tbuckley/cabot-search huggingface dataset:
Abstract 248: Aberrant TGFβ Signaling as an Etiology of Left Ventricular Non-compaction Cardiomyopathy
Authors: Kazuki Kodo, Sang-Ging Ong, Fereshteh Jahanbani, Vittavat Termglinchan, Kolsoum InanlooRahatloo, Antje D Ebert, Praveen Shukla, Oscar J Abilez, Jared M Churko, Ioannis Karakikes, Gwanghyun Jung, Michael P Snyder, Daniel Bernstein, Joseph C Wu
Journal: Circulation Research (2015)

Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and has a unique phenotype with characteristically extensive hypertrabeculation of the left ventricle, similar to the embryonic left ventricle, suggesting a developmental defect of the embryonic myocardium. However, studying this disease has been challenging due to the lack of an animal model that can faithfully recapitulate the clinical phenotype of LVNC. To address this, we showed that patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from a family with LVNC history recapitulated a developmental defect consistent with the LVNC phenotype at the single-cell level. We then utilized hiPSC-CMs to show that increased transforming growth factor beta (TGFβ) signaling is one of the central mechanisms underlying the pathogenesis of LVNC. LVNC hiPSC-CMs demonstrated decreased proliferative capacity due to abnormal activation of TGFβ signaling (Figs A-B). Exome sequencing demonstrated a mutation in TBX20, which regulates TGFβ signaling through upregulation of ITGAV, contributing to the LVNC phenotype. Inhibition of abnormal TGFβ signaling or genetic correction of the TBX20 mutation (Figs C-D) using TALEN reversed the proliferation defects seen in LVNC hiPSC-CMs. Our results demonstrate that hiPSC-CMs are a useful tool for the exploration of novel mechanisms underlying poorly understood cardiomyopathies such as LVNC. Here we provide the first evidence of activation of TGFβ signaling as playing a role in the pathogenesis of LVNC.
Abstract 3904: Rspondin-1 contributes to tumor cell proliferation via Wnt signaling pathway
Authors: So Hyun Park, Sol Kim, Min Yeong Choi, Jiwoon Park, Shinae Kang, Hak-Zoo Kim
Journal: Cancer Research (2015)

Abstract Diabetes mellitus and pancreatic cancer have long been considered to be clinically related to each other. Despite the ample epidemiological evidences indicating relevance between two major human diseases, the precise mechanism to link both of these diseases are still unclear. We demonstrated altered beta-catenin and Wnt3a protein expression in pancreas of diabetic mouse in age-dependent manner, which indicates the chronic diabetic condition may contribute to the pancreatic cancer progression of peri-islet region through elevated Wnt signaling. We also identified the altered expression level of Rspondin-1, secreted agonist of Wnt signaling pathway, in in vivo diabetic mouse model, which showed a similar expression pattern of Wnt3a and beta-catenin. Finally we demonstrated the effect of in vitro diabetic condition on Rspondin expression level of mouse pancreatic beta cell(Min6) and pancreatic cancer cell lines(Panc-1, AsPc-1). The expression level of Rspondin-1 was down-regulated in Min6 cells cultured in high glucose condition, whereas up-regulated in pancreatic cancer cells cultured in in vitro diabetic condition, which correlates with in vivo Rspondin-1 expression study. These results provide new insights about the Wnt signaling and related proteins as molecular linkers of chronic diabetes and pancreatic cancer. Citation Format: So Hyun Park, Sol Kim, Min Yeong Choi, Jiwoon Park, Shinae Kang, Hak-Zoo Kim. Rspondin-1 contributes to tumor cell proliferation via Wnt signaling pathway. [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 3904. doi:10.1158/1538-7445.AM2015-3904
PO25DISTRIBUTION OF MG, FE, CU AND ZN IN GLIOBLASTOMA, MENINGIOMA I AND II USING INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS)
Authors: T. Mudariki, R.W. Lea, K. Ashton, T. Dawson, C. Davis, J.A. Smith
Journal: Neuro-Oncology (2015)

