tbuckley/cabot-search huggingface dataset:
Abstract CT103: A phase II study to evaluate outpatient magnetic resonance image-guided laser focal therapy for prostate cancer: A 20-year survival study (seven-year interim results)
Authors: Bernadette Marie Greenwood, John F. Feller, Stuart T. May, Wes Jones, Axel Winkel
Journal: Cancer Research (2017)

Abstract Purpose: In the United States alone, new prostate cancer cases for 2016 were estimated at 180,890 and deaths at 26,120. Focal therapies for low risk and intermediate risk localized prostate cancer are increasingly being explored. Additionally, new treatments for patients with biochemical recurrence of prostate cancer are also under investigation. Our objective is to investigate the safety and feasibility of using outpatient MR-guided laser focal therapy for MR visible prostate cancer utilizing a transrectal approach for laser applicator placement and therapy delivery in an outpatient setting. Method and Materials: All MRI-guided therapy was delivered using a 1.5 Tesla MRI system for both image acquisition and real-time thermometry. Commercially available hardware and software were used for image analysis and interventional planning. Laser therapy was delivered using a 15W, 980 nm diode laser applicator with fiber-cooling catheter introduced transrectally using a commercially available MRI-compatible introducer system. Results: 80 men were treated. 112 cancer foci were treated. Total procedure time was between 1.5 and four hours MRI volume of coagulation necrosis ranged from 0.57 to 22.93 cc. No serious adverse events or morbidity were reported. 17 treatment regions were positive at six months biopsy, consistent with residual or recurrent cancer 26% of subjects 18% of treated regions.We observed a 40% decrease in mean PSA at 1 year post therapy and no statistically significant change in IPSS and SHIM scores at 6 months post-treatment. Conclusion: Our data indicate that outpatient, transrectally delivered MRI-guided laser focal therapy for prostate cancer is both safe and feasible. Clinical Relevance/Application: In the current climate of cost-reduction and emphasis on minimally-invasive treatment of cancer, focal treatment of prostate cancer may be an attractive option. The precise energy delivery under MRI-guidance may have favorable results for cost control and quality of life without eliminating the possibility of whole-gland treatment in the patient’s future. Citation Format: Bernadette Marie Greenwood, John F. Feller, Stuart T. May, Wes Jones, Axel Winkel. A phase II study to evaluate outpatient magnetic resonance image-guided laser focal therapy for prostate cancer: A 20-year survival study (seven-year interim results) [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 CT103. doi:10.1158/1538-7445.AM2017-CT103
Abstract 4130: Characterization of URST1 as a prognostic biomarker and therapeutic target for lung cancer
Authors: Atsushi Takano, Yohei Miyagi, Yataro Daigo
Journal: Cancer Research (2017)

Abstract Lung cancer is the most frequent cause of cancer deaths worldwide and its overall prognosis remains poor. Therefore, next generation of biomarkers and therapeutic strategies for lung cancer are eagerly awaited. We selected genes that were overexpressed in the majority of lung cancer using our gene expression profile database. During this process, we identified URST1 (Up-regulated in solid tumor 1) as a candidate. Immunohistochemical staining showed that URST1 expression was observed in the majority of non-small cell lung cancer (NSCLC) patients (P = 0.0013 by log rank test). Multivariate analysis revealed high level of URST1 expression was an independent prognostic factor for NSCLC patients. Moreover, reduction of URST1 by siRNA or treatment with URST1 inhibitor significantly suppressed lung cancer cell growth probably through cell cycle arrest at G2/M. Exposure of cancer cells to URST1 inhibitor significantly suppressed These data suggest that URST1 is a possible prognostic biomarker and therapeutic target for lung cancer. Citation Format: Atsushi Takano, Yohei Miyagi, Yataro Daigo. Characterization of URST1 as a prognostic biomarker and therapeutic target for lung 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 4130. doi:10.1158/1538-7445.AM2017-4130
Abstract 5289: Assessment of environmental influences, behavioral risk factors and genetic differences among a cohort of 819 African American community members
Authors: Jacquelyn Bucci, Ming Chin Yeh, Khursheed Navder, Joel Erblich, Elizabeth Blackman, Grace X. Ma, Camille Ragin
Journal: Cancer Research (2017)

