tbuckley/cabot-search huggingface dataset:
Abstract 1873: GlycoConnect™ ADCs based on topoisomerase 1 inhibitor exatecan (SYNtecan E™) show excellent in vivo efficacy and tolerability
Authors: Floris van Delft
Journal: Cancer Research (2021)

Abstract Camptothecins form a powerful class of chemotherapy drugs (e.g. irinotecan, topotecan, belotecan), based on their ability to inhibit topoisomerase I. Some camptothecins, such as DXd and SN-38, have also proven powerful payloads for antibody-drug conjugates (ADCs), as exemplified by the recent market approval of Enhertu® and Trodelvy®, respectively. We have reported earlier that the native glycan of monoclonal antibodies is a priviliged conjugation site for ADCs (GlycoConnect™)1, while the highly polar spacer technology (HydraSpace™)2 enables the conjugation of any cytotoxic payload, providing ADCs with significantly expanded therapeutic index (TI) versus mainstream ADC technologies. We here show that exatecan (DX-8951f), a clinically validated and potent campothecin, is readily combined with HydraSpace™ technology to provide linker-payload (SYNtecan E™). Homogeneous and stable GlycoConnect™ADCs were generated from trastuzumab and SYNtecan E™ and compared head-to-head with DXd or SN-38payload, as well as deruxtecan, the linker-payload applied in Enhertu®. Complete tumor regression was observed in a mouse xenograft study (BT-474) after a single dose, while safety studies in mouse corroborated the high tolerability of SYNtecan E™ ADCs. Taken together, these studies demonstrate the potential of SYNtecan E™ for application in stable and site-specific ADCs with excellent therapeutic index. 1 van Geel et al. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of NativemAbs Provides Homogeneous and Highly Efficacious Antibody−Drug Conjugates. Bioconj. Chem. 2015, 26, 2233-2242. 2 Verkade et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012. Citation Format: Floris van Delft. GlycoConnect™ ADCs based on topoisomerase 1 inhibitor exatecan (SYNtecan E™) show excellent in vivo efficacy and tolerability [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 1873.
Abstract 9902: Food Restriction Induces Cardiac BDNF/TrkB Signaling and Improves Physical Activity in Obese Mice
Authors: Tsugiyasu Kanda, Takuro Mizuno, Daisuke Sakamoto
Journal: Circulation (2011)

Introduction -Brain-derived neurotrophic factor (BDNF) gene is not only expressed in neuron but cardiac muscle and modulate cardiac function. We hypothesized that cardiac expression of BDNF can be induced by food restriction in obesity and that induced BDNF signaling can be beneficial in cardiac dysfunction. Methods -Obese KKAy mice were ad libitum as a control (CF) or 60% restriction of that eaten by ad libitum (RF). Mice were sacrificed on day 0, 7, 28, and 84 after food restriction. Results -Body weight and liver weight / body weight ratio in RF were significantly lower than that in CF on days 7, 28 and 84 (P&lt;0.05) but heart weight/ body weight ratio were not changed between mice with CF and RF. Comparative expression of cardiac BDNF mRNA in RF was significantly higher than that in CF (1.2+0.3 vs. 0.8+0.2, P&lt;0.05). Cardiac expression of TrkB in RF was significantly increased than that in CF on day 84. Cardiac expression of brain natriuretic peptide was significantly lower in mice with FR compared with those with CF. Hippocampal expressions of BDNF in RF and were significantly increased compared with those in CF on days 28 and 84. Hippocampal expression of TrkB in RF was significantly higher than in CF on days 28 and 84. Hippocampal weight / body weight ratio was also significantly higher in mice with RF compared with those with CF on days 28 and 84. Daily activity in RF was significantly increased compared with that in FF on day 28 (P&lt;0.05). Conclusions -Food restriction can induce cardiac BDNF/TrkB signaling with the increase of daily activity in obese mice. Cardiac BDNF plays a role in recovery from obesity. These data indicate that induced expression of BDNF/TrkB signaling can improve cardiac dysfunction in obese mice with the combination of induced expression of hippocampal BDNF/TrkB.
STONE (STent Or NEphrostomy) study
Authors: N. Hendriks, G.M. Kamphuis, H.P. Beerlage, R.C.M. Pelger, A. Hendrikx, J.E. Bosmans, R.G. Duijnhoven, S. Weltings, R.W. Van Der Meer, J. Verdult, B.M.A. Schout
Journal: European Urology (2021)
Abstract 174: In-depth transcriptomic comparisons provide novel insights into cancer metastasis
Authors: KE LIU, Benjamin S. Glicksberg, Shreya Paithankar, Bin Chen
Journal: Cancer Research (2021)