INTRODUCTION: The body absorbs a wide variety of elements from the environment whose concentration in the blood is regulated by homeostatic mechanisms catalysed and regulated by enzymes and enzyme inhibitors. Trace elements act as cofactors in enzymes and their increase or decrease correlates with physiological changes. Trace element increase or deficiency has been linked to cancer development and progression. METHOD: Serum samples from 55 patients was collected and stored at -80°C until analysis. 100 µL of serum from each sample was taken and 100 µL of internal standard (Bi) was added and run alongside multi-element standard. Certified reference material (CRMs) Dort-4, Tort-2 and Bovine liver were used for quality control. ICP-MS analysis was carried out using a Thermo X-Series machine. RESULTS: Glioblastoma, Meningioma I and II investigated showed a deficiency of Mg, Fe, Cu and Zn concentrations based on reported levels from healthy individuals in the literature. There was no significant difference between gender and sex against concentration of Mg, Fe, Cu and Zn across the four tumour groups investigated (F = 1.829, DF = 3 and 1, P = 0.154). CONCLUSION: Concentrations of trace elements in serum could be used to monitor cancer relapse in patients who are in remission. The process is less invasive and does not require constant irradiation from imaging techniques.
765. Detection of Treatment-Resistant Infectious HIV After Genome-Directed Antiviral Endonuclease Therapy
Authors: Daniel Stone, Harshana S. De Silva Feelixge, Harlan L. Pietz, Pavitra Roychoudhury, Alex L. Greninger, Joshua T. Schiffer, Martine Aubert, Keith R. Jerome
Journal: Molecular Therapy (2016)

Incurable chronic viral infections are a major cause of morbidity and mortality worldwide. One newly emerging approach to cure persistent viral infections is via the use of targeted endonucleases. To date, endonucleases have been used as therapeutic agents targeting the genomes of viruses including EBV, JCV, HBV, HCV, HIV, HPV, HSV and HTLV, and have been shown to inhibit viral replication and subsequently persistence. Nevertheless, a potential concern for endonuclease-based antiviral therapies is the emergence of treatment resistance. Here we detect for the first time an endonuclease-resistant infectious virus that is found with high frequency after antiviral endonuclease therapy. While testing the activity of a panel of four HIV pol-specific zinc finger nucleases (ZFNs) we identified a provirus encoding a treatment-resistant and infectious mutant virus that was derived from a ZFN2-mediated disruption of reverse transcriptase (RT). Although ZFN-mediated disruption of HIV protease (ZFN1), RT (ZFN2 & ZFN3) and integrase (ZFN4) coding sequences could inhibit viral replication, a RT mutant provirus was detected that produced a replication competent and ZFN2 cleavage resistant HIV. Mutant virus ZFN2(+3) contained a single amino acid insertion that introduced a Leucine-Leucine (LL) motif in the thumb domain of RT. The RT of mutant virus ZFN2(+3) likely remained functional since a LL motif is also found in the RT of several hominid, old world monkey or equine spumaviruses. In ZFN2-treated HEK293 and CD4+ SupT1 T cells, we found that up to 25% and 6% of all ZFN2 HIV pol target site mutations detected by Illumina sequencing encoded the ZFN2(+3) mutant respectively. We found that ZFN2(+3) mutant virus could replicate at levels comparable to wild type HIV in primary CD4+ T cells, but importantly remained susceptible to treatment with both NRTi and NNRTi antiretroviral inhibitors. When secondary ZFN-derived mutations were introduced into other RT or integrase domains of mutant virus ZFN2(+3), replication could be abolished. Our observations suggest that caution should be exercised during endonuclease-based antiviral therapies; however, combination endonuclease therapies may prevent the emergence of resistance.
Abstract 2053: Overexpressed Rab1A is associated poor prognosis and promotes oncogenic growth and metastasis through mTORC1 activation in hepatocellular carcinoma
Authors: Bi-Hong Xu, Xiao-Xing Li, Hui-yun Wang, X.F. Steven Zheng
Journal: Cancer Research (2015)

