tbuckley/cabot-search huggingface dataset:
Abstract 2809: Bifidobacterium species BB_003 identified through metatranscriptomic analysis with experimentally validated antitumor actions
Authors: Xuan-Mei Piao, Kyungchan Min, Young Joon Byun, Chuang-Ming Zheng, Seon-Kyu Kim, Seong-Hwan Park, Sungmin Moon, Kyeong Kim, Ho Won Kang, Won Tae Kim, Seok Joong Yun, Hansoo Park
Journal: Cancer Research (2024)

Abstract Introduction &amp; Objectives: A host's microbiome influences both gene expression and phenotype. Whole transcriptome sequencing (WTS) provides information about the microbiome in addition to gene expression. This research probes the correlation between microbial abundance, host gene transcription, and therapeutic efficacy, pinpointing a beneficial microbial strain and its mechanism of action. Materials &amp; Methods: Bladder tissue biopsies from NMIBC patients underwent WTS and subsequent bioinformatic analysis. After in silico evaluation, in vitro assays including WST, quantitative PCR, and immune cell profiling were performed on mouse splenocytes. These assays were followed by in vivo assessment in both subcutaneous and orthotopic murine tumor models. Results: Among 59 biopsies, non-recurrence correlated with heightened presence of Lactococcus species LC_001 and Bifidobacterium species BB_003. Notably, BB_003 was associated with an extended recurrence-free survival (RFS). Gene set enrichment analysis (GSEA) implicated BB_003 in mediating a pro-inflammatory cascade, accentuating macrophages and interferons. In vitro WST assays showed the antitumor potential of BB_003_β, characterized by upregulated pro-inflammatory gene transcription. This strain increased effector CD8 T cells and M2 macrophages. In vivo, direct live BB_003_β introduction into subcutaneous tumors curtailed tumor proliferation. An increase in effector CD8 T cell populations within tumors and elevated cDC1 and M1 macrophage counts in tumor-draining lymph nodes were observed. Intravesical administration of live bacteria markedly decreased bladder weight, amplifying interferon alpha and beta gene expressions compared to controls. Conclusions: According to this study, BB_003_β inhibits tumor growth and is involved in immune response. Our study confirmed the antitumor properties of BB_003_β and suggested that cytokine and immune cell stimulation play a key role in its mechanism of action. Augmented insights warrant further exploration, particularly in synergy with intravesical BCG treatment. Citation Format: Xuan-Mei Piao, Kyungchan Min, Young Joon Byun, Chuang-Ming Zheng, Seon-Kyu Kim, Seong-Hwan Park, Sungmin Moon, Kyeong Kim, Ho Won Kang, Won Tae Kim, Seok Joong Yun, Hansoo Park. Bifidobacterium species BB_003 identified through metatranscriptomic analysis with experimentally validated antitumor actions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2809.
