tbuckley/cabot-search huggingface dataset:
Abstract 9914: Cardiomyocyte-specific Overexpression of GTP Cyclohydrolase 1 Improves Cardiac Function in Streptozotocin-induced Diabetic Cardiomyopathy
Authors: Zhi-Dong Ge, Shelley L Baumgardt, Mark Paterson, Yanan Liu, Shigang Qiao, David C Warltier, Judy R Kersten
Journal: Circulation (2013)

Background: Emerging evidence suggests that GTP cyclohydrolase 1 (GTPCH) is critical for activity of nitric oxide synthase and sarcoplasmic reticulum Ca 2+ ATPase and myocardial relaxation in normal myocardium. We hypothesized that increased expression of GTPCH ameliorates cardiac dysfunction in streptozotocin (STZ)-induced diabetic cardiomyopathy. Methods: Transgenic mice with cardiomyocyte-specific overexpression of human GTPCH gene (GTPCH-Tg) and their wild-type littermates were injected with 50 mg/kg/day STZ (i.p.) for 5 consecutive days to induce diabetes or vehicle as control. Structure and function of the left ventricle were evaluated using echocardiography and in Langendorff-perfused hearts. Western blotting was used to measure expression of GTPCH and p38 mitogen-activated protein kinase (p38 MAPK). Cardiac biopterins were determined by HPLC. Results: Blood glucose concentrations were significantly increased in both GTPCH-Tg and wild-type mice 2 to 12 weeks after STZ injection. There were no significant differences in cardiac structure and function between vehicle-treated GTPCH-Tg and wild-type groups throughout the experiment. Twelve weeks after the injection, STZ-induced diabetes resulted in significant decreases in fractional shortening, the mitral E/A ratio, and ±dP/dt in wild-type mice (fractional shortening: 23±3% vs. 40±3% in vehicle; E/A: 1.36±0.10 vs. 1.87±0.12 in vehicle, n=10, P&lt;0.05) but not GTPCH-Tg mice. The ratio of GTPCH/GAPDH was lower in STZ-treated wild-type than vehicle-treated wild-type mice (0.05±0.01 vs. 0.24±0.05 in vehicle, n=4, P&lt;0.05). In contrast, the ratio of phosphorylated p38 MAPK/total p38 MAPK was significantly higher in STZ-treated wild-type than vehicle-treated wild-type mice. These negative effects of STZ-induced diabetes were abolished by GTPCH overexpression. Cardiac tetrahydrobiopterin levels were dramatically higher in GTPCH-Tg than wild-type mice in both vehicle- and STZ-treated groups. Conclusions: Decreased GTPCH contributes to cardiac dysfunction in STZ-induced diabetic cardiomyopathy. Cardiac overexpression of GTPCH improves cardiac function in diabetic cardiomyopathy by decreasing activation of p38 MAPK and increasing cardiac tetrahydrobioptein levels.
Rituximab-based maintenance therapy in Waldenström macroglobulinemia: A case control study.
Authors: Saurabh Zanwar, Jithma P. Abeykoon, Morie A. Gertz, Shaji Kumar, David James Inwards, Luis F. Porrata, Carrie A. Thompson, Thomas E. Witzig, Thomas Matthew Habermann, Ronald S. Go, Martha Lacy, S. Vincent Rajkumar, Angela Dispenzieri, Francis Buadi, Wilson I. Gonsalves, Nelson Leung, Suzanne R. Hayman, Robert A. Kyle, Stephen M. Ansell, Prashant Kapoor
Journal: Journal of Clinical Oncology (2019)

