tbuckley/cabot-search huggingface dataset:
Response to neo-adjuvant exemestane in post-menopausal breast cancer patients: correlation with biological factors measured by real-time quantitative RT-PCR (QRT-PCR)
Authors: M. Tubiana-Hulin, F. Spyratos
Journal: Journal of Clinical Oncology (2004)

538 Background: The effects of aromatase inhibitors on tumor biological factors in the neo-adjuvant setting are still not well documented and predictive factors of response are needed in addition to hormone receptor status. Methods: 41 postmenopausal women with estrogen and/or progesterone receptor (ER, PR) positive operable breast cancer received neoadjuvant exemestane 25 mg once daily, during 16 weeks. Frozen and formalin-fixed tumor tissues were collected before treatment and at surgery for pathological and biological markers measured by immunohistochemistry (IHC) and QRT-PCR. We analyzed ERα, PgR, Ki67, HER2 at the protein and mRNA level (IHC and QRT-PCR) and ERβ, aromatase and COX-2 (QRT-PCR). Results: QRT-PCR was performed on pre-treatment biopsies in 31 cases. The median quantity of total RNA was 4,5 μg (range: 0.3–22,7). For each target gene, median and range mRNA values relative to the TBP reference gene were : ERα : 306 (48–893) ; ERβ: 34.6 (3.5–278.5) ; PgR: 263 (2–2738) ; Ki67: 18.5 (3.3–66.5) ; HER2: 532.5 (2–10467); Aromatase: 515.5 (55–3608); COX-2: 5.1 (1–59.2). There was a statistically significant positive correlation between IHC and QRT-PCR measurements of PgR, Ki-67 and HER2 (r=0.81 p<0.0001; r=0.56 p=0.001; r=0.53 p=0.002). Aromatase mRNA expression was positively correlated with COX-2 (0.51 p=0.001) and ERβ mRNA (0.39 p=0.02). A clinical response was observed in 31 patients (75.6%) ; a pathological response (Sataloff score>50%) in 6 patients (17.6%). No significant relation was found between any initial biological factor and clinical or histological response. Exemestane treatment was associated with no change in ERα expression and a significant reduction in PgR and Ki-67 expression (IHC and QRT-PCR). Conclusions: Quantitative assessment of gene expression at the mRNA level is feasible and reproducible on small biopsies by QRT-PCR. So far, no correlation was found between pre-treatment biological factors and response; post-treatment QRT-PCR measurements will be compared to pre-treatment data and response. No significant financial relationships to disclose.
Abstract 708: Androgen receptor activation inhibits papillary thyroid carcinoma cell cycle progression
Authors: Melanie Elizabeth Jones, Timmy O'Connell, Anvita Gupta, Hong Zhao, Codrin Iacob, Augustine Moscatello, Edward Shin, Zbigniew Darzynkiewicz, Raj K. Tiwari, Jan Geliebter
Journal: Cancer Research (2015)