Abstract Objectives: This study was designed to address genetic, environmental and lifestyle risk factors for cancer in populations of African Ancestry. We have established a non-cancer control registry which involves the collection of epidemiological, lifestyle, culture and cancer prevention behaviors (such as cancer screening and diet, etc). Methods: Data was coded and analyzed using Stata from initial study surveys. Results: At analysis, the cohort consisted of 819 participants. The cohort was 65.9% female, ages 18-89 (23.5% within 50-59 age group), 35.9% college graduates, and 17.4% with income level $20,000-$25,000. Two-thirds of the cohort had BMI greater than 25, indicating overweight or obese. When stratified by country of birth, participants born in the US &amp; Territories were more likely to be current smokers (23.3%) and have higher rates of environmental exposure to smoking than any other region of birth analyzed. Participants from US &amp; Territories had the highest access to health care (85.9%). Pap smears were the only screening test with statistically significant difference between the regions, with US &amp; Territories having the highest rates of screening (p &amp;lt; 0.001). Conclusions &amp; Implications: Overall, the cohort and its data provide researchers with a resource to further investigate health disparities in cancer as well as other chronic diseases and tailor culturally relevant education materials to help decrease the rates of cancer in this vulnerable population. Citation Format: Jacquelyn Bucci, Ming Chin Yeh, Khursheed Navder, Joel Erblich, Elizabeth Blackman, Grace X. Ma, Camille Ragin. Assessment of environmental influences, behavioral risk factors and genetic differences among a cohort of 819 African American community members [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 5289. doi:10.1158/1538-7445.AM2017-5289
Abstract 972: Improving pre-clinical cancer pharmacogenomics with novel drug sensitivity metrics based on growth rate inhibition
Authors: Marc Hafner, Mario Niepel, Peter K. Sorger
Journal: Cancer Research (2017)

Abstract Drug sensitivity in growing cells is conventionally quantified by IC50, AUC, or Emax values, but these metrics suffer from a fundamental flaw: they highly depend on the division rate of cell lines. This dependency creates artefactual correlations between genetic alterations and drug sensitivity which impede biomarker discovery. To address this issue, we recently developed novel drug response metrics insensitive to the number of divisions occurring during the assay. These are based on estimating growth rate inhibition (GR) under treatment using fixed assays. Here, we illustrate the flaws of using IC50 values for pharmacogenomic studies by reanalyzing a recently published large dataset of drug sensitivity and showing cases in which differences in division rates drive associations between IC50 values and tissue type or genetic alterations. Using GR50 values prevents these artificial correlations and restores known associations between drug resistance and genomic markers such as PTEN loss driving lapatinib resistance in breast cancer cell lines. We also show how use of GRmax values, a measure of drug efficacy, allows quantifying differences in the phenotypes and distinguishing cytostatic from cytotoxic response. For drugs that have a narrow range of GR50 values like taxanes, efficacy is the most relevant metric: in many ovarian BCL2-deleted cell lines, docetaxel induces a cytotoxic response (negative GRmax values), whereas wild-type lines elicit a cytostatic response (positive GRmax values). Because efficacy (GRmax) varies independently of potency (GR50), we conclude that both metrics are complementary for pharmacogenomics and should be studied jointly. Adopting GR metrics requires only modest changes in experimental protocols and analysis is facilitated by our interactive website: GRcalculator.org. We expect GR metrics to improve the identification of reliable drug response biomarkers and enhance the reproducibility of large-scale sensitivity studies. Citation Format: Marc Hafner, Mario Niepel, Peter K. Sorger. Improving pre-clinical cancer pharmacogenomics with novel drug sensitivity metrics based on growth rate inhibition [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 972. doi:10.1158/1538-7445.AM2017-972
Abstract LB-102: Landscape analysis of the initial data release from AACR Project GENIE
Authors: Ethan Cerami, Alexander S. Baras, Justin Guinney, Eva Lepisto, Trevor J. Pugh, Nikolaus Schultz, Thomas Stricker, Shawn M. Sweeney, Laura J. van't Veer, Gerrit A. Meijer, Fabrice Andre, Victor E. Velculescu, Kenna R. Shaw, Mia A. Levy, Philippe L. Bedard, Barrett J. Rollins, Charles L. Sawyers
Journal: Cancer Research (2017)

