tbuckley/cabot-search huggingface dataset:
Abstract 3068: Integrative tcga analyses identify key microRNAs involved in chemoresistance
Authors: Fangrong Shen, Sehgal Vasudha, Sherry Wu, Ehsanipour Ehsan A, Olson Robert C, Ivan Cristina, Baggerly Keith A, Ram Prahlad, Sood Anil K
Journal: Cancer Research (2015)

Abstract Objective. High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian carcinoma. Our study aims to identify key microRNAs (miRs) that are responsible for promoting chemoresistance in HGSOC. Methods. We developed fast and robust computational algorithm to identify miRs that are significantly associated with improved or worsened survival in HGSOC patients. We subsequently used this algorithm to mine The Cancer Genome Atlas (TCGA) ovarian cancer database to identify miRs that are up-regulated in tumors from patients whose cancer had progressed within 6 months of diagnosis (chemoresistant group) compared to tumors from patients who had no disease progression for more than 2 years (chemosensitive group). We also constructed miRNA-mRNA functional networks for the key miRs identified. The biological roles of selected miRs were subsequently examined in multiple chemoresistant (SKOV3-TR, HeyA8-MDR, and A2780-CP20) ovarian cancer cell lines. Results. From our integrative analyses, we identified several miRs being highly up-regulated or down-regulated in chemoresistant HGSOC (p&amp;lt;0.05, top 10%). To examine the functional roles of these miRs, we transfected miR mimics and anti-miR constructs into taxane or platinum resistant cell lines. We showed that anti-miR-1271 significantly enhanced the sensitivity of taxane-resistant cancer cells (SKOV3-TR and HeyA8-MDR) to paclitaxel and docetaxel treatments. In contrast, transfecting anti-miR-1271 did not alter the sensitivity of A2780-CP20 cells to cisplatin treatment. Conclusion. These data provide the first integrated and functional approach for overcoming chemoresistance using miRs. Citation Format: Fangrong Shen, Sehgal Vasudha, Sherry Wu, Ehsanipour, Ehsan A, Olson Robert C, Ivan, Cristina, Baggerly, Keith A, Ram, Prahlad, Sood, Anil K. Integrative tcga analyses identify key microRNAs involved in chemoresistance. [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 3068. doi:10.1158/1538-7445.AM2015-3068
Delivery of Adjuvant Oxaliplatin for Colon Cancer: Insights From Routine Clinical Practice
Authors: Natasha Satkunam, Xuejiao Wei, James J. Biagi, Sulaiman Nanji, Christopher M. Booth
Journal: Journal of the National Comprehensive Cancer Network (2016)

Adjuvant oxaliplatin is now a standard treatment option for patients with early-stage colon cancer. However, treatment delivery and outcomes achieved in routine practice are not well described.All cases of colon cancer diagnosed in Ontario from 2002 to 2008 were identified using the Ontario Cancer Registry. Pathology reports were obtained for a 25% random sample to identify stage II and III cases; patients treated with adjuvant oxaliplatin were included in this analysis. Treatment records were reviewed to identify oxaliplatin dose reductions or omissions. Modified Poisson regression was used to evaluate factors associated with dose reduction/omission. Cox proportional hazards model was used to explore factors associated with cancer-specific survival (CSS) and overall survival (OS).The study population included 532 patients; 88% (469/532) had stage III disease. The mean/median number of oxaliplatin cycles delivered was 10/12. A dose reduction/omission of oxaliplatin occurred in 54% of cases (288/532), and the dose was subsequently escalated in 34% of these (97/288). Women were more likely than men to have dose reduction/omission (relative risk, 1.29; 95% CI, 1.10-1.51). Dose reduction/omission was not associated with inferior CSS (hazard ratio [HR], 0.76; 95% CI, 0.51-1.14) or OS (HR, 0.81; 95% CI, 0.59-1.13). Five-year CSS and OS of all cases were 77% (95% CI, 72-81) and 72% (95% CI, 68-76), respectively. On-treatment mortality rates were 1% and 3% within 30 and 90 days of oxaliplatin, respectively.Dose reductions of adjuvant oxaliplatin are common in routine practice but are not associated with inferior survival. Long-term survival achieved in the general population is comparable to the results of clinical trials.
