tbuckley/cabot-search huggingface dataset:
Abstract 5303: GSTP1 positive prostate cancer
Authors: Igor D. Vidal, Stephanie Glavaris, Tracy Jones, Jessica Hicks, Bruce J. Trock, Srinivasan Yegnasubramanian, William Nelson, Angelo M. De Marzo
Journal: Cancer Research (2020)

Abstract Introduction: GSTP1 is a member of the Glutathione-S-transferase family, known to be silenced by CpG island DNA methylation in approximately 90% of prostatic adenocarcinomas. However, the cases that are not densely methylated have not been extensively characterized in terms GSTP1 expression or clinico-pathological features. Description of experimental procedures: We analytically validated an automated IHC assay against human GSTP1 using well-known cell line controls and human prostate cancer tissues. We examined 33 TMAs from 1296 prostatectomy patients using the index tumor with 4-fold redundancy from patients from 1993 to 2015. TMA slides stained for GSTP1 were scanned and uploaded to a web based image scoring platform (TMAJ). The images were reviewed by two different pathologists with expertise in prostate cancer. The scoring system followed a two-tiered approach, noted as positive (carcinomas with any nuclear and/or cytoplasmic staining), and as negative (carcinoma cells with no nuclear or cytoplasmic stain) in the presence of benign stromal or inflammatory cells that served as internal controls. The GSTP1 positive staining was correlated with Gleason grade groups, pathological stage, and age. Results: After exclusion for inadequate tissue staining, GSTP1 was evaluated in 4326 TMA cores with carcinoma. GSTP1 IHC staining was positive in 190 cores (4.3%), corresponding to 75 patients (5.9% of patients had GSTP1 positive cancer). Of these 190 positive cores, 109 showed homogeneous (100% positive) tumor cell staining while 81 showed heterogeneous staining, with mixed positive and negative regions. In 43 patients (3.3%), all TMA cores containing carcinoma stained positively. In a number of standard slides from prostatectomies, GSTP1 positive IHC staining cases were also found to be positive for GSTP1 mRNA by in situ hybridization. There was no correlation between GSTP1 positive staining, Gleason grade group, pathological stage, margin status or patient age. Preliminary analysis in a subset of cases showed no correlation with TMPRSS2-ERG status or PTEN loss. Conclusion: GSTP1 protein is present in approximately 5.9% of clinically localized prostate cancers and in approximately 50% of these positive cases, all TMA cores with carcinoma stained positively. Citation Format: Igor D. Vidal, Stephanie Glavaris, Tracy Jones, Jessica Hicks, Bruce J. Trock, Srinivasan Yegnasubramanian, William Nelson, Angelo M. De Marzo. GSTP1 positive prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5303.
Circular RNA circPDE4D Protects against Osteoarthritis by Binding to miR-103a-3p and Regulating FGF18
Authors: Yizheng Wu, Zhenghua Hong, Wenbin Xu, Junxin Chen, Qingxin Wang, Jiaxin Chen, Weiyu Ni, Zixuan Mei, Ziang Xie, Yan Ma, Jiying Wang, Jianhong Lu, Chao Chen, Shunwu Fan, Shuying Shen
Journal: Molecular Therapy (2020)