Abstract Background: The mammalian target of rapamycin complex 1 (mTORC1) is a pivotal regulator of cell growth and proliferation in response to nutrition and various factor. In recent years, studies have focus on over-activation of mTORC1 in normal cells leading to tumorigenesis and malignant tumor development. However, the precise factors of mTORC1 hyperactivation to promote the growth of hepatocellular carcinoma (HCC) or other cancers are still not well characterized. Thus, in this study, we aimed to clarify a novel gene -Rab1A, and it's expression and functional role in mTORC1 signal in of HCC. Methods: We analyzed the Rab1A protein in HCC and para-cancer samples from 143 patients and the correlation with its survival. To identify Rab1A's role in tumor progression, a serious of functional study were applied including overexpression and knockdown Rab1A in different cell lines both in vivo and in vitro. For mechanism research, western bolt was demonstrated to identify the signal dysregulation between Rab1A abnormity and mTORC1 pathway under involvement of irritants. Results: Our results showed that, compared with normal livers, Rab1A was frequently overexpressed in HCC and significantly associated with HCC prognosis. Functional study demonstrated that overexpression of Rab1A in HCC cells increased cell growth, cell migration, cell cycle progression and tumor formation in vivo and/or in vitro, all of which were effectively inhibited when Rab1A was silenced by shRNA. We further provided evidences that Rab1A promotes HCC growth and migration through phosphorylation of S6K, the consequence of activating mTORC1 signaling pathway. Mechanism research of the signal pathway between Rab1A and mTORC1 suggest that Rab1A is likely to stimulate mTORC1 directly, with the cooperation of Amino acid stimulation but not depend on the pathway of PI3K/AKT and MAPK/ERK.. Citation Format: Bi-Hong Xu, Xiao-Xing Li, Hui-yun Wang, X.F. Steven Zheng. Overexpressed Rab1A is associated poor prognosis and promotes oncogenic growth and metastasis through mTORC1 activation in hepatocellular carcinoma. [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 2053. doi:10.1158/1538-7445.AM2015-2053
Do genetic polymorphisms predict risk of recurrence in patients with localized renal cell carcinoma? Results from a cohort study.
Authors: F. A. B. Schutz, K. P. Gray, M. Pomerantz, M. B. Atkins, J. E. Rosenberg, M. S. Hirsch, D. F. McDermott, G. M. Lee, S. Signoretti, P. W. Kantoff, M. L. Freedman, T. K. Choueiri
Journal: Journal of Clinical Oncology (2011)

4506 Background: Gene polymorphisms in critical signaling pathways may impact recurrence in patients with localized renal cell cancer (RCC) Methods: Germline DNA was extracted from 425 patients of European-American ancestry that were enrolled in a prospective protocol with full baseline and follow up clinical data. Using the Sequenom iPLEX Gold platform, genotyping was performed for select genes involved in RCC pathogenesis, angiogenesis, metabolism, and immune regulation, including VHL, HIF-1, HIF-2, VEGF, VEGFR-2, CAIX, mTOR, PI3K, CTLA4, PD1, and B7H1. The primary endpoint was recurrence free interval (RFI), defined as time from surgery to recurrence or last follow-up. Cox Proportional Hazards model was used to evaluate and identify single nucleotide polymorphisms (SNPs) associated with RFI. A multivariate model adjusted for clinical factors which predict recurrence. The false discovery rate (pFDR) was used to control for the number of tests performed. With 45% RFI events, and 10% variant prevalence, there was 86% power to detect HR=2.0 (two sided alpha=0.05) Results: The median follow-up time was 49.1 months. Clinical factors associated with RFI included age at diagnosis (log-rank p=0.02), clinical stage (p<0.001), Fuhrman nuclear grade (p<0.001), performance status (p<0.001), and tumor size (p<0.001). Three SNPs in 2 genes were found to be highly predictive of RFI in univariate analysis; HIF2A (2 SNPs with p=6.00 E-4 for each) and ABCB1 (1 SNP with p=3.00 E-4). The prognostic features of these SNPs remain significant after adjusting for clinical factors (p=0.004 for the SNP in the ABCB1 gene and p=0.009 for the SNPs in the HIF-2 gene). The SNP associated with the highest recurrence risk resides in the ABCB1 gene, which codes for the multidrug resistance P-glycoprotein. Homozygotes for the risk haplotype have an adjusted HR of 2.88 (95% CI, 1.4-5.9; p=.004) for shorter RFI, compared to patients with other haplotypes Conclusions: This is the first study to implicate germline variations in critical signaling pathways with cancer recurrence in patients with localized RCC. Validation of these findings in an independent population is planned.
Efficacy and Safety of Nilotinib In Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (Pts) with Type 2 Diabetes In the ENESTnd Trial.
Authors: Giuseppe Saglio, Richard A. Larson, Timothy P. Hughes, Surapol Issaragrisil, Anna G. Turkina, David Marin, Maria Zanichelli, Hirohiko Shibayama, Matt E. Kalaycio, Francoise Rigal-Huguet, Neil J. Gallagher, Marcia Kayath, Ming Zheng, Hagop Kantarjian, Andreas Hochhaus
Journal: Blood (2010)
Abstract 3046: Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth
Authors: Lingtao Jin, Dan Li, Gina Alesi, Jun Fan, Hee-Bum Kang, Lu Zhou, Titus Boggon, Kelly Magliocca, Chuan He, Martha Arellano, Hanna Khoury, Dong Shin, Fadlo Khuri, Sumin Kang
Journal: Cancer Research (2015)