Prevention of Post Transplantation Lymphoproliferative Disorders by Adapted Management of EBV Reactivations. A Monocentric Prospective Study on 101 Patients.
Authors: Sylvain Choquet, Shaida Varnous, Claire Deback, Corinne Amiel, Jean Louis Golmar, Iradj Gandjbackhch, Martine Raphael, Veronique Leblond
Journal: Blood (2006)
Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia
Authors: Jing Fang, Lyndsey C Bolanos, Kwangmin Choi, Xiaona Liu, Susanne Christie, Shailaja Akunuru, Rupali Kumar, Dehua Wang, Xiaoting Chen, Kenneth D Greis, Peter Stoilov, Marie-Dominique Filippi, Jaroslaw P Maciejewski, Guillermo Garcia-Manero, Matthew T Weirauch, Nathan Salomonis, Hartmut Geiger, Yi Zheng, Daniel T Starczynowski
Journal: Nature Immunology (2016)
Abstract 2869: SChLAP1 mediated epigenetic modifications in prostate cancer
Authors: Udit Singhal, Anirban Sahu, John R. Prensner, Qi Cao, Arul M. Chinnaiyan
Journal: Cancer Research (2015)

Abstract Prostate cancer is the leading cancer diagnosis in men, but only a subset of patients die from the disease. Understanding the molecular basis of aggressive prostate cancer remains elusive and few genomic biomarkers exist to guide clinical management. Long non-coding RNAs (lncRNAs) have emerged as a class of regulatory genes that play a role in several biological and disease processes, including cancer. Recently, we identified SChLAP1, a novel, prognostic lncRNA expressed in a subset of prostate tumors. Mechanistically, SChLAP1 interacts with and inhibits genome-wide binding of the SWI/SNF nucleosome-remodeling complex. Additionally, SWI/SNF plays a key role in the epigenetic control of gene expression and has been shown to have tumor suppressive ability. Given the emerging role of SChLAP1 in the pathogenesis of aggressive prostate cancer and its interaction with the tumor suppressive SWI/SNF complex, exploring the detailed mechanism of action of SChLAP1 warranted further investigation. To identify the regions of SChLAP1 necessary for its function, we created 250 base pair deletion constructs of SChLAP1 and measured RNA-enrichment following SWI/SNF pull-down as well as cell invasion using a Boyden chamber matrigel assay. To investigate whether SChLAP1 preferentially interacts with specific components of the SWI/SNF complex, we performed RNA immunoprecipitation assays using antibodies targeting various enzymatic subunits of SWI/SNF. SChLAP1 enrichment was measured by qPCR. Our results indicate that there is a 250bp region of SChLAP1 that mediates its interaction with SWI/SNF and promotes an invasive phenotype. Furthermore, SChLAP1 shows binding specificity for certain SWI/SNF subunits. Future studies to elucidate the details of this interaction will provide a more comprehensive understanding of the biological and therapeutic consequences of SChLAP1 in prostate cancer progression. Citation Format: Udit Singhal, Anirban Sahu, John R. Prensner, Qi Cao, Arul M. Chinnaiyan. SChLAP1 mediated epigenetic modifications in prostate cancer. [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 2869. doi:10.1158/1538-7445.AM2015-2869
A Phase II Trial of Combined Bendamustine, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis
Authors: Jesus G. Berdeja, Daniel R. Couriel, Patrick Murphy, Ralph V. Boccia, Victor Priego, John D. Hainsworth, Inés M. Macias-Pérez, Ian W. Flinn
Journal: Blood (2011)
67. AptmR: A High Throughput Rational Aptamer Truncation Algorithm
Authors: Thomas Bair, Robert J. Miller, James Schappet, Paloma H. Giangrande, William H. Thiel
Journal: Molecular Therapy (2015)

Aptamer development as both a therapeutic moiety and as a delivery tool is a rapidly growing field, with many aptamers in the clinical pipeline and one FDA-approved aptamer, Macugen. Aptamers are synthetic, single-stranded DNA or RNA oligonucleotides that recognize targets with similar specificity and affinity as antibody/antigen interactions. Current development of new aptamers uses a selection process (SELEX) coupled with high-throughput sequencing (HTS) and bioinformatics, followed by optimization and validation steps. Bioinformatics algorithms such as clustering algorithms have been applied to narrow down the millions of sequences attained by HTS to a handful that can be tested empirically. However, an important optimization step in aptamer development for clinical use is the identification of the minimum sequence required for target binding. This is necessary in order to increase the efficiency and reduce the cost of large-scale chemical synthesis. Herein we report the development of a truncation algorithm designed to identify the minimum aptamer sequence that retains functionality. Using published sequences of full-length aptamers and functional truncations, we first established a set of rules to identify the optimal site for truncation, with an accuracy of ~60% within 1-2 nucleotides