7559 Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma commonly treated with rituximab (R)-based therapy. The use of rituximab maintenance (mR) in WM is controversial. We present a case-control study of patients (pts) with WM treated with mR. Methods: Pts evaluated at Mayo Clinic, Rochester with active WM that received mR between 1/2000 &amp; 6/2018 were included. Cases comprised pts who received mR following R-based induction as primary therapy. Cases were matched based on the time of diagnosis in 1:2 ratio with a control group treated with R-based primary induction therapy without mR. Time to event analyses were performed from initiation of R-based induction. Results: Of 776 pts with active WM, 42 (5%) cases received mR and 84 pts were selected as controls. The median follow-up and the proportion of high risk pts were comparable between the two cohorts (Table). Pts in the mR cohort show a trend toward longer time to next therapy (TTNT) and a significantly longer overall survival (OS) compared to the control group (Table). The R-based induction therapies were comparable in the two cohorts (p = 0.6). Median duration of mR was 1.9 yrs (95% CI 1.6-2) and mR was used most frequently every (q) 2 (range 1-6) months. Of the 42 mR pts, 25 (60%) received an R-based combination for induction and 17 (40%) received R monotherapy as induction. Five (12%) pts discontinued mR due to toxicity, infections were reported in 13 pts (31%) during mR therapy and 3 pts (7%) received IVIg infusions for recurrent infections. Conclusions: R-based induction followed by mR demonstrates a longer OS in WM compared to R-treated control population not receiving mR, albeit at a high rate of infections. Despite limitations of a retrospective study, with a heterogeneously treated cohort, these data add to the body of literature supporting Rituximab maintenance. Results from an ongoing randomized controlled trial are awaited. [Table: see text]
Abstract 3897: Stability and safety evaluation of STRO-002, a site-specific anti-folate receptor alpha antibody-drug conjugate for the potential treatment of ovarian and endometrial cancers
Authors: Willy Solis, Venita De Almeida, Cristina Abrahams, Xiaofan Li, Tyler Heibeck, Maureen Bruhns, Adam Galan, Heidi Hoffman, Robert Kiss, Trevor Hallam, Mark Lupher
Journal: Cancer Research (2019)

Abstract Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for multiple oncology indications. Folate receptor alpha (FolRα) is a glycosylphosphatidylinositol-linked cell-surface glycoprotein that is overexpressed in ovarian, endometrial, lung, and triple negative breast cancers. In contrast, FolRα is minimally expressed on normal tissues, thus, making it an amenable ADC target. STRO-002, a site-specific ADC, is comprised of 3-aminophenyl hemiasterlin cytotoxic drug (SC209) conjugated to an aglycosylated anti-FolRα IgG1 antibody through a protease-cleavable linker at two engineered non-natural amino acids in each heavy chain (DAR ~4). In vitro and in vivo stability studies, showed that STRO-002 is highly stable in circulation, with the warhead SC209 predominantly accumulating in tumor tissue. Toxicology and toxicokinetic studies were conducted to determine the safety profiles for STRO-002 and its metabolite SC209 in cynomolgous monkeys and rats, respectively. In single-dose toxicology studies in rats, SC209 was tolerated up to 0.6 mg/kg with the main toxicity findings predominantly found in hematopoietic/lymphoid tissue, consistent with tubulin targeting chemotherapeutic drugs. In a tissue cross-reactivity study with normal human tissues, STRO-002-specific membranous staining was detected in Fallopian tubes, kidney (tubules), and placenta (trophoblasts). In a definitive safety study in cynomolgus monkeys, pharmacologically relevant model for toxicity testing, STRO-002 was tolerated at up to 9 mg/kg when intravenously administered on days 1 and 22 followed by a 4-week observation period. The most prominent STRO-002-related antigen-independent toxicity finding was dose-related, minimal to marked, and cyclical neutropenia. There were no antigen-dependent toxicity findings and no evidence of ocular toxicity. Toxicokinetic analysis confirmed dose proportional STRO-002 exposures (total antibody, ADC, and SC209 catabolite) at all doses tested. In summary, STRO-002 ADC has a favorable nonclinical safety and pharmacokinetic profiles and a Phase I study of STRO-002 in patients with ovarian and endometrial cancer has been initiated. Citation Format: Willy Solis, Venita De Almeida, Cristina Abrahams, Xiaofan Li, Tyler Heibeck, Maureen Bruhns, Adam Galan, Heidi Hoffman, Robert Kiss, Trevor Hallam, Mark Lupher. Stability and safety evaluation of STRO-002, a site-specific anti-folate receptor alpha antibody-drug conjugate for the potential treatment of ovarian and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3897.
Reparative T lymphocytes in organ injury
Authors: Franco R. D’Alessio, Johanna T. Kurzhagen, Hamid Rabb
Journal: Journal of Clinical Investigation (2019)