Abstract How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1), commonly upregulated in human cancers, is predominantly important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (a-KG) and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a ROS scavenging enzyme glutathione peroxidase 1 (GPx1) to regulate redox homeostasis, which provides a proliferative advantage to cancer cells and tumor growth. Our findings not only provide novel insights into understanding of the role of glutaminolysis in redox homeostasis but also suggest a novel signaling function of fumarate that regulates GPx1, allowing additional crosstalk between glutaminolysis, TCA cycle and redox status. Targeting GDH1 by shRNA or a newly identified small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth. Thus, our findings provide proof-of-principle suggesting GDH1 as a promising therapeutic target in the treatment of human cancers associated with elevated glutamine metabolism. Citation Format: Lingtao Jin, Dan Li, Gina Alesi, Jun Fan, Hee-Bum Kang, Lu Zhou, Titus Boggon, Kelly Magliocca, Chuan He, Martha Arellano, Hanna Khoury, Dong Shin, Fadlo Khuri, Sumin Kang. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. [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 3046. doi:10.1158/1538-7445.AM2015-3046
Integrative algorithm to determine the metastatic carcinoma tissue of origin using next generation sequencing (NGS)
Authors: Hidetoshi Hayashi, Shuta Tomida, Yosuke Togashi, Kazuko Sakai, Yoshihiko Fujita, Junji Tsurutani, Issei Kurahashi, Takayasu Kurata, Kazuhiko Nakagawa, Kazuto Nishio
Journal: Annals of Oncology (2015)
EXPAND: A Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in Patients with Myelofibrosis (MF) and Low Platelet Counts (50 × 109/L to 99 × 109/L) at Baseline
Authors: Alessandro M. Vannucchi, Heinz Gisslinger, Claire N. Harrison, Haifa Kathrin Al-Ali, Ester Pungolino, Jean-Jacques Kiladjian, Francoise Boyer-Perrard, Franck E. Nicolini, Shuyuan Mo, Edric Atienza, Prashanth Gopalakrishna, Peter A. te Boekhorst
Journal: Blood (2015)
Abstract 494: MYC, dominant negative p53 and AKT transform human neural stem cells into primitive neuro-ectodermal tumors sensitive to glutaminase inhibitors
Authors: Isabella Taylor, Sama Ahsan, Antoinette Price, Charles Eberhart, Eric H. Raabe
Journal: Cancer Research (2015)

