tbuckley/cabot-search huggingface dataset:
Abstract 5296: Evaluation of p16/Ki-67 dual stain, cytology, and HPV16/18 genotyping for triage of HPV-positive women in a large screening population
Authors: Nicolas A. Wentzensen, Barbara Fetterman, Renee Bremer, Philip Castle, Diane Tokugawa, Nancy Poitras, Elizabeth Hosfield, Thomas Lorey, Mark Schiffman, Walter Kinney
Journal: Cancer Research (2017)

Abstract Objectives: Primary HPV testing has been approved in the United States. Screening intervals can be safely extended for HPV-negative women, but the challenge lies in discriminating transient HPV infections from precancers among HPV-positives. In a large study at Kaiser Permanente Northern California (KPNC), candidate strategies for triage of HPV-positive women are being evaluated, including cytology, p16/Ki-67 dual stain (DS, CINtec PLUS) and HPV16/18 genotyping (cobas). Methods: Over 13,000 HPV-positive women participating in cervical cancer screening at KPNC were enrolled. The dual stain and HPV genotyping assays were implemented and conducted at KPNC. Baseline results for 7,124 women are available and detection of CIN3 is currently evaluated only in cytology-positive women. Results: Among 7,124 HPV-positive women, 4,107 (57.7%) were cytology-positive (ASC-US+), 3,056 (42.9%) were DS-positive, and 1,406 (19.7%) were positive for HPV16 or HPV18. Among all 3,017 HPV-positive, cytology-negative women, 911 (30.2%) were DS- positive, and 508 (16.8%) were positive for HPV16 or HPV18. Of 315 CIN3 detected so far, 280 (88.9%) were DS-positive and 176 (55.9%) were positive for HPV16 or HPV18. Major triage strategies including cytology alone, DS alone, as well as combinations of cytology and genotyping, and DS and genotyping will be presented at the meeting. Discussion: In one of the largest clinical implementation studies of triage strategies, we showed that primary HPV screening followed by DS can reduce colposcopy referral compared to HPV-cytology co-testing while achieving high sensitivity. Additional follow-up is underway to evaluate the programmatic performance of several major candidate strategies. Citation Format: Nicolas A. Wentzensen, Barbara Fetterman, Renee Bremer, Philip Castle, Diane Tokugawa, Nancy Poitras, Elizabeth Hosfield, Thomas Lorey, Mark Schiffman, Walter Kinney. Evaluation of p16/Ki-67 dual stain, cytology, and HPV16/18 genotyping for triage of HPV-positive women in a large screening population [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 5296. doi:10.1158/1538-7445.AM2017-5296
Abstract 3784: Expression of estrogen receptor specific signaling transcriptome in epithelial cell adhesion molecule (EpCAM) captured circulating tumor cells from patients with breast cancer
Authors: Ashok Singh, Jamie M. Sperger, Jennifer Schehr, Tessa Witkowski, Beth A. Weaver, Mark E. Burkard, Joshua M. Lang
Journal: Cancer Research (2017)

Abstract Background: Breast cancer (BC) is the second leading cause of cancer related death in American women. There is a critical need for new biomarkers to evaluate treatment response and emerging mechanisms of resistance. The identification and characterization of new biomarkers such as Circulating Tumor Cells (CTCs) may be helpful tools for these purposes as well as understanding the biology of metastatic BC. Methods: Blood samples were processed with a Ficoll gradient to isolate nucleated cells. CTCs were isolated from these samples using an exclusion-based sample preparation technology known as the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. EpCAM positive CTCs were captured in the VERSA followed by mRNA extraction for gene expression profiling for the estrogen receptor (ER) and other breast cancer relevant targets. CTCs were defined as Hoechst positive, CD45/CD11b/CD14 negative, and cytokeratin positive. Captured CTCs were evaluated for ER protein staining intensity and localization. Results: The VERSA platform was validated to capture and enumerate CTCs from patients with breast cancer using EpCAM capture and immunofluorescent staining for intact nucleus, ER, and cytokeratin while negative for multiple immune markers (CD45, CD11b, CD14). The VERSA can capture cells with &amp;gt;90% capture efficiency with EpCAM antibody in MCF7 and T47D cell lines. ER specific transcriptome analysis in BC patient CTCs and cell lines was performed. We evaluated expression of ER signaling pathway, prognostic, metastatic/EMT; stemness; epithelial