tbuckley/cabot-search huggingface dataset:
Modulating macrophage phenotype for accelerated wound healing with chlorogenic acid-loaded nanocomposite hydrogel
Authors: Shuangqing Wang, Yanhong Liu, Xusheng Wang, Liqing Chen, Wei Huang, Tianning Xiong, Nuoya Wang, Jianpeng Guo, Zhonggao Gao, Mingji Jin
Journal: Journal of Controlled Release (2024)
Abstract LB421: Entinostat alters cell cycle in ovarian cancer cells
Authors: Vijayalaxmi G. Gupta, Heng Liu, Rugang Zhang, Michael Onken, Andrew Wilson, Fiona Yull, Marta Crispens, Mary Mullen, Dineo Khabele
Journal: Cancer Research (2024)

Abstract Introduction: We have reported that Class I/II HDACi sensitize PARPi resistant tumors, creating a possibility to expand the use of PARPi beyond homologous recombination deficient tumors. However, the underlying mechanism is still unknown. Here, we report leads obtained from differential gene expression in ovarian cancer cells treated with entinostat and olaparib. Methods: OVCAR3 cells were treated with 0.5 µM entinostat and 10 µM olaparib (alone and combined) for 6h, followed by RNA Seq. Cell cycle was analyzed by flow cytometry in SKOV-3 cells treated with olaparib and entinostat (alone and combined) for 24h, 48h and 72h. Results: RNA-Seq analysis showed reduced expression of genes that regulate G2/M checkpoint progression with both entinostat and olaparib. This correlated with flow cytometry results in SKOV-3 cells, where we observed accumulation of G2/M phase cells when treated with entinostat and olaparib. At 24h post treatment, olaparib and entinostat treated cells had higher population of cells in G2/M phase compared to control (18.5% and 16.7% respectively compared to 14.7% in control). Olaparib combined with entinostat further increased G2/M population to 21.7%. At 48h olaparib treated cells had 17.4% cells in G2/M compared to 14% in control. Entinostat treated cells had 18% G2/M cells. Combination treated cells had 19.7% G2/M cells. At 72h, olaparib and control had similar number of G2/M cells (9.2% and 9.7% respectively). Entinostat treated cells had 12% G2/M cells and combination treated cells had 13.6% cells at G2/M cells. This indicates that entinostat and olaparib disrupt progression of cells from G2/M phase, potentially leading to cell death before they can enter mitosis/cell division. Cell cycle analysis in OVCAR3 cells is in progress. Conclusion: Entinostat and olaparib cause G2/M cell cycle arrest in ovarian cancer cells. Entinostat maintains G2/M cell cycle arrest longer than olaparib, potentially extending the window of efficacy of the combination therapy. Validation of G2/M markers and other gene targets/pathways is in progress. Citation Format: Vijayalaxmi G. Gupta, Heng Liu, Rugang Zhang, Michael Onken, Andrew Wilson, Fiona Yull, Marta Crispens, Mary Mullen, Dineo Khabele. Entinostat alters cell cycle in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB421.
Incidence and predictors of heart failure with reduced and preserved ejection fraction after <scp>ST</scp>‐elevation myocardial infarction in the contemporary era of early percutaneous coronary intervention
Authors: Chris Lenselink, Kim W.L.M. Ricken, Hilde E. Groot, Tijs J. de Bruijne, Tom Hendriks, Pim van der Harst, Adriaan A. Voors, Erik Lipsic
Journal: European Journal of Heart Failure (2024)
Abstract LB396: The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets
Authors: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci
Journal: Cancer Research (2024)

Abstract The capabilities of artificial intelligence (AI) and machine learning (ML) are pivotal for refining patient stratification and subtype discrimination in clinical trials. Conventional ML methods often rely on large data sets for meaningful discoveries. NetraAI is a novel ML approach designed and trained to work with smaller data sets. The challenge with smaller data sets is that they do not reflect the totality of the disease that they represent. NetraAI employs a novel approach termed “Sub-Insight Learning”, utilizing validated mathematical methods to analyze even small patient data sets. This allows the system to decompose the data sets into high and low confidence patient subpopulations, enhancing predictive model accuracy and reducing overfitting. Further, the system explains what variables are driving the etiology defining the subpopulations of patients. Using two non-small cell lung cancer (NSCLC) data sets (GSE18842 and GSE10245) consisting of only 104 samples from adenocarcinoma (ADC) and squamous cell carcinoma (SCC), NetraAI distinguished the two subtypes through unique genetic signatures. Notably, nine of the ten variables identified correlate with known NSCLC markers, with PIGX emerging as a novel target. Leveraging protein-protein interaction networks (PPI) revealed connections between PIGX and BACE1. BACE1 has been implicated as a driver of NSCLC brain metastasis. These findings shed light on the biology of membrane proteins and their post-translational modifications, a factor implicated in various diseases, prompting further exploration. NetraAI demonstrates a significant breakthrough in precision medicine for oncology, capable of generating meaningful insights from small data sets. The discovery of novel biomarkers and their implications in cancer and other diseases underline the potential of this AI-driven approach in advancing current research paradigms and patient-specific treatments. Citation Format: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci. The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB396.
Abstract LB404: ATR inhibitors synergize with DHFR inhibitors in rhabdomyosarcoma cells by disrupting DNA damage checkpoint
Authors: Ukhyun Jo, George K Annor, Jack F. Shern
Journal: Cancer Research (2024)

