tbuckley/cabot-search huggingface dataset:
Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism
Authors: Jiao Liu, Francesca Edgington-Giordano, Courtney Dugas, Anna Abrams, Prasad Katakam, Ryousuke Satou, Zubaida Saifudeen
Journal: Journal of the American Society of Nephrology (2017)

Nephron progenitor cells (NPCs) show an age-dependent capacity to balance self-renewal with differentiation. Older NPCs (postnatal day 0) exit the progenitor niche at a higher rate than younger (embryonic day 13.5) NPCs do. This behavior is reflected in the transcript profiles of young and old NPCs. Bioenergetic pathways have emerged as important regulators of stem cell fate. Here, we investigated the mechanisms underlying this regulation in murine NPCs. Upon isolation and culture in NPC renewal medium, younger NPCs displayed a higher glycolysis rate than older NPCs. Inhibition of glycolysis enhanced nephrogenesis in cultured embryonic kidneys, without increasing ureteric tree branching, and promoted mesenchymal-to-epithelial transition in cultured isolated metanephric mesenchyme. Cotreatment with a canonical Wnt signaling inhibitor attenuated but did not entirely block the increase in nephrogenesis observed after glycolysis inhibition. Furthermore, inhibition of the phosphatidylinositol 3-kinase/Akt self-renewal signaling pathway or stimulation of differentiation pathways in the NPC decreased glycolytic flux. Our findings suggest that glycolysis is a pivotal, cell-intrinsic determinant of NPC fate, with a high glycolytic flux supporting self-renewal and inhibition of glycolysis stimulating differentiation.
Abstract SY23-03: How does HTLV-1 cause leukemia
Authors: Charles Bangham
Journal: Cancer Research (2017)

Abstract The retrovirus human T-lymphotropic virus type 1 (HTLV-1) causes an aggressive, rapidly fatal malignancy of CD4+ T cells, called adult T-cell leukemia/lymphoma (ATL), in 5% of infected individuals. Recent evidence on the clonal diversity and molecular virology of HTLV-1 and on the host genetic and immune response is changing the understanding of oncogenesis in HTLV-1 infection. It was previously believed that HTLV-1 was latent in vivo and persisted by continuous oligoclonal proliferation of about 100 clones of HTLV-1-infected CD4+ T cells, and that this oligoclonal proliferation predisposed to the malignancy ATL. However, we have shown that a typical individual carries between 104 and 105 clones and that the proviral load–the chief correlate of disease–is determined by the number of clones, not by oligoclonal proliferation. The central challenge remains to explain the regulation of HTLV-1 latency in vivo and the role of the host immune response in determining the set-point proviral load and the risk of ATL. I propose here three hypotheses. First, that ATL results from the accumulation of replicative mutations in HTLV-1-infected T-cell clones that persist for decades, typically over 40 years. Second, that the quality of the host immune response, chiefly the CTL response, determines the size and clonal diversity of the HTLV-1 reservoir, the net proliferation rate of HTLV-1-infected T cells, and therefore the risk of ATL. Third, that abnormal chromatin looping in the host genome caused by HTLV-1 can deregulate host gene expression and so contribute to the risk of ATL. Citation Format: Charles Bangham. How does HTLV-1 cause leukemia [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 SY23-03. doi:10.1158/1538-7445.AM2017-SY23-03
Racial Differences in PAM50 Subtypes in the Carolina Breast Cancer Study
Authors: Melissa A. Troester, Xuezheng Sun, Emma H. Allott, Joseph Geradts, Stephanie M. Cohen, Chiu-Kit Tse, Erin L. Kirk, Leigh B. Thorne, Michelle Mathews, Yan Li, Zhiyuan Hu, Whitney R. Robinson, Katherine A. Hoadley, Olufunmilayo I. Olopade, Katherine E. Reeder-Hayes, H. Shelton Earp, Andrew F. Olshan, Lisa A. Carey, Charles M. Perou
Journal: JNCI Journal of the National Cancer Institute (2017)

