tbuckley/cabot-search huggingface dataset:
Effect Of Age and Gender On Human Platelet mRNA and Micro-RNA Levels
Authors: Lukas M Simon, Leonard C. Edelstein, Srikanth Nagalla, Angela Bergeron, Edward Chen, Xianguo Kong, Lin Ma, Satya P. Kunapuli, Michael Holinstat, Steven E. McKenzie, Jing-fei Dong, Chad Shaw, Paul F Bray
Journal: Blood (2013)
Abstract 395: Patient stratification and drug combination strategy based on drug response and genomic information from PDX clinical trials (PCTs)
Authors: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Xin K. Ye, Zhenyu Gu
Journal: Cancer Research (2016)

Abstract Cancer is a heterogeneous disease with various molecular lesions and drug response profiles within the same tumor type. Patient stratification in clinical trials based on molecular features has contributed to recent success of several targeted cancer drugs on molecular aberrations such as BCR-ABL translocation in CML, Her2 amplification in breast and gastric cancers, EGFR mutations and ALK fusions in lung cancer and BRAF mutation in melanoma. However, in most cancers, the molecular features which can be used for patient stratification are not as simple as a single genetic aberration. Multiple drug resistance mechanisms caused by various mutations in cancer signaling pathways can also increase the uncertainty of clinical outcomes. To increase the chance of success in human clinical studies, patient-derived xenograft (PDX) clinical trials (PCTs) have increasingly been used for predictive biomarker validation, resistance mechanism investigation and combination therapy selection. PDX tumor models have been demonstrated to have high correlations with human patients in tumor pathology, molecular characteristics and drug responses. Large scale PCTs have also shown consistency in results when compared to related human clinical trials. At GenenDesign, we have established over 1000 PDX tumor models and more than 100 resistance models against various cancer drugs. Many of these PDX models have been characterized at RNA/Exome sequence, gene expression, gene copy number and hot-spot mutation levels. We carried out our PDX clinical trials by testing multiple approved drugs and clinical drug candidates such as targeted inhibitors against FGFRs, c-Met/ALK, HER2, EGFR, cell cycle regulators, Ras/Raf pathway, PI3K/Akt pathway, as well as chemotherapy drugs in biomarker-driven multi-drug multi-arm expanded PDX clinical trials. So far, we have accumulated more than 3000 efficacy data sets and associated PD samples. Analysis of drug response and associated genomic information from PDX clinical trials yielded rich information for predictive biomarker identification and validation. At the same time, many potential resistance mechanisms were also revealed. These information can make human clinical trial better prepared, more efficient and focused. More importantly, testing of a targeted drug with multiple chemotherapies in the same models can also provide guidance on future combination selection strategy. Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Xin K. Ye, Zhenyu Gu. Patient stratification and drug combination strategy based on drug response and genomic information from PDX clinical trials (PCTs). [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 395.
Novel role of X-linked inhibitor of apoptosis protein (XIAP) in bladder cancer cell invasion and prediction of disease progression.
Authors: Lan Mo, Fang-Ming Deng, Abraham Chachoua, William C. Huang, Hilary Y. Ma, Herbert Lepor, Chuanshu Huang, Xue-Ru Wu
Journal: Journal of Clinical Oncology (2014)