Osteoarthritis (OA) is a common, age-related, and painful disease characterized by cartilage destruction, osteophyte formation, and synovial hyperplasia. This study revealed that circPDE4D, a circular RNA derived from human linear PDE4D, plays a critical role in maintaining the extracellular cellular matrix (ECM) during OA progression. circPDE4D was significantly downregulated in OA cartilage tissues and during stimulation with inflammatory cytokines. The knockdown of circPDE4D predominantly contributed to Aggrecan loss and the upregulation of matrix catabolic enzymes, including MMP3, MMP13, ADAMTS4, and ADAMTS5, but not proliferation or apoptosis. In a murine model of destabilization of the medial meniscus (DMM), the intraarticular injection of circPDE4D alleviated DMM-induced cartilage impairments. Mechanistically, we found that circPDE4D exerted its effect by acting as a sponge for miR-103a-3p and thereby regulated FGF18 expression, which is a direct target of miR-103a-3p. In conclusion, our findings highlight a novel protective role of circPDE4D in OA pathogenesis and indicate that the targeting of the circPDE4D-miR-103a-3p-FGF18 axis might provide a potential and promising approach for OA therapy. Osteoarthritis (OA) is a common, age-related, and painful disease characterized by cartilage destruction, osteophyte formation, and synovial hyperplasia. This study revealed that circPDE4D, a circular RNA derived from human linear PDE4D, plays a critical role in maintaining the extracellular cellular matrix (ECM) during OA progression. circPDE4D was significantly downregulated in OA cartilage tissues and during stimulation with inflammatory cytokines. The knockdown of circPDE4D predominantly contributed to Aggrecan loss and the upregulation of matrix catabolic enzymes, including MMP3, MMP13, ADAMTS4, and ADAMTS5, but not proliferation or apoptosis. In a murine model of destabilization of the medial meniscus (DMM), the intraarticular injection of circPDE4D alleviated DMM-induced cartilage impairments. Mechanistically, we found that circPDE4D exerted its effect by acting as a sponge for miR-103a-3p and thereby regulated FGF18 expression, which is a direct target of miR-103a-3p. In conclusion, our findings highlight a novel protective role of circPDE4D in OA pathogenesis and indicate that the targeting of the circPDE4D-miR-103a-3p-FGF18 axis might provide a potential and promising approach for OA therapy.
Abstract 3630: Comprehensive integrated HBV DNA profiling in HCC patients with GGH by HBV-targeted NGS and <i>PacBio sequencing</i> analysis
Authors: Yu-Lan Kao, Yih-Ping Su, Hung-Wen Tsai, Ih-Jen Su, Selena Lin, Wei Song, Ying-Hsiu Su
Journal: Cancer Research (2020)

Abstract Despite current antiviral therapy success in reducing viral load in patients with chronic hepatitis B virus (HBV), persistent viral surface antigen (HBsAg) remains a risk factor of HCC. Recent evidence has shown that integrated HBV can serve as a source for continued viral antigen expression, despite the lack of detectable replication. Given the oncogenicity of pre-S mutant proteins and its expression in type II ground glass hepatocytes (GGH) even in the absence of viral replication, we assessed the likelihood of GGH as a pre-malignant state as compared to other adjacent-to-tumor non-GGH “normal” tissue by investigating the integrity of integrated HBV DNA. We developed a sensitive HBV-targeted NGS and downstream bioinformatics pipeline, ChimericSeq, to identify HBV-host junctions. A pilot study of 10 HBV-HCC patients, each with six micro-dissected FFPE tissue sections (2 tumor, 2 GGH, 2 HBsAg-negative), was subjected to HBV-targeted NGS and ChimericSeq analysis. We identified integrated HBV DNA in 90% of HCC as well as its matched GGH, and identified PreS2 deletions, for instance, deletion at nt. 43-52. Surprisingly, the recurrent insertional driver mutations of TERT, CCNE1, and ABCC13 integration were detected in 9 of 10 (90%) of this GGH/HCC patient cohort. Next we performed PacBio amplicon sequencing of integrated HBV DNA including Pre-S sequences to comprehensively profile the integrity of the integrated HBV DNA, such as insertional mutations or deletion, and mutations across the different frozen tissue sections (tumor, GGH, HBsAg-negative). Our data suggest that HBV integration of cancer driver genes occurs early during course of infection and integrated DNA evolved over time during carcinogenesis. Overall, a sensitive workflow to comprehensively profile integrated HBV DNA in HCC patients enables further investigation of the role of HBV integration during tumorigenesis. Citation Format: Yu-Lan Kao, Yih-Ping Su, Hung-Wen Tsai, Ih-Jen Su, Selena Lin, Wei Song, Ying-Hsiu Su. Comprehensive integrated HBV DNA profiling in HCC patients with GGH by HBV-targeted NGS and PacBio sequencing analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3630.
CaCO3 crystals as versatile carriers for controlled delivery of antimicrobials
Authors: Ana M. Ferreira, Anna S. Vikulina, Dmitry Volodkin
Journal: Journal of Controlled Release (2020)