Abstract 5775: Structure and dynamics of the major <i>PDGFR-</i>β oncogene promoter G-quadruplex and insights into its cellular regulation
Authors: Yichen Han, Jonathan Dickerhoff, Danzhou Yang
Journal: Cancer Research (2024)

Abstract Overexpression of the receptor tyrosine kinase PDGFR-β promotes cancer growth and metastasis. PDGFR-β is a validated cancer target but PDGFR-β kinase inhibitors suffer from lack of selectivity and side effects. G-quadruplexes are an exciting class of non-B DNA secondary structures with functional importance. The G-quadruplex formed in the PDGFR-β promoter is a transcription repressor and targetable by small molecules. Therefore, the PDGFR-β promoter G-quadruplex is an attractive molecular target for anticancer drugs. Structural information of the PDGFR-β promoter G-quadruplex is crucial for understanding its cellular function and rational drug design. Herein, we used nuclear magnetic resonance (NMR) spectroscopy and biophysical methods to determine the structure and dynamics of the major G-quadruplex formed in the human PDGFR-β promoter. Unlike canonical G-quadruplexes formed by four runs of three continuous guanines (G), the major PDGFR-β G-quadruplex adopts a novel broken-strand structure where a two-G segment is continued by a non-adjacent guanine. The broken-strand G-quadruplex has a vacancy-G-tetrad (vG4) which is filled-in intramolecularly by a distal guanine. Interestingly, we discovered that the major PDGFR-β G-quadruplex is a novel mixture of two equilibrating broken-strand G-quadruplexes. Both structures adopt overall parallel-stranded folding with all 1-nt chain-reversal loops. However, a different 3’-filled-in guanine is delivered by a lateral loop, which forms structurally similar hairpin with a unique capping G-G base-pair. The formation of the equilibrating broken-strand G-quadruplexes and unique capping structures are both specific to the PDGFR-β promoter sequence. Intriguingly, the observed dynamic equilibrium between the two co-existing structures with different intramolecular fill-in guanines indicates a novel vG4 intermediate, which could be filled-in by cellular guanine metabolites such as cGMP. Therefore, our study provides critical insights into how the dynamics of the major PDGFR-β G-quadruplex lead to vG4 formation and potential regulation of gene transcription by cellular guanine metabolites. The determined molecular structures of the novel broken-strand G-quadruplexes provide a structural basis for rational design of small molecules to specifically target the major PDGFR-β promoter G-quadruplex for cancer therapeutics. Citation Format: Yichen Han, Jonathan Dickerhoff, Danzhou Yang. Structure and dynamics of the major PDGFR-β oncogene promoter G-quadruplex and insights into its cellular regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5775.
Abstract 4797: Impact of COVID-19 pandemic on breast cancer screening and diagnosis stage in a large midwestern United States academic medical center
Authors: Kimberly J. Johnson, RJ Waken, Caitlin P. O'Connell, Derek Brown
Journal: Cancer Research (2024)

Abstract Background: Access to breast cancer screening mammogram services decreased in association with the COVID-19 pandemic. There is also evidence for increases in late-stage breast cancer diagnoses. Our objectives were to determine: 1) the COVID-19-affected period on mammogram screening, 2) the proportion of pandemic-associated missed or delayed mammogram screening visits overall and by race/ethnicity and age group, and 3) evidence for pandemic-associated shifts in diagnosis stage. Methods: Screening mammogram encounter data between 1-1-2019 and 12-31-2022 were extracted from EPIC for females ≥ 40 years old for the screening analysis. We used Bayesian state space models to describe weekly screening mammogram counts, modeling an interruption that phased in and out from 3-1-2020 to 9-1-2020. We used the posterior predictive distribution to simulate differences between a predicted, uninterrupted process and the observed screening mammogram counts. Breast cancer diagnoses at ≥ 21 years from the tumor registry between 12-1-2018 and 11-30-2021 were included in the stage analysis. We used logistic regression models to estimate late-stage diagnosis odds comparing matched three-month periods during the pandemic to before the pandemic. Results: A total of 319,492 encounters among 146,644 women were included. Model-estimated screening mammograms dropped by 98.8% (95% CI 95.1 to 100) between 3-15-2020 and 5-24-2020, returning to pre-pandemic levels or higher after this period. Drops in screening mammogram encounters did not vary significantly by race/ethnicity or age group (p &amp;gt; .75). Among 4,669 breast cancer diagnoses, we found no significant differences in the odds of late-stage diagnoses for any period vs. the same period before the pandemic (Table). Conclusions: These data suggest a short-term pandemic effect on screening mammograms. Evidence for increases in late-stage diagnoses is limited. These results may inform future pandemic planning. OR (95% CI) Period comparison 1.19 (0.74 to 1.91) 3/2020 to 5/2020 vs. 3/2019 to 5/2019 1.05 (0.69 to 1.60) 6/2020 to 8/2020 vs. 6/2019 to 8/2019 1.14 (0.73 to 1.78) 9/2020 to 11/2020 vs. 9/2019 to 11/2019 0.92 (0.60 to 1.41) 12/2020 to 2/2021 vs. 12/2019 to 2/2020 1.08 (0.71 to 1.65) 3/2021 to 5/2021 vs. 3/2019 to 5/2019 0.89 (0.59 to 1.33) 6/2021 to 8/2021 vs. 6/2019 to 8/2019 1.31 (0.84 to 2.04) 9/2021 to 11/2021 vs. 9/2019 to 11/2019 Citation Format: Kimberly J. Johnson, RJ Waken, Caitlin P. O'Connell, Derek Brown. Impact of COVID-19 pandemic on breast cancer screening and diagnosis stage in a large midwestern United States academic medical center [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4797.