African American breast cancer patients have lower frequency of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative disease and higher subtype-specific mortality. Racial differences in molecular subtype within clinically defined subgroups are not well understood.Using data and biospecimens from the population-based Carolina Breast Cancer Study (CBCS) Phase 3 (2008-2013), we classified 980 invasive breast cancers using RNA expression-based PAM50 subtype and recurrence (ROR) score that reflects proliferation and tumor size. Molecular subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) and ROR scores (high vs low/medium) were compared by race (blacks vs whites) and age (≤50 years vs > 50 years) using chi-square tests and analysis of variance tests.Black women of all ages had a statistically significantly lower frequency of Luminal A breast cancer (25.4% and 33.6% in blacks vs 42.8% and 52.1% in whites; younger and older, respectively). All other subtype frequencies were higher in black women (case-only odds ratio [OR] = 3.11, 95% confidence interval [CI] = 2.22 to 4.37, for Basal-like; OR = 1.45, 95% CI = 1.02 to 2.06, for Luminal B; OR = 2.04, 95% CI = 1.33 to 3.13, for HER2-enriched). Among clinically HR+/HER2- cases, Luminal A subtype was less common and ROR scores were statistically significantly higher among black women.Multigene assays highlight racial disparities in tumor subtype distribution that persist even in clinically defined subgroups. Differences in tumor biology (eg, HER2-enriched status) may be targetable to reduce disparities among clinically ER+/HER2- cases.
Abstract 5126: Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer
Authors: Sue-Ming Chang, Ming-Hsi Wu, Hima Bindu Pidugu, Tsann-Long Su, Te-Chang Lee
Journal: Cancer Research (2017)

Abstract Small cell lung cancer (SCLC) is an aggressive type of lung cancer and accounts for 10% to 15% of all lung cancer cases. The malignancy has a greater tendency to be widely disseminated by the time of diagnosis as well as to develop early resistance to conventional treatments, a cure is difficult to achieve. The current standard therapy for SCLC treatment, either with monotherapy (platinum based drugs) or combination therapy (e.g., cisplatin with irinotecan or topotecan), was shown to cause serious side effects and inevitably evoke drug resistance in a short time period. We have recently synthesized a series of novel bis(hydroxymethyl)indolizino[8,7-b]indole hybrids by fusing β-carboline and bis(hydroxymethyl)pyrrole moieties for antitumor evaluation. These hybrid molecules displayed diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Our results also showed that they significantly inhibited the cell growth of various human tumor cell lines. Of the tested tumor cell lines, the SCLC cells (H526 and H211) were the most susceptible to compounds BO-2239 and BO-2329. These hybrids induced cell cycle arrest at the G2/M phase and triggered tumor cell apoptotic death. Intriguingly, the substituent at N11 (H or Me) played a critical role in modulating Topo II inhibition and DNA cross-linking. Compared to the compounds with N11-Me group, derivatives having N11-H group profoundly increased Topo II inhibition activity but reduced DNA cross-linking activity. Among these hybrids, BO-2239 (with N11-H) was as potent as irinotecan, but more effective than cisplatin, in nude mice bearing SCLC H526 xenografts. Accordingly, hybrid BO-2239 may be further developed as a potential agent for the treatment of SCLC. Citation Format: Sue-Ming Chang, Ming-Hsi Wu, Hima Bindu Pidugu, Tsann-Long Su, Te-Chang Lee. Novel indolizino[8,7-b]indole hybrids with potent activity against small cell 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 5126. doi:10.1158/1538-7445.AM2017-5126
Abstract 1126: Potent inhibition of HCMV by modulating the cellular SNARE syntaxin 5
Authors: Dhimant H. Desai, Linda Cruz, Nicholas T. Streck, Trisha D. Desai, Aron Lukacher, Shantu G. Amin, Nicholas J. Buchkovich
Journal: Cancer Research (2017)

