tbuckley/cabot-search huggingface dataset:
Abstract 5812: FOXD1 mediates G2/M transition in clear cell renal cell carcinoma
Authors: Kyle Henry Bond, Ryan Jaikaran, Suizhen Qiu, Leif Oxburgh
Journal: Cancer Research (2020)

Abstract The forkhead family of transcription factors are highly conserved and essential during embryonic development. There have been reports showing increased expression of forkheads in various cancers, but little is known about the role of these proteins in the disease context. Analysis of 500 clear cell renal cell carcinoma (ccRCC) transcriptomes in The Cancer Genome Database revealed that FOXD1 is overexpressed in ccRCC and correlates with poor patient outcomes (median survival FOXD1-low=2830 days; FOXD1-high=1913 days). Immunohistochemistry of 46 patient tumors showed that FOXD1 is expressed the majority of tumor cells (95% CI [50.6%, 79.4%]). To understand the biological role of FOXD1, we generated FOXD1-null variants of the 786-O ccRCC cell line. Using an in vivo xenograft model, FOXD1-null cells had smaller initiating tumor sizes (parent=71.05mm3; FOXD1-null=36.39mm3) and stunted tumor growth. In vitro, FOXD1-null lines had significantly reduced growth rates compared to the parental line, and showed increased cell size. Cell cycle analysis revealed that FOXD1-null cells had an increased number of cells in G2 compared to the parental line (parent=21.1%; FOXD1-null=37.1%). After G1 synchronization, all lines progressed through G1, S, and G2 at similar rates (parent=10 hours; FOXD1-null=10 hours). However, FOXD1-null clones spent increased time in G2 compared to the parental line (parent= 4 hours; FOXD1-null= 8 hours). Western blot analysis revealed decreased levels of Cyclin B1 and p-H3, as well as increased levels of p27 10 hours post-synchronization in FOXD1-null cells compared to the parent line. Staining with yH2AX did not indicate any significant change in the number of double strand breaks at any phase. These findings suggest that FOXD1 is a mediator of the transition between G2 and M, and that its loss initializes the G2/M checkpoint. Extrapolating back to our clinical observation, we propose that increased FOXD1 expression in tumor cells accelerates the transition between G2 and M, a point that is normally critical for survey and repair of DNA damage. This could result in greater tolerance for DNA damage, accelerating tumor evolution. Citation Format: Kyle Henry Bond, Ryan Jaikaran, Suizhen Qiu, Leif Oxburgh. FOXD1 mediates G2/M transition in clear cell renal cell 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 5812.
Abstract PR06: Tumor-infiltrating B cells colocalize with CD4 T effector cells within tertiary lymphoid structures to present antigen and educate the antitumor immune response in human primary tumors
Authors: Ayana T. Ruffin, Anthony R. Cillo, Sheryl Kunning, Robert L. Ferris, Dario A.A. Vignali, Tullia C. Bruno
Journal: Clinical Cancer Research (2020)

Abstract Despite the success of checkpoint blockade immunotherapies, i.e., anti-PD1, only 20% of patients produce a durable response to these treatments. Thus, a need exists to develop additional therapeutic strategies to treat these patients, which includes evaluation of other tumor-infiltrating immune cells that could further augment the CD8+ and CD4+ T-cell response. Tumor-infiltrating B cells (TIL-B) represent a possible target for immunotherapy due to their predominance in the tumor microenvironment and crucial role in the immune response. In fact, current evidence suggests an antitumor role for TIL-Bs. Specifically, detection of TIL-Bs within tertiary lymphoid structures (TLS) correlates with both increased survival in patients with solid tumors and enhanced response to anti-PD1 immunotherapy. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 TILs within TLS. Utilizing single-cell RNAseq and high-level flow cytometry, we observed increased numbers of activated TIL-Bs in the primary tumors of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) patients. We further assessed the location of TIL-Bs within the TME and determined that they predominantly sit adjacent to CD4+ tumor-infiltrating lymphocytes (TILs) within TLS. Thus, we generated an antigen presentation assay in vitro, and we observed increased CD4+ TIL responses when TIL-Bs presented autologous tumor antigens. Further, there was a differential impact on CD4+ TIL phenotype; specifically, if TIL-Bs were activated (CD27+), the CD4+ TILs were T helper (anti-tumor) CD4+ T cells and if the TIL-Bs were nonactivated (CD27-), the CD4+ TILs were T regulatory cells (protumor). These data suggest that TIL-Bs influence the phenotype and function of CD4+ TILs in patient tumors within TLS. Ultimately, results from this study will increase effective targeting of TIL-Bs within patient primary tumors. Citation Format: Ayana T. Ruffin, Anthony R. Cillo, Sheryl Kunning, Robert L. Ferris, Dario A.A. Vignali, Tullia C. Bruno. Tumor-infiltrating B cells colocalize with CD4 T effector cells within tertiary lymphoid structures to present antigen and educate the antitumor immune response in human primary tumors [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr PR06.
An ultrasensitive hybridization chain reaction-amplified CRISPR-Cas12a aptasensor for extracellular vesicle surface protein quantification
Authors: Shan Xing, Zedong Lu, Qi Huang, Huilan Li, Yu Wang, Yanzhen Lai, Yi He, Min Deng, Wanli Liu
Journal: Theranostics (2020)

