tbuckley/cabot-search huggingface dataset:
Abstract 2303: Entacapone and prostate cancer in patients with Parkinson’s disease: A large Veterans Health Administration study
Authors: Jacqueline M. Major, Francesca Cunningham, Diane Dong, Kunthel By, Kwan Hur, David C. Shih, Simone P. Pinheiro, Gerald D. Podskalny, David J. Graham
Journal: Cancer Research (2017)

Abstract Background: An increased risk of prostate cancer was observed in Parkinson’s disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial. Objective: To investigate a potential association between entacapone use and prostate cancer in an ambulatory setting. Methods: Using data from the Department of Veterans Affairs (VA) healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via VA cancer registry linkage. Cox proportional hazards regression with time-dependent exposure was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Confounding was controlled by using inverse probability treatment weighting calculated from propensity scores. Results: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the group treated with entacapone comprised 5,257 subjects. Twenty-three prostate cancers occurred in the entacapone cohort and 97 in the control cohort. The overall incidence of prostate cancer was 1.8 per 1000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) were also examined. Conclusion: In this cohort of PD patients, extended duration of entacapone use was not associated with an increased incidence of prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Jacqueline M. Major, Francesca Cunningham, Diane Dong, Kunthel By, Kwan Hur, David C. Shih, Simone P. Pinheiro, Gerald D. Podskalny, David J. Graham. Entacapone and prostate cancer in patients with Parkinson’s disease: A large Veterans Health Administration study [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 2303. doi:10.1158/1538-7445.AM2017-2303
Novel Cranial Implants of Yttria‐Stabilized Zirconia as Acoustic Windows for Ultrasonic Brain Therapy
Authors: Mario I. Gutierrez, Elias H. Penilla, Lorenzo Leija, Arturo Vera, Javier E. Garay, Guillermo Aguilar
Journal: Advanced Healthcare Materials (2017)

Abstract Therapeutic ultrasound can induce changes in tissues by means of thermal and nonthermal effects. It is proposed for treatment of some brain pathologies such as Alzheimer's, Parkinson's, Huntington's diseases, and cancer. However, cranium highly absorbs ultrasound reducing transmission efficiency. There are clinical applications of transcranial focused ultrasound and implantable ultrasound transducers proposed to address this problem. In this paper, biocompatible materials are proposed for replacing part of the cranium (cranial implants) based on low porosity polycrystalline 8 mol% yttria‐stabilized‐zirconia (8YSZ) ceramics as acoustic windows for brain therapy. In order to assess the viability of 8YSZ implants to effectively transmit ultrasound, various 8YSZ ceramics with different porosity are tested; their acoustic properties are measured; and the results are validated using finite element models simulating wave propagation to brain tissue through 8YSZ windows. The ultrasound attenuation is found to be linearly dependent on ceramics' porosity. Results for the nearly pore‐free case indicate that 8YSZ is highly effective in transmitting ultrasound, with overall maximum transmission efficiency of ≈81%, compared to near total absorption of cranial bone. These results suggest that 8YSZ polycrystals could be suitable acoustic windows for ultrasound brain therapy at 1 MHz.
Abstract 5346: Combining droplet tagged short read sequencing with optical DNA mapping technology for improved assembly of cancer genomes
Authors: Yuan Jiang, Sven Bilke, Paul S. Meltzer
Journal: Cancer Research (2017)