and ~90% accuracy within 10 nucleotides. Based on these rules, we then created an algorithm that could be applied to individual aptamer sequences to identify truncations. The algorithm was expanded to analyze HTS Illumina HiSeq reads from multiple rounds of aptamer selection. We next used our previously reported HTS aptamer clustering algorithms (Thiel, et al., PLoS ONE 2012) to identify conserved aptamer truncation domains in a selection. Specifically, truncation sequences were clustered based on sequence similarity (edit distance) or structural similarity (tree distance). Ongoing studies are determining the effects of truncation on aptamer functionality. In future studies, we will use the truncation algorithm to enable the direct identification of shortened aptamer sequences from HTS aptamer data, potentially bypassing the need to empirically test full-length sequences. The truncation algorithm will be integrated into an open-access online aptamer bioinformatics platform that also includes the clustering algorithms. Such tools have the potential to accelerate aptamer development and thereby improve the efficiency of translating aptamers to clinic application.
Intensity-modulated radiotherapy and cetuximab for frail patients with loco-regionally advanced head and neck cancer
Authors: B. Bocci, F. Broggio, F. Crepaldi, M. Violati, N. Battisti, C. Careri, V. Bordin, S. Caldiera, C. Codecà, A. Luciani, S. Zonato, G. Cassinelli, P. Foa, D. Ferrari
Journal: Annals of Oncology (2015)
Normal and Chronic Lymphocytic Leukemia (CLL) Lymphocytes Can Be Distinguished in Flow-Cytometry-Based Automated Differential Cell Counts by Their Positional Parameters.
Authors: Fuensanta Millá, Angels Barberá, Albert Oriol, Tomas Navarro, Jordi Juncà, Lluis Rodriguez, Josep-Maria Ribera
Journal: Blood (2004)
Abstract 4048: HPV16 immunity induced by immune responses to mutations in E6 and E7 proteins
Authors: Maria Agarwal, Ashley Saint-Fleur, Jie Fu, Hyam Levitsky, Cornelia L. Trimble
Journal: Cancer Research (2015)

Abstract Human papillomavirus (HPV) causes 30% of cancers attributable to infectious pathogens. HPV16 causes most cervical, anal, vaginal, vulvar, and oropharyngeal cancers. Although preventive vaccines targeting HPV16 and 18 are available, rates of vaccination are uneven. The incidence of HPV-associated cancers for which no screening algorithms have been validated continues to increase. Development of squamous cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN) 2/3 is associated with integration of HPV genome into the host genome, and expression of the HPV E6 and E7- gene products, which inactivate p53 and pRb respectively. Since E6 and E7 are constitutively expressed in cervical carcinomas and CIN, they present attractive immunotherapeutic targets. Development of immunotherapies has been limited, in part, by modest immunogenicity of vaccines tested to date. The purpose of this study is to augment the immunogenicity of the E6 and E7 antigens through mutational screening. A subset of CIN2/3 do undergo complete regression. Our lab has carried out a series of prospective clinical studies, including immunotherapeutic interventions, in subjects with CIN2/3. Peripheral blood T cell responses to E6 and E7 are marginal, and do not distinguish regressors in either vaccinated or unvaccinated subjects. However, in vaccinated subjects, the lesion microenvironment is comprised of new tertiary lymphoid structures, evidence of T cell proliferation elicited by cognate antigen, and clonally expanded TCRs. Tissue T cells in vaccinated subjects access dysplastic epithelium, in contrast to T cells in persistent lesions, which were confined to the stromal compartment. These findings suggest that T cells that could mediate regression can be elicited by vaccination. However, strategies to enhance immunogenicity would likely increase therapeutic effect. Here we present an approach designed to determine the effect of mutations in E6 and E7 on antigenicity. Mutations can enhance immune responses to antigens by several mechanisms, including altering antigen processing, trafficking, glycolsylation, and affinity to major histocompatibility complexes. Using error prone PCR, we generated libraries containing random mutations in the coding sequence of E6 and E7. Clones from each library are currently being screened in vitro to identify immunogenic mutants, which could be potentially used for multi-epitope vaccines. Citation Format: Maria Agarwal, Ashley Saint-Fleur, Jie Fu, Hyam Levitsky, Cornelia L. Trimble. HPV16 immunity induced by immune responses to mutations in E6 and E7 proteins. [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 4048. doi:10.1158/1538-7445.AM2015-4048
Lympho Node Enlargement in Adult’s Patients Referred to Hematologist: A Frequent Not Classified Clinical Problem. Results from a Retrospective Study.