Abstract AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) is a multi-phase, multi-year, international data-sharing consortium whose goal is to generate an evidence base for precision cancer medicine by integrating and linking clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. The project fulfills an unmet need in oncology by providing the statistical power necessary to identify novel therapeutic targets, to understand genomic determinants of response to therapy, to design new biomarker-driven clinical trials and ultimately, to improve clinical decision-making and the care delivered to patients. Here we describe the goals, structure and data standards of the GENIE consortium and conclusions from a high-level analysis of the first public release of genomic and limited clinical data from approximately 19,000 patients treated at eight cancer centers obtained during this initial phase of the project. We also explore the clinical utility of these genomic data by examining rates of clinical actionability across multiple cancer types and by estimating patient enrollment rates to the NCI MATCH Trial. Based on yearly rates of sequencing at each of the eight founding institutions, together with the planned addition of new members, we estimate the GENIE database could grow to &amp;gt;100,000 samples within five years. Consistent with the goals of the proposed Cancer Moonshot National Cancer Data Ecosystem, GENIE is committed to the principles of generating interoperable, open access data that can be widely shared across the entire scientific community. Citation Format: Ethan Cerami, Alexander S. Baras, Justin Guinney, Eva Lepisto, Trevor J. Pugh, Nikolaus Schultz, Thomas Stricker, Shawn M. Sweeney, Laura J. van't Veer, Gerrit A. Meijer, Fabrice Andre, Victor E. Velculescu, Kenna R. Shaw, Mia A. Levy, Philippe L. Bedard, Barrett J. Rollins, Charles L. Sawyers, on behalf of the AACR Project GENIE Consortium. Landscape analysis of the initial data release from AACR Project GENIE [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 LB-102. doi:10.1158/1538-7445.AM2017-LB-102
Abstract 639: Morphological changes in mitochondria induced by CD137 (4-1BB) co-stimulation on CD8 T cells
Authors: Sara Labiano, Álvaro Teijeira, Arantza Azpilikueta, Ángela Aznar, Elixabet Bolaños, Ignacio Melero
Journal: Cancer Research (2017)