Abstract Comparison of the transcriptome between primary and metastatic cancer is frequently performed to study cancer metastasis; however, distilling plausible biology from the comparison results remains a big challenge. We show that in the differential expression (DE) analysis performed on bulk RNAseq data a large proportion of DE genes are identified due to technical issues instead of biological differences between primary and metastatic cancer cells. Next, we develop a computational pipeline DEBoost to minimize such artifacts and apply it to five cancer types. We perform comprehensive analysis on the retained tumor-intrinsic DE genes to explore the biological mechanisms underlying the metastasis of different cancer types. Many of the DE genes are associated with the progression of primary cancer, suggesting the differential expression may have already been established before metastasis. Clustering analysis on DE genes identifies CNVs that account for the transcriptomic change and we further confirm 19p13.12 amplification drives the metastasis of primary Basal-like breast cancer via activating NOTCH signaling pathway. We also find that cell cycling is more active in metastatic prostate cancer than in primary cancer, suggesting the difference of responses to treatment like cell cycling inhibitors. Finally, we show that some metastatic cancer cells tend to express genes whose expression is normally observed at the metastasis site and we experimentally validate this phenomenon in colorectal cancer liver metastasis. Our pan-cancer liver metastasis study provides novel biological insights into cancer metastasis and meanwhile demonstrates the feasibility of characterizing tumor-intrinsic DE genes in cancer metastasis using our computational pipeline. Citation Format: KE LIU, Benjamin S. Glicksberg, Shreya Paithankar, Bin Chen. In-depth transcriptomic comparisons provide novel insights into cancer metastasis [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 174.
Abstract 1895: caAtlas: An immunopeptidome atlas of human cancer
Authors: Xinpei Yi, Yuxing Liao, Bo Wen, Kai Li, Yongchao Dou, Sara R. Savage, Bing Zhang
Journal: Cancer Research (2021)