Tumor-derived extracellular vesicle (TEV) protein biomarkers facilitate cancer diagnosis and prognostic evaluations. However, the lack of reliable and convenient quantitative methods for evaluating TEV proteins prevents their clinical application. Methods: Here, based on dual amplification of hybridization chain reaction (HCR) and CRISPR-Cas12a, we developed the apta-HCR-CRISPR assay for direct high-sensitivity detection of TEV proteins. The TEV protein-targeted aptamer was amplified by HCR to produce a long-repeated sequence comprising multiple CRISPR RNA (crRNA) targetable barcodes, and the signals were further amplified by CRISPR-Cas12a collateral cleavage activities, resulting in a fluorescence signal. Results: The established strategy was verified by detecting the TEV protein markers nucleolin and programmed death ligand 1 (PD-L1). Both achieved limit of detection (LOD) values as low as 102 particles/µL, which is at least 104-fold more sensitive than aptamer-ELISA and 102-fold more sensitive than apta-HCR-ELISA. We directly applied our assay to a clinical analysis of circulating TEVs from 50 µL of serum, revealing potential applications of nucleolin+ TEVs for nasopharyngeal carcinoma cancer (NPC) diagnosis and PD-L1+ TEVs for therapeutic monitoring. Conclusion: The platform was simple and easy to operate, and this approach should be useful for the highly sensitive and versatile quantification of TEV proteins in clinical samples.
Palladium-based nanomaterials for cancer imaging and therapy
Authors: Yongchun Liu, Jingchao Li, Mei Chen, Xiaolan Chen, Nanfeng Zheng
Journal: Theranostics (2020)

In recent decade, palladium-based (Pd-based) nanomaterials have shown significant potential for biomedical applications because of their unique optical properties, excellent biocompatibility and high stability in physiological environment. Compared with other intensively studied noble nanomaterials, such as gold (Au) and silver (Ag) nanomaterials, research on Pd-based nanomaterials started late, but the distinctive features, such as high photothermal conversion efficiency and high photothermal stability, have made them getting great attention in the field of nanomedicine. The goal of this review is to provide a comprehensive and critical perspective on the recent progress of Pd-based nanomaterials as imaging contrast agents and therapeutic agents. The imaging section focuses on applications in photoacoustic (PA) imaging, single-photon emission computed tomography (SPECT) imaging, computed tomography (CT) imaging and magnetic resonance (MR) imaging. For treatment of cancer, single photothermal therapy (PTT) and PTT combined with other therapeutic modalities will be discussed. Finally, the safety concerns, forthcoming challenges and perspective of Pd-based nanomaterials on biomedical applications will be presented.
Abstract 6030: Role of immature CD44 o-glycosylation in enrichment of cancer stem cell population for aggressive pancreatic cancer
Authors: Frank Leon, Rama K. Nimmakayala, Seema Chugh, Rohitesh Gupta, Satyanarayana Rachagani, Surinder K. Batra, Moorthy P. Ponnusamy
Journal: Cancer Research (2020)

