tbuckley/cabot-search huggingface dataset:
Abstract 2304: Regulation of the oncogenic tyrosine kinase ACK1 through ubiquitin-dependent mechanism
Authors: Eranga Roshan Balasooriya Loku Balasooriyage, Jacob Owen, Jack Gashler, Colin Muir, Katie Pennington, James Moody, Joshua L. Andersen
Journal: Cancer Research (2021)

Abstract ACK1 is an oncogene in the ACK family of non-receptor tyrosine kinases (NRTK). In humans, ACK1 is located on chromosome 3q29, a region that is frequently amplified in a variety of cancers including prostate, lung and breast. The ACK kinase family has a unique domain arrangement with, most notably, a putative ubiquitin association (UBA) domain at their C-termini. In the present study, we focus on understanding the ubiquitin-binding nature of the ACK1 UBA and its role in kinase regulation. Structural modeling and sequence analysis suggest that the ACK1 UBA diverges from many other UBAs but shares similarities with the ACK family kinase, TNK1. We found that the ACK family UBA has a remarkably high affinity for diverse poly-ubiquitin linkages with dissociation constants in the low nanomolar range. Our preliminary data suggest that a non-covalent interaction between the UBA and ubiquitin is necessary for ACK kinase activation in cell culture systems. Furthermore, our preliminary data suggest this interaction is sufficient to induce ACK1 activation in vitro. In support of the idea that the UBA is important for ACK1 activation, we identified a variety of cancer patient mutations that disrupt the ACK1 UBA, which we are currently testing for oncogenic activity. Lastly, we have identified small molecule inhibitors of ACK with low nanomolar IC50 values in ACK1-driven cells. Altogether, our data suggest a model of ACK1 activation that involves direct, non-covalent interaction with ubiquitin and potential therapeutic approaches to inhibit ACK1 in cancer. Citation Format: Eranga Roshan Balasooriya Loku Balasooriyage, Jacob Owen, Jack Gashler, Colin Muir, Katie Pennington, James Moody, Joshua L. Andersen. Regulation of the oncogenic tyrosine kinase ACK1 through ubiquitin-dependent mechanism [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 2304.
Highly Replicated Evolution of Parapatric Ecotypes
Authors: Maddie E James, Henry Arenas-Castro, Jeffrey S Groh, Scott L Allen, Jan Engelstädter, Daniel Ortiz-Barrientos
Journal: Molecular Biology and Evolution (2021)

Abstract Parallel evolution of ecotypes occurs when selection independently drives the evolution of similar traits across similar environments. The multiple origins of ecotypes are often inferred based on a phylogeny that clusters populations according to geographic location and not by the environment they occupy. However, the use of phylogenies to infer parallel evolution in closely related populations is problematic because gene flow and incomplete lineage sorting can uncouple the genetic structure at neutral markers from the colonization history of populations. Here, we demonstrate multiple origins within ecotypes of an Australian wildflower, Senecio lautus. We observed strong genetic structure as well as phylogenetic clustering by geography and show that this is unlikely due to gene flow between parapatric ecotypes, which was surprisingly low. We further confirm this analytically by demonstrating that phylogenetic distortion due to gene flow often requires higher levels of migration than those observed in S. lautus. Our results imply that selection can repeatedly create similar phenotypes despite the perceived homogenizing effects of gene flow.
Abstract 1931: Evaluation of cholecystokinin receptor expression and function in non-small cell lung cancer
Authors: Alexander C. Miller, Shelby J. Subry, Manijeh M. Assar, Krista Pearman, Jeffrey William Norris
Journal: Cancer Research (2021)