markers with concordant expression of RPLPO and HPRT1. We identified expression of ER in 6 out of 7 BC samples. Expression of PR and HER2 in a subset of samples confirms capture of breast cancer cells for further molecular interrogation. Conclusion: In conclusion, we report the expression profiles of ER signaling genes in EpCAM captured CTCs from BC patients. These tools will be used to compare subpopulations of CTCs from patients with BC as predictive and pharmacodynamic biomarkers of response to targeted therapies or chemotherapies. Citation Format: Ashok Singh, Jamie M. Sperger, Jennifer Schehr, Tessa Witkowski, Beth A. Weaver, Mark E. Burkard, Joshua M. Lang. Expression of estrogen receptor specific signaling transcriptome in epithelial cell adhesion molecule (EpCAM) captured circulating tumor cells from patients with 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 3784. doi:10.1158/1538-7445.AM2017-3784
Abstract 423: Detection of genetic alterations to predict the chemotherapeutic responses in unresectable pancreatic ductal adenocarcinomas
Authors: Joo Kyung Park, Kwang Hyuck Lee, Donghyun Park, Woong-Yang Park, Dae-Soon Son, Jong Kyun Lee, Kyu Taek Lee
Journal: Cancer Research (2017)

Abstract Background &amp; Aims: Next-generation sequencing (NGS) that enables the analyses of massively parallel sequences of DNA can advance the understanding of the underlying molecular pathophysiologies of cancer. Such recent genomic analyses have revealed a complex mutational landscape for PDACs. The aims of this study were to investigate the genomic profile to predict the chemotherapy response in unresectable PDACs. Methods: The total of 80 pathologically confirmed PDACs were enrolled and genomic DNA was extracted and quality control metrics of DNA analytes were measured. The specimens that passed a quality control test underwent targeted deep sequencing using a customized cancer panel (CancerSCAN) enriched in the exons of 83 genes. Results: Clinical prognostic factors associated with survival in PDAC were gender, tumor mass size, stage and chemotherapy response rate. (P=0.078, 0.009, 0.052 and &amp;lt;0.001, respectively). Multivariate Cox proportional-hazards analysis revealed chemotherapy response rate (P &amp;lt; 0.001, hazard ratio (HR) = 1.908, 95% CI, 1.281 to 2.840) is an independent prognostic factor. There were 56 (71%) and 9 (11%) study patients who underwent gemcitabine based chemotherapy and FOLFIRINOX respectively. Response rate of study patients were as follows; CR+PR 14 (20%), SD (27%) and PD 28 (41%). There were only 9 (16%) and 4 (50%) patients who had CR+PR response gemcitabine based chemotherapy and FOLFIRINOX respectively. Conclusion: Targeted sequencing using EUS-FNA specimens in PDAC showed excellent compatibilities to analyze genomic profiles of PDACs. Furthermore, novel genes associated with survival, metastasis and chemotherapy response in PDAC were identified. Citation Format: Joo Kyung Park, Kwang Hyuck Lee, Donghyun Park, Woong-Yang Park, Dae-Soon Son, Jong Kyun Lee, Kyu Taek Lee. Detection of genetic alterations to predict the chemotherapeutic responses in unresectable pancreatic ductal adenocarcinomas [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 423. doi:10.1158/1538-7445.AM2017-423
Abstract 2155: Small molecule NSC59984 suppresses cancer cell growth under hypoxia
Authors: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract Hypoxia is one of the main features of solid tumors, contributes to drug resistance and is associated with poor prognosis. We have reported that a small-molecule NSC59984 restores p53 signaling and degrades mutant p53 protein in cancer cells. We find that NSC59984-mediated p53 signaling restoration and mutant p53 degradation is significantly blocked by NAC, an inhibitor of reactive oxygen species (ROS), while, further enhanced by BSO, a chemical compound increasing ROS in cells. These results suggest that ROS is a factor required for the effect of NSC59984 on cancer cells. Cellular ROS is produced by hypoxia in solid tumors. We investigated the effect of NSC59984 on p53 pathway and cell death in p53 mutant colorectal cancer (CRC) cells cultured under hypoxia. NSC59984 increases p53 signaling in p53 mutant cancer cells under hypoxia, as it does under normoxia. The effect of NSC59984 under hypoxia is blocked by NAC. Moreover, NSC59984 decreases cancer cell viability in a dose-dependent manner under hypoxia