Acute organ injuries such as acute cerebrovascular accidents, myocardial infarction, acute kidney injury, acute lung injury, and others are among the leading causes of death worldwide. Dysregulated or insufficient organ repair mechanisms limit restoration of homeostasis and contribute to chronic organ failure. Studies reveal that both humans and mice harness potent non-stem cells that are capable of directly or indirectly promoting tissue repair. Specific populations of T lymphocytes have emerged as important reparative cells with context-specific actions. These T cells can resolve inflammation and secrete reparative cytokines and growth factors as well as interact with other immune and stromal cells to promote the complex and active process of tissue repair. This Review focuses on the major populations of T lymphocytes known to mediate tissue repair, their reparative mechanisms, and the diseases in which they have been implicated. Elucidating and harnessing the mechanisms that promote the reparative functions of these T cells could greatly improve organ dysfunction after acute injury.
Abstract 4329: Pharmaceutical means of targeting the fusion oncogene EWS-FLI1 in the Ewing family of tumors
Authors: Daniel A. Heisey, Timothy Lochmann, Marissa Calbert, Maninderjit Ghotra, Yuki Kato Maves, Sosipatros Boikos, Cyril Benes, C. Patrick Reynolds, Anthony Faber
Journal: Cancer Research (2019)

Abstract The EWS-FLI1 translocation is the hallmark genomic alteration in the Ewing Family of Tumors (EWFT) a malignancy of the bone and surrounding tissue, predominantly affecting children and adolescents. Although significant progress has been made for the treatment of localized disease, patients with metastasis or who relapse after chemotherapy have less than a 30% five year survival rate. EWS-FLI is currently not pharmaceutically druggable, driving the need for more effective targeted therapies. It is well known that the EWS-FLI1 translocation induces a variety of epigenetic changes which impact tumorigenesis and disease progression. Using high throughput drug screening we have identified a novel epigenetic susceptibility in EWFT to the H3K27 demethylase inhibitor GSK-J4 (GlaxoSmithKline). Subsequent treatment with GSK-J4 leads to a decrease in H3K27 acetylation and ultimately silencing of EWS-FLI1 gene targets. We sought to fully characterize the hypersensitivity of EWFT to GSK-J4 and to elucidate the mechanisms of histone modifications caused by the EWS-FLI1 translocation in EWFT. We are examining key shifts in histone modifications at FLI1 target gene enhancer elements in the presence of GSK-J4 as a means of directly regulating FLI1 tumorigenesis. Additionally, we seek to determine the efficacy of GSK-J4 in combination with a CDK7 inhibitor (THZ1), which have shown synergy in vitro, through the utilization of patient derived xenograft models (PDX) and the identification of biomarkers of sensitivity to rationalize the use of this combination for clinical trials. Citation Format: Daniel A. Heisey, Timothy Lochmann, Marissa Calbert, Maninderjit Ghotra, Yuki Kato Maves, Sosipatros Boikos, Cyril Benes, C. Patrick Reynolds, Anthony Faber. Pharmaceutical means of targeting the fusion oncogene EWS-FLI1 in the Ewing family of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4329.
Abstract 1594: Transcriptome-wide association study analysis of nasopharyngeal carcinoma
Authors: Wen-Hui Su, Fu-Chun Chan
Journal: Cancer Research (2019)

Abstract Arising from the epithelial cells in nasopharynx, nasopharyngeal carcinoma (NPC) is highly prevalent in Southeastern China, including Hong Kong and Taiwan. Genetic and environmental factors play important role in NPC susceptibility. Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) located in major histocompatibility complex (MHC) region with strong evidence for association with NPC. Recently, combination of GWAS and expression quantitative trait loci (eQTL) datasets, transcriptome-wide association study (TWAS) was used to identify novel associations in transcriptome level. In this study, we conducted TWAS in NPC using two in house GWAS datasets and GTEx eQTL datasets from public domain. Most of the significant results were located in chromosome six MHC region. Our analysis identified significant TWAS genes that explain the most of the GWAS signals : HLA-A, GABBR1 and HLA-F genes with P values of 5.08E-13, 5.78E-09 and 2.30E-08, respectively. One of the novel genes, ZNRD1 (P = 8.22 E-08), was known to be involved in the tumorigenesis of esophageal cancer and liver cancer. Further analysis should be needed to understand the mechanisms between ZNRD1 association in NPC. Citation Format: Wen-Hui Su, Fu-Chun Chan. Transcriptome-wide association study analysis of nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1594.
The discovery of novel mechanisms for lymphangioleiomyomatosis pathogenesis through GWAS: a rarity in rare respiratory disorders
Authors: Arnold S. Kristof, Victor E. Ortega
Journal: European Respiratory Journal (2019)