Abstract Introduction: Lung cancer is the leading cause of cancer-related death in the United States, with nearly 85% of cases histologically classified as non-small cell lung cancer (NSCLC). A recent epidemiological study provides evidence of an increased risk ratio for NSCLC in association with adherence to a Western dietary pattern, which has a higher dietary fat content, compared to vegetarian or Tex-Mex dietary patterns. Our laboratory and others have measured increased tumor burden in murine models of NSCLC when feeding diets are high in fat compared to a standard rodent cereal diet. In our laboratory, increased tumor burden is associated with increased tumor multiplicity, but no change in proliferative markers (Ki-67 and pS6) were observed. Dietary fat increases both tumorigenesis in mouse models of pancreatic cancer and circulating levels of the gastrointestinal hormone cholecystokinin (CCK). Inhibition of CCK receptors antagonizes progression of precursor lesions in murine models of pancreatic cancer. Although CCK receptor expression has not been detected in normal human pulmonary tissue, the CCK-B receptor has been identified immunohistologically in human lung tumors. Further, the CCK-A receptor is expressed in normal murine pulmonary epithelium. Hypothesis: At concentrations approximating circulating levels in mice fed a high fat diet, CCK reduces apoptosis of NSCLC cells in vitro. Materials and Methods: The murine NSCLC cell line IO33 was grown in serum-replete RPMI 1640 or serum-deprived RPM 1640 with 0 to 1000 pM exogenous CCK-8 peptide added. Expression of CCK-A and CCK-B receptors were measured in IO33 and human NSCLC cell lines by qPCR. Apoptosis was assessed using a Caspase-3/7 peptide cleavage assay. Results: Expression of CCK-A and CCK-B receptors are reported in IO33 cells and 11 human lung cancer cell lines. Apoptosis of IO33 cells was significantly decreased by greater than 30% at CCK concentrations greater than 100pM (P &amp;lt; 0.03), which is the circulating concentration of CCK in mice fed a high fat diet. Conclusions: CCK receptors are expressed in human and murine NSCLC cells and circulating CCK may reduce NSCLC cell apoptosis. Citation Format: Alexander C. Miller, Shelby J. Subry, Manijeh M. Assar, Krista Pearman, Jeffrey William Norris. Evaluation of cholecystokinin receptor expression and function in non-small cell lung 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 1931.
Spike-antibody waning after second dose of BNT162b2 or ChAdOx1
Authors: Madhumita Shrotri, Annalan M D Navaratnam, Vincent Nguyen, Thomas Byrne, Cyril Geismar, Ellen Fragaszy, Sarah Beale, Wing Lam Erica Fong, Parth Patel, Jana Kovar, Andrew C Hayward, Robert W Aldridge
Journal: The Lancet (2021)

Vaccines based on the spike glycoprotein of SARS-CoV-2 are being rolled out globally to control transmission and limit morbidity and mortality due to COVID-19. Current evidence indicates strong immunogenicity and high short-term efficacy for BNT162b2 (Pfizer–BioNTech) and ChAdOx1 nCoV-19 (Oxford–AstraZeneca).1–3 Both vaccines are delivered through a prime-boost strategy, and many countries, including the UK, have used dose intervals longer than 3–4 weeks, expecting to maximise first-dose coverage and immunogenicity.
Abstract 828: Common genetic variants influence the composition of the tumor immune microenvironment and host anti-tumor responses
Authors: Meghana Pagadala, Hyo Kim, Andrea Castro, Cristian Gonzalez-Colin, Victoria Wu, Steven Cao, Benjamin Schmiedel, Rany Salem, Silvio Gutkind, Wes Thompson, Vijayanand Pandurangan, Hannah Carter
Journal: Cancer Research (2021)

Abstract Developing effective therapies to intervene in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Germline variation is a major component of interindividual variability usually studied by large-scale genome-wide association studies (GWAS) in the context of disease risk; yet, there is still a gap in our understanding of germline variation specifically in the tumor immune microenvironment. To address this, we systematically characterized the immune effects of germline genetic polymorphisms across 33 human cancer types in the TCGA. Immune microenvironment phenotypes include immune infiltration levels as calculated by CIBERSORTx and expression of immunomodulator genes obtained through literature curation. PCA analysis reduced dimensionality of immune phenotypes, with macrophage regulation and EP300/Proteosome expression mediating most variability amongst individuals. We identified 482 SNP-immune gene associations, where a subset of SNPs affected multiple immune phenotypes. Using cell-type and epigenetic analyses, we further characterized immune microenvironment variants to act through macrophage and dendritic cell-specific manners and alter immune-cell specific epigenetic regions. Through burden analysis, we found several of these variants interact to have stronger immune microenvironment effects. Lastly, using ICB-trial cohorts, we found several variants affecting LILRB2, LILRB4, LAIR1, CCBL2, and CTSW modulate response to immune checkpoint blockade. Our results provide better understanding of how germline variation modifies tumor immune microenvironment dynamics and will set up further studies to identify predictive biomarkers of the tumor immune microenvironment. Citation Format: Meghana Pagadala, Hyo Kim, Andrea Castro, Cristian Gonzalez-Colin, Victoria Wu, Steven Cao, Benjamin Schmiedel, Rany Salem, Silvio Gutkind, Wes Thompson, Vijayanand Pandurangan, Hannah Carter. Common genetic variants influence the composition of the tumor immune microenvironment and host anti-tumor responses [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 828.
Determinants of variation in radical local treatment for men with high-risk localised or locally advanced prostate cancer in England
Authors: M.G. Parry, J.M. Boyle, J. Nossiter, M. Morris, A. Sujenthiran, B. Berry, P. Cathcart, A. Aggawal, J. Van Der Meulen, H. Payne, N.W. Clarke
Journal: European Urology (2021)
Abstract 1284: P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation
Authors: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry
Journal: Cancer Research (2021)