similar to normoxia. Our results suggest that NSC59984 inhibits cancer cell growth under hypoxia. Hypoxia has been known to increase cancer stem cells in tumors, which is one of the reasons causing drug resistance. We then evaluate the effect of NSC59984 on the stem cell growth. NSC59984 significantly reduces colonosphere formation of SW480, DLD-1 and HT29 cells. CRC stem cell markers such as CD44 and ALDH are decreased in colonospheres upon NSC59984 treatment, suggesting that NSC59984 inhibits stem cell self-renewal or/and growth. Our results provide the rationale for administration of NSC59984 in solid tumors with or without hypoxia and in combination treatment with ROS activators. Citation Format: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 suppresses cancer cell growth under hypoxia [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 2155. doi:10.1158/1538-7445.AM2017-2155
Abstract 4212: Natural compounds alone and in combination with platinum drugs found to show significant anti-tumour activity against ovarian cancer cell lines
Authors: Md Sheikh Anwar, Jun Qing Yu, Philip Beale, Fazlul Huq
Journal: Cancer Research (2017)

Abstract Acquired drug resistance remains major problem in platinum based chemotherapy against ovarian cancer. It is believed that elevated expression of NF-kB and AKT/PKB is one of the prime reasons for acquired drug resistance. Since tumour active natural compounds can dampen NF-kB and AKT/PKB expression, it is thought that platinum drugs in combination with the natural compounds may produce synergism in killing tumor cells. The present study aimed to apply combinations of platinum drugs cisplatin, oxaliplatin, and carboplatin with natural compounds mycophenolic acid, honokiol, cholecalciferol and 6-shogaol to four ovarian cancer cell lines: A2780, A2780CisR, A2780ZD0473R and SKOV-3 towards overcoming drug resistance. IC50 values of single compounds were determined followed by administration of binary combinations. Studies on DNA damage, cellular platinum accumulation, and platinum-DNA binding levels were carried out. Proteomic studies will be done to explore the key proteins involve with drug resistance. Mycophenolic acid (IC50: 1.34-7.83 μM) from Penicillium brevicompactum and 6-shogaol (IC50: 6.79-10.20 μM) from Zingiber officinale showed significant activity against ovarian cancer cell lines. Ginger derived pure compound 6-shogaol showed prominent synergism in combination with platinums when administered as a bolus (0/0h) and with 0/4 h sequence. Honokiol from Magnolia virginia alone and in combination with cisplatin showed significant DNA damage in A2780 cell line whereas cholecalciferol did the same to A2780cisR cell line. Bolus combination of cisplatin and 6-shogoal produced increased cellular platinum accumulation and 3 times more Pt-DNA binding than cisplatin alone treated A2780 cells. Though honokiol and cisplatin (0/0 h) combination have half cellular platinum accumulation in compare to cisplatin alone treated A2780 cells but showed 9 times higher Pt-DNA binding. Cholecalciferol and 6-shogaol in combination with cisplatin also showed promising Pt-DNA in A2780CisR cell line. In conclusion, 6-shogaol, cholecalciferol and honokiol showed significant activity alone and in combination with cisplatin and oxaliplatin against ovarian cancer tumour models. Note: This abstract was not presented at the meeting. Citation Format: Md Sheikh Anwar, Jun Qing Yu, Philip Beale, Fazlul Huq. Natural compounds alone and in combination with platinum drugs found to show significant anti-tumour activity against ovarian cancer cell lines [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 4212. doi:10.1158/1538-7445.AM2017-4212
Abstract 5878: Trichostatin A overcomes chemotherapeutic resistance of urothelial carcinoma cells through the inactivation of c-Raf/ERK pathway
Authors: Kuan-Lin Kuo, Chung-Sheng shi, Ju-Tong Hsieh, Shiang-Peng Chen, Wei-Chou Lin, Shih-Ming Liao, Shing-Hwa Liu, Kuo-How Huang
Journal: Cancer Research (2017)