Abstract Kataegis, chromothripsis, chromoplexy and forms of structural hyper-mutation generically described as chromoanagenesis are found in many cancer types. Structural rearrangements can result in deletions, translocations, inversions and insertions, and gene amplification with important functional consequenes as cancer drivers and clonal diversity. Whole genome sequencing is increasingly used to sensitively detect strucutural rearrangements. Yet, it remains difficult to detect these events reliably without an excessive number of false positives. This is largely a consequence of the still relatively short read-length of commonly used sequencing platforms. As a result, in larger cohorts, PCR based methods are generally not feasible for validating all predicted structural rearrangements. Accordingly, new approaches for robust mapping of both simple and complex rearrangements are needed. Here we used a hybrid of two technologies, 10X genomics droplet tagged Illumina sequencing (10X Genomics ) and DNA fiber molecular imaging (BioNano Irys) for high throughput validation. First, utilizing a sequencing-assisted synthetic genome: for each rearrangement predicted by NGS, we build a “pseudo-chromosome” offering this structure as one alternative to the BioNano aligner. This combination compensates for the weaknesses of each platform resulting in a more robust result. In this way, even short reads can validate structural rearrangements, as the requirement for split reads is obviated. Provided that sufficient coverage is achieved, statistical analysis can be used to confidently recognize NGS false positive predictions. This allows the cataloging of complex repetitive regions and large-scale rearrangements. In our study we have evaluated this combined approach to large scale genome mapping to identify hallmark fusions and other rearrangements from the highly complex genomes of osteosarcoma cancer cell lines. Citation Format: Yuan Jiang, Sven Bilke, Paul S. Meltzer. Combining droplet tagged short read sequencing with optical DNA mapping technology for improved assembly of cancer genomes [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 5346. doi:10.1158/1538-7445.AM2017-5346
Abstract 2121: Deguelin-derivative, L80 suppresses tumor growth and metastasis via inhibition of STAT3 activation in triple-negative breast cancer
Authors: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Ji Young Kim, Jeewoo Lee, Jae Hong Seo
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer TNBC is associated with aggressive metastasis and poor clinical outcomes due to a lack of effective treatment options. Therefore, new drugs that effectively target both cancer cell proliferation and metastasis are needed to improve clinical outcomes. The 90-kDa molecular chaperone heat-shock protein, HSP90 has been implicated in cancer progression and metastasis by modulating the stabilization and maturation of many oncogenic proteins. Our objective was to investigate the mechanism of action of C-terminal HSP90 inhibitor, deguelin-derivative L80 on TNBC proliferation and metastasis in vitro and in vivo. L80 induced apoptosis and suppression of cell viability in TNBC cell lines via inhibition of Akt activation with concomitant nuclear accumulation of p27. L80 treatment also caused a marked suppression of cell migration and invasion. These responses were associated with inhibition of STAT3 phosphorylation (Tyr705) as evidenced by downregulation of STAT3 downstream target genes including cyclin D1 and survivin. The syngeneic orthotopic mouse model with 4T1 cells, L80 administration resulted in significant reduction in tumor growth together with decreased number of Ki-67-positive cells and downregulation of phospho-STAT3. Double-label immunofluorescence analysis showed that individuals receiving L80 exhibited a marked reduction in co-localization and expression of HIF-1α and HSP90 compared to their control groups in vivo. Finally, we observed that L80 administration significantly suppressed lung metastasis, as determined by in vivo bioluminescent imaging system. Our findings suggest that L80 may be potentially effective for the treatment for metastatic TNBC patients. Note: This abstract was not presented at the meeting. Citation Format: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Ji Young Kim, Jeewoo Lee, Jae Hong Seo. Deguelin-derivative, L80 suppresses tumor growth and metastasis via inhibition of STAT3 activation in 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 2121. doi:10.1158/1538-7445.AM2017-2121
Abstract 3722: <i>In vitro</i> induced regulatory T cells for understanding the nature of peripherally induced regulatory cells in relation to cell mediated immunotherapy for cancer
Authors: Upendra P. Hegde, Nitya G. Chakraborty
Journal: Cancer Research (2017)

Abstract Background: pTregs are appearing to be one of the major obstacles of cellular immunotherapy of cancer. Tumor specific in vivo induced Cytotoxic T lymphocytes (CTL) are rapidly eliminated with concomitant expansion of pTreg cells. In human melanoma in ex vivo condition, tumor antigen specific CTL generated with CD8+ cells persisted for months while ex vivo induced CTL with whole PBL stimulated with Mart-127-35 A2 (tumor antigen) pulsed autologousDC, died within three weeks. Whereas Influenza (Flu 58-66) antigen specific CTL continued to expand and remained functional beyond four weeks. Method: Peripheral blood and tumors were obtained from patients diagnosed with metastatic melanoma after informed consent. Blood derived dendritic cells, PBL, CD4+ and CD8+ cells were isolated for in vitro co-cultures with Mart-1 or Flu peptide pulsed autologous DC or autologous tumor cells. CD8+ CTL response and CD4+ positive Treg responses were measured. Freshly obtained tumor tissue derived lymphocytes (TIL) were also used for the study. Results: Our results show that CTL response against Flu survived longer in culture with total PBL than CTL response against Mart-1 in identical culture conditions. CTL response using autologous tumor cells with PBL in culture lasted for a shorter duration but growth of Treg cells were observed. Cytokine analysis with expanding Treg cells showed secretion of IL-10 upon re-stimulation with autologous DC or anti-CD3 ab. Similarly, CD4+ cells isolated from freshly obtained tumor tissue (TIL, representing in vivo condition), suppressed T cell activation and secreted high amount of IL-10 upon re-stimulation. Conclusion: These findings suggested that in vitro induced iTreg from cultures or pTreg from TILs (in vivo), work identical way, to negatively regulate effector immune response by secreting IL-10. Further analysis with iTregs for their use of metabolic pathways would be important to identify the specific signaling molecules used by autologous (person specific) pTregs , as target molecules, to block the expansion of such pTregs for the better outcome for CTL mediated immunotherapy for cancer. Citation Format: Upendra P. Hegde, Nitya G. Chakraborty. In vitro induced regulatory T cells for understanding the nature of peripherally induced regulatory cells in relation to cell mediated immunotherapy for 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 3722. doi:10.1158/1538-7445.AM2017-3722
Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation
Authors: Yi Yin, Rui Li, Kangling Xu, Sentai Ding, Jeffrey Li, GuemHee Baek, Susmita G. Ramanand, Sam Ding, Zhao Liu, Yunpeng Gao, Mohammed S. Kanchwala, Xiangyi Li, Ryan Hutchinson, Xihui Liu, Solomon L. Woldu, Chao Xing, Neil B. Desai, Felix Y. Feng, Sandeep Burma, Johann S. de Bono, Scott M. Dehm, Ram S. Mani, Benjamin P.C. Chen, Ganesh V. Raj
Journal: Cancer Research (2017)

