tbuckley/cabot-search huggingface dataset:
Abstract LB-148: DDX5 promotes ARF gene expression and apoptosis induced by deregulated E2F1
Authors: Kenta Kurayoshi, Kiyoshi Ohtani
Journal: Cancer Research (2016)

Abstract The transcription factor E2F, the main target of the tumor suppressor pRB, plays central roles not only in cell proliferation but also in tumor suppression. E2F promotes cell proliferation by activating growth-related genes in response to normal growth stimulation. On the other hand, E2F contributes to tumor suppression by activating pro-apoptotic and growth-suppressive genes such as ARF and TAp73 when deregulated from pRB upon dysfunction of pRB, a major oncogenic change. ARF is an upstream activator of the tumor suppressor p53, one of the two major tumor suppressors in addition to pRB. TAp73 is a member of the p53 family and activates p53-responsive genes. Importantly, physiological E2F activity induced by growth stimulation does not activate the latter genes, underscoring importance of deregulated E2F activity in tumor suppression upon oncogenic changes. However, the regulatory mechanism of deregulated E2F activity is not known in detail. We found that deletion of N-terminal domain of E2F1 dramatically reduced its ability to activate ARF and TAp73 promoter, suggesting that E2F1 interacts with a factor(s) through its N-terminal domain to activate the tumor suppressor genes. Hence we explored novel E2F1-interacting factors using co-immunoprecipitation and LC/MS. Among the candidates, we found DEAD box 5 (DDX5) that functions not only RNA helicase but also transcriptional coactivator. DDX5 is reported to function as a coactivator for p53. Furthermore, E2F1 activity is regulated in similar manners as p53 such as by Chk1 and PRMT5. These observations suggest that DDX5 enhances not only p53 activity but also deregulated E2F1 activity. We thus examined effect of DDX5 on deregulated E2F1 activity induced by overexpression of E2F1. DDX5 enhanced E2F1 activation of ARF promoter depending on the integrity of N-terminal domain of E2F1. DDX5 mutant lacking RNA helicase activity retained the ability to enhance E2F1 activation of ARF promoter, indicating that the enhancement is independent of helicase activity. Furthermore, DDX5 enhanced endogenous ARF gene expression and apoptosis induced by E2F1 without affecting E2F1 expression level. Finally, knock down of DDX5 reduced E2F1-mediated activation of ARF promoter and ARF gene expression. These results suggest that DDX5 upregulates deregulated E2F1 activity and contributes to E2F1-induced apoptosis to protect cells from tumorigenesis. Citation Format: Kenta Kurayoshi, Kiyoshi Ohtani. DDX5 promotes ARF gene expression and apoptosis induced by deregulated E2F1. [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-148.
Abstract 217: Mitochondrial reprogramming regulated cancer pathway in triple negative breast cancer
Authors: Jun H. Park, Sajna Vithayathil, Danli Wu, Vasanta Putluri, Pi-Lin Sung, Efrosini Tsouko, Vadiraja B. Bhat, Cristian Coarfa, Daniel E. Frigo, Michael T. Lewis, Arun Sreekumar, Patricia Yotnda, Chad J. Creighton, Nagireddy Putluri, Lee-Jun C. Wong, Benny A. Kaipparettu
Journal: Cancer Research (2016)

Abstract Compared to other subtypes of tumors, triple negative breast cancers (TN BCa) currently suffer from limited knowledge on its etiology and treatment options. Transmitochondrial cybrids (cybrid) and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in TN BCa. Analysis of cybrids and established BCa cell lines showed that metastatic TN BCa maintain high levels of ATP through fatty acid β-oxidation and activate Src oncoprotein by its autophosphorylation. Inhibition and induction of β-oxidation including the shRNA mediated knockdown strategies, and analysis of patient derived xenograft (PDX) models confirmed the role of mitochondrial β-oxidation in Src activation and metastasis. Analysis of BCa clinical data further reaffirmed the role of mitochondrial β-oxidation in Src regulation and their significance in BCa metastasis. This study is innovative in showing the mitochondrial reprogramming mediated regulation of a major cancer pathway by its post-translation modification. Citation Format: Jun H. Park, Sajna Vithayathil, Danli Wu, Vasanta Putluri, Pi-Lin Sung, Efrosini Tsouko, Vadiraja B. Bhat, Cristian Coarfa, Daniel E. Frigo, Michael T. Lewis, Arun Sreekumar, Patricia Yotnda, Chad J. Creighton, Nagireddy Putluri, Lee-Jun C. Wong, Benny A. Kaipparettu. Mitochondrial reprogramming regulated cancer pathway in triple negative breast 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 217.
NSCLC in Louisiana: Thymidylate synthase and pemetrexed therapy.
Authors: A. G. Silva, J. T. Cole
Journal: Journal of Clinical Oncology (2010)