Abstract Trichostatin A (TSA), a potent histone deacetylase (HDAC) inhibitor, has been reported to elicit anti-proliferative response in various tumors. Here, we investigated antitumor effect of TSA alone or in combination with conventional chemotherapeutic agents on urothelial carcinoma (UC) cells. We use one high-grade UC cell line (T24) and another UC cells (NTUUC) obtained by primary culture from the surgical specimen of a women with high-grade and metastatic bladder UC. The cytotoxicity and apoptosis induced by TSA alone , chemotherapeutic agents (cisplatin, gemcitabine and doxorubicin) and combined treatment were assessed by MTT assay and fluorescence-activated cell sorting and flow cytometry. The expression of phosphor c-Raf, phosphor-MEK1/2, and phosphor-ERK1/2 were measured by Western blot. urther elucidation on the role of Raf/MEK/ERK pathoway on the TSA-enhanced cytoxicity were exmained by using ERK1 siRNA knockdown and the specific MEK inhibitor (PD98059). Our results showed TSA markedly enhances the cytotoxicity and apoptosis of three chemotherapeutic agents in UC cells with concurrent suppression of Raf/MEK/ERK signaling pathway. Consistently, inhibition of Down-regulation of ERK by MEK inhibitor or by ERK 1 siRNA knockdown potentiated the chemotherapeutic agnet-induced cytotoxicity of TSA in UC cells. We concluded that TSA potentiates the therapeutic efficacy of cisplatin, gemcitabine and doxorubicin in human UC cells through Raf/MEK/ERK signaling pathway. These findings provide a new treatment strategy against UC. Note: This abstract was not presented at the meeting. Citation Format: Kuan-Lin Kuo, Chung-Sheng shi, Ju-Tong Hsieh, Shiang-Peng Chen, Wei-Chou Lin, Shih-Ming Liao, Shing-Hwa Liu, Kuo-How Huang. Trichostatin A overcomes chemotherapeutic resistance of urothelial carcinoma cells through the inactivation of c-Raf/ERK pathway [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 5878. doi:10.1158/1538-7445.AM2017-5878
Abstract 3461: The Nek2 mitotic kinase drives centrosome amplification, mitotic dysfunction, and invasion in mammary epithelial and breast cancer cells
Authors: Yainyrette Rivera-Rivera, Mihaela Marina, Miyoung Lee, Harold I. Saavedra
Journal: Cancer Research (2017)

Abstract Despite findings reported by The Cancer Genome Atlas (TCGA) that the most common human tumors have undergone at least one genomic doubling, the roles of polyploidy and chromosome instability (CIN) in cancer are poorly understood. Defective mitosis, and centrosome amplification (CA) are major sources of CIN, which generally associates with poor prognosis of patients. Prevalence of CA and CIN in hormone receptor negative (ER-PR-Her2- or ER-PR-Her2+) breast cancer patients, who have the poorest outcomes among all intrinsic subtypes, suggest that CA and CIN play major roles in the disease. CA in breast cancers correlates with poor survival, metastasis and high tumor grade, suggesting roles in tumor progression. Our laboratory, using an inducible K-RasG12D transgenic mouse that directed its expression to mammary epithelial cells, demonstrated CA appeared in precancerous mammary epithelial lesions, suggesting a role in tumor initiation. Despite these observations, the role of CA as cancer driver or promoter has not been tested experimentally. To understand that role, drivers of CA in cancer must be identified, and our laboratory showed that dysregulated E2F1, E2F2 and E2F3a, and their mitotic targets, including Nek2, TTK, and SgoI sustain CA and CIN in mammary epithelial and breast cancer cells. In fact, orthotopic models of breast cancer demonstrated that silencing of E2F3 leads to slow tumor growth that correlates with reduced mitosis, CA and Nek2 levels. We find that overexpression of the E2F target Nek2 in non-transformed mammary epithelial cells results in large acinar structures, CA, CIN, and changes in relevant EMT markers that include vimentin. Our findings indicate that deregulated E2F pathway contribute to mammary tumorigenesis in part by deregulating kinases that control mitosis, including Nek2, and in turn these affect mitotic progression, CIN, EMT and invasion. Thus, centrosome/kinases downstream of the E2F pathway may represent future targets for intervention in highly-malignant HR- breast cancers. Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Miyoung Lee, Harold I. Saavedra. The Nek2 mitotic kinase drives centrosome amplification, mitotic dysfunction, and invasion in mammary epithelial and breast 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 3461. doi:10.1158/1538-7445.AM2017-3461
Abstract 741: Rapid detection of necrosis in breast cancer with <i>ex vivo</i> and <i>in situ</i> mass spectrometry analysis methods
Authors: Arash Zarrine-Afsar, Bindesh Shrestha, Alessandra Tata, Michael Woolman, Manuela Ventura, Nicholas Bernards, Milan Ganguly, Howard Ginsberg, Jinzi Zheng, Emma Bluemke