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. RMS tumors are classified into four subtypes: embryonal, alveolar, spindle cell/sclerosing, and pleomorphic. Treatment options for RMS include a combination of surgery, chemotherapy, and radiation therapy and regimens for patients with relapsed and metastatic RMS remain limited. However, a recent study has reported that pharmacological inhibitors targeting ataxia telangiectasia and Rad3-related protein (ATR) are currently undergoing phase I/II trials and may be utilized for the treatment of alveolar RMS. Interestingly, we identified that the gene signature of replication stress positively correlated with dihydrofolate reductase (DHFR) expression in the cancer cell line database (CellMinerCDB, discover.nci.nih.gov/cellminercdb; Pearson correlation (r)=0.66). DHFR is an important therapeutic target for cancer and autoimmune diseases, and its inhibitors are routinely used and clinically approved. DHFR inhibitors are known to exhibit their anticancer effects by inhibiting nucleotide synthesis and DNA replication. In this study, we aimed to explore a potential synergistic interaction using a combination treatment of ATR inhibitors (elimusertib and ceralasertib) and DHFR inhibitors (pralatrexate, methotrexate, and raltitrexated) in multiple RMS cell lines. We used a drug matrix reduction format and found that combined treatment of ATR inhibitors and DHFR inhibitors induced a synergistically decreased RMS cell viability, showing higher synergy in fusion-positive RMS cells than in fusion-negative RMS cells. Mechanistically, ATR inhibitors abrogated DNA damage response checkpoint CHK1 activation caused by DHFR inhibitor, leading to increased γH2AX and decreased DNA replication activity. Accordingly, the accumulation of DNA damage in combination with ATR inhibitor and DHFR inhibitor triggered higher cell cycle arrest and apoptotic cell death than single agent treatment of DHFR inhibitor. Our findings warrant further research into identifying genomic regions where the DNA damage is enriched in combination treatment by using END-sequencing and synthesis-associated with repair sequencing (SAR-seq). In conclusion, this study provides promising rationale for the combination treatment of ATR and DHFR inhibitors to treat RMS patients, including those with advanced, relapsed, and metastatic states. Citation Format: Ukhyun Jo, George K Annor, Jack F. Shern. ATR inhibitors synergize with DHFR inhibitors in rhabdomyosarcoma cells by disrupting DNA damage checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB404.
Abstract LB097: Sensitive detection of central nervous system tumors using a sequencing based cerebrospinal fluid test
Authors: Christopher B. Douville, Chetan Bettegowda
Journal: Cancer Research (2024)

Abstract The current approach to diagnosing and monitoring tumors of the central nervous system relies almost exclusively on radiographic imaging and neurosurgical procedures. Cerebrospinal fluid (CSF) is appealing for diagnosis because it is already part of the standard of care for the diagnosis or management of several types of CNS disease, including cancer, and the tumor DNA is more highly concentrated inside the blood brain barrier than in plasma or other bodily fluids. Even though cytology is widely used, sensitivity remains low ranging from 2% to 50%, depending on cancer type. We report an analytic technique that efficiently introduces identical molecular barcodes to both strands of CSF template DNA molecules for the identification of cancer specific somatic mutations and copy number alterations. We apply this approach to 126 CSF samples obtained from individuals with known primary or metastatic tumors involving the brain and 36 CSF samples obtained from individuals with non-neoplastic neurological conditions such as multiple sclerosis and another neurologic conditions. We correctly detect 91% of cancers at a specificity of 94.5%. In cases (n=20) where standard of care cytology was available, cytology detected 25% of cancers while our molecular assay detected 90%. Our approach has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain. Positives n= Sensitivity GBM 42 46 91.3% Lymphoma 22 24 91.7% Medulloblastoma 14 16 87.5% Metastases 37 40 92.5% Citation Format: Christopher B. Douville, Chetan Bettegowda. Sensitive detection of central nervous system tumors using a sequencing based cerebrospinal fluid test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB097.
An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders
Authors: Marie-France Dorion, Diana Casas, Irina Shlaifer, Moein Yaqubi, Peter Fleming, Nathan Karpilovsky, Carol X.-Q. Chen, Michael Nicouleau, Valerio E. C. Piscopo, Emma J. MacDougall, Aeshah Alluli, Taylor M. Goldsmith, Alexandria Schneider, Samuel Dorion, Nathalia Aprahamian, Adam MacDonald, Rhalena A. Thomas, Roy W. R. Dudley, Jeffrey A. Hall, Edward A. Fon, Jack P. Antel, Jo Anne Stratton, Thomas M. Durcan, Roberta La Piana, Luke M. Healy
Journal: Molecular Neurodegeneration (2024)