<b>This is the largest genome-wide association study of risk for sporadic LAM, a rare genetic disorder, from an international effort which identified novel variants for LAM pathogenesis in a plausible gene, independent of variation in <i>TSC1</i> and <i>TSC2</i></b>http://bit.ly/2X0SeZ1
Abstract 2252: YIV-906 (PHY906) enhanced the anti-tumor activity of immune checkpoint blockade therapy (Anti-PD1) against liver cancer by changing the tumor micro-environment associated with M1 macrophages infiltration
Authors: Wing Lam, Xiaochen Yang, Zaoli Jiang, Xue han, Fulan Guan, Rong Hu, Chang-Hua Xu, Wei Cai, William Cheng, Shwu-Huey Liu, Yuping Cai, Nicholas Rattray, Caroline Johnson, Lieping Chen, Yung-chi Cheng
Journal: Cancer Research (2019)

Abstract YIV-906 (PHY906) is inspired by a traditional 1800-year Chinese herbal formulation, “Huang Qin Tang”, which is commonly used for treating diarrhea. Following chemotherapy and radiation, preclinical and clinical results suggest that YIV-906 has the potential to improve the patient’s quality of life and prolonging survival. Consistent preparations of PHY906 could be manufactured apart 15 years. The effects of YIV-906 were studied on the anti-tumor activity of anti-PD1 using BDF1 mice bearing Hepa 1-6 tumors. Results indicated that anti-PD1 alone had moderate effects on tumor growth however YIV-906 plus anti-PD1 eradicated all tumors in all tumor bearing mice. Further re-implantation of Hepa 1-6 cells did not grow in the “cured” mice, but implanted CMT167 (non-small lung carcinoma) cells or Pan02 (Pancreatic Ductal Adenocarcinoma) cells did grow; suggesting that YIV-906 plus anti-PD1 created a tumor-specific vaccine-like effect. The combination treatment exhibited a highly inflamed tumor microenvironment with more M1-like macrophage expression over M2. In culture YIV-906 could potentiate the action of IFNg (interferon gamma) to polarize bone marrow-derived macrophages (BMDM) into M1 macrophages while inhibiting IL4 action for M2 macrophage polarization. YIV-906 potentiated IFNg action through: 1) stimulating IFNg secretion, 2) phosphorylation of JAK1/2 and STAT1 and 3) increasing IRF1 protein expression. Scutellaria baicalensis Georgi (S) and its flavonoids of YIV-906 were responsible for potentiate the IFNg to polarize macrophage into M1. In conclusion, YIV-906 enhanced the anti-tumor activity of anti-PD1 by enhancing inflammation in the tumor microenvironment and enriching M1-like macrophages. This suggests the potential use of combination YIV-906 and anti-PD1 in cancer treatment. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Xiaochen Yang, Zaoli Jiang, Xue han, Fulan Guan, Rong Hu, Chang-Hua Xu, Wei Cai, William Cheng, Shwu-Huey Liu, Yuping Cai, Nicholas Rattray, Caroline Johnson, Lieping Chen, Yung-chi Cheng. YIV-906 (PHY906) enhanced the anti-tumor activity of immune checkpoint blockade therapy (Anti-PD1) against liver cancer by changing the tumor micro-environment associated with M1 macrophages infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2252.
Abstract 3571: Identification of a novel imatinib upregulated lncRNA family that is required for efficient cellular transformation by Abl oncogene
Authors: Jilong Chen, Xuefei Wang
Journal: Cancer Research (2019)

