tbuckley/cabot-search huggingface dataset:
Abstract 1023: Functional genomics reveals dependency on 6-phosphogluconate dehydrogenase in OXPHOS-deficient tumors
Authors: Yuting Sun, Madhavi Bandi, Timothy Lofton, Melinda Smith, Christopher Bristow, Norma Rogers, Chang Edward, Mary Geck Do, Yongying Jiang, Pietro Morlacchi, Florian Muller, Faika Mseeh, Barbara Czako, Wylie Palmer, Carlo Toniatti, Philip Jones, Giulio Draetta, Timothy Heffernan, Joseph Marszalek
Journal: Cancer Research (2016)

Abstract Cancer cells display metabolic properties distinct from normal cells and are therefore believed to be dependent on key metabolic enzymes. The effectiveness of targeting metabolism for cancer therapy has been largely restricted due to metabolic adaptability. We postulate that tumors with metabolic vulnerabilities will be limited in such adaptation, thus providing a unique opportunity for therapeutic intervention. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is a metabolically vulnerable cancer, due to mutations in a key TCA cycle enzyme - fumarate hydratase (FH), thus rendering them deficient in oxidative phosphorylation (OXPHOS). We performed a loss-of-function genetic screen in a FH-null HLRCC model (UOK262 cells) and identified 6-phosphogluconate dehydrogenase (6PGD) - a rate-limiting enzyme in the non-oxidative arm of pentose phosphate pathway - as a critical regulator of cell growth. Inhibition of 6PGD using either dox-inducible shRNA or a small molecule inhibitor dramatically blocks the growth of UOK262 cells, and in contrast, has no effect on 6PGD-deficient NB1 cells. The growth inhibition from knockdown is fully rescued by expressing shRNA-resistant 6PGD. Conversely, ectopic expression of 6PGD in NB1 cells results in a gain of function phenotype. Importantly, in vivo, 6PGD knockdown causes robust regression of established UOK262 xenografts. Mechanistically, 6PGD inhibition causes the accumulation of 6-phosphogluconate, blocks glycolysis, and induces ROS production. Furthermore, in tumors with intact TCA cycle, 6PGD inhibition shows synergism with OXPHOS Complex I inhibitor IACS-10759. Together, our data suggest that 6PGD is a bona fide oncology target and provide a strong rationale for developing small molecule inhibitors that could be used to treat OXPHOS-deficient tumors as single agent, or combined with inhibitors of OXPHOS. Citation Format: Yuting Sun, Madhavi Bandi, Timothy Lofton, Melinda Smith, Christopher Bristow, Norma Rogers, Chang Edward, Mary Geck Do, Yongying Jiang, Pietro Morlacchi, Florian Muller, Faika Mseeh, Barbara Czako, Wylie Palmer, Carlo Toniatti, Philip Jones, Giulio Draetta, Timothy Heffernan, Joseph Marszalek. Functional genomics reveals dependency on 6-phosphogluconate dehydrogenase in OXPHOS-deficient tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1023.
The effect of ADT on objective cognitive performance and self-reported cognitive functionin men with prostate cancer.
Authors: S. Marzouk, S. Duff Canning, G. Naglie, G. A. Tomlinson, M. Leach, F. Hussain, I. Tannock, S. M. Alibhai
Journal: Journal of Clinical Oncology (2010)

4560 Background: ADT is used to treat almost 50% of prostate cancer (PC) patients. Despite slowing disease progression and prolonging survival, ADT is associated with numerous side effects. However, the impact of ADT on self-reported and objective cognitive function remains unclear. Methods: Three groups of males age 50+ were included; PC patients starting continuous ADT (n=77), PC controls not receiving ADT (n=85), and healthy controls (n=83). A self-reported cognitive function questionnaire (FACT-Cog) and a battery of neuropsychological tests examining 8 cognitive domains were administered at baseline, 6 months and 12 months later. The FACT-Cog scores and the battery test scores were compared between groups at baseline, and change scores over the 12 month period were analyzed using ANOVA and multi-variable linear regression. To examine whether changes in objective cognitive scores correlated with changes in FACT-Cog scores, Pearson correlations were calculated. Results: FACT- Cog scores obtained at baseline did not significantly differ between the 3 groups (p>0.05). ADT users did not report a greater decline in self-cognitive function overtime compared to PC controls or healthy controls (p=0.21). Attention and Processing Speed, Visual Memory, Language and Executive Function scores did not significantly differ between groups (p>0.05). At 12 months, ADT users had significantly declined on the Longest Digit Span Forwards (Immediate Memory), Spatial Span Backwards (Working Memory), and Card Rotations tasks (Visuospatial Ability) (p<0.05). Correlations between FACT-Cog and objective cognitive test scores were weak at baseline and overtime (all r<0.20). Conclusions: Preliminary analyses suggest little or no deleterious effect of ADT on self-reported cognitive function over 12 months. Objective cognitive performance of ADT users declined over 12 months on 3 cognitive tests, indicating a possibility of ADT's long-term impact on selected cognitive domains. Correlations between FACT-Cog scores and objective cognitive performance were poor. No significant financial relationships to disclose.
A Randomized Phase III Trial of Thalidomide and Prednisone as Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT) In Patients with Multiple Myeloma (MM): The NCIC CTG MY.10 Trial
Authors: A. Keith Stewart, Suzanne Trudel, Nizar J Bahlis, Darrell J White, Waleed Sabry, Andrew Belch, Tony Reiman, Jean Roy, Chaim Shustik, Michael J. Kovacs, Jonathan Sussman, Ralph M. Meyer, Erica L Harnett, Danila Oana, Judy A Chapman, Lois Shepherd
Journal: Blood (2010)
Abstract 181: Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer
Authors: Daoxiang Zhang, Lin Li, Hongmei Jiang, Jinsheng Yu, Brett Knolhoff, Richard Head, Albert C. Lockhart, David G. DeNardo, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim
Journal: Cancer Research (2016)