Abstract The American Cancer Society predicts 62,980 new cases of thyroid cancer and 1,890 deaths due to the disease in 2014, making thyroid cancer the most prevalent endocrine malignancy. This is particularly concerning for women who have an approximately three-fold higher incidence of thyroid cancer than men. Significant research has been done to elucidate the role of estrogen as a driver of thyroid cancer. Taking the reverse approach, that men have a much lower incidence of thyroid cancer, led us to hypothesize that androgens and/or androgen receptors play a protective role and that PTC represents the escape from androgen-mediated cell regulation. Analysis of AR expression in 24 PTC patient tissue samples indicated a 2.7 fold reduction in AR expression compared to matched normal tissue (P&amp;lt;0.005). This suggests that the reduction of AR levels in the neoplastic process of thyroid tissue may be one mechanism of escape from androgen regulation. To more fully understand the function of androgen/AR in thyroid cells, the AR was stably transfected into 8505C anaplastic/PTC cells. Addition of DHT to the 8505C-transfected clone, 84E7, resulted in AR translocation into the nucleus and a 70% reduction in proliferation, as well as a shift in the cell cycle toward G1 arrest. Transcription profiling using RNA-Seq and gene ontology analysis revealed significant changes in genes associated with proliferation, cell cycle, and cell cycle regulation confirming the proliferation assay and cell cycle analysis above. Further, when we examined G1 associated cell cycle proteins, we found significant decreases in cell cycle progression proteins cdc25a, CDK6, CDK4, and CDK2 as well as significant increases in the inhibitors p27 and p21. Thus, protein, RNA and cell cycle analysis data are concordant and demonstrate an accumulation of cells in G1 when treated with DHT. Together these data demonstrate that expression of androgen/AR in normal thyroid cells may play a protective, anti-proliferative role that is lost in PTC resulting in dysregulation of genes normally under AR control. The differential expression of androgen/AR in males verses females may provide new insight into the different clinical presentations and outcomes between women and men. Citation Format: Melanie Elizabeth Jones, Timmy O'Connell, Anvita Gupta, Hong Zhao, Codrin Iacob, Augustine Moscatello, Edward Shin, Zbigniew Darzynkiewicz, Raj K. Tiwari, Jan Geliebter. Androgen receptor activation inhibits papillary thyroid carcinoma cell cycle progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2015-708
Two case reports of MDS with chromosome 7 abnormalities after treatment of AIDS-related Burkitt lymphoma occurring in patients on HAART therapy.
Authors: D. A. Levitan, S. Lyerly, M. Sweet, M. Manuel, D. P. Berenzon, T. S. Pardee, L. R. Ellis, B. L. Powell
Journal: Journal of Clinical Oncology (2011)

e18561 Background: Burkitt lymphoma (BL) follows a rapidly progressive course, in both HIV infected and non-infected patients (pts). Non-HIV infected pts fare better with multiagent, dose intensive regimens. The role of these regimens in HIV infected pts remains unclear, particularly in the era of HAART therapy. Methods: This is an observational case report. Results: Case 1: 37yo HIV+ male diagnosed with Stage IIIE BL by rectal mass biopsy. Bone marrow, and CSF were negative. He was treated according to CALGB 10002. HAART was continued during therapy with good control of HIV viremia. He achieved a CR. He developed progressive cytopenias. Bone marrow 6 months after completing therapy was consistent with MDS. FISH for 7q- was positive in 15.5% of cells. The pt underwent RIC sibling donor stem cell transplant. Despite engraftment, the patient developed AML 2 months after his transplant. The patient elected not to receive induction therapy and died 2 months later due to complications of AML. Case2: 41 year old HIV+ female diagnosed with Stage IV BL by liver biopsy. She was treated according to CALGB 10002. HAART therapy was given, but despite multiple combinations the patient had persistently detectable HIV viral load. CR was achieved. She remained cytopenic after completion of chemotherapy. Bone marrow biopsy 4 months after chemotherapy showed monosomy 7 by FISH in 20% of cells, without increased blasts. The pt had ongoing CMV and HIV viremia, therefore no therapy for MDS was given. Her BL recurred one month later. She entered hospice, and died of complications of BL. Conclusions: We report 2 cases of tMDS with chromosome 7 abnormalities occurring after concurrent HAART and aggressive chemotherapy for AIDS related BL. This limited series raises concern that there may be a potential interaction of HAART and chemotherapy causing increased risk of MDS. One hypothesis is that mitochondrial damage, which has been reported from nucleoside analogue antiretrovirals, could lead to increased reactive oxygen species, which could further increase the known risk of tMDS in pts treated with dose intense regimens for BL.
Abstract 4800: Identification of candidate predisposition genes for familial uterine leiomyomas
Authors: Hanna-Riikka Heinonen, Outi Uimari, Jaana Tolvanen, Markku Ryynänen, Lauri A. Aaltonen, Pia Vahteristo
Journal: Cancer Research (2015)