Abstract Pancreatic cancer (PC) is an aggressive malignancy expected to be the second leading cause of cancer death by 2030. Accumulating reports demonstrate that truncated o-glycans are largely observed in PC and correlates with poor prognosis and reduced patient survival. We have previously shown that loss of C1GALT1 (Core 1 n-acetylgalactose transferase) expression in PC results in the upregulation of genes associated with aggressive PC and metastasis. To study the involvement of immature O-glycophenotype in pancreatic cancer stem cells (CSCs), we selected the single-transmembrane CD44 glycoprotein based on our unbiased approach using proteomics and RNA-sequence analysis.This highly o-glycosylated protein with diverse cellular activity is essential in cell-cell recognition and is a widely occurring CSC marker identified in several cancers. However, the functional properties of CD44 o-glycan variation in pancreatic CSCs are not well understood. Thus, we hypothesize that truncation of o-glycans on CD44 imparts activation of downstream targets responsible for self-renewal and maintenance of CSC in aggressive PC. Using a proteomics approach of enriched truncated o-glycans, we discovered CD44 as one of the top identified proteins in CRISPR/Cas9 C1GALT1 knockout PC cells. We observed enhanced expression of markers responsible for CSC self-renewal and characteristics as measured by FACS-based side-population analysis and tumor sphere formation as a result of a loss in C1GALT1. To determine a potential mechanism by which truncated o-glycans on CD44 enhances CSC properties, we deleted C1GALT1 and CD44 in PC cells. A loss of CD44 o-glycan truncation significantly reduced expression of the self-renewal CSC marker Nanog and phosphorylated p65, a major component in the NF-κB signaling pathway. Furthermore, pancreatic tumorigenesis was significantly reduced in athymic mice injected with PC cells as a result of C1GALT1 and CD44 deletion. These results provide a novel mechanism by which truncated o-glycans on CD44 is responsible for activating downstream targets for self-renewal and maintenance of CSCs. Our findings begin to contextualize the contributions of aberrant glycosylation on glycoproteins to accelerate metastatic properties by enhanced expression and characteristics of pancreatic CSC. Citation Format: Frank Leon, Rama K. Nimmakayala, Seema Chugh, Rohitesh Gupta, Satyanarayana Rachagani, Surinder K. Batra, Moorthy P. Ponnusamy. Role of immature CD44 o-glycosylation in enrichment of cancer stem cell population for aggressive pancreatic 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 6030.
Abstract 3197: Serum CEA change predicts tumor regression and prognosis in locally advanced rectal cancer
Authors: Zerong Cai, Lingyu Huang, Ping Lan, Xiaojian Wu
Journal: Cancer Research (2020)

Abstract Objective: To investigate the value of carcinoembryonic antigen (CEA) change in predicting pathological tumor regression and outcome for locally advanced rectal cancer (LARC) patients received neoadjuvant therapy. Material and methods: LARC patients who received neoadjuvant therapy and radical tumor resection were retrospectively collected. The predictive value of baseline CEA, post-treatment CEA and post/pre-treatment CEA ratio for tumor regression grade (TRG), overall survival and diseases free survival were estimated by logistic regression or cox proportional hazard regression. Results: 700 LARC patients were enrolled in the study with 475 (67.9%) cases of male patients and median age of 56 (20-87). Of the all patients enrolled, multivariate analysis showed post-treatment CEA (OR=1.142, 95% CI: 1.073-1.215, P&amp;lt;0.001) was an independent predictor for TRG. 284 patients with elevated baseline CEA were analyzed. Among them, 168 patients (59.2%) have normalized CEA. Multivariate analysis showed post-treatment CEA (OR=1.068, 95% CI: 1.007-1.133, P=0.027), CEA ratio (OR=3.463, 95% CI: 1.269-9.446, P=0.015) were independent predictors for TRG(Table 1). Of the all patients enrolled, multivariate analysis showed low preoperative albumin level (HR=0.919, 95% CI: 0.886-0.952, P&amp;lt;0.001), tumor deposit (HR=3.226, 95% CI: 1.470-7.077, P=0.003), nerve infiltration (HR=3.602, 95% CI: 1.736-7.476, P=0.001), high post-treatment CEA (HR=1.029, 95% CI: 1.010-1.049, P=0.003) were independent unfavored predictors for overall survival of LARC patients. 700 patients were divided into 3 groups: A group with normal baseline CEA (n=416,59.4%); B group with normalized CEA (n=168,24.0%); C group with elevated baseline and post-treatment CEA (n=116,16.6%). The overall survival and disease free survival of group B were comparable to that of group A (P=0.588,0.053) and significantly better than that of group C (B vs. C: P=0.010, 0.003; A vs. C: P=0.007, &amp;lt;0.001). Conclusion: 1. Post-treatment CEA is an independent predictor for TRG of LARC patients and higher post-treatment CEA precdicted poor overall survival. 2. Post/pre-treatment CEA ratio is an independent predictor for TRG of LARC patients with elevated baseline CEA. Citation Format: Zerong Cai, Lingyu Huang, Ping Lan, Xiaojian Wu. Serum CEA change predicts tumor regression and prognosis in locally advanced rectal 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 3197.
HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma
Authors: Xuejing Zou, Dongyan Zhang, Yang Song, Shanshan Liu, Qian Long, Liheng Yao, Wenwen Li, Zhijiao Duan, Dehua Wu, Li Liu
Journal: Theranostics (2020)