Abstract Human cytomegalovirus (HCMV), also referred to as human herpesvirus-5 (HHV-5), can cause serious and even fatal disease in immunocompromised individuals and newborns, namely individuals with AIDS, solid organ transplant recipients, chemotherapy patients and recipients of bone marrow and stem cell transplants. HCMV is a ubiquitous virus found throughout all geographic regions and socioeconomic groups, infecting greater than 50% of adults in industrialized countries and as many as 100% in developing countries. Although current therapeutics improves clinical outcomes, they are limited by toxicity, intravenous infusion and the development of resistance by the virus. Thus, there is a pressing need to develop novel therapeutics to prevent HCMV infections with concomitant organ toxicity. Formation of the cytoplasmic viral assembly compartment (cVAC) is an important step for efficient HCMV assembly. To do this, the virus must alter and repurpose the normal cellular balance of membrane and protein flux, a process that is not well understood. We have identified a compound Retro94, which potently inhibits production of infectious HCMV virions in cells by operating against a host cell process, rather than directly targeting the virus. The presence of Retro94 results in the severely impaired production of infectious virions, as great as 5 logs (99-99.99%). Here we discuss in vitro, in vivo, stability, and binding study of Retro94. Overall, our findings have identified Retro94, as novel agent that affects key cellular trafficking factors important for supporting HCMV infection. Citation Format: Dhimant H. Desai, Linda Cruz, Nicholas T. Streck, Trisha D. Desai, Aron Lukacher, Shantu G. Amin, Nicholas J. Buchkovich. Potent inhibition of HCMV by modulating the cellular SNARE syntaxin 5 [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 1126. doi:10.1158/1538-7445.AM2017-1126
Abstract 4487: A critical role of PARylation in regulating the functions of OVOL2
Authors: Rui Zhang, Boan Li, Yih-Cherng Liou
Journal: Cancer Research (2017)

Abstract Poly(ADP-ribosyl)ation (PARylation) is one of the post-translational modifications, by which the ADP-ribose (PAR) polymers are added to the specific protein by a PAR polymerase (PARP). In the about 50 years' studies, this specific modification has been verified to be related to multiple important biological functions including cell death, cell differentiation, histone modification, transcriptional regulation, DNA repair and genome stability. Ovo-like 2 (OVOL2), a novel zinc finger transcriptional factor, contains a Snail/Gli (SNAG) motif at the N-terminal to possess a transcriptional regulatory activity and four DNA-binding Cys2-His2 (C2H2) zinc finger domains at the C-terminal to bind with DNA. OVOL2 is demonstrated to be involved in the cranial neural tube, angiogenesis, heart and placental development. In addition, OVOL2 can also suppress cell cycle and terminate differentiation of keratinocyte by directly inhibiting of c-Myc and Notch1. However, the regulation and biological function of OVOL2 are still largely unknown. In this study, we identify the binding targets, PARP1 and NPM1, of OVOL2. In addition, we report that the function of OVOL2 is regulated by PARP1 through PARylation, which modifies on C2H2 zinc finger domains and plays an important role in the regulation of OVOL2 functions. PARylated OVOL2, but not the 3K mutant, alters focal adhesion and cell cycle, resulting in the formation of polyploidy in cells. Our findings not only have significant implications for the cellular functions of OVOL2, but also provide a better understanding on the multiple biological functions of the PARylation. Citation Format: Rui Zhang, Boan Li, Yih-Cherng Liou. A critical role of PARylation in regulating the functions of OVOL2 [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 4487. doi:10.1158/1538-7445.AM2017-4487
Abstract 3708: RAS-MAPK signal is required for enhanced PD-L1 expression in human lung cancers
Authors: Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo
Journal: Cancer Research (2017)