Abstract Uterine leiomyomas are benign smooth muscle tumors that cause considerable morbidity. They are among the most common human tumors and are the leading indication for hysterectomy. Genetic factors play an important role in the development of these hormone-dependent tumors. First-degree relatives of uterine leiomyoma patients are at increased risk for developing leiomyomas. Twin studies have shown that an inherited predisposition is likely to contribute to the formation of these lesions. Furthermore, the clinical and molecular features of familial leiomyomas differ from those of sporadic cases. Thus far, the only known high risk predisposition defect is dominantly inherited loss of function mutations in fumarate hydratase (FH) that underlie a tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC). The aim of this study is to identify novel candidate high risk susceptibility genes for uterine leiomyomas. The study material consists of five FH mutation-negative families, which have at least four individuals diagnosed with uterine leiomyomas, originating from Northern Finland. Genomic DNA extracted from peripheral blood lymphocytes from one affected individual from each family has been exome sequenced. Exome sequencing data have been analyzed for rare non-synonymous variants with allele frequencies less than 0.1% in 4 019 controls. All protein-truncating variants as well as missense and splice site variants affecting the same gene in at least two individuals that are predicted to be protein-damaging have been included for further analysis. Preliminarily 25 candidate susceptibility genes have been shortlisted. Relevant variant calls will be verified by direct sequencing, followed by segregation analysis and assessment of loss of heterozygosity in the corresponding tumor samples. Identification of novel genes predisposing to familial uterine leiomyomas may provide a better understanding into the tumorigenic mechanisms and could lead to new prevention approaches and personalized medical treatments in the future. Citation Format: Hanna-Riikka Heinonen, Outi Uimari, Jaana Tolvanen, Markku Ryynänen, Lauri A. Aaltonen, Pia Vahteristo. Identification of candidate predisposition genes for familial uterine leiomyomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4800. doi:10.1158/1538-7445.AM2015-4800
Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study
Authors: Christine A. Parkinson, Davina Gale, Anna M. Piskorz, Heather Biggs, Charlotte Hodgkin, Helen Addley, Sue Freeman, Penelope Moyle, Evis Sala, Karen Sayal, Karen Hosking, Ioannis Gounaris, Mercedes Jimenez-Linan, Helena M. Earl, Wendi Qian, Nitzan Rosenfeld, James D. Brenton
Journal: PLoS Medicine (2016)

Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP).
Improvement in 5-year mortality in incident rheumatoid arthritis compared with the general population—closing the mortality gap
Authors: Diane Lacaille, J Antonio Avina-Zubieta, Eric C Sayre, Michal Abrahamowicz
Journal: Annals of the Rheumatic Diseases (2016)

Objective Excess mortality in rheumatoid arthritis (RA) is expected to have improved over time, due to improved treatment. Our objective was to evaluate secular 5-year mortality trends in RA relative to general population controls in incident RA cohorts diagnosed in 1996–2000 vs 2001–2006. Methods We conducted a population-based cohort study, using administrative health data, of all incident RA cases in British Columbia who first met RA criteria between January 1996 and December 2006, with general population controls matched 1:1 on gender, birth and index years. Cohorts were divided into earlier (RA onset 1996–2000) and later (2001–2006) cohorts. Physician visits and vital statistics data were obtained until December 2010. Follow-up was censored at 5 years to ensure equal follow-up in both cohorts. Mortality rates, mortality rate ratios and HRs for mortality (RA vs controls) using proportional hazard models adjusting for age, were calculated. Differences in mortality in RA versus controls between earlier and later incident cohorts were tested via interaction between RA status (case/control) and cohort (earlier/later). Results 24 914 RA cases and controls experienced 2747 and 2332 deaths, respectively. Mortality risk in RA versus controls differed across incident cohorts for all-cause, cardiovascular diseases (CVD) and cancer mortality (interactions p&lt;0.01). A significant increase in mortality in RA versus controls was observed in earlier, but not later, cohorts (all-cause mortality adjusted HR (95% CI): 1.40 (1.30 to 1.51) and 0.97 (0.89 to 1.05), respectively). Conclusions In our population-based incident RA cohort, mortality compared with the general population improved over time. Increased mortality in the first 5 years was observed in people with RA onset before, but not after, 2000.
Role of D-dimer (DD) Assays in the Diagnostic Evaluation of Pulmonary Embolism (PE) in patient with cancer: a new “tailored” cut-off value for D-D, preliminary results of a mono-institutional study
Authors: G. Gallucci, A.M. Capobianco, A. Cammarota, A. Traficante, M. Gioioso, L.G. Sisti, M. Aieta
Journal: Annals of Oncology (2015)
Deaths and hospitalizations related to 2009 pandemic influenza a (H1N1) - Greece, May 2009-February 2010.
Authors: P. Efstathiou, M. Tseroni, A. Baka, Z. Manolidou, K. Karageorgou, V. Sypsa, A. Hatzakis
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
Abstract 2862: MBD3 regulates chromatin accessibility at active promoters
Authors: Takashi Shimbo, Christopher Lavender, Sara A. Grimm, Makiko I. Doi, Telmo Henriques, Kimberly R. Cannady, Kevin J. Murphy, Daniel A. Gilchrist, Adam Burkholder, Jeffrey J. Hayes, Karen Adelman, Trevor K. Archer, Kenneth S. Zaret, Paul A. Wade
Journal: Cancer Research (2015)