Abstract Bcr-Abl oncogene is generated by a reciprocal translocation between chromosome 9 and 22 in human genome, giving Bcr-Abl protein with constitutive tyrosine kinase activity that causes chronic myeloid leukemia (CML) . Few acute lymphoblastic leukemia (ALL) patients also contain Bcr-Abl oncogene. Owing to the development of imatinib, over 90% of CML patients can be cured in recent years. However, the functional relevance of lncRNAs in Bcr-Abl-mediated leukemia remains obscure. Here, we identified a conserved, imatinib-upregulated lncRNA (IUR) family, named lncRNA-IUR37. Upregulation of lncRNA-IUR37 has been detected in both human and mouse Abl-transformed cell lines after imatinib treatment. Interestingly, lncRNA-IUR37 expression levels were significantly lower in leukemic cells derived from Bcr-Abl-positive ALL patients than those in normal control group. Furthermore, altering lncRNA-IUR37 expression remarkably affected survival of Abl-transformed leukemic cells, and tumorigenesis induced by these leukemic cells in xenograft mouse model. Knockdown of lncRNA-IUR37 in transgenic mice significantly promoted Bcr-Abl-mediated primary bone marrow transformation, and leukemia development in leukemia mouse model. These results indicate that lncRNA-IUR37 functions as a suppressor gene in Bcr-Abl-induced tumorigenesis. In addition, we demonstrated that lncRNA-IUR37 directly bound and affected the phosphorylation of STAT5, thereby impacting expression of transferrin receptor protein (TfR or CD71) to regulate leukemic cell survival. Together, our observations suggest that lncRNA-IUR37 is critically involved in Bcr-Abl-mediated leukemogenesis, and provide novel insights into complicated mechanisms underlying cellular transformation by Bcr-Abl oncogene. Citation Format: Jilong Chen, Xuefei Wang. Identification of a novel imatinib upregulated lncRNA family that is required for efficient cellular transformation by Abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3571.
Incidence, characteristics, and risk factors of venous thromboembolism in adolescent and young adult acute lymphoblastic leukemia patients receiving peg-asparaginase.
Authors: Brynne Underwood, Qiuhong Zhao, Alison R. Walker, Alice S. Mims, Sumithira Vasu, Gregory Behbehani, James Stewart Blachly, Karilyn T.M. Larkin, Tzu-Fei Wang, Bhavana Bhatnagar
Journal: Journal of Clinical Oncology (2019)

e18520 Background: Venous thromboembolism (VTE) is common in acute lymphoblastic leukemia (ALL) patients (pts) receiving peg-asparaginase (ASNase) however there is limited data regarding the incidence of VTE and risk factors for VTE in adolescent and young adults (AYA) treated with ASNase. Methods: This is a single institutional retrospective analysis of AYA pts with ALL who received ASNase from January 2013 to December 2018. Time to VTE was calculated from date of starting treatment to onset of VTE or censored at last assessment date, treating death as a competing risk. The cumulative incidence of VTE was estimated and the Fine and Gray regression models accounting for competing risks were used to examine the association between risk factors and VTE. Results: Forty-six AYA ALL patients were included. Pt characteristics are shown in the Table. Twenty pts had a VTE following ASNase with the cumulative incidence rate of 35% (95% CI: 22-48%) at 100 days. The most common VTE sites were cerebral (n=6) and upper extremity (n=6). Nine pts (43%) had at least one recurrent VTE. After initial VTE, ASNase was continued in 13 pts (62%), stopped in 6 pts (29%), and dose reduced in 2 pts (10%). Nine pts (45%) of those who developed VTE received antithrombin. Out of the 6 pts with VTE who had ASNase discontinued or dose reduced, 2 (33%) had progression of ALL. The hazard ratios (HR) for risk of VTE from univariable regression models are listed in Table 1. Male sex was associated with increased VTE risk, with HR=3.33 (95% CI: 1.13-9.77). Conclusions: Our study estimated the incidence of VTE in the AYA cohort. Only male sex was identified as a risk factor for VTE. Additional studies are needed to assess VTE risk factors in AYA pts with ALL. Pt characteristics and hazard ratios for risk of VTE. [Table: see text]
Meta-Omics Reveals Genetic Flexibility of Diatom Nitrogen Transporters in Response to Environmental Changes
Authors: Greta Busseni, Fabio Rocha Jimenez Vieira, Alberto Amato, Eric Pelletier, Juan J Pierella Karlusich, Maria I Ferrante, Patrick Wincker, Alessandra Rogato, Chris Bowler, Remo Sanges, Luigi Maiorano, Maurizio Chiurazzi, Maurizio Ribera d’Alcalà, Luigi Caputi, Daniele Iudicone
Journal: Molecular Biology and Evolution (2019)

Diatoms (Bacillariophyta), one of the most abundant and diverse groups of marine phytoplankton, respond rapidly to the supply of new nutrients, often out-competing other phytoplankton. Herein, we integrated analyses of the evolution, distribution, and expression modulation of two gene families involved in diatom nitrogen uptake (DiAMT1 and DiNRT2), in order to infer the main drivers of divergence in a key functional trait of phytoplankton. Our results suggest that major steps in the evolution of the two gene families reflected key events triggering diatom radiation and diversification. Their expression is modulated in the contemporary ocean by seawater temperature, nitrate, and iron concentrations. Moreover, the differences in diversity and expression of these gene families throughout the water column hint at a possible link with bacterial activity. This study represents a proof-of-concept of how a holistic approach may shed light on the functional biology of organisms in their natural environment.