Abstract Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) is related to immune evasion by cancer, and it is a molecular target of immune checkpoint therapies. Since the precise mechanisms responsible for ectopic PD-L1 expression remains obscure, we analyzed the molecular mechanisms of ectopic PD-L1 expression in human lung cancers, focusing on the MAPK signal. Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p &amp;lt; 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines. The MEK inhibitor U0126 (20 μM) significantly decreased the surface PD-L1 levels by 50-60% compared with dimethyl sulfoxide (p &amp;lt; 0.0001). Phorbol 12-myristate 13-acetate stimulation (100 nM, 15 min) increased (p &amp;lt; 0.05) and two ERK2 siRNAs as well as KRAS siRNAs decreased (p &amp;lt; 0.05) PD-L1 expression. Post-transcriptional mechanism by miR-200s appears not to be in general under the downstream of MAPK in the PD-L1 expression. The transcriptional activity of the potential AP-1 site (+4785 to +5056 from the transcription start site) in the PD-L1 gene was demonstrated by luciferase assays, which was inhibited by U0126. The chromatin immunoprecipitation assay demonstrated the binding of cJUN to the AP-1 site. Two STAT3 siRNAs decreased PD-L1 expression by 10-32% in two of the three KRAS-mutant lung adenocarcinoma cell lines (p &amp;lt; 0.05), while the PI3K inhibitor LY294002 (40 μM) did not change the expression level. Supervised cluster analysis and gene set enrichment analysis between the PD-L1-high and -low NSCLCs revealed a correlation between PD-L1 expression and genes/pathways related to cell motility/adhesion. These results indicate that MAPK signaling is the dominant downstream signal responsible for ectopic PD-L1 expression at a transcriptional level, in which STAT3 is also involved to some extent. Furthermore, MAPK signaling may control the expression of PD-L1 and several genes related to enhanced cell motility. Our findings suggest that MAPK is important for determining PD-L1 expression, which could be useful for targeted therapies against lung cancers. Citation Format: Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo. RAS-MAPK signal is required for enhanced PD-L1 expression in human lung cancers [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 3708. doi:10.1158/1538-7445.AM2017-3708
Abstract 1841: Characterization of neuronal alterations in a new mouse model of low grade glioma
Authors: Daniela Torres, Angeliki Mela, Sohani Das Sharma, Nicholas Hornstein, Peter Sims, Peter Canoll
Journal: Cancer Research (2017)

Abstract Diffusely infiltrating gliomas are the most common type of primary brain tumor seen in adults. Patients with low grade glioma (LGG) can survive for many years, but often suffer from seizures and cognitive impairment, and these symptoms are associated with an unfavorable prognosis. Glioma cells diffusely infiltrate cortical tissue, where tumor cells aggregate around neuronal cell bodies, a growth pattern referred to as perineuronal satellitosis, however the effects of tumor cells on neurons has not been well defined. To address this important issue we generated a mouse model that recapitulates the genetic and histological features of diffusely infiltrating LGG. In our model tumor growth is driven by PDGFA overexpression and p53 deletion in a RiboTag-Camk2a-Cre transgenic mouse. The RiboTag system allows for the isolation and sequencing of ribosome-bound transcripts from Camk2a neurons to obtain a measure of transcription and translation. Our analysis in non-tumor bearing brains identified neuron-specific genes that are highly regulated at the level of translation. mTOR signaling regulates cell growth, proliferation, and translation in response to diverse stimuli. To characterize mTOR signaling in our model we used immunohistochemical staining of pS6 as a marker of mTOR activity and found that neurons within the glioma infiltrated cortex have lower levels of pS6 staining compared to neurons in the surrounding cortex. To further assess these results we are using the RiboTag system to identify alterations in neuronal transcription and translation that occur in our model during glioma formation and in response to mTOR targeted treatments. These studies will provide new insights into the neuronal alterations contributing to seizures and cognitive impairment in glioma and enable the identification of potential molecular targets for novel therapies to treat the devastating consequences of cortical dysfunctions associated with glioma. Citation Format: Daniela Torres, Angeliki Mela, Sohani Das Sharma, Nicholas Hornstein, Peter Sims, Peter Canoll. Characterization of neuronal alterations in a new mouse model of low grade glioma [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 1841. doi:10.1158/1538-7445.AM2017-1841
Abstract 1: Galectins in glioblastoma: opportunities for combined therapy
Authors: David Cachia, Arindam Rano Chatterjee, William Alexander Vandergrift, Sunil J. Patel, Gabriel A. Rabinovich, Arabinda Das
Journal: Cancer Research (2017)

