tbuckley/cabot-search huggingface dataset:
Abstract 912: CLDN6 and CLDN9 dual targeting antibody drug conjugates for the treatment of ovarian and endometrial cancers
Authors: Liang Du, Hongyan Zhang, Lina Jin, Yali Chen, Tingting Wan, Liuliu Xu
Journal: Cancer Research (2021)

Abstract Claudins (CLDNs) are tight junction proteins that regulate epithelial-cell barrier function and polarity. Up-regulation of certain CLDN proteins has been associated with the malignant phenotype. Embryonic, stem-cell specific CLDN6 is absent in normal adult tissues. Our in-house data showed that it is highly expressed in serous ovarian (66% cases showed 2+/3+/4+ expression of CLDN6), and testis cancers (100% cases showed 4+ expression of CLDN6) in Chinese population, and is an “ideal” target in these cancer types. CLDN9, sharing high homology with CLDN6 exhibits similar distribution patterns with CLDN6, like the absence in normal tissues and up-regulation in ovarian and endometrial cancer. We propose to simultaneously target both CLDN6 and CLDN9 for treatment of ovarian cancer and endometrial cancer to achieve better anti-tumor efficacy and expand the treatment to a larger population of patients. To this end, we designed a high-through-put antibody screening process and discovered two antibodies GB7008-03 and GB7008-05, both of which binds CLDN6 and CLDN9 with high affinity, while sparing other CLDN members. Both candidates demonstrated superior antibody-mediated antigen internalization than ASP1650, the forerunner in clinical trials. GB7008-03 and GB7008-05 also showed good ADCC potency on CLDN6 expressing tumor cell lines. Currently we are developing antibody-drug-conjugates based on these two antibodies. In vivo efficacy of these ADCs in CDX models will be presented. Citation Format: Liang Du, Hongyan Zhang, Lina Jin, Yali Chen, Tingting Wan, Liuliu Xu. CLDN6 and CLDN9 dual targeting antibody drug conjugates for the treatment of ovarian and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 912.
Abstract SY42-02: Stem cell clonality and the niche
Authors: Leonard I. Zon
Journal: Cancer Research (2021)

Abstract Hematopoietic stem cell transplantation involves the homing of stem cells to the marrow, an active process of engraftment, and the self-renewal of the blood stem cells. We have been using the zebrafish as a model to study the molecular biology of this process. Blood stem cells are born in the dorsal aorta of the developing embryo. By imaging RUNX1 GFP+ cells arriving in the next site of hematopoiesis (the caudal hematopoietic territory), engraftment can be visualized. The endothelial cells of the niche cuddle the hematopoietic stem cells, and the stem cells divide in the niche. We have used RNA tomography to find transcripts that are restricted in expression to the niche endothelial cells. After sorting these endothelial cells, we used ATAC seq to reveal regions of chromatin that are open. The regions function in enhancer assays to drive expression of GFP in the niche. By computing the binding sites in these regions, and examining RNA seq, we found transcription factors that may participate in niche endothelial development. Overexpression of three of these transcription factors is sufficient to reprogram embryonic cells to express the markers of the niche. New niches form in ectopic locations and HSPCs arrive in the new niche, akin to extramedullary hematopoiesis, are cuddled by endothelial cells and divide. Using a brainbow color barcoding system, we previously demonstrated that zebrafish produce 20-30 HSCs from the developing aorta. HSCs traffic to the embryonic niche where they exit circulation and divide. To evaluate a possible role of macrophages in attenuating HSC clone number, we depleted macrophages in our brainbow barcoding system. Unique color barcodes were induced in individual HSCs at 24 hpf, just prior to stem cell emergence, and clodronate loaded liposomes injected into circulation. On average, animals injected with clodronate liposomes had only 14 HSC color clones, compared to 24.6 HSC clones in sibling controls (p = 0.0002). Our studies show that there is a transcriptional code for niche endothelial cells and that macrophages are required for establishing clonality. Citation Format: Leonard I. Zon. Stem cell clonality and the niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY42-02.
Donor-Specific Antibody Is Associated with Increased Expression of Rejection Transcripts in Renal Transplant Biopsies Classified as No Rejection
Authors: Katelynn S. Madill-Thomsen, Georg A. Böhmig, Jonathan Bromberg, Gunilla Einecke, Farsad Eskandary, Gaurav Gupta, Luis G. Hidalgo, Marek Myslak, Ondrej Viklicky, Agnieszka Perkowska-Ptasinska, Philip F. Halloran
Journal: Journal of the American Society of Nephrology (2021)