e18142 Background: To analyze all patients treated for metastatic non-small cell lung cancer (NSCLC) at our institution and identify factors that influence responses and prognosis, including histological subtype, chemotherapy regimen and possibly biomarkers. Methods: Patients with diagnosis of NSCLC were identified by ICD-9 codes using the Institutional Tumor Registry and data was extracted and analyzed. Patient who received pemetrexed as part of their treatment had the specimen stained for thymidylate synthase (TS) expression by immunohistochemistry (IHC). Results: Four hundred and thirty charts were reviewed and 70 identified patients received palliative chemotherapy for metastatic NSCLC at our institution between 2005 and 2007. Median age at diagnosis was 65 years (46-81). Seventy five percent of patients had definitive histology, adenocarcinoma being the most common. The overall response rate (ORR) for first line therapy was 40%, with a median time to progression (TTP) of 5 months. Patients who received either cisplatin or bevacizumab containing regimens appeared to have higher RR and longer TTP. In second line, ORR was 20% and TTP 3 months. Patient who were able to receive combination chemotherapy had higher response rates and longer TTP, as did patients receiving pemetrexed. In these patients, non-squamous histology had significant higher response rates and TS expression by IHC testing is underway to evaluate its potential as a marker for response. Third line chemotherapy and above, even when given to selected patients, was rarely effective. Conclusions: Our data at Ochsner Clinic Foundation appears to correlate with the most recent national data. Efforts should be made in other to identify patient who will respond to specific drugs and TS might be an important predictor of pemetrexed therapy sensitivity. No significant financial relationships to disclose.
Abstract 2393: Kidneys of VHL patients reveal the origin of renal clear cell carcinoma
Authors: Mayyan Mubarak, Samuel Sommaruga, David Voigt, Xiacao Xu, Steve Kim, Ailin Song, Alexander O. Vortmeyer
Journal: Cancer Research (2016)

Abstract VHL disease is a classic tumor suppressor gene syndrome characterized by development of specific types of tumors in selective organs with nervous system and kidney being most consistently affected. Detailed studies on human spinal cord and cerebellum have previously revealed earliest stages of CNS tumorigenesis and the morphologic sequence resulting in development of frank tumors. To elucidate earliest stages of renal clear cell carcinoma, we performed a similar approach in kidney tissues of four VHL patients and three sporadic control cases. From all cases, blocks of interest were procured, followed by serial sectioning and 3dimensional reconstruction of potential precursor lesions. The results reveal an abundance of foci with aberrant mesonephric clear cell proliferations that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by microscopic invasive clear cell aggregations which represent tumor precursor structures. This study presents evidence for a consistent morphologic sequence for renal clear cell carcinogenesis. Molecular analysis of early steps within this sequence will allow for identification of earliest genetic and proteomic changes in the future. Therapeutic targeting of earliest changes may allow to develop preventive strategies for renal cancer development for VHL patients, potentially also for the non-VHL population. Citation Format: Mayyan Mubarak, Samuel Sommaruga, David Voigt, Xiacao Xu, Steve Kim, Ailin Song, Alexander O. Vortmeyer. Kidneys of VHL patients reveal the origin of renal clear cell carcinoma. [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 2393.
Abstract 3920: Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations
Authors: Sung Yong Eum, Eunkyung Lee, Jean L. Wright, Christiane Takita, Eden R Martin, Susan Slifer, Jennifer J. Hu
Journal: Cancer Research (2016)