Abstract At the core of immunotherapy is the T cell recognition of tumor antigens. Thus, comprehensive characterization of tumor antigens is essential for the design of effective and safe cancer immunotherapy strategies. Mass spectrometry (MS)-based immunopeptidomics allows high-throughput, direct identification of major histocompatibility complex (MHC)-bound peptides in vivo. Here, we collected 42 published human immunopeptidomic datasets, which include 327 cancer samples covering nine cancer types and 216 non-cancerous samples. A systematic, quality-controlled analysis of all 51.6 million MS/MS spectra using an open search algorithm identified 364,283 peptides, including 11,647 modified peptides associated with 80 types of modifications. Unmodified peptides showed high levels of predicted binding affinities by NetMHCpan; however, the predicted binding affinities for the modified peptides were much lower, suggesting a deficiency of existing computational tools in making predictions for modified peptides. Analysis of the 416 phosphorylated and 1,239 acetylated HLA class I peptides revealed distinct sequence motifs, and the pattern for the phosphopeptides was consistent with previous reports. Further interrogation of all identified peptides revealed evidence for tumor specific-presentation of hundreds of known and novel cancer-testis antigens as well as tumor associated antigens. We also found non-tumor-specific presentation of 44 previously annotated cancer-testis antigens. Applying NeoQuery, a newly developed computational pipeline, to our dataset identified immunopeptidomic evidence for more than 1,000 somatic mutation-derived neoantigens, and a subset of them were further validated through a traditional MS/MS peptide identification pipeline. We make all these data together with annotated MS/MS spectra supporting each individual antigen identification in a publicly accessible, easily browsable web portal named cancer antigen atlas (caAtlas, http://www.zhang-lab.org/caatlas/). caAtlas provides a fundamental resource for the selection and prioritization of MHC-bound peptides for immunogenicity testing and cancer immunotherapy development. Citation Format: Xinpei Yi, Yuxing Liao, Bo Wen, Kai Li, Yongchao Dou, Sara R. Savage, Bing Zhang. caAtlas: An immunopeptidome atlas of human cancer [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 1895.
Abstract 1087: CXCR2 and its ligands modulate chemotherapy resistance in pancreatic ductal adenocarcinoma
Authors: Caitlin Molczyk, Dipakkumar R. Prajapati, Sugandha Saxena, Paran Goel, Michelle Varney, Rakesh K. Singh
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest survival rates of cancers, with a five-year relative survival of 9%. The significant factor contributing to low survivorship is the intrinsic resistance to chemotherapy. In the present study, we elucidate a targetable pathway that facilitates resistance in these cells. One inflammatory pathway used in cancer progression is CXCR2, which binds chemokines CXCL 1-3 and 5-8. Our group and others have shown an association of CXCR2 with tumor progression, angiogenesis and metastasis in PDAC, and chemotherapy resistance in other cancers. In this study, we test the hypothesis that CXCR2 is integral in PDAC chemotherapy resistance. We generated gemcitabine resistant cell lines (GemR) from the parent cell lines of T3M4 (WT KRAS) and CD18/HPAF (Mutant KRAS) with 40- and 67-fold higher resistance in comparison to the parent cell lines, respectively. Using qRT-PCR and ELISA, we profiled chemokines' expression, CXCL1, 5, and 8, on parent- and GemR-cell lines. We observed a higher basal level expression of CXCL1, 5, and 8 ligands in GemR cells than the parent cell lines. Further treatment with gemcitabine, the parent cell lines had a higher increase in CXCL1 and 8 ligand expression in comparison with GemR cell lines. With further investigation of T3M4, we found a dose-dependent and time-dependent increase for CXCL1 and CXCL8. CXCL5 had a constant high expression with all doses of gemcitabine. With our initial observations of gemcitabine treatment enhancing CXCR2 ligands in PDAC cells, we evaluated the effects of the small molecule CXCR2 antagonist SCH 479833 (SCH 47) in combination with gemcitabine treatment on the parent and GemR cell lines. We used the relative IC50 and half the relative IC50 for both the gemcitabine and SCH 47 treatment doses. We observed that a lower concentration of gemcitabine in the presence of the SCH 47 was more effective than the higher concentration of gemcitabine without SCH 47 for the GemR-cell lines. Together, our observations show chemotherapy-resistant PDAC cell lines express higher CXCR2 ligand levels at baseline, with parent cell lines increasing expression with chemotherapy treatment. We also show an advantageous combination treatment of CXCR2 antagonist with lower gemcitabine concentration. Overall, these results show a promising future for CXCR2 antagonism in the treatment of resistant PDAC tumors. Citation Format: Caitlin Molczyk, Dipakkumar R. Prajapati, Sugandha Saxena, Paran Goel, Michelle Varney, Rakesh K. Singh. CXCR2 and its ligands modulate chemotherapy resistance in pancreatic ductal adenocarcinoma [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 1087.
Primary Care Health Care Use for Patients With Type 2 Diabetes During the COVID-19 Pandemic
Authors: Anita D. Misra-Hebert, Bo Hu, Kevin M. Pantalone, Elizabeth R. Pfoh
Journal: Diabetes Care (2021)

The coronavirus disease 2019 (COVID-19) pandemic may have delayed care for chronic disease (1). We sought to examine factors associated with total and virtual health care use for primary care visits for patients with type 2 diabetes (T2D) during the pandemic.