Donor -specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no rejection (NR). We explored whether in some NR kidneys DSA has subtle effects not currently being recognized.We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%).DSA positivity in NR biopsies was associated with mildly increased expression of antibody-mediated rejection (ABMR)-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive versus DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described "ABMR probability" classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P<2 × 10-16). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over 3 years.Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus, mild molecular ABMR-related pathology is more common than previously realized.
Diagnostic performance of vesical imaging-reporting and data system for detecting muscle-invasive bladder cancer in real clinical setting: Comparison to diagnostic cystoscopy
Authors: K. Shigeta, R. Kufukihara, K. Ogihara, Y. Arita, H. Akita, T. Suzuki, R. Mizuno, E. Kikuchi, M. Jinzaki, M. Oya
Journal: European Urology (2021)
Administration of 3, 5-Cholestadiene and Dicholesteryl Ether to Mice and Rats
Authors: Larsen, C. Donald, Barrett, Morris K.
Journal: JNCI Journal of the National Cancer Institute (1944)

Journal Article Administration of 3, 5-Cholestadiene and Dicholesteryl Ether to Mice and Rats Get access C. Donald Larsen, C. Donald Larsen research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Morris K. Barrett Morris K. Barrett acting assistant surgeon National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 6, June 1944, Pages 587–594, https://doi.org/10.1093/jnci/4.6.587 Published: 01 June 1944
Abstract 2485: Metabolic implications of TIGAR in glioblastoma multiforme
Authors: Joseph Sahagun
Journal: Cancer Research (2021)

Abstract The incidence of glioblastoma multiforme (GBM) has been rising throughout the last decade, yet interventional medical advances have not been able to keep up. With current literature focusing on hypoxia-inducible factor 1 and angiogenic properties of GBM, our study focuses on Tp53 glycolysis and apoptosis regulator (TIGAR) enzyme in order to supplement the limited amount of published literature. Recent literature implicates Tp53 glycolysis and apoptosis regulator (TIGAR) in tumor survival and proliferation by shunting glycolytic intermediates to generate NADPH and activation of AKT, respectively. In this study, we aimed at establishing TIGAR's dependence on p53 and whether pifithrin-α blocks transcription of TIGAR within the proneuronal subtype of glioblastoma. This cell line is of interest due to its frequent mutations and loss of heterogeneity within p53 and association with chemotherapy resistance in GBM. In this cell line, both p53 and TIGAR protein expression were confirmed using western blot. An MTT assay determined the minimal concentration of pifithrin-α required to inhibit p53 expression in the proneuronal cell line. A known p53 null line, SAOS-2, was used to monitor TIGAR expression using real-time PCR to determine the dependence of p53 expression. Through this study, we determined that TIGAR behaves independently of p53 expression, and a knockdown of p53 with pifithrin-α has no influence on the transcription of TIGAR. We hypothesize that p53 is required to act as a barrier against TIGAR overexpression in GBM. Citation Format: Joseph Sahagun. Metabolic implications of TIGAR in glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2485.
Evaluation of Cancer Testis Antigens (CTAs) As Immuno-Therapeutic Targets in Pediatric AML
Authors: Rhonda E. Ries, Jenny L. Smith, Tim Triche, Jason E. Farrar, Todd A Alonzo, Yussanne Ma, Lisa Wei, Jaime Guidry Auvil, Daniela S. Gerhard, Marco A Marra, Alan S Gamis, Anders Kolb, Hamid Bolouri, Soheil Meshinchi
Journal: Blood (2017)
Neurodevelopment of the association cortices: Patterns, mechanisms, and implications for psychopathology
Authors: Valerie J. Sydnor, Bart Larsen, Danielle S. Bassett, Aaron Alexander-Bloch, Damien A. Fair, Conor Liston, Allyson P. Mackey, Michael P. Milham, Adam Pines, David R. Roalf, Jakob Seidlitz, Ting Xu, Armin Raznahan, Theodore D. Satterthwaite
Journal: Neuron (2021)
Postoperative complications and functional outcome parameters in patients undergoing salvage lymph-node dissection due to nodal-recurrent prostate cancer
Authors: M.T. Grabbert, A. Sigle, L. Lang, M. Von Büren, M. Mix, C. Zamboglou, C. Gratzke, W. Schultze-Seemann, C.A. Jilg
Journal: European Urology (2021)
Risk of atrial fibrillation in athletes: a systematic review and meta-analysis
Authors: William Newman, Gemma Parry-Williams, Jonathan Wiles, Jamie Edwards, Sabina Hulbert, Konstantina Kipourou, Michael Papadakis, Rajan Sharma, Jamie O'Driscoll
Journal: British Journal of Sports Medicine (2021)