Authors: Agostino Tafuri, Luisa Bizzoni, Angela Rago, Alice Di Rocco, Rossana Crispino, Angelo Fama, Stefania Trasarti, Angela Capobianchi, Sergio Mecarocci, Claudio Cartoni, Pietro Martino, Robert Foa, Giuseppe Gentile
Journal: Blood (2006)
Treatment of cancer patients with capsid modified double controlled oncolytic adenovirus Ad5/3-Cox2L-D24
Authors: Sari Pesonen, Petri Nokisalmi, Ari Ristimaki, Teemu Kantola, Gerd Bauerschmitz, Anna Kanerva, Timo Joensuu, Akseli Hemminki
Journal: Cancer Research (2008)

2818  Oncolytic adenoviruses are a promising experimental approach for treatment of cancers refractory to currently available modalities. The purpose of this study was to construct viruses selective for cyclooxygenase 2 (cox-2) overexpressing and Rb/p16 pathway mutant cells and test their utility in vitro, in animal models and in cancer patients. A 24 bp deletion (”D24”) was engineered in the constant region 2 of adenovirus E1A, which renders the virus unable to bind Rb. This interaction is necessary for induction of an S-phase like state needed for productive virus replication in normal cells. However, in tumor cells Rb/p16 pathway mutations are ubiquitous and therefore this interaction is not required. Further selectivity was achieved by replacing the native E1A promoter with the cox-2 promoter. High cox-2 expression is a hallmark of many types of aggressive carcinomas. The feasibility of combining D24 with the cox-2 promoter was confirmed in vitro and in orthotopic murine models of ovarian cancer. Adding D24 to the cox-2 promoter increased specificity without loss of efficacy. Adding the promoter to D24 reduced efficacy marginally but increased specificity significantly. Out of various combinations of promoter and deletion variants, Ad5/3-Cox2L-D24 emerged as the optimal construct with regard to efficacy and selectivity in vitro and in vivo. Because the coxsackie-adenovirus receptor CAR is variably expressed and frequently dysfunctional in many advanced tumors, we tested a number of approaches for increasing gene delivery to various types of advanced and aggressive tumors, including NSCLC, gastric, pancreatic, ovarian, cervical, SCCHN, colorectal, renal, breast and prostate cancer. While polylysine and RGD-4C modification of the adenoviral fiber knob were both effective for many tumor types, and far superior over CAR binding viruses, serotype chimerism with the Ad3 knob emerged as an approach with wide utility and is therefore featured in Ad5/3-Cox2L-D24. Following promising preclinical efficacy and safety data, treatment of patients with tumors refractory to all available modalities was initiated. By abstract submission, 4 patients with NSCLC, colon cancer, pancreatic cancer or malignant fibrous histiosarcoma have been safely treated intratumorally, intraperitoneally and intravenously. By the meeting, we expect to have treated half a dozen more. Efficacy and safety data will be presented. In summary, we propose that Ad5/3-Cox2L-D24 is a promising agent for treatment of cox-2 expressing tumors refractory to available modalities.