e15504 Background: While XIAP is known to inhibit apoptosis, our group recently identified a new role of XIAP in promoting cancer cell invasion by regulating via its RING domain E3 ligase and RhoGDI. Here, we explored whether XIAP affects bladder cancer (BCa) invasion in vitro, associates with biological behaviors of BCa in transgenic models and can distinguish low-grade non-invasive from high-grade muscle-invasive BCa in humans, thus serving as a novel prognostic predictor. Methods: Cell lines from different grades of human BCa, tumors from transgenic mice exhibiting low-grade non-invasive or high-grade invasive BCa, and specimens from patients (12 normal urothelia, 43 low-grade and 53 high-grade BCa) were subject to immunohistochemistry and Western blotting for XIAP expression. siRNA-knockdown of XIAP and restoration of XIAP in the knockdown cells were performed followed by invasion assays. Results: Low- and high-expression of XIAP were closely associated with cell lines from low- and high-grade human BCa, respectively. The same trend held in low-grade non-invasive versus high-grade invasive BCa from transgenic mice. Depletion of XIAP in BCa cell lines markedly reduced cell migration and invasion; conversely, restoration of XIAP in the knockdown cells restored the invasive property. In human BCa, XIAP was undetectable in normal urothelia (0/12) and in 10/43 low-grade BCa. The majority of low-grade BCa (30/33, 90.9%) expressed low XIAP (1+), with only 3/33(9.1%) expressing moderate levels (2+). In contrast, all high grade BCa expressed XIAP, with 4 (7.5%) expressing low (1+), 38 (71.7%) moderate (2+) and 11 (20.8%) high level (3+) (Fisher’s test; P<0.0001). A strong correlation existed between high XIAP expression and high-grade BCa, suggesting that XIAP expression and tumor-grade are predictors for muscle invasive BCa. Conclusions: Overexpression of XIAP is strongly associated with high-grade, advanced stage of human BCa and may serve as a useful biomarker for predicting disease progression and a target for BCa therapy.
Abstract 87: Clustered somatic mutations are frequent in transcription factor binding motifs in melanoma and other cutaneous malignancies
Authors: Andrew J. Colebatch, Leon di Stefano, Stephen Q. Wong, Anthony T. Papenfuss, Grant A. McArthur
Journal: Cancer Research (2016)

Abstract We sought to explore the etiology, frequency and clinicopathologic associations of clustered noncoding hotspot mutations in cutaneous malignancies (melanoma, basal cell carcinoma (BCC) and Merkel cell carcinoma (MCC)). We did so by applying a sliding window approach which identified clusters in melanoma whole exome and genome sequencing data. These regions were then evaluated for recurrence in other skin malignancies by using whole exome data from BCC and MCC samples; motifs were extracted using a maximum expectation algorithm. We then sequenced 170 annotated melanoma clinical samples using a targeted amplicon panel which permitted analysis of clinicopathological correlations. Numerous recurrent clustered hotspot mutations were identified in melanoma whole exome and genome data sets in proximal promoters, with some gene-associated clusters present in up to 25% of cases. Mutations were clustered around canonical ETS and SP1 transcription factor binding sites and had a clear UV signature. These promoter mutations correlated with overall mutation load and NF1 mutation status, and showed significant enrichment in specific melanoma subtypes (desmoplastic and lentigo maligna melanoma), sun exposed anatomical locations, male gender, ulceration and increasing age. Identical clusters were identified in BCC and MCC samples, including several previously annotated in melanoma. In conclusion, we identify a novel class of mutation in cutaneous malignancies which rather than being defined by a particular genomic position are related to a position in a transcription factor binding motif. These mutations are also independent of cell of origin. Clinicopathologic correlation and mutation analysis support an etiologic role for chronic UV irradiation. Citation Format: Andrew J. Colebatch, Leon di Stefano, Stephen Q. Wong, Anthony T. Papenfuss, Grant A. McArthur. Clustered somatic mutations are frequent in transcription factor binding motifs in melanoma and other cutaneous malignancies. [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 87.
Abstract 651: Male mouse model of canine and human inflammatory breast cancer (IBC)
Authors: Sara Caceres, Laura Peña, Maria J. Illera, Gema Silvan, Paloma J. de andres, Hui Gao, Wendy A. Woodward, James M. Reuben, Juan C. Illera
Journal: Cancer Research (2016)