Objective A systematic review, meta-analysis and meta-regression were performed on selected studies to investigate the incidence of atrial fibrillation (AF) among athletes compared with non-athlete controls. Design Meta-analysis with heterogeneity analysis and subsequent meta-regression to model covariates were performed. The mode of exercise (endurance and mixed sports) and age were the a priori determined covariates. Data sources PubMed, MEDLINE, Science Direct, SPORTDiscus and the Cochrane library were searched. Eligibility criteria Research articles published after 1990 and before 2 December 2020 were included if they reported the number of AF cases in athletes with non-athlete (physically active or inactive) control groups, were case–control or cohort studies and if data allowed calculation of OR. Results The risk of developing AF was significantly higher in athletes than in non-athlete controls (OR: 2.46; 95% CI 1.73 to 3.51; p&lt;0.001, Z=4.97). Mode of exercise and risk of AF were moderately correlated (B=0.1259, p=0.0193), with mixed sport conferring a greater risk of AF than endurance sport (B=−0.5476, p=0.0204). Younger (&lt;55 years) athletes were significantly more likely to develop AF compared with older (≥55 years) athletes (B=−0.02293, p&lt;0.001). Conclusion Athletes have a significantly greater likelihood of developing AF compared with non-athlete controls, with those participating in mixed sport and younger athletes at the greatest risk. Future studies of AF prevalence in athletes according to specific exercise dose parameters, including training and competition history, may aid further in delineating those at risk.
Abstract 2366: Malignant ascites-derived extracellular vesicles promote metastasis of ovarian cancer by transferring miR-1246 and miR-1290
Authors: Wenyu Wang, HyunA Jo, Yong Sang Song
Journal: Cancer Research (2021)

Abstract Background and purpose: Ovarian cancer is the most lethal gynecologic cancer in females worldwide. The high mortality rate is due primarily to the lack of early diagnosis strategies and the high rate of recurrence. Ascites is detected in over one-third of ovarian cancer patients at initial diagnosis and present in almost all the patients with recurrence. Extracellular vesicles (EVs) are double-membrane particles secreted by cells into extracellular space. EV-mediated intercellular communication in the tumor microenvironment is crucial in cancer progression. Additionally, EVs are present in various body fluids, serving as fine analytes for liquid biopsy. Our research is aimed to explore the role of malignant ascites-derived EVs in ovarian cancer metastasis and the underlying mechanisms focusing on the miRNA cargos. Methods: Patient-derived samples were collected from Seoul National University Hospital with the approval of the Institutional Review Board. EVs were isolated from ascites using the commercial kit and identified through transmission electron microscopy, nanoparticle tracking analysis and western blotting. Transwell assay was performed to investigate the effects of ascites-derived EVs on ovarian cancer cells. MiRNA sequencing was carried out in EVs derived from malignant ascites(n=10) and benign peritoneal fluids(n=9). Results: Malignant ascites-derived EVs were characterized as double-membrane particles sizing ranging from 30nm to 150nm with the expression of CD63 and CD81. Those EVs significantly promoted the invasion and migration ability of ovarian cancer cells. MiRNA sequencing data showed that 118 miRNAs were upregulated and 44 miRNAs were downregulated in the ascites-derived EVs compared with benign peritoneal fluid-derived EVs. Among those, miR-1246 and miR-1290 were the top two upregulated miRNAs, which were negatively associated with the overall survival of ovarian cancer patients. Moreover, miR-1246 and miR-1290 could enhance the invasion and migration ability through activating Wnt/β-catenin signaling pathway via binding to RAR-related orphan receptor alpha (RORα). Conclusion: Malignant ascites-derived EVs could facilitate the metastatic potential of ovarian cancer cells through transferring miR-1246 and miR-1290. Targeting miR-1246 and miR-1290 might be a promising therapeutic strategy in ovarian cancer treatment. Citation Format: Wenyu Wang, HyunA Jo, Yong Sang Song. Malignant ascites-derived extracellular vesicles promote metastasis of ovarian cancer by transferring miR-1246 and miR-1290 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2366.
Orodispersible Ticagrelor in Acute Coronary Syndromes
Authors: Guido Parodi, Giuseppe Talanas, Enrico Mura, Mario E. Canonico, Roberta Siciliano, Simona Guarino, Alessandro Marini, Filippo Dossi, Paolo Franca, Mario Raccis, Pier Sergio Saba, Giuseppe D. Sanna
Journal: Journal of the American College of Cardiology (2021)
Abstract 1775: Metformin-mediated natural killer cell cytotoxicity in head and neck squamous cell carcinoma
Authors: McKenzie Crist, Maria Lehn, Trisha Wise-Draper
Journal: Cancer Research (2021)