Abstract 3153: Critical roles of chemo-resistant effector and regulatory T cells in cancer immunotherapy during hemostatic proliferation
Authors: Ko Sato, Satoshi Watanabe, Yu Saida, Tomohiro Tanaka, Junko Baba, Aya Ohtsubo, Satoshi Shoji, Daisuke Ishikawa, Rie Kondo, Masaaki Okajima, Satoru Miura, Junta Tanaka, Hiroshi Kagamu, Hirohisa Yoshizawa, Ichiei Narita
Journal: Cancer Research (2015)

Abstract Antitumor immunity has been well established to be augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naïve and effector T cells proliferate extensively and show enhanced antitumor effects during homeostatic proliferation when they were adoptively transferred into tumor-bearing hosts that were lymphodepleted with cytotoxic agents or by whole body irradiation. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8+ T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents, such as fludarabine, cisplatin, etoposide, paclitaxel or gemcitabine; however, the percentage of CD4+CD25+Foxp3+ Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemo-resistant Tregs following CPA treatment and transfer of naïve CD4+ T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8+ T cells were responsible for this augmentation. Using Rag2−/− mice or depletion of recipient CD8+ T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4+ T cells enhanced the proliferation of CD8+ T cells and the priming of tumor-specific CD8+ T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies. Citation Format: Ko Sato, Satoshi Watanabe, Yu Saida, Tomohiro Tanaka, Junko Baba, Aya Ohtsubo, Satoshi Shoji, Daisuke Ishikawa, Rie Kondo, Masaaki Okajima, Satoru Miura, Junta Tanaka, Hiroshi Kagamu, Hirohisa Yoshizawa, Ichiei Narita. Critical roles of chemo-resistant effector and regulatory T cells in cancer immunotherapy during hemostatic proliferation. [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 3153. doi:10.1158/1538-7445.AM2015-3153
393. Engineering Armored T Cell Receptor-Mimic (TCRm) Chimeric Antigen Receptor (CAR) T Cells Specific for the Intracellular Protein Wilms Tumor 1 (WT1) for Treatment of Hematologic and Solid Malignancies
Authors: Sarwish Rafiq, Terence Purdon, Tao Dao, Chen Liu, David Scheinberg, Renier J. Brentjens
Journal: Molecular Therapy (2016)

Adoptive therapy with chimeric antigen receptor (CAR) T cells specific for CD19 is clinically successful in a limited set of leukemias and most CARs studied are targeted against external antigens. Wilms Tumor Antigen 1 (WT1) protein (WT1) is an intracellular antigen overexpressed in many cancers, including leukemias and solid malignancies and is thus an appealing, broadly applicable target. We have engineered the first armored T cell receptor-mimic (TCRm) CAR against WT1. Derived from the ESK1 antibody, the second generation CAR, WT1-28z, is reactive with the RMFPNAPYL peptide of WT1 that is processed and presented on the surface of cells in the context of HLA-A*02:01. WT1-28z was further modified to secrete human IL-12 cytokine, thus creating the armored CAR WT1-28z/IL-12. T cells expressing WT1-28z or WT1-28z/IL-12 are cytotoxic against a range of both hematological and solid tumors. Importantly, both WT1-directed T cells are specific for the WT1-HLA-A*02:01 complex and are not reactive against cells that do not express both HLA-A*02:01 and WT1. In established SCID/Beige mouse models of either acute leukemia or ovarian cancer, one dose of WT1-28z T cells prolongs survival of mice over untreated or irrelevant antigen-specific CAR T cell treated mice. Furthermore, one dose of the armored WT1-28z/IL12 CAR T cells further significantly prolongs survival of mice in both models over WT1-28z CAR T cell treated mice, with a subset of mice whose disease was eradicated. The armored TCRm CAR T cells against WT1 are effective in eradicating disease in both hematologic and solid tumors and may hold great clinical potential to expand on the success of CAR T cell therapy.
Development of a Unique In Vitro and In Vivo Model System of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph-ALL) with Emphasis on Cell to Cell Interaction.
Authors: Arinobu Tojo, Kiyoko Izawa, Rieko Sekine, Tokiko Nagamura-Inoue, Seiichiro Kobayashi
Journal: Blood (2006)