CaCO3 crystals have been known for a long time as naturally derived and simply fabricated nano(micro)-sized materials able to effectively host and release various molecules. This review summarises the use of CaCO3 crystals as versatile carriers to host, protect and release antimicrobials, offering a strong tool to tackle antimicrobial resistance, a serious global health problem. The main methods for the synthesis of CaCO3 crystals with different properties, as well as the approaches for the loading and release of antimicrobials are presented. Finally, prospects to utilize the crystals in order to improve the therapeutic outcome and combat antimicrobial resistance are highlighted. Ultimately, this review intends to provide an in-depth overview of the application of CaCO3 crystals for the smart and controlled delivery of antimicrobial agents and aims at identifying the advantages and drawbacks as well as guiding future works, research directions and industrial applications.
Abstract 1007: Orphan nuclear receptor TLX regulates the antitumor immune response through transcriptional regulation of programmed death ligand 1 in glioma
Authors: Jiayi Zhou, Xiaojuan Pei, Zhu Wang, Weijie Gao, Franky Leung Chan, Xin Li, Jie Mao, Dinglan Wu
Journal: Cancer Research (2020)

Abstract High-grade gliomas are rapidly progressing tumors of the central nervous system (CNS) with a very poor prognosis and novel treatment are urgently needed to improve patient outcomes. Clinical trials of immunotherapies for glioma including PD1/PD-L1 inhibition have performed but the outcome was not optimistic. In this study, we found that orphan nuclear recepter TLX and PD-L1 were both significantly upregulated in glioma lesions and the expression of TLX and PD-L1 in glioma was positively correlated. Moreover, the expression pattern of TLX also associated with a suppression microenvironment in glioma. Functional study revealed that suppression of TLX inhibited glioma cell growth and immune response, which accompanied with down-regulation of PD-L1. We also characterized that TLX could bind directly to PD-L1 promoter and activate PD-L1 gene transcription. Together, our present study shows, for the first time, that TLX can contribute to glioma immune escape via promoting the expression of PD-L1, targeting the druggable TLX may have a potential therapeutic significance in glioma immune therapy. Citation Format: Jiayi Zhou, Xiaojuan Pei, Zhu Wang, Weijie Gao, Franky Leung Chan, Xin Li, Jie Mao, Dinglan Wu. Orphan nuclear receptor TLX regulates the antitumor immune response through transcriptional regulation of programmed death ligand 1 in glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1007.
Abstract 3444: Intratumor regulatory T cells prevent IFN-gamma-dependent tumor vessel regression and can be selectively targeted by anti-CD25 near-infrared photoimmunotherapy
Authors: Yutaka Kurebayashi, Peter L. Choyke, Hisataka Kobayashi, Noriko Sato
Journal: Cancer Research (2020)