Using our electronic medical record, we identified patients in the Cleveland Clinic Health System with a diagnosis of T2D with a prepandemic primary care visit between 1 August 2019 and 14 March 2020 (period 0), with follow-up data collected during two pandemic periods: period 1, from 15 March 2020 to 30 June 2020, when in-person visits were rapidly converted to virtual (telephone or video); and period 2, from 1 July 2020 to 15 November 2020, when in-person visits resumed. We obtained demographic characteristics including age, sex, race, insurance type, median income estimated by zip code based on the American Community Survey 2014–2018 5-year estimates (2), and baseline glycosylated hemoglobin (HbA1c).

Patient characteristics were summarized with appropriate descriptive statistics. We assessed factors associated with completing any follow-up visits using logistic regression and then assessed factors associated with completing virtual visits using a mixed-effects logistic regression model with a random intercept at the patient level. All statistical analyses were performed in R (cran.r-project.org), and statistical significance was established at two-sided P values <0.05.

There were 76,015 patients with T2D …
Abstract 40: Targeting SOX10-deficient cells to reduce resistance to targeted therapy in melanoma
Authors: Claudia Capparelli, Timothy J. Purwin, Manoela Tiago, Nicole Wilski, Danielle Pomante, McKenna Glasheen, Sheera Rosenbaum, Mai Q. Nguyen, Weijia Cai, Richard Zheng, Gaurav Kumar, Inna Chervoneva, Ayako Shimada, Adam E. Snook, Paolo Fortina, Xiaowei Xu, Kim Hookim, Edna Cukierman, Michael A. Davies, Meenhard Herlyn, Andrew E. Aplin
Journal: Cancer Research (2021)

Abstract Intratumoral heterogeneity and cellular plasticity enable tumors to alter phenotypes and adapt to foreign microenvironments and resist targeted inhibitors. While the ability to switch between phenotypic states has been broadly characterized, the key mechanisms that underlie tumor plasticity remain poorly understood. We studied the neural crest lineage transcription factor, SOX10, in the context of cutaneous melanoma and resistance to targeted therapies. SOX10 is heterogeneously expressed in melanoma samples. Using bio-informatics as well as in vivo and 3D in vitro melanoma models, SOX10 loss was sufficient to induce an invasive but slow proliferating phenotype in vitro and in vivo that was associated with expression of a mesenchymal gene set. Interestingly, while SOX10 knockout initially induced a targeted inhibitor tolerant state, longer exposure of co-mixed populations of SOX10 proficient and SOX10 deficient to targeted therapy drives the clonal selection of SOX10 knockout cells. Furthermore, cell lines generated from xenograft tumors that have acquired resistance to either vemurafenib, paradox-breaking BRAFi or the combination of BRAFi + MEKi showed dramatically reduced SOX10 expression compared to their parental counterparts. Altogether these data suggest that acquired resistant clones may arise from drug tolerant persister cells. As a strategy to selectively target this invasive, drug-tolerant SOX10-deficient sub-population, we screened a drug compound library and identified a class of cIAP1/2 inhibitors to be synthetically lethal for SOX10-deficient cells. Our preliminary data suggest that birinapant can delay or prevent resistance to BRAFi/MEKi in vivo. Together, these data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma and enables tumor adaptation to altered microenvironments and drug treatments which could be targeted using cIAP1/2 inhibitors. Citation Format: Claudia Capparelli, Timothy J. Purwin, Manoela Tiago, Nicole Wilski, Danielle Pomante, McKenna Glasheen, Sheera Rosenbaum, Mai Q. Nguyen, Weijia Cai, Richard Zheng, Gaurav Kumar, Inna Chervoneva, Ayako Shimada, Adam E. Snook, Paolo Fortina, Xiaowei Xu, Kim Hookim, Edna Cukierman, Michael A. Davies, Meenhard Herlyn, Andrew E. Aplin. Targeting SOX10-deficient cells to reduce resistance to targeted therapy in melanoma [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 40.
Abstract 2082: Deciphering the nucleosome acidic patch binding at amino acid resolution
Authors: Aleksandra Skrajna, Holly Simmons, Charlotte Smith, Jeanne-Marie E. Mcpherson, Dennis Goldfarb, Robert K. McGinty
Journal: Cancer Research (2021)