Abstract In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745–54. ©2017 AACR.
Abstract 5078: EZH2 methyltransferase regulates disseminating tumor cells in breast cancer metastasis
Authors: Shira Yomtoubian, Seongho Ryu, Sharrell Lee, Geoff Markowitz, Dingcheng Gao, Vivek Mittal
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC, ER-, PR-, HER2-) exhibits the worst outcome due to higher rates of metastasis compared to non TNBC subtypes. Despite this clinical significance, there is a conspicuous lack of FDA approved molecularly targeted anti-metastatic therapies for TNBC. The enhancer of zeste homolog 2 (EZH2), a catalytic core subunit of the Polycomb repressive complex 2 (PRC2) with histone methyltransferase (HMT) activity is associated with the worst clinical outcome in breast cancer patients. Using a combination of genetic and pharmacological approaches, we show that EZH2 HMT blockade did not impact primary tumor growth, but significantly reduced distal metastases. Metastasis suppression was associated with a marked reduction of tumor-initiating cells (TICs) in primary tumor, circulating tumor cells (CTCs) in the blood and impaired lung colonization. Using a SOX2/OCT4 promoter reporter system, we identified EZH2-sensitive metastatic cells with GATA3 low luminal progenitor phenotypes in the primary tumor, and EZH2 HMT blockade restored GATA3 expression, promoted differentiation of luminal progenitors and impaired metastasis. These key preliminary findings have led to the hypothesis that EZH2 promotes metastasis, and that inhibition of EZH2 HMT may constitute a viable anti-metastatic approach. We will also discuss the potential of EZH2 inhibition in combination with chemotherapy as an effective strategy against TNBC metastasis. Citation Format: Shira Yomtoubian, Seongho Ryu, Sharrell Lee, Geoff Markowitz, Dingcheng Gao, Vivek Mittal. EZH2 methyltransferase regulates disseminating tumor cells in breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5078. doi:10.1158/1538-7445.AM2017-5078
Dense fine-mapping study identifies novel disease loci and implicates coding and non-coding variation in primary Mary cirrhosis risk
Authors: JZ Liu, Al, Marri, M, D Gaffney, GF Mells, L Jostins, HJ Cordell, SJ Ducker, D Day, MA Heneghan, J Neuberger, PT Donaldson, A Bathgate, AK Burroughs, MH Davies, DE Jones, GJ Alexander, JC Barrett, RN Sandford, CA Anderson
Journal: Hepatology (2012)
Abstract 2241: Diosmetin induces apoptosis in human prostate carcinoma cells via the Rictor pathway invitro and inhibits tumor growth in vivo
Authors: Riddhi Patel, Rebecca Pakradooni, Ahmad Khalifa, Natarajan Bhaskaran, Sanjeev Shukla
Journal: Cancer Research (2017)