Abstract Regulatory T cells (Tregs) play pivotal roles in inhibiting anti-tumor immunity at different phases and locations (priming phase in lymph node and effector phase in tumor tissue) through their ability to suppress the function of T, NK, and antigen-presenting cells. However, our knowledge about the roles of Tregs in tumor immunity has largely derived from analyses after systemic depletion of Tregs or systemic manipulation of Treg functions in murine tumor models. The specific roles that intra- and extra-tumor Tregs play remain unclear due to technical difficulties to deplete or manipulate Tregs in a spatially specific manner. In order to achieve spatially specific depletion of Tregs in a clinically applicable manner, we have previously developed an anti-CD25 F(ab')2 near-infrared photoimmunotherapy (NIR-PIT), in which an intravenous injection of IR700-conjugated anti-CD25 F(ab')2 followed by irradiation of near-infrared light on tumors achieves selective depletion of intratumor Tregs and suppresses tumor growth. The suppression of tumor growth by the anti-CD25 F(ab')2 NIR-PIT depends on CD8 T and NK cells and their production of IFN-γ; however, the exact target of IFN-γ and the mechanisms of tumor regression remain to be elucidated. In this study, we aimed to dissect the mechanisms of the anti-tumor effect of intratumor Treg depletion by anti-CD25 F(ab')2 NIR-PIT using a series of Ifngr1 knockout mice models including bone-marrow chimera and conditional knockout models. Unexpectedly, we found that the target of IFN-γ in anti-CD25 F(ab')2 NIR-PIT was endothelial cells of tumor vessels. In both MC38 and EO771 tumor models (murine colon and breast cancer, respectively), CD8 T cells, NK cells, and Tregs were mainly located along the tumor vessels, and depletion of intratumor Tregs by anti-CD25 F(ab')2 NIR-PIT induced IFN-γ expression from these perivascular CD8 T and NK cells for up to 6 hours. This transient but synchronized induction of IFN-γ/STAT1 signaling along tumor vessels caused rapid vessel regression, intratumor ischemia, and apoptotic death of tumor cells. Combination with IL-15 treatment further eradicated residual tumor cells to achieve complete remission of MC38 and EO771 tumors. Citation Format: Yutaka Kurebayashi, Peter L. Choyke, Hisataka Kobayashi, Noriko Sato. Intratumor regulatory T cells prevent IFN-gamma-dependent tumor vessel regression and can be selectively targeted by anti-CD25 near-infrared photoimmunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3444.
Abstract 1896: Whole transcriptome analysis identifies TNS4 as a key effector of cetuximab and a regulator of the oncogenic activity of KRAS mutant colorectal cancer cell lines
Authors: Sujin Kim, Nayoung Kim, Keunsoo Kang, Wonkyung Kim, Jonghwa Won, Jeonghee Cho
Journal: Cancer Research (2020)

Abstract Targeting of activated epidermal growth factor receptor (EGFR) with therapeutic anti-EGFR monoclonal antibodies (mAbs) such as cetuximab and panitumumab has been used as an effective strategy in treatment of colorectal cancer (CRC). However, its clinical efficacy occurs only in the limited number of patients. Here, we performed whole-transcriptome analysis in xenograft mouse tumors induced by KRASG12D mutation-bearing LS174T CRC cells following treatment with either cetuximab or PBS. By integrated analyses of differential gene expression with TCGA and CCLE public database, we identified TNS4, overexpressed in CRC patients and KRAS mutation-harboring CRC cell lines, significantly downregulated by cetuximab. While ablation of TNS4 expression via shRNA results in significant growth inhibition of LS174T, DLD1, WiDr, and DiFi CRC cell lines, conversely, its ectopic expression increases the oncogenic growth of these cells. Furthermore, TNS4 expression is transcriptionally regulated by MAP kinase signaling pathway. Consistent with this finding, selumetinib, a MEK1/2 inhibitor, suppressed oncogenic activity of CRC cells and this effect is more profound in combination with cetuximab. Altogether, we propose that TNS4 plays a crucial role in CRC tumorigenesis and that suppression of TNS4 would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including KRAS activating mutations. Citation Format: Sujin Kim, Nayoung Kim, Keunsoo Kang, Wonkyung Kim, Jonghwa Won, Jeonghee Cho. Whole transcriptome analysis identifies TNS4 as a key effector of cetuximab and a regulator of the oncogenic activity of KRAS mutant colorectal cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1896.
Abstract 4585: LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth
Authors: Claire Buchta Rosean, Pratima Sinha, David M. Koelle, Paul Nghiem, Teri Heiland
Journal: Cancer Research (2020)

Abstract The majority of Merkel cell carcinomas (MCC), a rare and highly-aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of a truncated form of the viral large T antigen (LT) in infected cells and making LT an attractive target for therapeutic cancer vaccines. While induction of tumor-reactive CD8+ T cells is a major goal of cancer therapy, CD4+ T cells provide essential support to CD8+ T cells by promoting their expression of cytotoxic effector molecules and increasing their migratory capacity. Cytokines secreted by CD4+ T cells, such as IFNγ, can also exert desirable effects on the tumor microenvironment. Therefore, we set out to design a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPyV-LT. To activate antigen-specific CD4+ T cells in vivo, we utilized our nucleic acid platform, UNITE (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and a balanced T cell response. LTS220A, encoding a mutated form of MCPyV-LT that abrogates its pro-oncogenic properties, was introduced into the UNITE platform. Intradermal vaccination with LTS220A-UNITE promoted a potent, antigen-specific CD4+ T cell response to MCPyV-LT. Additionally, prophylactic vaccination with LTS220A-UNITE prevented growth of B16F10 tumors expressing LTS220A in 100% of mice. Therefore, we find that DNA vaccination using the UNITE platform enhances CD4+ T cell responses to MCPyV-LT and prevents tumor growth when given prophylactically. Future studies will test the efficacy of LTS220A-UNITE for use as a therapeutic cancer vaccine. Citation Format: Claire Buchta Rosean, Pratima Sinha, David M. Koelle, Paul Nghiem, Teri Heiland. LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4585.
Abstract 3457: Plasma metabolomic changes in mice with time restricted feeding-attenuated pulmonary metastasis of Lewis lung carcinoma
Authors: Lin Yan, Bret M. Rust, Matthew J. Picklo
Journal: Cancer Research (2020)