Background: Tumor necrosis factor receptor 1 (TNFR1) signaling plays a pleiotropic role in the development of hepatocellular carcinoma (HCC). The formation of TNFR1-complex I supports cell survival while TNFR1-complex II leads to apoptosis, and the underlying mechanisms of the transformation of these TNFR1 complexes in HCC remain poorly defined. Methods: The interaction protein of TNFR1 was identified by GST pulldown assay, immunoprecipitation and mass spectrometry. In vitro and in vivo assay were performed to explore the biological features and mechanisms underlying the regulation of TNFR1 signals by histidine-rich glycoprotein (HRG). Data from the public databases and HCC samples were utilized to analyze the expression and clinical relevance of HRG. Results: HRG directly interacted with TNFR1 and stabilized TNFR1 protein by decreasing the Lys(K)-48 ubiquitination mediated-degradation. The formation of TNFR1-complex II was prompted by HRG overexpression via upregulating Lys(K)-63 ubiquitination of TNFR1. Besides, overexpression of HRG suppressed expression of pro-survival genes by impairing the activation of NF-κB signaling in the presence of TNFR1. Moreover, downregulation of HRG was a result of feedback inhibition of NF-κB activation in HCC. In line with the pro-apoptotic switch of TNFR1 signaling after HRG induction, overexpression of HRG inhibited cell proliferation and increased apoptosis in HCC. Conclusions: Our findings illustrate a crucial role for HRG in suppressing HCC via inclining TNFR1 to a pro-apoptotic cellular phenotype. Restoring HRG expression in HCC tissues might be a promising pharmacological approach to blocking tumor progression by shifting cellular fate from cell survival to apoptosis.
Intraoperative SpyGlass to determine extension of pancreatic resection in main duct intraductal papillary mucinous neoplasm associated with pancreas divisum
Authors: José C. Ardengh, Eloy Taglieri, André O. Ardengh, Arthur F. De Almeida, Rodrigo C. Surjan, Fabio Makdissi, Marcel A. Machado
Journal: Endoscopy (2020)

The International Association of Pancreatology recommends that main duct intraductal papillary mucinous neoplasm (IPMN) be treated with partial pancreatectomy [1] if surgical margins are negative for high-grade dysplasia (HGD) and invasive carcinoma, avoiding total pancreatectomy [2]. However, it is difficult to determine the exact margins of resection during duodenopancreatectomy for main duct IPMN. The latest guidelines recommend SpyGlass to obtain precise measures of margin extension before surgery [1].
The clinical and pathological features of plasma cell myeloma post solid organ transplantation
Authors: Kenneth Ofori, Craig R. Soderquist, Vundavalli V. Murty, David Park, George Vlad, Rebecca J. Leeman‐Neill, Suzanne Lentzsch, Bachir Alobeid, Govind Bhagat
Journal: American Journal of Hematology (2020)