Abstract Radiotherapy-induced skin toxicity is one of the critical quality of life issues in breast cancer patients receiving adjuvant radiation therapy (RT). Finding a biomarker which can predict the development of acute RT-induced toxicity prior to RT is critical to improve precision medicine in radiation oncology. This study evaluated the association of single nucleotide polymorphisms (SNPs) in DNA-repair genes in 268 breast cancer undergoing adjuvant RT. We analyzed 3,747 polymorphisms in 119 DNA repair-related genes; 15 genes in base excision repair (BER), 11 in mismatch repair (MMR), 26 in nucleotide excision repair (NER), 15 in homologous recombination, 5 in non-homologous end-joining (NHEJ), 15 in DNA polymerases, and 47 in other DNA repair-related pathways. Skin toxicity was assessed at post-RT using the modified NCI's Common Toxicity Criteria for Adverse Events (CTCAE) and multiple logistic regression analyses were conducted to assess the associations between SNPs and grade ≥ 4 skin toxicity n = 115). After controlling for covariates, 221 SNPs were significant at p &amp;lt;0.05 and 34 at p &amp;lt; 0.01. Significant associations (p&amp;lt;0.01) were found in 7 SNPs in PAPD5 gene, 1 in POLD1, POLE, and POLI in DNA polymerase; 5 in RAD51L1 and 1 in RAD54L in HR; 4 in MMS19 in NER; 2 in MSH4 and 1 in PMS1 in MMR; 2 in RPA3 in BER; 2 in RAD18, and 1 in UBE2V2 in Rad6 pathway; 2 in CHEK2 in DNA damage response pathway; 1 in MGMT in direct reversal of DNA damage; and 1 in BLM in diseases associated with sensitivity to DNA damaging agents pathways. Among these, most significant association was found in BLM variant (s16944918) which showed that carrying at least one minor T allele was associated with increased risk of RT-induced skin toxicity (odds ratio [OR] = 3.36; 95% confidence interval (CI) = 1.62-6.97, p = 0.001). For RPA3 (rs11978293), carriers with at least one minor G allele were more likely to develop RT-induced skin toxicity (OR = 2.17, 95% CI = 1.34-3.52, p = 0.002). The current study suggests that genetic variations in multiple DNA-repair genes/pathways may contribute to inter-individual variation in RT-induced normal tissue toxicity in breast cancer patients and suggests the possibility of potential predictive values of genetic polymorphisms in RT sensitivity. Further validation studies with larger sample size are warranted. Citation Format: Sung Yong Eum, Eunkyung Lee, Jean L. Wright, Christiane Takita, Eden R, Martin, Susan Slifer, Jennifer J. Hu. Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations. [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 3920.
Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders
Authors: Anna Sara Oberg, Brian M. D’Onofrio, Martin E. Rickert, Sonia Hernandez-Diaz, Jeffrey L. Ecker, Catarina Almqvist, Henrik Larsson, Paul Lichtenstein, Brian T. Bateman
Journal: JAMA Pediatrics (2016)

Induction of labor is a frequently performed obstetrical intervention. It would thus be of great concern if reported associations between labor induction and offspring risk of autism spectrum disorders (ASD) reflected causal influence.To assess the associations of labor induction with ASD, comparing differentially exposed relatives (siblings and cousins discordant for induction).Follow-up of all live births in Sweden between 1992 and 2005, defined in the Medical Birth Register. The register was linked to population registers of familial relations, inpatient and outpatient visits, and education records. Diagnoses of ASD were from 2001 through 2013, and data were analyzed in the 2015-2016 year.Induction of labor.Autism spectrum disorders identified by diagnoses from inpatient and outpatient records between 2001 and 2013. Hazard ratios (HRs) quantified the association between labor induction and offspring ASD. In addition to considering a wide range of measured confounders, comparison of exposure-discordant births to the same woman allowed additional control for all unmeasured factors shared by siblings.The full cohort included 1 362 950 births, of which 22 077 offspring (1.6%) were diagnosed with ASD by ages 8 years through 21 years. In conventional models of the full cohort, associations between labor induction and offspring ASD were attenuated but remained statistically significant after adjustment for measured potential confounders (HR, 1.19; 95% CI, 1.13-1.24). When comparison was made within siblings whose births were discordant with respect to induction, thus accounting for all environmental and genetic factors shared by siblings, labor induction was no longer associated with offspring ASD (HR, 0.99; 95% CI, 0.88-1.10).In this nationwide sample of live births we observed no association between induction of labor and offspring ASD within sibling comparison. Our findings suggest that concern for ASD should not factor into the clinical decision about whether to induce labor.
Abstract 4650: Effect of prescription CYP3A inducers and inhibitors on response to anti-androgen therapy in prostate cancer
Authors: Ranjana Mitra, Oscar B. Goodman
Journal: Cancer Research (2016)