Abstract Erratic eating behavior disrupts diurnal rhythms of metabolism and may contribute to obesity. Time-restricted feeding (TRF), in which food is available in the active period of the day (the dark phase for nocturnal animals), restores metabolic homeostasis in mice. In a mouse model of Lewis lung carcinoma (LLC), we found that TRF (12 hours, dark phase) attenuates obesity-enhanced spontaneous metastasis to the lungs in a study that compared differences in the extent of metastasis among four dietary groups: non-LLC-bearing mice fed the standard AIN93G diet and LLC-bearing mice fed the AIN93G, an obesogenic high-fat diet (HFD) or TRF with the HFD. With the goal of determining potential plasma fingerprints underlying TRF efficacy, we performed untargeted metabolomic analysis upon the plasma samples from this study. Using gas chromatography time-of-flight mass spectrometry, we identified 152 compounds of which 24 differed among the four groups. Ten analytes that were the most influential in treatment separation were alpha-tocopherol, phenylalanine, isoleucine, leucine, pyruvic acid, dihydrocholestrol, arachidonic acid (ARA), docosahexaenoic acid (DHA), lactic acid, and cholesterol. In mice fed the AIN93G diet, compared to non-LLC-bearing mice LLC elevated alpha-tocopherol, ARA, isoleucine, phenylalanine, cholesterol, lauric acid, and 4-hydroxybenzoate and decreased lactic acid, lactamide, and pyruvic acid. In LLC-bearing mice, compared to the AIN93G diet the HFD elevated asparagine, leucine, phenylalanine, dehydrocholesterol, p-cresol sulfate, and hexuronic acid and decreased 1,5-anhydroglucitol, palmitoleic acid, myristic acid, lauric acid, and 4-hydrobenzoate. Compared to the HFD, TRF elevated linoleic acid and 2-hydroxyhexanoic acid and decreased alpha-tocopherol, asparagine, isoleucine, leucine, phenylalanine, dihydrocholesterol, p-cresol sulfate, hexuronic acid, and DHA. This study showed that LLC metastatic growth and an increase in dietary fat consumption disrupted metabolic homeostasis, as reflected in plasma analyte changes compared to their respective controls. TRF, through its temporal regulation of food intake, restored HFD-mediated metabolic disruption and may have contributed to its inhibition of obesity-enhanced LLC metastasis. Citation Format: Lin Yan, Bret M. Rust, Matthew J. Picklo. Plasma metabolomic changes in mice with time restricted feeding-attenuated pulmonary metastasis of Lewis lung carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3457.
Too early to allow pregnancies with genome edited embryos, says commission
Authors: Jacqui Wise
Journal: BMJ (2020)

An international commission has concluded that editing of embryo genomes is not yet ready to be performed safely and effectively in humans.1

The commission was set up in the wake of a Chinese researcher’s controversial announcement in November 2018 that twins had been born after genome editing he had performed on early embryos.2 The researcher, He Jiankui, faced widespread criticism and was eventually sentenced to three years’ imprisonment by a Chinese court.3

After reviewing the scientific literature on CRISPR and other ways to modify DNA, the International Commission on the Clinical Use of Human Germline Genome Editing concluded, “There should be no attempt to establish a pregnancy with a human embryo that has undergone genome editing unless and until it has been clearly …