Abstract Constitutive activation of the NF-κb transcription factor is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of pancreatic cancer. Understanding the molecular mechanisms that activate NF-κB will provide novel therapeutic opportunities to improve the dismal outcome of pancreatic cancer patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated in a majority of pancreatic cancer cell lines and patients samples, and are major drivers of NF-κB activity. Notably, we found that constitutive phosphorylation of IRAK4 is associated with poor patient prognosis. Suppression of IRAK1 and IRAK4 with small molecule inhibitor or RNA-interference in pancreatic cancer cells significantly reduces NF-κB activity, three-dimensional growth, invasiveness, production of inflammatory, and augment their sensitivity to chemotherapeutic agents in vitro. Notably, we showed that the NF-κB activity of pancreatic cancer cell with IRAK4 ablated using CRISPR technology can be restored with wild-type, but not kinase-dead IRAK4 mutant, supporting development of IRAK4 inhibitor as a novel therapeutic agent in pancreatic cancer. Silencing of IRAK1 or IRAK4, and more potently both, significantly abrogated the tumorigenic potential of human and murine pancreatic cancer cells as xenograft in mice. Lastly, we showed that IRAK1/4 inhibitor augments the therapeutic effect of gemcitabine in tumor-bearing mice by suppressing proliferation and increasing apoptosis of neoplastic cells, and reducing stromal fibrosis. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in pancreatic cancer. Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Jinsheng Yu, Brett Knolhoff, Richard Head, Albert C. Lockhart, David G. DeNardo, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 181.
Abstract LB-277: Induction chemotherapy induces enrichment of leukemic stem cells in PDX models of acute myeloid leukemia
Authors: Cathy C. Zhang, Zhengming Yan, Bernadette Pascual, Stephen Huang, Qing Zong, Mark Elliot, Patrick Lappin
Journal: Cancer Research (2016)

Abstract Human leukemic stem cells may be one of the leading causes for resistance or treatment failure in acute myeloid leukemia patients. To gain insights into the mechanisms underlying chemo-resistance of AML disease, we evaluated the biomarkers and the pharmacological properties of minimal residual disease post induction therapy. The PDX models were established by iv injecting acute myeloid leukemia patient cells in NOD/SCID/Il2rg(-/-) mice (NSG). The disease progression was tracked by the AML counts in peripheral blood and bone marrow via FACS analysis. In the PDX models, daunorubicin/cytarabine (DA) chemotherapy showed early antileukemic efficacy through apoptosis induction and antiproliferation. However, treatment showed minimal survival benefits and all treated leukemic mice relapsed due to the minimal residual disease (MRD). FACS analysis showed that DA therapy induced enrichment of CD34+ and CLL1+/CD117- cells in the MRD of the BM0407 and BM2407 AML PDX models, respectively. Subsequently, we performed self-renewal functional test by in vivo reimplantation of sorted CD34+ and CLL1+/CD117- cells. The limiting delusion analysis showed that the chemo- resistant CD34+ and CLL1+/CD117- cells are much more tumorigenic than their counterpart CD34- and CLL1+/CD117+ cells, respectively. This work provides insights into the mechanism of chemo-resistance and helps identifying new strategies to improve AML therapy. Citation Format: Cathy C. Zhang, Zhengming Yan, Bernadette Pascual, Stephen Huang, Qing Zong, Mark Elliot, Patrick Lappin. Induction chemotherapy induces enrichment of leukemic stem cells in PDX models of acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-277.
Impact of prostate cancer national guidelines on brachytherapy monotherapy practice patterns.
Authors: Yolanda Diana Tseng, Alan T Paciorek, Neil E Martin, Anthony Victor D'Amico, Matthew R. Cooperberg, Paul Linh Nguyen
Journal: Journal of Clinical Oncology (2013)