Journal: Cancer Research (2017)

Abstract Necrosis is a form of cell death that is often associated with highly aggressive forms of cancer, is of prognostic value in treatment planning. Mass Spectrometry (MS) is a highly sensitive analytic platform capable of providing a molecular profile of cancer on the basis of mass to charge (m/z) ratio of tissue constituent molecules. MS analysis of ex vivo tissue slices from metastatic murine xenograft tumors from LM2-4 cell line with Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) allowed direct comparisons with histology images to determine the molecular profile of necrotic tissues. The necrotic tissue is characterized by the presence of a ceramide absent from the viable cancer regions. The spatial distribution of this ion fully correlated to necrotic areas from pathology in additional independent tumor samples examined. The same ion was detected from in situ necrotic tissue using tissue aerosols generated by hand-held ablation probes coupled to evaporative ionization interface in only a few seconds of sampling. These developments further establish MS as a novel tool for rapid pathology that is highly complementary to current histology based methods widely used in characterization of cancer in both imaging mode (to provide spatial information on cancer border) and profiling mode (to provide information on cancer type and subtype); all based on unique molecular profile associated with each cancer type and subtype. Current efforts in creating cancer molecular profile libraries will facilitate translation. Citation Format: Arash Zarrine-Afsar, Bindesh Shrestha, Alessandra Tata, Michael Woolman, Manuela Ventura, Nicholas Bernards, Milan Ganguly, Howard Ginsberg, Jinzi Zheng, Emma Bluemke. Rapid detection of necrosis in breast cancer with ex vivo and in situ mass spectrometry analysis methods [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 741. doi:10.1158/1538-7445.AM2017-741
Abstract 4946: Host tissue stiffness regulates chemotherapy-induced cancer cell dormancy
Authors: Alisya Anlas, Celeste M. Nelson
Journal: Cancer Research (2017)

Abstract This study investigates how the tumor microenvironment, namely host tissue stiffness, affects the propensity of disseminated tumor cells to become dormant at secondary sites. Approximately 90% of cancer-related deaths result from metastasis. In breast cancer, disseminated cancer cells cannot be detected at the time of diagnosis of the primary tumor because they form “dormant” micrometastases that are not clinically detectable. Thus, metastases in secondary sites such as the lungs, bone marrow, liver and brain are usually discovered months or years after the initial diagnosis and/or treatment of the primary tumor. A 2D polyacrylamide gel-based tissue culture model was used to investigate the effects of host tissue stiffness on the proliferative behavior of breast cancer cells. To assess the dormant phenotype, Ki67 and RNA staining were used to quantify proliferation and RNA content, respectively. Additionally, changes in levels of cell-cycle regulators were determined by quantitative RT-PCR. Dormant cells have decreased levels of transcription and proliferation. We found that both tamoxifen and 5-fluorouracil induce dormancy in estrogen receptor-positive breast cancer cells cultured on soft and stiff substrata. After repeated rounds of 5-fluorouracil treatment and recovery, cells cultured on soft substratum, mechanical properties of which represent common metastatic sites, had a higher tendency to recover. This suggests that cell growth at secondary sites favors a soft microenvironment, characteristic of organs where breast cancer metastases often become clinically overt. Dormant cancer cells, or minimal residual disease, cannot be detected with current diagnostic tools and cannot be targeted by conventional therapies. Therefore, current clinical practices rely on estimating the probability of recurrence from various prognostic factors including the grade and the stage of the disease. Elucidating the mechanisms that regulate the switch from dormancy to proliferation at metastatic sites will pave the way for new treatments to control this incurable disease. Citation Format: Alisya Anlas, Celeste M. Nelson. Host tissue stiffness regulates chemotherapy-induced cancer cell dormancy [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 4946. doi:10.1158/1538-7445.AM2017-4946