are driven by a cellular sub-population that displays stem cell properties. These cancer stem cells (CSC’s) mediate metastasis and contribute to treatment resistance highlighting the importance of elucidating CSC regulatory pathways. Nuclear proteins and lncRNAs involved in the maintenance of chromatin structure have been shown to play roles in CSC regulation. Among them the polycomb proteins bmi-1 and EZH2 are involved in epigenetic regulation of CSC’s in breast and other cancers. SHARP/SPEN, an RNA binding protein, has been previously been found to bind the lncRNA Xist which, by recruiting the PRC2 polycomb complex mediates transcriptional repression of the X chromosome. We utilized breast cancer cell lines and xenograft models to examine the role of the SHARP/Xist complex in the regulation of breast CSC’s. In a series of breast cancer cell lines including MCF7 (luminal )and SUM 159 (basal/claudin low) cells, SHARP mRNA and protein as well as the lncRNA Xist were more highly expressed in cells expressing aldehyde dehydrogenase as accessed by the Aldefluor assay than in ALDH -cells . Conditional knockdown of SHARP or Xist in SUM159 significantly decreased the ALDH+ CSC population without affecting cell growth in vitro. Furthermore, SHARP or Xist knockdown significantly reduced tumor initiating capacity and growth of SUM 159 cells in NOD/SCID mice. To determine the mechanism of breast CSC regulation by the SHARP complex we compared mRNA expression patterns of control and SHARP knockdown SUM 159 cells using RNAseq. There was significant overlap between the genes regulated by SHARP with genes regulated by the PCR1 and PRC2 polycomb complexes in addition to many histone genes. These studies suggest that the SHARP/Xist complex my regulate breast CSC’s through epigenetic regulatory histone and polycomb genes. Since SHARP expression is elevated in a number of cancers including breast cancer this pathway may represent a novel therapeutic target. Citation Format: Yongyou Zhu, Li Shang, Justin Colacino, Michael Brooks, Ramdane Harouaka, Chang-Ching Lin, Ming Luo, Max S. Wicha. A SHARP /Xist complex regulates breast cancer stem 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 4768. doi:10.1158/1538-7445.AM2017-4768
Abstract 1132: Lactate dehydrogenase expression in African American women with triple-negative breast cancer
Authors: Odalys J. Torres-Luquis, Sulma Mohammed
Journal: Cancer Research (2017)

Abstract The incidence of breast cancer in African American women (AAW) is much lower than those of their Caucasian counterparts. However, the age adjusted mortality rates are much greater for AAW compared to Caucasian American women (CAW). These differences in survival between AAW and CAW were attributed to socioeconomic factors and access to health care. Yet, after adjusting these differences, AAW still had lower survival rates than CAW. Genetic and immunohistochemical studies have revealed that biological variations may account for this disparity. These studies have suggested as a causative: a higher prevalence of basal-like tumors in premenopausal AAW and low prevalence of luminal tumor. These are characterized by being high-grade aggressive tumors that are estrogen receptor negative (ER-), progesterone receptor negative (PR-), human epidermal growth factor receptor-2 (HER-2) +/-; with high rate of lymph node involvement. Despite this understanding, there is little evidence to indicate which genetic or non-genetic factors contribute to causing aggressive breast cancer thereby limiting the development of prevention and treatment option. We proposed that the phenotypic diversity of breast cancer might be accompanied by a corresponding diversity in protein expression patterns that can be reveal using proteomic technologies. We hypothesized that in addition to ER- and PR-, and the absence in expression of HER-2, the protein composition of triple-negative tumors varies among African-American and Caucasian. Two-dimensional gel electrophoresis, mass spectrophotometry and data analysis of protein from breast cancer tissues were used to identify differentially expressed proteins from African American and Caucasian women. Western blot of luminal and TNBC cell lines were used to confirm the expression of identified proteins. We have found that many proteins were differentially expressed in AAW breast cancer tissues compared to CAW. One of these is lactate dehydrogenase which was found to be overexpressed in tissues from AAW. Western blot analysis confirmed expression. Citation Format: Odalys J. Torres-Luquis, Sulma Mohammed. Lactate dehydrogenase expression in African American women with triple-negative breast 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 1132. doi:10.1158/1538-7445.AM2017-1132
Abstract 4170: Targeting androgen receptor overcomes resistance to tyrosine kinase inhibitors in advanced clear cell renal cell carcinoma
Authors: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, May Elbanna, Ben Elzey, Nur Damayanti, Kiersten M. Miles, Chinghai Kao, Piergiorgio Pettazzoni, Giulio F. Draetta, Roberto Pili
Journal: Cancer Research (2017)

Abstract Background: Advanced renal cell carcinoma (RCC) responds initially to anti-angiogenic therapies but eventually develop resistance which may be driven by the expression of key intratumoral pro-survival protein and overall kinome reprogramming. Androgen receptor (AR) expression has been reported in clear cell renal cell carcinoma (ccRCC) but its biological role remains elusive and its association with resistance to tyrosine kinase inhibitors (TKIs) has not been studied. Here we report the role of AR and its association with resistance to TKIs in advanced RCC. Methods: Human RCC cell lines; 786-0, 786-0R (with induced sunitinib resistance), ACHN, URMC2 (with intrinsic sunitinib resistance) were used to assess the combination effect of sunitinib and the AR antagonist enzalutamide in vitro. In vivo studies utilizing 786-0 tumors assessed the combination effect of enzalutamide and sunitinib following acquired resistance to sunitinib. AR expression was detected by qRT-PCR and Western blot analysis, and AR localization by immunofluorescence in treated and non-treated cells. Gene array was used to assess 93 AR associated genes in sensitive and resistant cells. Results: Quantitative RT-PCR data revealed a significant increase in AR expression with sunitinib resistance (&amp;gt;100 folds; p&amp;gt;0.001). In vitro and in vivo studies indicated significant increase in nuclear and cytoplasmic expression of AR with sunitinib treatment in resistant cells which was abrogated with single agent enzalutamide and combination treatment. More interestingly, combination treatment of enzalutamide and sunitinib significantly decreased cell growth and induced tumor regression in vitro and in vivo, respectively. Conclusion: Our data suggest the role of AR both in intrinsic and acquired sunitinib resistance in ccRCC and provide a rationale for combination strategies to restore TKI sensitivity that can be tested in the clinical setting. Citation Format: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, May Elbanna, Ben Elzey, Nur Damayanti, Kiersten M. Miles, Chinghai Kao, Piergiorgio Pettazzoni, Giulio F. Draetta, Roberto Pili. Targeting androgen receptor overcomes resistance to tyrosine kinase inhibitors in advanced clear cell renal cell carcinoma [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 4170. doi:10.1158/1538-7445.AM2017-4170