Abstract Inflammatory breast cancer (IBC) is an aggressive type of breast cancer with poor survival in women. Canine IBC has been proposed as a good surrogate model for the study of the human disease. Male breast cancer is a rare disease, accounting for less than 1% of all malignancies in men. Although rarely, IBC has been also found in men. The aim was to evaluate the capacity of male SCID mice to develop IBC tumors after the injection of canine and human IBC cell lines (IPC-366 and SUM149, respectively). Eighty SCID mice: 40 male and 40 females, 6-8 weeks old were used. Suspensions of 106 IPC-366 and SUM149 cells were implanted subcutaneously into the fourth inguinal mammary gland in 20 male and 20 female mice (of each cell line), respectively. Mice were inspected twice a week for the development of tumors. Tumors were monitored by palpation and measured by calipers. Mice were sacrificed when tumors reached 1.5 cm3 and tumors and organs were removed for immunohistochemical (IHC) characterization. A portion of tumor was used for hormonal analysis (Progesterone, Estradiol, Estrone sulphate, Testosterone, Androstenedione). Results revealed that IPC-366 reproduced tumors in 90% (male) vs 100% (female) after 2 weeks p.i. SUM149 reproduced tumors in 40% (male) vs 80% (female) at 4 weeks p.i. Both cell lines produced metastasis in lungs. Higher metastatic rates found in females than in males (IPC-366: 90% vs 20%; SUM149: 80% vs 50%). EIA hormonal analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors (p&amp;lt; 0.05). IHC analysis revealed that male and female tumors shared immunophenotipic characteristics. All xenografts were highly proliferative (high Ki-67 indexes), triple negative (ER-, PR-, HER-2-), vimentin positive and contained less than 10% of cells positive to AE1-AE3 and CK-14. In conclusion, IPC-366 and SUM149 cell lines can reproduce tumors in male mice capable of metastasize. Male and female xenograft models shared immunophenotypic characteristics. Male mice model would be useful for future IBC research using a different endocrine environment that could help to better understand the androgens function in canine and human IBC. Citation Format: Sara Caceres, Laura Peña, Maria J. Illera, Gema Silvan, Paloma J. de andres, Hui Gao, Wendy A. Woodward, James M. Reuben, Juan C. Illera. Male mouse model of canine and human inflammatory breast cancer (IBC). [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 651.
Hemophagocytic Lymphohistiocytosis (HLH) in 44 Adults: Results from the Retrospective Polish Registry
Authors: Rafal Machowicz, Piotr Boguradzki, Joanna Drozd-Sokolowska, Edyta Cichocka, Renata Guzicka-Kazimierczak, Agnieszka Piekarska, Justyna Gil, Krzysztof Madry, Bartosz Garus, Dorota Zdunczyk, Slawomir Rejowski, Patrycja Zielinska, Lukasz Bolkun, Patrycja Mensah-Glanowska, Malgorzata Paszkowska-Kowalewska, Anna Waszczuk-Gajda, Michal Gorka, Katarzyna Romanowska-Prochnicka, Alina Swiderska, Mateusz Ziarkiewicz, Emilian Snarski, Katarzyna Brzezniakiewicz-Janus, Agnieszka Szymczyk, Wanda Knopinska-Posluszny, Jadwiga Dwilewicz-Trojaczek, Wieslaw Wiktor-Jedrzejczak
Journal: Blood (2015)
Waxing and Waning Pruritic Cutaneous Lesions Refractory to Antibiotic Treatment
Authors: Seongseok Yun, Utkarsh Acharya
Journal: JAMA Oncology (2016)

A man in his 30s reported a 2-year history of waxing and waning pruritic papules involving his left popliteus, contralateral popliteus, groin, and penis with minimal response to antibiotics. What is your diagnosis?
Abstract 4450: Silencing NKD2 by promoter region hypermethylation promotes esophageal cancer progression by activating Wnt signaling
Authors: Mingzhou Guo, Baoping Cao, Weili Yang, Yongshuai Jin, Meiying Zhang, Tao He, Qimin Zhan, James G. Herman, Guanglin Zhong
Journal: Cancer Research (2016)