Abstract Metabolism has emerged as a fundamental biological process in the control of immunological functions of T cells, playing essential roles in survival and differentiation of these immune cells. Mitochondria are key organelles in controlling these processes by performing fundamental steps in aerobic respiration, fatty acid metabolism and in the control of apoptosis. Recently, Carl June and colleagues showed that CARs engineered with the cytoplasmic tail of 4-1BB were able to promote oxidative phosphorylation in T cells as a result of enhanced mitochondrial biogenesis. CD137 (4-1BB) is an immunostimulatory receptor of the TNFR family expressed on the surface of antigen-activated T cells. Treatment with agonist monoclonal antibodies targeting 4-1BB is showing promising results for immunotherapy of cancer. In this work, we observed that stimulation of 4-1BB with agonistic mAbs was able to raise the mitochondrial membrane potential on human CD8 T cells. 4-1BB co-stimulated CD8 T cells showed enlarged mitochondria (up to 3μm diameter) with a round shape when observed by confocal or transmission electron microscopy. We observed that CD8 T cells from DLNs (drainig lymph nodes) of tumors in mice treated with agonistic anti-4-1BB antibodies also contained enlarged mitochondria. By double fluorescence labeling of mitochondria prior and after activation, we could ascertain that enlarged mitochondria were a product of preexisting mitochondria rather than de novo generated organelles. This observation prompted us to study the regulation of mitochondrial dynamics by 4-1BB receptor. 4-1BB stimulation induced an increase in expression of the mitochondrial fusion protein OPA-1. By Super-resolution microscopy with AiryScan detectors we observed more pronounced co-localization of OPA-1 with mitochondrial membrane in 4-1BB co-stimulated T cells than in T cells activated only by CD3 crosslinking. Our results indicate an important role of 4-1BB in the regulation of mitochondrial morphology and performance in such a way that can be relevant for various T cell functions. Citation Format: Sara Labiano, Álvaro Teijeira, Arantza Azpilikueta, Ángela Aznar, Elixabet Bolaños, Ignacio Melero. Morphological changes in mitochondria induced by CD137 (4-1BB) co-stimulation on CD8 T 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 639. doi:10.1158/1538-7445.AM2017-639
Abstract 3070: Lenalidomide and SMAC mimetic LCL161 show combination activity in cells harboring loss of chromosome 5q
Authors: Nafeeza Hafeez, Alex Gaither, Dale Porter
Journal: Cancer Research (2017)

Abstract LCL161 is a small molecule SMAC mimetic that binds to cIAP1, cIAP2, and XIAP and sensitizes cancer cells to TNF-alpha as well as other inducers of cell death. An siRNA screen was performed in the SK-OV-3 cancer cell line to identify genes that when knocked down prevent LCL161-mediated cell death. As expected, siRNAs targeting RIPK1 rescued cells from LCL161-induced death. Unexpectedly, siRNAs targeting GPR68 also rescued cells from LCL161-induced death. Since knockdown of GPR68 has been reported to rescue myelodysplastic syndrome (MDS)-derived cells harboring loss of chromosome 5q from lenalidomide treatment, we tested for combination activity with lenalidomide plus LCL161 in 7-day in vitro proliferation assays. Interestingly, combination activity was observed in the SET-2 cell line harboring cytogenetic features of MDS including loss of chromosome 5q. These data suggest that, in combination, LCL161 may improve responses to lenalidomide in subsets of MPN and MDS patients and potentially additional contexts where lenalidomide is active. Citation Format: Nafeeza Hafeez, Alex Gaither, Dale Porter. Lenalidomide and SMAC mimetic LCL161 show combination activity in cells harboring loss of chromosome 5q [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 3070. doi:10.1158/1538-7445.AM2017-3070
The Prevalence of Extended-Spectrum Beta-Lactamase-Producing Multidrug-Resistant <i>Escherichia Coli</i> in Poultry Chickens and Variation According to Farming Practices in Punjab, India
Authors: Charles H. Brower, Siddhartha Mandal, Shivdeep Hayer, Mandeep Sran, Asima Zehra, Sunny J. Patel, Ravneet Kaur, Leena Chatterjee, Savita Mishra, B.R. Das, Parminder Singh, Randhir Singh, J.P.S. Gill, Ramanan Laxminarayan
Journal: Environmental Health Perspectives (2017)