Abstract Chromatin structure is tightly regulated in cells and its dysregulation is associated with diseases such as cancer. The Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex is postulated to organize chromatin structure using its nucleosome remodeling and histone deacetylase activities. MBD3 is an integral component of NuRD, which potentially targets the complex to the specific sites of the genome. Recently, we have demonstrated that MBD3/NuRD targets regulatory elements of active genes, a finding diametrically opposed to historical models depicting NuRD as a co-repressor localized to transcriptionally non-permissive chromatin. Moreover, MBD3 co-localized with RNA polymerase II (pol II) at loci where promoter-enhancer loops are formed. Although our previous findings shed light on the role of NuRD in the regulation of active genes, the detailed mechanism of how NuRD is involved in transcriptional regulation is yet not fully understood. To investigate this question, we have developed a next generation, tagmentation based chromatin immunoprecipitation method followed by massively parallel sequencing (ChIP-nexo), which substantially increased the resolution of the MBD3/NuRD mapping. ChIP-nexo defined MBD3/NuRD localization at high resolution, showing accumulation of MBD3 at active promoters with a dip at transcription start site, suggesting an active role of NuRD in modulation of the cell-type specific transcriptional network. To interrogate the detailed functions of NuRD at active promoters, we conducted MNase-seq using conditions which measures both nucleosome positioning and sensitivity, in MBD3 depleted cells. Depletion of MBD3 changed the accessibility of nucleosomes at promoters, while maintaining overall nucleosome positioning. These data indicate an active regulatory function of NuRD in fine tuning the transcriptional network by modulating transcription rates of pol II. We propose that NuRD may be involved in establishing cell type specific gene expression patterns in diverse cell types by organizing promoter nucleoprotein architecture. Citation Format: Takashi Shimbo, Christopher Lavender, Sara A. Grimm, Makiko I. Doi, Telmo Henriques, Kimberly R. Cannady, Kevin J. Murphy, Daniel A. Gilchrist, Adam Burkholder, Jeffrey J. Hayes, Karen Adelman, Trevor K. Archer, Kenneth S. Zaret, Paul A. Wade. MBD3 regulates chromatin accessibility at active promoters. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2862. doi:10.1158/1538-7445.AM2015-2862
634. Translation of a Neural Stem Cell-Mediated Enzyme/Prodrug Gene Therapy for Metastatic Neuroblastoma
Authors: Margarita Gutova, Zesheng Wan, Anahit Hovsepyan, Lyudmila S. Tsurkan, Marianne Metz, Timothy W. Synold, Robert Seeger, Clarke Anderson, Philip M. Potter, Rex Moats, Karen S. Aboody
Journal: Molecular Therapy (2015)