Abstract Cell growth is a fundamental biological process, where mTOR (mammalian target of rapamycin) pathway has its role, regulates cell growth by coordinating energy and nutrient signals with growth factor. mTOR protein kinase have two different complexes; complex-I contains major component raptor; a target of rapamycin and complex II; insensitive to rapamycin, has major component rictor. Rictor is important as it phosphorylates Ser-473 of Akt/PKB, which is essential for full Akt/PKB activation. Reports suggested that overexpression of mTOR in prostate cancer tissues, which may have potential role in prostate cancer progression. The known mTOR inhibitor rapamycin is not specific for mTOR-II complex, as it doesn’t inhibit main component Rictor. We need to have effective chemo-preventive agents, which can modulate Rictor signaling cascade to inhibit prostate cancer. Diosmetin (5, 7-Trihydroxy-4′-methoxyflavone), a natural flavonoid present in citrus plant, has anti-mutagenic and anti-allergic properties. Earlier we demonstrated growth factors Insulin-like growth factor-1 and cytokine (IL-6) induces Rictor expression, and phosphorylated Akt at Ser-473. Using diosmetin in concentration dependent fashion (5-40µM) to LNCaP and PC-3 cells down regulated phosphorylation of Rictor (Thr1135), Akt (Ser-473) and PKCα (Ser-657) expressions. This resulted in downregulation of survival molecules; Survivin and X-linked inhibitor of apoptosis protein, which induced apoptosis and inhibited cells growth. Luciferase tag PC-3 cells orthotopic implant in ventral prostate of nude mice represented significant decrease in tumor volume of diosmetin (20 and 50µg/animal/day) fed mice compared to control mice. Similarly bioluminescence imaging of orthotopically implanted mice represented decreased tumor luciferase activity after diosmetin feeding than control mice. Moreover, diosmetin feeding to tumor bearing nude mice reduced the phosphorylation of Rictor, (Thr1135), Akt (Ser-473) and PKCα (Ser-657) expressions and induced apoptotic events to inhibit tumor growth significantly. Based on results we may suggest diosmetin can be developed as an anticancer agent for prostate cancer. Citation Format: Riddhi Patel, Rebecca Pakradooni, Ahmad Khalifa, Natarajan Bhaskaran, Sanjeev Shukla. Diosmetin induces apoptosis in human prostate carcinoma cells via the Rictor pathway invitro and inhibits tumor growth in vivo [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 2241. doi:10.1158/1538-7445.AM2017-2241
Abstract 5867: Reversal of drug resistance in prostate cancer using PBM nanoparticle
Authors: Santosh K. Singh, James W. Lillard, Rajesh Singh
Journal: Cancer Research (2017)

Abstract Multidrug-resistance (MDR) is the major reason behind the failure of prostate cancer (PCa) therapy. ATP-binding cassette (ABC) transporters contribute to drug resistance via ATP-dependent drug efflux. P-glycoprotein (Pgp), which is encoded by MDR1 gene, confers resistance to certain anticancer agents. The development of agents able to modulate MDR mediated by Pgp and other ABC transporters remained a major goal for PCa therapy. The proposed study evaluated a novel method for targeted delivery of resveratrol alone or in combination with docetaxel at desired rates for reversal of drug resistance. We described a proprietary planetary ball milling approach (PBM) that uses a natural polysaccharide (starch; FDA approved) to create a drug-polysaccharide nanoparticle as a core that is subsequently coated with novel folate-conjugated poly (ϵ-caprolactone) / poly (ethylene glycol) co-polymer, which allows binding to high-affinity folate receptors presents on PCa cells. The resulting PBM nanoparticles were shown to be rapidly internalized and induce significant cancer cell apoptosis at lower doses compared to unformulated resveratrol and/or docetaxel. Our data showed that resveratrol potently synergizes with docetaxel to inhibit proliferation and induce cell death in resistance PCa cells. The up-regulation of pro-apoptotic (BAX, BID, BAK), p53 and down regulation of anti-apoptotic (BCL-2, MCL-1), Pgp and NF-κB protein confirmed that a synergistic combination of resveratrol-docetaxel with targeted delivery to tumor cells could provide a more potent therapeutic effect at lower drug concentrations and improve the therapeutic index. These results suggested that the co-delivery of resveratrol, and a cytotoxic agent in a PBM nanoparticle might potentially improve the treatment of drug-resistant tumors. [This work is supported from Grant # 5SC1CA193758-03] Citation Format: Santosh K. Singh, James W. Lillard, Rajesh Singh. Reversal of drug resistance in prostate cancer using PBM nanoparticle [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 5867. doi:10.1158/1538-7445.AM2017-5867
Corticosteroids for IgA Nephropathy
Authors: Michelle M. O’Shaughnessy, Richard A. Lafayette
Journal: JAMA (2017)

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