Abstract A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression. Citation Format: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry. P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation [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 1284.
Abstract 1535: Allogenic CAR iNKT as a cell therapy platform targeting tumor antigen Isomesothelin
Authors: Anupama Gopisetty, Yibin Chen, Quynh Nguyen, Maurizio Chiriva-Internati
Journal: Cancer Research (2021)

Abstract Effective chimeric antigen receptor (CAR) T-cell therapy targeting B-cell malignancies has paved the way for alternate strategies targeting cancer. Current active research is directed towards development of safe, allogeneic off the shelf cell (OTS) therapy products. This could be potentially a step forward in the targeted cancer immunotherapy field. Invariant NKT cells (iNKT) are deemed as one of the unconventional T-cell populations with semi invariantly re-arranged TCR. They recognize lipid antigens Via CD1d, an MHC Class 1 like molecule. Recognition of CD1d expressed on various hematopoietic cells is important for targeted tumor specific iNKT cytotoxicity in various leukemia, lymphoma malignancies. Through the recent years, CAR-iNKT adoptive cell therapy has drawn excitement and interest because of their intrinsic anti-tumor property. More specifically CAR-iNKTs have been shown to target solid tumors such as neuroblastoma in preclinical studies and proceeded to phase 1 clinical trials. The innate ability of iNKT cells to kill tumor cells and also cause very less GVHD provides an extremely attractive platform for developing OTS product. Allogeneic CAR iNKT cells have been less explored for cancer immunotherapy. Although the relative percentage of iNKTs are very low in peripheral blood (~0.01% of T-lymphocytes), we report an efficient method of enrichment and expanding a large and pure population of iNKTs and genetically modify them for targeting solid tumor antigens such as Isomesothelin (IsoMSLN), an alternative splice variant of mesothelin. Many pre-clinical studies have been assessed targeting mesothelin, a tumor associated antigen overexpressed in malignant cells. A safe allogenic CAR targeted therapy for IsoMSLN has yet to be demonstrated. iNKTs expanded and transduced with our novel protocol targeting IsoMSLN, are highly cytotoxic and suggests a central memory phenotype that could potentially persist longer in vivo. Citation Format: Anupama Gopisetty, Yibin Chen, Quynh Nguyen, Maurizio Chiriva-Internati. Allogenic CAR iNKT as a cell therapy platform targeting tumor antigen Isomesothelin [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 1535.
Abstract 1676: A comprehensive whole blood CyTOF immune monitoring panel with expanded surface and intracellular markers using the Maxpar Direct Immune Profiling Assay
Authors: Shariq Mujib, Stephen K. Li, Nick Zabinyakov, Christina Loh
Journal: Cancer Research (2021)

Abstract In-depth monitoring of the immune response to cancer and infection is vital to ascertain disease status and to assess immunotherapeutic options. Time-of-flight technology, the basis of CyTOF® mass cytometry, enables multiplex proteomic cellular phenotyping with 50 or more markers, making it ideal for comprehensive immune profiling. Unlike fluorescence-dependent approaches, which require signal compensation that makes the development of larger panels more challenging, CyTOF utilizes monoisotopic metal-tagged antibodies that exhibit minimal background signal, enabling the highest-resolution multiparametric landscape of a single cell. The Maxpar® Direct™ Immune Profiling Assay™ is a pre-titrated dried-down 30-antibody cocktail preparation for immune profiling of human whole blood or PBMC. This assay is used with Maxpar Pathsetter™ software, which resolves whole blood into 37 immune populations comprising major lineage populations and their subsets, such as CD4 Th subsets and B and T cell memory cells, as well as stratifications of myeloid populations. The resulting system is a simple sample-to-answer solution for immune monitoring studies. Here, we expanded the 30-marker assay with 14 additional antibodies comprising pertinent targets of immunotherapy, including the exhaustion markers PD-1, PD-L1, Tim-3 and CTLA-4, and co-stimulation markers 4-1BB and ICOS. We also demonstrated the compatibility of the assay with downstream intracellular staining for cytoplasmic markers IFN-γ, TNF-α, IL-2, perforin and granzyme B for assessment of cellular function in 4h PMA/ionomycin-stimulated whole blood cultures. Next, we modified the existing Pathsetter model to automate the analysis of whole blood stained with the expanded panel to generate reports on key immune cell populations, percentages of exhausted cells and cell subsets producing cytokines. Last, to demonstrate the ability of this expanded panel to identify antigen-specific T cell subsets accompanied by their in-depth phenotypic assessment, we tested this panel against CMV peptide-stimulated whole blood samples. We demonstrated the flexibility of the Maxpar Direct Immune Profiling Assay in panel customization and a streamlined workflow for automated analysis to enable comprehensive immune profiling of human whole blood. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Shariq Mujib, Stephen K. Li, Nick Zabinyakov, Christina Loh. A comprehensive whole blood CyTOF immune monitoring panel with expanded surface and intracellular markers using the Maxpar Direct Immune Profiling Assay [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 1676.
Abstract 2803: Classification of lung cancer histology images using deep learning
Authors: Yan YANG, Tiantian ZHEN, Huijuan SHI, Weidong XIE, Anjia HAN, Xunzhang WANG
Journal: Cancer Research (2021)