Neuroblastoma (NB), a neuroendocrine tumor, is the most common extracranial solid tumor of childhood. Forty-five percent of these patients are diagnosed with metastatic high-risk tumors, for which treatment options are limited both in anti-tumor efficacy and patient tolerance. We have previously shown that neural stem cells (NSCs), engineered to secrete a modified rabbit carboxylesterase (CE), can home to metastatic NB tumor foci, and convert the prodrug CPT-11 (Irinotecan; IRN) to the 1000-fold more potent anti-cancer agent SN-38, resulting in significant therapeutic efficacy. The goal of our current biodistribution, efficacy and safety/toxicity IND-enabling studies is to identify the optimal dose and schedule of intravenously administered clinically relevant NSCs secreting a modified human CE (hCE1m6), followed by human equivalent doses of irinotecan. This would ideally provide a tumor selective, more effective and less toxic treatment for children with high-risk NB. In vitro cytotoxicity studies demonstrated IC50 values for four human NB tumors were significantly more sensitive to CPT-11 in the presence of hCE1m6 (similar to treatment with SN-38) compared to IRN alone. The sensitivity of NB tumor cells to CPT-11 was enhanced ≈6000-fold by hCE1m6 for KCNR tumor, while the sensitivity of SKNAS cells was enhanced ≈1200-fold for SKNAS, and approximately 150 to 600-fold decrease in IC50s of IRN for CHLA-136 and CHLA-255 NB cells. In vivo qPCR and MRI studies demonstrate NSC clearance through normal circulation and organs (lung, liver, brain) in naïve non-tumor bearing Es1e/SCID mice is 24h following intravenous adminstration. In subcutaneous models of human NB we have quantified NSC tumor distribution and performed pharmacokinetics studies demonstrating a significant increase in tumor specific conversion of IRN to SN-38 with the CE-NSCs. Therapeutic efficacy studies are ongoing. If successful, we plan to be in Phase I studies in pediatric patients with refractory or relapsed high-risk neuroblastoma. This would be a first-in-human use of NSC-mediated enzyme/prodrug therapy in metastatic cancer patients.
Abstract 858: Periodontal bone loss and risk of epithelial ovarian cancer in the Nurses’ Health Study
Authors: Ana Babic, Elizabeth M. Poole, Kathryn L. Terry, Daniel W. Cramer, Ricardo P. Teles, Shelley S. Tworoger
Journal: Cancer Research (2015)

Abstract Periodontitis, a chronic inflammatory reaction to dysbiotic oral microbiota, is common in the adult population in the United States. It is associated with increased risk of several medical conditions, including cardiovascular diseases, and potentially with lung, oral and pancreatic cancer. One of the proposed mechanisms behind these associations is systemic inflammation, which has also been implied in ovarian cancer etiology. We investigated association between periodontal bone loss, a marker of periodontitis, and risk of epithelial ovarian cancer among 60,560 participants of the Nurses’ Health Study. We did not observe an increased risk of ovarian cancer among participants suffering from periodontal bone loss (HR = 0.86, 95% CI: 0.64-1.15). Association was unchanged after adjusting for numerous factors including smoking. Among women younger than 69 years periodontal bone loss was associated with a 40% (HR = 0.60, 95% CI: 0.36-0.98) decreased ovarian cancer risk, while there was no association in those older than 69 (HR = 1.09, 95% CI: 0.75-1.58), although this difference did not reach a statistical significance (p-heterogeneity = 0.06). There also was a suggestive decreased risk for serous tumors (HR = 0.76, 95% CI: 0.53-1.09). The number of natural teeth and number of root canals, which are other metrics of oral health, were not associated with ovarian cancer risk. Our results do not support an increased risk of ovarian cancer for women with periodontal bone loss; however, given the unexpected associations in younger women, further research is warranted. Note: This abstract was not presented at the meeting. Citation Format: Ana Babic, Elizabeth M. Poole, Kathryn L. Terry, Daniel W. Cramer, Ricardo P. Teles, Shelley S. Tworoger. Periodontal bone loss and risk of epithelial ovarian cancer in the Nurses’ Health Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 858. doi:10.1158/1538-7445.AM2015-858