5024 Background: In 1999, the American Brachytherapy Society (ABS) recommended brachytherapy monotherapy (BT) be limited to low-risk prostate cancer, in part because a high-impact 1998 publication suggested that intermediate or high-risk disease had worse outcomes with BT than with external beam radiation (EBRT) or radical prostatectomy (RP). We studied temporal patterns of BT use before and after the 1999 ABS published guidelines as compared with 4 other treatment options. Methods: A retrospective analysis was performed of all men with T1c-T3cN0M0 prostate cancer treated definitively in the United States from 1990 to 2011 in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Logistic regression was used to estimate adjusted odds ratios (AOR) comparing BT use with other treatment groups between the 1990-1998 and 1999-2011 periods, controlling for age, disease characteristics, and clinic site type. Results: 8128 men received BT (n=1117), BT+EBRT (n=313), EBRT alone (n=596), EBRT+androgen deprivation therapy (ADT, n=613), or RP (n=5489) for modified D’Amico low (n=3506), intermediate (n=2938) or high-risk (n=1684) disease. By t-tests, BT patients were younger than either EBRT or EBRT+ADT patients (both p&lt;0.001), older than RP patients (p&lt;0.001), and had lower risk disease than men in any of the four treatment groups (all Cochran-Mantel-Haenszel chi-square p&lt;0.001). BT comprised 6.1% and 16.6% of all treatments in 1990-1998 and 1999-2011, respectively (Pearson p&lt;0.01). The odds of BT use remained increased after adjusting for potential confounders (AOR 4.50, p&lt;0.001). Increased BT use was seen only among low (AOR 5.06, p&lt;0.001) and intermediate-risk patients (AOR 4.59, p&lt;0.001). Among men with low or intermediate-risk disease, BT use increased compared with EBRT (AOR LOW 10.00; AOR INT 12.66, both p&lt;0.001), EBRT+ADT (AOR LOW 2.90, p=0.0037; AOR INT 2.15, p=0.0041) and RP (AOR LOW 4.76; AOR INT 5.10, both p&lt;0.001). Conclusions: Despite national guidelines to the contrary, brachytherapy monotherapy for intermediate-risk prostate cancer increased over time relative to other treatments. Further studies are needed to identify factors that contribute to this evidence-practice gap.
Managing player load in professional rugby union: a review of current knowledge and practices
Authors: Kenneth L Quarrie, Martin Raftery, Josh Blackie, Christian J Cook, Colin W Fuller, Tim J Gabbett, Andrew J Gray, Nicholas Gill, Liam Hennessy, Simon Kemp, Mike Lambert, Rob Nichol, Stephen D Mellalieu, Julien Piscione, Jörg Stadelmann, Ross Tucker
Journal: British Journal of Sports Medicine (2016)

Background The loads to which professional rugby players are subjected has been identified as a concern by coaches, players and administrators. In November 2014, World Rugby commissioned an expert group to identify the physical demands and non-physical load issues associated with participation in professional rugby. Objective To describe the current state of knowledge about the loads encountered by professional rugby players and the implications for their physical and mental health. Findings The group defined ‘load’ as it relates to professional rugby players as the total stressors and demands applied to the players. In the 2013–2014 seasons, 40% of professional players appeared in 20 matches or more, and 5% of players appeared in 30 matches or more. Matches account for ∼5–11% of exposure to rugby-related activities (matches, team and individual training sessions) during professional competitions. The match injury rate is about 27 times higher than that in training. The working group surmised that players entering a new level of play, players with unresolved previous injuries, players who are relatively older and players who are subjected to rapid increases in load are probably at increased risk of injury. A mix of ‘objective’ and ‘subjective’ measures in conjunction with effective communication among team staff and between staff and players was held to be the best approach to monitoring and managing player loads. While comprehensive monitoring holds promise for individually addressing player loads, it brings with it ethical and legal responsibilities that rugby organisations need to address to ensure that players’ personal information is adequately protected. Conclusions Administrators, broadcasters, team owners, team staff and the players themselves have important roles in balancing the desire to have the ‘best players’ on the field with the ongoing health of players. In contrast, the coaching, fitness and medical staff exert significant control over the activities, duration and intensity of training sessions. If load is a major risk factor for injury, then managing training loads should be an important element in enabling players to perform in a fit state as often as possible.
Abstract 4865: Metformin improves multiple cytokine producing ability of exhausted peripheral CD8+ T cells of cancer patients
Authors: Mototsugu Watanabe, Shingo Eikawa, Takenori Uehara, Yuki Kunisada, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono
Journal: Cancer Research (2016)