Abstract Purpose: Prostate cancer affects elderly men who typically have multiple comorbidities requiring concomitant prescription medications, many of which are CYP inducers or inhibitors. Androgen deprivation therapy (ADT) is the mainstay therapy for treating advanced prostate cancer. Recently we demonstrated that CYP3A5 facilitates the nuclear translocation of androgen receptor (AR), promoting prostate cancer growth. As the mechanisms by which intratumoral CYP3A5 regulates AR in prostate cancer are not well understood, the clinical impact of concomitant drugs on the efficacy of ADT is presently unknown. This work describes a platform for assessing the effects of commonly prescribed drugs known to be CYP3A5 inducers or inhibitors on AR signaling and prostate cancer growth. Methods: We have created a lentiviral LNCaP based reporter system for monitoring changes in AR signaling utilizing a construct comprising a promotor containing AR inducible transcriptional response elements (TREs), fused with firefly luciferase, whereas the negative control (NC) lacks the TREs. We used both a mixed transfected pool and individually selected clones to monitor changes in AR activity. Results: We tested our assay system by inhibiting CYP3A5 gene expression in LNCaP cells using siRNA and then treating it with DHT. Our data indicate that CYP3A5 siRNA reduced DHT induced AR activity significantly as compared to non-target (NT) siRNA. We further tested our reporter system with rifampicin, phenytoin (both CYP3A inducers) and ritonavir, fluoxetine, amiodarone (CYP3A inhibitors). Rifampicin (antibiotic) and phenytoin (anticonvulsant) showed significant (P≤0.05) induction of AR activity as shown by increased luminescence units. Out of the three inhibitors which were tested amiodarone (antiarrhythmic) and ritonavir (antiretroviral) reduced the AR activity by 50% and 80% respectively whereas fluoxetine (antidepressant) did not result in any significant changes. Both amiodarone and ritonavir also inhibited R1881 (artificial androgen) induced AR activity as compared to control. Conclusion: Concomitant medications can alter the AR activity thus modifying the response to ADT therapy in prostate cancer patients. These finding support the notion that an CYP3A inhibitor-rich concomitant medical regimen may provide additional clinical benefit for men undergoing ADT and further support the concept of targeting nuclear translocation as a therapeutic adjunct in ADT. Citation Format: Ranjana Mitra, Oscar B. Goodman Jr. Effect of prescription CYP3A inducers and inhibitors on response to anti-androgen therapy in prostate 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 4650.
Splenic Marginal Zone Granulocytes Acquire an Accentuated Neutrophil B-Cell Helper Phenotype in Chronic Lymphocytic Leukemia
Authors: Marcel Gätjen, Franziska Brand, Michael Grau, Kerstin Gerlach, Ralph Kettritz, Jörg Westermann, Ioannis Anagnostopoulos, Peter Lenz, Georg Lenz, Uta E. Höpken, Armin Rehm
Journal: Cancer Research (2016)