Abstract Background: Despite the use of surgery or chemoradiotherapy to treat, esophageal cancer, its prognosis still remains poor, with a 5-year survival below 15%. Recent insights into the epigenetic mechanisms associated with multi-step carcinogenesis provide new opportunities to develop novel effective targeted therapies for esophageal squamous cell carcinoma. Naked cuticle homolog 2 (NKD2) was found frequently methylated in human breast cancer. The epigenetic changes and mechanisms of NKD2 in human esophageal cancer remain unclear. Methods: Nine esophageal cancer cell lines and 154 cases of primary esophageal cancer samples were analyzed using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. Results: Loss of NKD2 expression and complete methylation were found in KYSE150 and TE1 cells. Reduced expression and partial methylation were observed in KYSE30, KYSE70, KYSE410, KYSE140 and COLO680 cells. High level expression and unmethylation were detected in KYSE450 and TE8 cells. Re-expression of NKD2 was induced by 5-aza-2’-deoxycytidine in NKD2 unexpressed or reduced cells. NKD2 was methylated in 53.2% (82/154) of human primary esophageal cancer samples, and promoter region hypermethylation was associated with reduced expression of NKD2 significantly (p&amp;lt;0.01). NKD2 methylation was associated with TNM stage and lymph node metastasis (p&amp;lt;0.01). The results suggest that NKD2 is regulated by promoter region methylation and methylation of NKD2 may serve as a prognostic marker in esophageal cancer. Our further studies demonstrate that NKD2 suppresses cell proliferation, colony formation, cell invasion and migration, as well as induces G1/S check point arrest in esophageal cancer cells. NKD2 suppressed xenograft tumor growth and inhibited Wnt signaling in human esophageal cancer cells. Conclusions: NKD2 is frequently methylated in human esophageal cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses esophageal cancer progression by inhibiting Wnt signaling both in vitro and in vivo. Citation Format: Mingzhou Guo, Baoping Cao, Weili Yang, Yongshuai Jin, Meiying Zhang, Tao He, Qimin Zhan, James G. Herman, Guanglin Zhong. Silencing NKD2 by promoter region hypermethylation promotes esophageal cancer progression by activating Wnt signaling. [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 4450.
Abstract 2597: Breast and ovarian cancer risks associated with cancer predisposition gene mutations identified by multigene panel testing
Authors: Fergus J. Couch, David E. Goldgar, Steven N. Hart, Emily Hallberg, Raymond Moore, Huong Meeks, Robert Huether, Holly LaDuca, Elizabeth Chao, Jill Dolinsky
Journal: Cancer Research (2016)

Abstract Multigene panel testing (MGPT) for hereditary cancer is increasing in popularity in the USA. Many panels include genes identified as hereditary breast and/or ovarian cancer (HBOC) genes despite limited data regarding the precise cancer risks associated with mutations in these genes. Here we report on results from BreastNext and OvaNext panel testing of 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, TP53) in a cohort of 15,083 individuals. The majority of individuals were from high-risk breast and/or ovarian (Br/Ov) cancer families, with 92.4% of all probands meeting National Comprehensive Cancer Network HBOC testing criteria. Pathogenic mutations were identified in 9.4% of the overall cohort. To estimate gene-specific breast and ovarian cancer risks, case-control analyses were performed comparing the frequencies of pathogenic mutations from Caucasian breast or ovarian cancer cases from BreastNext and OvaNext with frequencies from Caucasian, non-Finnish, non-TCGA controls from the Exome Aggregation Consortium (ExAC) database. Mutations in the well studied ATM and CHEK2 genes were associated with moderate risks (OR&amp;gt;2) of breast cancer and mutations in PALB2 were associated with high-risks (OR&amp;gt;5) of breast cancer, consistent with previous reports. In addition, the study suggested that pathogenic mutations in MSH6, RAD51D, CDH1, and NF1 are associated with moderate to high risks of breast cancer. In contrast, RAD51C, RAD51D, and BRIP1 mutations were associated with high risks of ovarian cancer, PALB2 mutations were associated with moderate risks, but ATM and CHEK2 mutations were not associated with increased ovarian cancer risk. In addition, modeling of missense mutations in the predisposition genes using in silico prediction algorithms suggested that missense mutations in CDH1, CHEK2, MSH2, and MSH6 are associated with moderate risks of breast cancer and missense mutations in RAD51C increase risks of ovarian cancer. This large breast and ovarian cancer case-control analysis provides useful data for many predisposition genes previously lacking risk estimates, and should prove useful for clinical risk management of patients after clinical panel testing. Citation Format: Fergus J. Couch, David E. Goldgar, Steven N. Hart, Emily Hallberg, Raymond Moore, Huong Meeks, Robert Huether, Holly LaDuca, Elizabeth Chao, Jill Dolinsky. Breast and ovarian cancer risks associated with cancer predisposition gene mutations identified by multigene panel testing. [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 2597.
Specific gene signatures and oligo clonal expansion of b cell repertoire with responders of anti-PD-1 antibody, nivolumab for ovarian cancer: Novel predictive biomarkers.
Authors: Junzo Hamanishi, Ryusuke Murakami, Masaki Mandai, Noriomi Matsumura, Kaoru Abiko, Ken Yamaguchi, Tsukasa Baba, Ikuo Konishi
Journal: Journal of Clinical Oncology (2016)