Abstract Background: We have recently shown that metformin, a prescribed drug for type 2 diabetes, can increase the number of CD8+ tumor infiltrating lymphocytes (CD8+ TILs) that can produce triple cytokines, thus, IFN-ã, IL-2 and TNF-á in mouse models. Increased numbers of such multifunctional CD8+ TILs have well correlated with tumor retardation, suggesting an underlying mechanism of metformin in tumor immunity. In the current study, we examined the effects of direct exposure of metformin in vitro to CD8+ T cells of cancer patients. Methods: Peripheral blood mononuclear cells (PBMC) from cancer patients and healthy volunteers were obtained for the analysis. We cultured the PBMC with or without metformin overnight, followed by stimulation with phorbol 12-myristate 13-acetate (PMA) / ionomycin in vitro in various glucose concentrations for 6 hours. Expressions of markers for immune-check points (PD-1 and Tim-3) were examined together with accumulated intracellular cytokines, IFN-ã, IL-2 and TNF-á by flow cytometry analysis. Results: PD-1 and Tim-3 expressions of cancer patients’ PBMC were apparently higher than those of healthy volunteers’. Increased production of multiple cytokines was observed in CD8+ T cells of almost all cancer patients by metformin pretreatment, whereas no changes were detected in the samples from healthy volunteers. Moreover, deprivation of glucose clearly limited the production of cytokines on CD8 + T cells in a cancer patient. These results suggested patient’ CD8 + T cells showed lower activity of glycolysis compared with a healthy volunteer and metformin might stimulate glycolysis followed by reversion of mitochondrial respiration in exhausted CD8 + T cells. Conclusion: Metformin treatment might be useful in reversion of exhausted CD8+T cells in cancer bearing patients. Citation Format: Mototsugu Watanabe, Shingo Eikawa, Takenori Uehara, Yuki Kunisada, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono. Metformin improves multiple cytokine producing ability of exhausted peripheral CD8+ T cells of cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4865.
Abstract LB-039: Genetic dissection of mechanisms underlying epidermal growth factor receptor-independent colorectal cancer development
Authors: Carolina Mantilla-Rojas, Ming Yu, David Threadgill
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the United States. Substantial effort has gone into understanding molecular mechanisms governing CRC progression with the goal of developing potent targeted therapies. Epidermal growth factor receptor (EGFR) was one of the first molecular targeted therapies. However clinical trials using EGFR inhibitors are not as efficient, suggesting an alternative and independent EGFR-CRC progression mechanism. In this study, we also evaluated the importance of ERBB3, a related EGF receptor, in EGFR-independent colorectal cancer progression. Using intestine-specific genetic ablation of Egfr in the ApcMin/+ (genetic) and axozymethane (carcinogenic) CRC mouse models, we show that 10% of colonic tumors arise independent of EGFR activity. Molecular analysis confirmed the lack of Egfr in these tumors and the formal proof for the existence of an EGFR-independent pathway. Tumors developing in absence of EGFR are larger in size than those developing under normal EGFR activity suggesting that EGFR independent tumors may have a faster growth rate. We also have evidence that ERBB3 may mediate compensatory pathways. Using intestinal specific ablation of Erbb3 (Erbb3f/f) we previously showed that the number of intestinal tumors in the ApcMin/+ model is greatly reduced. Importantly, polyps forming in absence of ERBB3 are significantly smaller than controls, suggesting that normal levels of ERBB3 signaling is essential for tumor growth in the ApcMin/+ model. More recently, we have generated a combinatorial model that conditionally inactivates both Erbb3 and Egfr in the intestinal epithelia. These models will provide powerful tools to genetically dissect molecular pathways contributing to CRC, and aid in identifying molecular biomarkers that can differentiate EGFR-independent from EGFR-dependent CRC. These studies may advance understanding of ERBB biology during colonic tumorigenesis and help design better therapies in combination with EGFR-targeted agents. Citation Format: Carolina Mantilla-Rojas, Ming Yu, David Threadgill. Genetic dissection of mechanisms underlying epidermal growth factor receptor-independent colorectal cancer development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-039.
The Effect of Lymph Node Dissection on the Survival of Patients With Operable Gastric Carcinoma
Authors: Simone Mocellin
Journal: JAMA Oncology (2016)

What is the effect of different extents of lymph node dissection (D1, D2, and D3 lymphadenectomy) in patients affected with operable gastric carcinoma?Compared with D1 lymphadenectomy (the most conservative type of lymph node dissection), D2 lymphadenectomy (but not D3) is associated with better disease-specific survival, although a more extended dissection is burdened by a higher postoperative mortality rate.