Abstract In all eukaryotic cells, nucleosomes provide basic organization of genomic DNA and serve as signaling hubs for gene expression, DNA replication and DNA damage repair. These genome-templated processes are tuned by chromatin enzymes that introduce chemical modifications to nucleosomes and control their positioning and occupancy. Mutations in genes encoding chromatin enzymes are highly correlated with numerous cancer types. A thorough exploration of how these chromatin enzymes act on their physiologic target, the nucleosome, is critical to understanding abnormal DNA methylation, histone posttranslational modifications, and chromatin composition, leading to cancer. In our recent nucleosome interactome proteomic screen, we demonstrated that the vast majority of nuclear proteins require a group of acidic residues on the nucleosome disk surface to interact with nucleosomes. This acidic patch and an adjacent region were recognized by over 50% and 18% of nuclear proteins, respectively, while almost half of the nucleosome disk surface contributed only minimally to nucleosome recognition. Overall, we paired about 300 proteins representing diverse nuclear functions including DNA methylation (DNMT1 and 3, Tet1), histone modification (HAT complexes, kinases), nucleosome remodeling (SWI/SNF), DNA repair (MRN complex), DNA replication (ORC complex), RNA processing, and cell cycle progression (APC/C) with specific nucleosome surface requirements. We have now repeated our screen at amino acid resolution using a library of fifteen nucleosomes containing single point mutations in and around the acid patch, including potential histone oncomutations identified to be overrepresented in cancers. Using our nucleosome library, we preformed pulldowns from human embryonic kidney 293 cell nuclear lysates to comprehensively evaluate the role of single histone residues in nucleosome recognition. Overall, this study dissects the primary nucleosome binding hot-spot at high resolution and provide a robust resource for further exploration of the nucleosome interactome in normal and cancer cell biology. Citation Format: Aleksandra Skrajna, Holly Simmons, Charlotte Smith, Jeanne-Marie E. Mcpherson, Dennis Goldfarb, Robert K. McGinty. Deciphering the nucleosome acidic patch binding at amino acid resolution [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 2082.
Metagenomic Analysis Reveals a Possible Association Between Respiratory Infection and Periodontitis
Authors: Zhenwei Liu, Tao Zhang, Keke Wu, Zhongshan Li, Xiaomin Chen, Shan Jiang, Lifeng Du, Saisai Lu, Chongxiang Lin, Jinyu Wu, Xiaobing Wang
Journal: Genomics Proteomics & Bioinformatics (2021)

Periodontitis is an inflammatory disease that is characterized by progressive destruction of the periodontium and causes tooth loss in adults. Periodontitis is known to be associated with dysbiosis of the oral microflora, which is often linked to various diseases. However, the complexity of plaque microbial communities of periodontitis, antibiotic resistance, and enhanced virulence make this disease difficult to treat. In this study, using metagenomic shotgun sequencing, we investigated the etiology, antibiotic resistance genes (ARGs), and virulence genes (VirGs) of periodontitis. We revealed a significant shift in the composition of oral microbiota as well as several functional pathways that were represented significantly more abundantly in periodontitis patients than in controls. In addition, we observed several positively selected ARGs and VirGs with the Ka/Ks ratio > 1 by analyzing our data and a previous periodontitis dataset, indicating that ARGs and VirGs in oral microbiota may be subjected to positive selection. Moreover, 5 of 12 positively selected ARGs and VirGs in periodontitis patients were found in the genomes of respiratory tract pathogens. Of note, 91.8% of the background VirGs with at least one non-synonymous single-nucleotide polymorphism for natural selection were also from respiratory tract pathogens. These observations suggest a potential association between periodontitis and respiratory infection at the gene level. Our study enriches the knowledge of pathogens and functional pathways as well as the positive selection of antibiotic resistance and pathogen virulence in periodontitis patients, and provides evidence at the gene level for an association between periodontitis and respiratory infection.