5513 Background: Previously we reported a phase II clinical trial for platinum resistant ovarian cancer (n = 20) with anti PD-1 antibody, nivolumab and showed RR was 15% including two CRs and one PR (Hamanishi. JCO. 2015). Here we present biomarker data using the tumor and blood samples from patients in this clinical trial. Methods: RNA expression microarray of tumor samples was applied to gene signature of ovarian cancers including clear cell (CCC) gene signature (Yamaguchi. Oncogene 2008) and four gene signatures (Proliferative, Mesenchymal, Differentiated and Immunoreactive) of The Cancer Genome Atlas (Verhaak. JCI 2013) by scoring with ssGSEA. Additionally, we analyzed TCR (α- and β-chain) and BCR (IgG and IgM) repertoires in 64 blood samples from 20 patients treated with nivolumab throughout the time courses of treatment with an unbiased repertoire analyses. The diversity of TCR and BCR repertoires were compared with Shannon-Weaver index (SWI) between clinical responders and non-responders. RNA expression microarray with blood samples of both pre- and post- treatment with Nivolumab was analyzed. Results: ssGSEA revealed the CCC signature score was significantly high in two CRs (p = 0.005), while proliferative signature scores were significantly higher in the patients with a PD. BCR repertoire analyses of post treatment in responders revealed significant decreasing of diversity of BCR-IgG repertoires compared to non-responders transiently (SWI, 0.84 vs 1.04, p < 0.05), while over 100 days later, the diversity of IgG-BCR went back to original expansion. However the diversity of TCRs nor BCR-IgM repertoire were not affected by nivolumab. RNA microarray with blood samples of post treatment in responders showed several B cell related genes such as IL-1R2, CD24,CD37 were upregulated compared to in non-responders (p < 0.05, each). Conclusions: This study, to our knowledge, is the first to describe upregulation of specific gene signatures of tumors and transient oligo clonal expansion of B cell with nivolumab for ovarian cancer. B cell analysis may lead to the early response biomarker and novel anti-tumor monitoring of nivolumab treatment.
Abstract 4183: Targeting mTOR signaling during gliomagenesis
Authors: Daniela Torres, Angelina Mela, Canoll D. Peter
Journal: Cancer Research (2016)

Abstract Diffusely infiltrating gliomas are the most common type of primary brain tumor seen in adults. In a subset of patients, these tumors present as low grade lesions that progress to high grade glioma (HGG). Conventional treatment for gliomas includes surgical resection followed by radiation and temozolomide. Glioma cells invade peripheral brain tissue making complete surgical resection impossible and despite aggressive treatment tumor recurrence is inevitable. Current research has focused on identifying new therapeutic targets, mainly in HGG. However, investigating the therapeutic targets at early stages of gliomagenesis could provide a novel approach for the treatment of low grade gliomas (LGG). Gliomas have been characterized by gene expression profiles and classified into distinct subtypes including proneural, classical and mesenchymal. Proneural gliomas, which account for the majority of LGG, show high expression of PDGFRα and frequently harbor p53 mutations. The resulting alterations in PDGFRα signaling and inactivation of p53 both induce an upregulation in mTOR signaling, which contributes to gliomagenesis via its regulation of cell growth and proliferation. Thus, inhibiting mTOR signaling should have a robust effect on glioma growth. However, inhibiting mTOR signaling in HGG has had limited success. This may be due to the accumulation of genetic alterations that occur during glioma progression resulting in loss of sensitivity to the anti-tumor effects of mTOR inhibitors. We hypothesize that inhibiting mTOR signaling at early stages of gliomagenesis will be more effective. To test this hypothesis we are characterizing the effects of mTOR inhibition at different stages of gliomagenesis in our proneural glioma mouse model. We assessed the effects of inhibiting mTOR with the ATP-competitive mTOR inhibitor (AZD8055) in vitro and in vivo. Our preliminary data show that AZD8055 inhibits mTOR activity and reduces glioma cell viability in vitro. Inhibition of mTOR in our proneural glioma model showed that AZD8055 crosses the blood brain barrier and effectively inhibits mTOR in glioma cells within the tumor, as well as in the surrounding brain tissue. In addition, we have characterized mTOR activity at different time points in glioma formation and show upregulation of mTOR activity during early stages of gliomagenesis. Our findings support the role of mTOR in early stages of gliomagenesis and motivate our ongoing studies to test the effects of AZD8055 for the treatment of LGG. Citation Format: Daniela Torres, Angelina Mela, Canoll D. Peter. Targeting mTOR signaling during gliomagenesis. [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 4183.