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer worldwide. Even with intensive treatment, up to 50% of patients will relapse. Checkpoint inhibitors, including antibodies targeting programmed death 1 (PD-1), have dramatically improved survival outcomes but only elicit a response in 20% of patients. PD-1 is expressed on both T-cells and Natural Killer (NK) cells, and depletion of NK cells has been linked to poor prognosis in several solid tumors. NK cells are essential to the innate immune response, do not require MHC-1 expression for recognition, and can stimulate an anti-cancer response through release of cytotoxic granules and direct killing of cancer cells. Upregulation of several interleukins including IL-6, which induces the JAK/STAT3 pathway and subsequently inhibits cancer cell apoptosis, is correlated with a poor prognosis in HNSCC patients. Importantly, inhibition of phosphorylated STAT3 (pSTAT3) increases NK-specific cancer cytotoxicity, NK cell cytokine release, and anti-tumor cell chemokines. Therefore, we hypothesize that impaired NK cell cytotoxicity results in a poor response to immunotherapy. We have shown that a common anti-diabetes drug with anti-cancer properties, metformin, downregulates NK pSTAT3 with subsequent increase in cytotoxicity of peripheral NK cells in HNSCC patients. Metformin also decreases pSTAT3 pathway related cytokine release from HNSCC cell lines. However, it remains unclear whether metformin-mediated enhanced NK cytotoxicity was through a direct effect on NK cells or indirect through inhibition of pSTAT3 in tumor cells and subsequent decrease in inhibitory cytokine release. In addition, inhibiting pSTAT3 could lead to further activation of innate immunity through activation of NK cell cytotoxicity complementing current PD-1 inhibitor therapy and improved treatment response. Here we report the contribution of metformin-mediated direct and indirect effects on NK cell cytotoxic functions and the combined effect of metformin and pembrolizumab using patient samples from a clinical trial and ex vivo models. Understanding metformin-mediated regulation of pSTAT3 and downstream pathways will provide necessary insight to potentially overcome resistance to PD-1 inhibitors and identifying novel treatment combinations for this disease. Citation Format: McKenzie Crist, Maria Lehn, Trisha Wise-Draper. Metformin-mediated natural killer cell cytotoxicity in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1775.
Abstract 2316: Analysis of <i>APC-1B</i> promoter region responsible for familial adenomatous polyposis
Authors: Saya Nakagawa, Kiyoshi Yamaguchi, Kimiko Saito, Kiyoko Takane, Tsuneo Ikenoue, Yoichi Furukawa
Journal: Cancer Research (2021)

Abstract APC (APC regulator of WNT signaling pathway) is not only a gene responsible for familial adenomatous polyposis (FAP), a hereditary disease characterized by hundreds or thousands adenomatous polyps in the colon, but also plays a crucial role in sporadic human cancers. Although most of FAP cases are caused by germline mutations in the coding region of APC, deletions or point mutations in the promoter regions are involved in a limited number of cases. Previously, we reported an FAP case with a large deletion of approximately 10 kb encompassing APC promoter 1B and exon1B of the APC gene. Since precise regulatory mechanism(s) of the transcription of APC remains to be clarified, we searched in this study the regulatory domain(s) in the deleted region. First, we performed cap analysis of gene expression (CAGE) analysis, and compared the amount of APC-1A and APC-1B transcripts in the peripheral blood cells of the patient with that of healthy volunteers. As a result, we found that the deletion decreased the amount of APC-1B to 39% - 45% in the patient compared to the healthy controls, and that it did not change the amount of APC-1A in the patient. In addition, an allele-specific expression analysis by deep cDNA sequencing revealed that the amount of APC transcripts from the mutated APC allele is reduced to 11.2% by the deletion in the patient, suggesting that the deletion resulted in the marked decrease of the transcription of the affected allele and that the remaining expression of deleted allele may be driven by other regulatory region(s) such as promoter 1A. Consistently, CAGE analysis demonstrated that APC-1B transcripts are more abundantly expressed than APC-1A transcripts in all tissues tested except for the brain, suggesting that promoter 1B plays a crucial role in the expression of APC transcription. Analysis of promoter 1B by reporter assay identified a critical region for the transcriptional activation between -117 bp and -49 bp of promoter 1B. These data will contribute to the better understanding of regulatory mechanisms of APC transcription and the evaluation of genetic variants located in promoter 1B. Citation Format: Saya Nakagawa, Kiyoshi Yamaguchi, Kimiko Saito, Kiyoko Takane, Tsuneo Ikenoue, Yoichi Furukawa. Analysis of APC-1B promoter region responsible for familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2316.