Abstract Background Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. Methods Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G &gt; A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL. Results The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 ( P2RY12 ) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam 3 CSK 4 . Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1R WT/KO and CSF1R WT/E633K iMGL compared to their respective isogenic controls. Conclusions We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities. Graphical Abstract
Impact of testosterone therapy on pulmonary function in transgender and gender expansive individuals assigned female at birth: A cross-sectional comparative study
Authors: Ali Heitzman, Jillian River Browy, Deanna Britton, Jeff Conn, Aaron Ziegler
Journal: International Journal of Transgender Health (2024)

Background Interpretation of pulmonary function tests (PFTs) currently uses normative data derived with a cisgender assumption for men and women, not taking into consideration transgender individuals who may have undergone interventions including hormonal therapy. If muscles involved for respiration change with exposure to testosterone therapy, normative PFT calculations for presumed cisgender individuals may not apply to transgender individuals. Thus, investigating pulmonary function in those who have undergone testosterone therapy will aid the accuracy of PFTs for this population.
Abstract LB405: CTP synthase 1 is a synthetic vulnerability in prostate cancer treated with supraphysiological androgen
Authors: Sheila Jonnatan, Rajendra Kumar, Varsha Vakkala, Karthik Vasan, Zachary R. Chalmers, Daniel R. Schmidt, Philip A. Beer, Matthew G. Vander Heiden, Samuel R. Denmeade, Navdeep S. Chandel, Laura A. Sena
Journal: Cancer Research (2024)

Abstract Bipolar androgen therapy (BAT) is the cyclical administration of supraphysiological androgen (SPA), which can be an effective treatment for 30-40% of patients with castration-resistant prostate cancer. We sought to improve the efficacy of BAT by better understanding its molecular consequences in prostate cancer. Given that the androgen receptor (AR) regulates cellular metabolism, we hypothesized that SPA induces dependencies on specific metabolic pathways that might be exploited therapeutically. A negative selection metabolism-focused CRISPR-KO screen in LNCaP cells treated with SPA suggested that the deletion of several enzymes involved in de novo nucleotide synthesis enhances growth suppression by SPA. A top hit was cytidine triphosphate synthase 1 (CTPS1). CTPS1 converts UTP to CTP in the final step of de novo pyrimidine synthesis. Exposure of SPA-treated prostate cancer cell lines to STP-B, a potent and highly selective inhibitor of CTPS1 (PMID 37008165), increased cell death in vitro and in vivo, indicating that CTPS1 constitutes a metabolic vulnerability in this context. Inhibition of CTPS1 with STP-B induced S phase cell cycle arrest and replication stress, as indicated by phosphorylation of RPA and CHEK proteins, which was augmented by treatment with SPA. CTPS1 likely becomes a vulnerability in SPA-treated prostate cancer due to the downregulation of MYC by SPA, which we found leads to a reduced abundance of enzymes required for nucleotide synthesis and nucleotides, particularly CTP. This rewires nucleotide synthesis and salvage pathway such that de novo synthesis of CTP is required to avoid replication stress and cell death. Altogether, this work suggests that inhibition of CTPS1 may enhance the efficacy of BAT through the induction of replication stress. Selective inhibitors of CTPS1 have entered clinical development (NCT05463263), increasing the feasibility of a combination therapy clinical trial design for patients with prostate cancer. Citation Format: Sheila Jonnatan, Rajendra Kumar, Varsha Vakkala, Karthik Vasan, Zachary R. Chalmers, Daniel R. Schmidt, Philip A. Beer, Matthew G. Vander Heiden, Samuel R. Denmeade, Navdeep S. Chandel, Laura A. Sena. CTP synthase 1 is a synthetic vulnerability in prostate cancer treated with supraphysiological androgen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB405.
A Manganese‐Based Nanodriver Coordinates Tumor Prevention and Suppression through STING Activation in Glioblastoma
Authors: Wenyuan Zhang, Liejing Lu, Zheng Zhu, Fuan Deng, Wenchang Zhang, Fengyi Wang, Ping Zeng, Haonan Shi, Tong Wang, Yichi Chen, Yue Song, Yiping Liu, Tianze Kang, Kai Li, Jie Mao, Zhengwei Liu, Lu Zhang
Journal: Advanced Healthcare Materials (2024)

Glioblastoma (GBM), the most prevalent and aggressive primary malignant brain tumor, exhibits profound immunosuppression and demonstrates a low response rate to current immunotherapy strategies. Manganese cations (Mn
Abstract CT291: A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1
Authors: Noboru Yamamoto, Toshihiko Doi, Manish R. Patel, Ignacio Garrido-Laguna, Sutun Wu, Satoshi Nishioka, Keiko Nakajima, Benedito A. Carneiro
Journal: Cancer Research (2024)

Abstract Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (deruxtecan [DXd]). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Trial design: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll a maximum of 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Citation Format: Noboru Yamamoto, Toshihiko Doi, Manish R. Patel, Ignacio Garrido-Laguna, Sutun Wu, Satoshi Nishioka, Keiko Nakajima, Benedito A. Carneiro. A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT291.