Agricultural use of antimicrobials in subtherapeutic concentrations is increasing in response to the rising demand for food animal products worldwide. In India, the use of antimicrobials in food animal production is unregulated. Research suggests that many clinically important antimicrobials are used indiscriminately. This is the largest study to date in India that surveys poultry production to test for antimicrobial resistance and the occurrence of extended-spectrum β-lactamases (ESBLs) modulated by farming and managerial practices.Our goal was to survey poultry production for resistance to eleven clinically relevant antimicrobials and phenotypic occurrence of ESBLs as modulated by farming and managerial practices.Eighteen poultry farms from Punjab were surveyed, and 1,556 Escherichia coli isolates from 530 birds were tested for susceptibility to 11 antimicrobials using the disk diffusion method and validated using VITEK 2 (bioMérieux, Marcy-L’Étoile, France). Samples from 510 of these birds were phenotypically tested for ESBL production using the combination disk method and confirmed using VITEK 2. Generalized linear mixed models were used to infer differences in resistance profiles associated with different farming practices and facility types.Resistance profiles were significantly different between broiler and layer farms. Broiler farms were 2.2 [ampicillin (AMP), p=0.017] to 23 [nalidixic acid (NX), p<0.001] times more likely to harbor resistant E. coli strains than layer farms. Adjusting for farm type (broiler vs. layer), the odds of resistance (although not statistically significant) to all antimicrobials except nitrofurantoin (NIT) were higher in independent facilities (IUs) as compared to contracted facilities (CFs). Increased prevalence of multidrug resistance (MDR; 94% compared to 60% in layers), including prevalence of ESBL-producing strains (87% compared to 42% in layers), was observed in broiler farms.Our findings suggest that unregulated use of clinically relevant antimicrobials in Indian broiler and layer farms may contribute to the emergence of resistance and support the need to curb the nontherapeutic use of medically important antimicrobials in food animal production. https://doi.org/10.1289/EHP292.
Abstract 793: Human endothelial progenitor cells: A new target for anti-vascular therapy
Authors: Ghada Ben Rahoma, Neha Tuli, Rachana Maniyar, Sanjukta Chakraborty, Sarnath Singh, Abraham Mittelman, Raj K. Tiwari
Journal: Cancer Research (2017)

Abstract Breast cancer affects one in eight women in the USA. Early diagnosis and newer treatment modalities have rendered breast cancer manageable. However, triple negative breast cancer is still difficult to treat and warrantes a search for newer targets. One strategy that has emerged in cancer research involves targeting of tumor associated blood vessels which provide growing tumors with oxygenated blood and growth factors necessary for maintenance and metastasis. Antiangiogenic drug therapy is transient and has not been able to gain mainstream therapeutic modality. We discovered that endothelial progenitor cells (EPCs) are mobilized from the bone marrow to the tumor site and contribute to the development of breast tumor vessel formation in an estrogen dependent manner. Therefore, characterization of tumor associated endothelial progenitor cells in breast cancer may provide a more specific antivascular therapy. Using the highly proliferative human umbilical cord blood derived EPCs, having the phenotype (CD133+, CD34+, VEGFR-2+), the effect of growth factor and chemokine rich EPCs conditioned medium (CM) was assessed in luminal (MCF-7), and post-EMT (MDA-MB-231) breast carcinoma cell lines. We observed an initial halt in cellular proliferation in MCF-7 followed by a significant increase in proliferation after forty eight hours of treatment. On the other hand, MDA-MB-231 showed decreased proliferation even after forty eight hours of treatment. Treating the EPCs with breast cancer conditioned medium resulted in morphological and cellular growth changes in the EPCs. MDA-MB-231 CM resulted in an increase of the EPCs proliferation and differentiation by increasing the number of spindle shaped attaching cells, and MCF-7 CM resulted only in an increase in the differentiation rate by increasing the number of cell clusters. This increase in EPCs proliferation and differentiation associated with MDA-MB-231 CM treatment might explain the invasiveness of this breast cancer cells through the increase in the tumor associated neovascularization. The analysis of the paracrine interaction between breast cancer cells and EPCs along with the associated cellular changes will facilitate identification of the interactive mediators and subsequent development of effective antivascular therapy. Citation Format: Ghada Ben Rahoma, Neha Tuli, Rachana Maniyar, Sanjukta Chakraborty, Sarnath Singh, Abraham Mittelman, Raj K. Tiwari. Human endothelial progenitor cells: A new target for anti-vascular therapy [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 793. doi:10.1158/1538-7445.AM2017-793