Abstract Primitive neuroectodermal tumors (PNET) are highly aggressive tumors that can arise in different regions of the brain. A subset of PNET have genomic amplification of MYC, and the MYC-regulator LIN28A is known to define a group of PNET. Both MYC and LIN28 regulate metabolism in normal and malignant cells. We hypothesized that a combination of dominant negative R248Wp53, MYC, AKT and hTERT would transform human neural stem cells into PNET-like tumors. We used lentiviral vectors to infect human neural stem cells derived from hindbrain and cortex with the same packages of oncogenic elements. Hindbrain neural stem cells transduced with MYC/R248Wp53/AKT/hTERT proliferated at an increased rate compared to control cells as measured by BrdU incorporation (Hindbrain pBABE vs. Hindbrain MYC/R248Wp53/AKT/hTERT: 4% vs. 50% BrdU positive, t-test p = 0.001). Similar results were observed in cortex derived human neural stem cells transduced with MYC/R248Wp53/AKT/hTERT (Cortex pBABE vs Cortex MYC/R248Wp53/AKT/hTERT: 5% vs. 24% BrdU positive, t-test p = 0.027). Both hindbrain and cortex derived human neural stem cells transformed with MYC /R248Wp53/hTERT, and MYC/R248Wp53/hTERT/AKT formed aggressive orthotopic xenograft tumors with histologic characteristics of PNET. The latency of tumor formation decreased with increasing addition of oncogenes. We detected increased glutaminase (GLS) in our MYC-driven human neural stem cell models compared to SV40 immortalized neural stem cells, and hypothesized that GLS inhibitors would inhibit the growth of MYC-driven and LIN28 driven brain tumors. The glutaminase inhibitors DON (6-Diazo-5-oxo-L-norleucine) and acivicin suppressed the growth of our MYC-driven neural stem cell models of PNET as well as the PNET cell line PFSK (p = 0.003) as measured by BrdU and MTT growth assay. Cell cycle analysis of MYC-transduced human neural stem cell models showed increased cell death as measured by sub G1 population after treatment with DON and acivicin. This data shows that glutaminase inhibition may be a useful therapeutic modality in PNET. Citation Format: Isabella Taylor, Sama Ahsan, Antoinette Price, Charles Eberhart, Eric H. Raabe. MYC, dominant negative p53 and AKT transform human neural stem cells into primitive neuro-ectodermal tumors sensitive to glutaminase inhibitors. [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 494. doi:10.1158/1538-7445.AM2015-494
“Early Lesion” of Follicular Lymphoma (FL) Precedes Clinically Overt FL: A Retrospective Study of Lymph Nodes (LNs) Obtained At Surgery with LNs Dissection for Preceding Cancer.
Authors: Yasunori Ota, Koji Izutsu, Hikari Ota, Aya Nishida, Kazuya Ishiwata, Masanori Tsuji, Hisashi Yamamoto, Go Yamamoto, Yuki Asano-Mori, Atsushi Wake, Takeshi Fujii, Shuichi Taniguchi
Journal: Blood (2012)
166. Lentiviral Hematopoietic Stem Cell Gene Therapy for Sjögren-Larsson Syndrome
Authors: Yoon-Sang Kim, Irudayam Maria Johnson, Dana S'Aulis, William B. Rizzo, Arthur W. Nienhuis
Journal: Molecular Therapy (2016)

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by scaling skin (ichthyosis), mental retardation, and spasticity. SLS is caused by mutations in the ALDH3A2 gene, which encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that is involved in the oxidation of fatty aldehyde and fatty alcohol. In SLS, FALDH deficiency and impaired fatty aldehyde oxidation results in lipid accumulation, which is responsible for the symptoms. Spurred by previous hematopoietic stem cell gene therapy trials for multi-systemic diseases, such as Adrenoleukodystrophy (ALD), Metachromatic leukodystrophy (MLD), and Cystinosis, we investigated the plausibility of hematopoietic stem cell gene transfer to correct FALDH deficiency and alleviate the phenotype in SLS. We designed the hematopoietic stem cell gene therapy using a lentiviral vector containing human ALDH3A2 cDNA based on our previous MND-WASP (Wiskott-Aldrich syndrome protein) vector design. The lentiviral vector contains the normal human ALDH3A2 coding sequence which was derived from PCR products using human mobilized peripheral blood CD34+ cDNA. The vector was tested for FALDH protein expression in transfected human HEK293T cells by western blot and the enzyme activity was confirmed using HPLC-MS/UV. A transplantation experiment was performed using the Aldh3a2-/- KO mouse model, where the lineage negative BM cells from CD45.1 Aldh3a2-/- KO mice (C57BL/6 background) were sorted and transduced with a lentiviral vector followed by transplantation into lethally irradiated CD45.2 Aldh3a2-/- KO mice (C57BL/6 background). These mice are being monitored for cell engraftment, vector copy numbers, and any phenotypic changes. An initial analysis for the grafts showed 56% transduction in the MND(a synthetic promoter that contains the U3 region of a modified MoMuLV LTR with myeloproliferative sarcoma virus enhancer)-GFP group and 31% transduction in the MND-ALDH3A2 group based on the CFU-C data. Flow cytometric analysis of peripheral blood on these mice at 6 and 12 post- transplant week showed 32% transduction in MND-GFP group. Further analysis including vector copy numbers and end point analysis for various tissues including liver, spleen, and brain are underway. This work provides the foundation for moving forward with potential lentiviral hematopoietic stem cell gene therapy for non-hematological disorders.