Abstract Background: Despite aggressive treatment, including surgical resection, radiation and chemotherapy, over 90% of glioblastoma (GB) patients experience tumor recurrence. This may be due to high migratory potential, angiogenesis, molecular heterogeneity and a strong immunosuppressive environment. GB expresses high levels of carbohydrate-binding galectin proteins and histone deacetylase (HDAC) activity. The aim of this study was: 1) identify the differential expressions of galectin 1-15 protein levels in human GB patient samples as compared to normal tissue (obtained from Institutional Tissue Bank) and (2) modulate the galectin functions with and without a HDAC inhibitor (DATS: Dially Triisulfide and SAHA: Suberoylanilide Hydroxamic Acid ) or bevacizumab in in vitro GB models. Methods: The effects of TMZ, ionizing radiation, or combined chemoradiation on galectin protein secretion and expression were assessed in human GB cells and human umbilical vein endothelial cells (HUVECs). Results: We found increased galectin-1 protein expression in human GB tissue. We also observed that HUVEC co-culture with GB cells increased galectin-1 protein expression by 14 - 20% following bevacizumab, and conferred a bevacizumab protective benefit to GB cells. Our in vitro models promisingly demonstrated that 72 hr treatments with 25 µM of galectin 1 inhibitor + HDAC inhibitor induce antitumor activity in GB cells. Western blot and activities assay results also demonstrated that combination blockade of HDAC activity and galectin-1 augmented apoptosis in GB cells, which mechanistically involves activation of caspase-3 and inhibition of anti-apoptotic protein (survivin, p-Akt, and Mcl-1 expression). Conclusion: Our in vitro culture results suggest possible benefit in combining a galectin inhibitor with an HDAC inhibitor in GB. Further studies in different animal models are warranted. Citation Format: David Cachia, Arindam Rano Chatterjee, William Alexander Vandergrift, Sunil J. Patel, Gabriel A. Rabinovich, Arabinda Das. Galectins in glioblastoma: opportunities for combined 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 1. doi:10.1158/1538-7445.AM2017-1
Abstract 3278: Particulate matter and traffic-related exposures in relation to breast cancer survival
Authors: Natalie DuPre, Elizabeth M. Poole, Michelle D. Holmes, Jaime E. Hart, Peter James, Andrew Beck, Peter Kraft, Francine Laden, Rulla Tamimi
Journal: Cancer Research (2017)

Abstract Background: Outdoor air pollution is considered a human carcinogen by the International Agency for Research on Cancer, particularly for its influence on lung cancer incidence and prognosis. While air pollution has not been consistently associated with breast cancer incidence, only one study has examined the impacts of air pollution on survival from breast cancer and was unable to consider important predictors of breast cancer mortality. We assessed whether PM exposures (PM2.5, PM2.510, and PM10) were associated with breast cancer specific-death and all-cause mortality. Methods: The Nurses’ Health Studies (NHS and NHSII) are ongoing nationwide cohorts with detailed longitudinal data on medical history, addresses, lifestyle factors, and causes of death. We included women with confirmed Stage I-III breast cancer and collected additional clinical information from medical records. PM was estimated using GIS-based spatio-temporal models linked to addresses between 1989-2007. We performed Cox proportional hazards models to assess associations of breast cancer specific-death and overall mortality with PM exposures starting at diagnosis and updated over follow-up through June 2014. Results: There were 1,211 breast-cancer specific deaths among 8,936 women with Stage I-III breast cancer. Overall, increases in PM were not associated with breast cancer survival (PM2.5: HR=1.09 95% CI 0.87, 1.36; PM2.5-10: HR=1.03 95% CI 0.85, 1.24; PM10: HR=1.05, 95% CI 0.89, 1.24, each per 10 μg/m3). However, each 10 μg/m3 increase in PM2.5 was associated with breast cancer death among participants with Stage I disease after adjusting for clinical, demographics and pre-diagnostic lifestyle factors (HR=1.69 95%CI 1.16, 2.47) and after additionally adjusting for post-diagnostic lifestyle factors (HR=1.64 95% CI 1.11, 2.43). Furthermore, PM exposures were associated with a 9-12% increase in all-cause mortality. Conclusion: Overall, PM exposures were not associated with breast cancer survival; however, increases in PM2.5 did appear to adversely impact prognosis among Stage I breast cancer patients. Acknowledgments: This work was funded by the NIH T32 CA 09001 and by a grant from the Susan G. Komen for the Cure ® (IIR13264020). We thank the NHS and NHSII participants and coordinators. Citation Format: Natalie DuPre, Elizabeth M. Poole, Michelle D. Holmes, Jaime E. Hart, Peter James, Andrew Beck, Peter Kraft, Francine Laden, Rulla Tamimi. Particulate matter and traffic-related exposures in relation to breast cancer survival [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 3278. doi:10.1158/1538-7445.AM2017-3278