Recruitment of tumor-associated macrophages and neutrophils (TAM and TAN) to solid tumors contributes to immunosuppression in the tumor microenvironment; however, their contributions to lymphoid neoplasms are less clear. In human chronic lymphocytic leukemia (CLL), tumor B cells lodge in lymph nodes where interactions with the microenvironment occur. Tumor cell homing stimulates proliferation, such that engagement of the B-cell receptor is important for malignant progression. In the Eμ-Tcl1 murine model of CLL, we identified gene expression signatures indicative of a skewed polarization in the phenotype of monocytes and neutrophils. Selective ablation of either of these cell populations in mice delayed leukemia growth. Despite tumor infiltration of these immune cells, a systemic inflammation was not detected. Notably, in progressive CLL, splenic neutrophils were observed to differentiate toward a B-cell helper phenotype, a process promoted by the induction of leukemia-associated IL10 and TGFβ. Our results suggest that targeting aberrant neutrophil differentiation and restoring myeloid cell homeostasis could limit the formation of survival niches for CLL cells. Cancer Res; 76(18); 5253-65. ©2016 AACR.
A Cutaneous Lymphoma International Consortium ‘CLIC’ study of Prognostic Parameters in Advanced Stages of Mycosis Fungoides and Sezary Syndrome: Progress Towards Establishing a Prognostic Index to Augment Clinical Staging
Authors: Julia J Scarisbrick, Pietro Quaglino, Maarten Vermeer, Sean Whittaker, Gary S. Wood, Madeleine Duvic, Miles Prince, Steven M. Horwitz, Richard T. Hoppe, Pierluigi Porcu, Rudolf Stadler, Felicity Evison, Youn H Kim
Journal: Blood (2014)
Association of black race and outcomes in patients with nonmetastatic triple-negative breast cancer (TNBC): Results from a U.S. local oncology practice.
Authors: B. A. Feinberg, L. Chen, L. Zhao, J. W. Gilmore, S. Haislip, M. N. Saleh, S. D. Sullivan, N. P. Christiansen
Journal: Journal of Clinical Oncology (2010)

6107 Background: TNBC carries a poor prognosis. African American (AA) race has been shown as an adverse prognostic factor in many cancers. The objective of this study was to evaluate, in a real-world context, the impact of AA on disease recurrence and survival among nonmetastatic TNBC patients treated with adjuvant chemotherapy (CT). Methods: The Georgia Cancer Specialist Database (2003- 2008) was used. Patients with stage (I-III) BC, confirmed TN status, treated with adjuvant CT were followed from initial BC diagnosis to the earliest of death, BC recurrence, or loss to follow-up. The primary outcome was disease-free survival (DFS). The secondary outcome was recurrence. DFS and recurrence were compared between AA and non-AA groups with Kaplan-Meier curves. The impact of AA status was further examined using multivariate Cox models adjusting for age, comorbidity, BMI, smoking status, initial BC stage, surgery, and radiation therapy. Results: Among 209 TNBC patients, 89 (42.6%) were AA. The two groups (AA vs. non-AA) were similar in mean age at BC diagnosis (53.2 vs. 54.4, p = 0.487), surgery and radiation rates (98.9% vs. 100%, p = 0.244; 68.5% vs. 62.5%, p = 0.365, respectively). Compared to non-AA, AA patients were more obese (BMI: 30.4 vs. 28.6, p=0.048), and more likely to be diagnosed at stage II (stage I: 31.5% vs. 51.7%; stage II: 64.0% vs. 43.3%; stage III: 4.5% vs. 5.0%; p = 0.0107). Compared to non-AA, AA patients had lower 5-year DFS rate (45.2% vs. 79.7%, p = 0.0005), and higher 5-year recurrence rate (42.5% vs. 7.0%, p = 0.0005). The median DFS was significantly shorter for AA than non-AA patients (615 vs. 775 days, p = 0.0005). The multivariate Cox models showed that AA was associated with lower likelihood for DFS (HR = 0.15, p = 0.0005), and higher risk for recurrence (HR = 8.16, p = 0.0006), compared to non-AA patients. Conclusions: This study suggested that AA race was associated with worse outcomes irrespective of later stage at presentation among TNBC patients who were treated with currently available adjuvant CT. Future studies need to explore genotypic as well as behavioral reasons for inferior outcomes associated with AA race. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis
A Chromatin-Associated Histone H3 Dementhylase Promotes the Immortalization of MEFs and the Cycling of HSC-Like Cells in Culture.
Authors: Raymond Pfau, Alexandros Tzatsos, Susan E. Bear, Christos Polytarchou, Sotirios Kampranis, Richard A. Van Etten, Philip N. Tsichlis
Journal: Blood (2007)
Increased Mortality in Patients with Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Meng Wang, Wenjia Wang, Ayesha Abeywardane, Malinthi Adikarama, Donal McLornan, Kavita Raj, Hugues de Lavallade, Stephen Devereux, Ghulam J. Mufti, Antonio Pagliuca, Victoria T Potter, Aleksandar Mijovic
Journal: Blood (2014)