Abstract The pathologist's diagnosis on glass slides is the basis for clinical and pharmaceutical research and, more importantly, for the decision on how to treat the patient. Diagnosing pathology slides at microscopy-level is a complicated task that requires years of pathologist training. Only in recent years, computational pathology has emerged to facilitate computer-assisted diagnostics and to enable a digital workflow for pathologists. Meanwhile, deep learning architectures have great potential in pathology imaging, since the enormous success and advancement had been achieved in solving image classification tasks, which would reform the digital workflow with higher efficiency, greater capacity. In this study, we utilize various computational methods based on deep learning framework and build a stand-alone diagnostic tool to effectively classify histopathology images. The dataset of tissue slides consists of 135,000 samples from eligible patients with lung cancer in the First Affiliated Hospital of Sun Yat-sen University. The slide images were intercepted in non-overlapping 1500 × 1000 pixel windows at a magnification of ×40. These tiles above were labeled, and split into a training set, for learning the CNN parameters, and validation set, for validating the model, and test set, for evaluating its performance. Then, features were extracted from the heat map to train a slide aggregation model. The malignant classification of lung cancer by the decision support system include the subtype of adenocarcinoma and squamous carcinoma. An accuracy of 86% for non-cancer (normal) vs. malignant (i.e. adenocarcinoma or squamous carcinoma) on slide tile model, as well as an accuracy of 99% for the multi-label classification on slide aggregation model was obtained in the test set. We believe that our method provides an innovative and reliable means for making diagnostic suggestions, and could be deploy as next-generation, artificial intelligence-enhanced CAD technology in diagnostic pathology,which would empower pathologists' efficiency and accuracy to ultimately provide better patient care. Citation Format: Yan YANG, Tiantian ZHEN, Huijuan SHI, Weidong XIE, Anjia HAN, Xunzhang WANG. Classification of lung cancer histology images using deep learning [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 2803.
Cardiac output states in patients with severe functional tricuspid regurgitation: impact on treatment success and prognosis
Authors: Matthias Unterhuber, Karl‐Patrik Kresoja, Christian Besler, Karl‐Philipp Rommel, Mathias Orban, Maximilian von Roeder, Daniel Braun, Lukas Stolz, Steffen Massberg, Jonel Trebicka, Markus Zachäus, Jörg Hausleiter, Holger Thiele, Philipp Lurz
Journal: European Journal of Heart Failure (2021)

To investigate whether there is evidence for distinct cardiac output (CO) based phenotypes in patients with chronic right heart failure associated with severe tricuspid regurgitation (TR) and to characterize their impact on TR treatment and outcome.A total of 132 patients underwent isolated transcatheter tricuspid valve repair (TTVR) for functional TR at two centres. Patients were clustered according to k-means clustering into low [cardiac index (CI) < 1.7 L/min/m2 ], intermediate (CI 1.7-2.6 L/min/m2 ) and high CO (CI > 2.6 L/min/m2 ) clusters. All-cause mortality and clinical characteristics during follow-up were compared among different CO clusters. Mortality rates were highest for patients in a low (24%) and high CO state (42%, log-rank P < 0.001). High CO state patients were characterized by larger inferior vena cava diameters (P = 0.003), reduced liver function, higher incidence of ascites (P = 0.006) and markedly reduced systemic vascular resistance (P < 0.001) as compared to TTVR patients in other CO states. Despite comparable procedural success rates, the extent of changes in right atrial pressures (P = 0.01) and right ventricular dimensions (P < 0.001) per decrease in regurgitant volume following TTVR was less pronounced in high CO state patients as compared to other CO states. Successful TTVR was associated with the smallest prognostic benefit among low and high CO state patients.Patients with chronic right heart failure and severe TR display distinct CO states. The high CO state is characterized by advanced congestive hepatopathy, a substantial decrease in peripheral vascular tone, a lack of response of central venous pressures to TR reduction, and worse prognosis. These data are relevant to the pathophysiological understanding and management of this important clinical syndrome.