Plasma cell neoplasms (PCNs), comprising plasma cell myelomas (PCMs) and plasmacytomas, which occur after solid organ transplantation, represent rare subtypes of monomorphic post-transplant lymphoproliferative disorders (M-PTLDs). Data regarding the clinical and pathological features of post-transplant (PT)-PCMs are limited. To gain a better understanding of disease biology, we performed comprehensive immunophenotypic analysis, reviewed cytogenetic analysis results and evaluated clinical outcomes of PT-PCMs diagnosed and treated at our institution. Fifteen PT-PCM (M: F - 4:1) and two PT-MGUS (two males) cases were identified. The median age of PT-PCM patients was 68 years (29-79 years) and PCMs presented at a median of 9.7 years (0.5-24.7 years) after transplantation. The PT-PCMs accounted for 11.6% of all M-PTLDs and the period prevalence was 9/3108 (0.29%), 3/1071 (0.28%), 2/1345 (0.15%) and 1/878 (0.11%) post kidney, heart, liver and lung transplantation. Lytic bone disease was observed in 1/11 (9%) patients. Marrow plasma cell infiltration ranged from 10%-70% (median 20%), with 10/15 (67%) and 5/15 (33%) cases manifesting immature and plasmablastic morphology. The immunophenotype of all cases and cytogenetic abnormalities, identified in 60% of cases, were similar to multiple myeloma (MM) of immunocompetent individuals. All PT-PCMs were EBER negative. Ten of 11 (91%) patients with active MM were treated, all with proteasome inhibitor-based therapy. Treatment response and 5-year overall survival (54.5%) was comparable to MM of immunocompetent individuals. However, the survival of patients with plasmablastic PCMs was inferior to those with immature PCMs. 0ur findings indicate PT-PCMs to be predominantly late onset PTLDs that have similar clinicopathologic characteristics as conventional MM.
Abstract 5310: Chromatin accessibility landscape and transcriptome of castration resistant prostate cancers reveals novel subtypes and diverse master regulators
Authors: Fanying Tang, Chen Khuan Wong, Sandra Cohen, Cindy Lee, Minwei Liu, Rohan Bareja, Kenneth Eng, Shaham Beg, Loredana Puca, Cora Sternberg, Juan Miguel Mosquera, Himisha Beltran, Andrea Sboner, Yu Chen, Ekta Khurana
Journal: Cancer Research (2020)

Abstract Castration-resistant prostate cancer (CRPC) is a heterogeneous disease with diverse drivers and mechanisms of resistance to androgen receptor (AR) therapy. We generated ATAC-seq and RNA-seq data for twenty-four metastatic human prostate cancer organoids and cell lines. Integration of chromatin accessibility profiles and transcriptomes revealed four subtypes: androgen-receptor(AR)-dependent, neuroendocrine, Wnt-dependent and epithelial mesenchymal transition (EMT). The transcriptomic signatures obtained from these four subtypes enable the classification of 100 metastatic prostate cancer patient samples from Institute Precision Medicine (IPM) and 270 published samples from SU2C study, revealing potential therapeutic vulnerabilities. Furthermore, using novel computational algorithms we constructed regulatory networks and identified the master regulators of each subtype. Currently we're carrying out western blot and quantitative PCR to confirm the subtypes of all prostate cancer models we use, and using drug sensitivity test, CRISPR knockout and cell competition assay to validate the functions of candidates in each subtype. Our study has characterized global chromatin accessibility landscape and transcriptome in the largest number of metastatic prostate cancer models, which revealed novel subtypes and corresponding tumor drivers. Collectively, these organoids, cell lines and matching sequence data provide a resource to the community to study various CRPC models. The molecular classification and corresponding master regulators reveal new drug targets and could potentially guide future therapeutic studies. Citation Format: Fanying Tang, Chen Khuan Wong, Sandra Cohen, Cindy Lee, Minwei Liu, Rohan Bareja, Kenneth Eng, Shaham Beg, Loredana Puca, Cora Sternberg, Juan Miguel Mosquera, Himisha Beltran, Andrea Sboner, Yu Chen, Ekta Khurana. Chromatin accessibility landscape and transcriptome of castration resistant prostate cancers reveals novel subtypes and diverse master regulators [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 5310.
Primary Care Treatment of Patients Following Bariatric Surgery in 2020
Authors: Yijun Chen, Zhaoping Li, Erik Dutson
Journal: JAMA (2020)

This JAMA Insights Clinical Update reviews long-term complications of bariatric surgery, including GERD, gallstones, hypoglycemia, substance use disorder, and vitamin and other nutritional deficiencies, and proposes a schedule of testing and management strategies for each.
Neuropeptides Modulate Local Astrocytes to Regulate Adult Hippocampal Neural Stem Cells
Authors: Brent Asrican, Josh Wooten, Ya-Dong Li, Luis Quintanilla, Feiran Zhang, Connor Wander, Hechen Bao, Chia-Yu Yeh, Yan-Jia Luo, Reid Olsen, Szu-Aun Lim, Jessica Hu, Peng Jin, Juan Song
Journal: Neuron (2020)
Abstract 14818: Pericyte-Specific PDGF Receptor Beta Knockout Inhibits Angiogenesis and Vessel Maturation
Authors: Alisha V Haug, Christoph Zehendner, Astrid Werner, Andreas M Zeiher, Stefanie Dimmeler
Journal: Circulation (2018)

Introduction: Vessel maturation is dependent on platelet derived growth factor (PDGF), which signals via tyrosine kinase receptors and facilitates recruitment of pericytes to endothelial cells (ECs...