Abstract 2214: Impacts of habitual and recent alcohol intake on gut microbiome diversity and composition among Black Americans
Authors: Lili Liu, Sang Nguyen, Qiuyin Cai, Martha Shrubsole, Wei Zheng, Danxia Yu
Journal: Cancer Research (2024)

Abstract Background: Alcohol intake can alter the gut microbiome, which may play a role in the development of cancer and other chronic diseases. However, there have been limited population-based studies investigating the associations of habitual and recent alcohol intake with the gut microbiome, particularly among Black Americans. Methods: We investigated the association of alcohol intake with the gut microbiome among 538 Black American participants of the Southern Community Cohort Study (150 men and 388 women). Habitual and recent alcohol intake was assessed at cohort baseline (2002-2009) and stool collection (2018-2021), respectively. DNA was extracted from fecal samples for gut microbiome profiling using shotgun metagenomic sequencing. Generalized linear models were employed to evaluate the associations between alcohol intake and gut microbiome diversity and composition, with adjustments for sociodemographic characteristics, other lifestyle factors, and comorbidities. False discovery rate (FDR)&amp;lt;0.1 was considered statistically significant. Results: The mean age at enrollment was 53.2 ± 7.7 years, with a mean interval of 13.8 years (range: 9.0-18.1 years) between baseline and stool collection. Neither habitual nor recent alcohol intake was associated with microbiome diversity indices, and recent alcohol intake was not associated with microbial taxa abundance either. However, habitual alcohol intake, both total amount and subtypes, showed significant associations with microbial taxa abundance primarily in men, including Actinobacteria, Proteobacteria, Firmicutes, and classes Bacilli and Clostridia within these phyla (all FDR&amp;lt;0.1). Specifically, total alcohol and red wine intakes were inversely associated with genus MGYG-HGUT-02719 in class Clostridia; beer consumption was inversely associated with genus Anaerostipes; white wine intake showed negative associations with order RF32 and genus Eubacterium and a positive association with genus Paenibacillus. Most of these associations remained significant after adjusting for BMI and history of cardiometabolic diseases or cancer. Conclusion: We identified gut microbiome taxa associated with habitual alcohol intake among Black American men, including several with anti- or pro-gastrointestinal-cancer properties. However, the magnitudes of these associations were generally small. Further research is needed to determine if these bacteria play a mediating or modifying role in alcohol-disease relationships. Citation Format: Lili Liu, Sang Nguyen, Qiuyin Cai, Martha Shrubsole, Wei Zheng, Danxia Yu. Impacts of habitual and recent alcohol intake on gut microbiome diversity and composition among Black Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2214.
Abstract 6637: The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment
Authors: Eileena F. Giurini, Sam G. Pappas, Kajal H. Gupta
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease projected to become the second leading cause of cancer deaths by 2030. First-line chemotherapies gemcitabine and FOLFIRINOX provide little therapeutic benefit and are accompanied by severe adverse toxicities, precluding long-term treatment. In addition, PDAC is notoriously refractory to checkpoint inhibitor immunotherapies, due to poor immunogenicity and a tumor microenvironment dominated by suppressive cell types. Thus, there is an unmet need for innovative, immune-based strategies to combat PDAC. A previous study utilized engineered bacteria to effectively kill PDAC tumor cells by directly delivering immunogenic tetanus toxoid to the tumor. Given the potential toxicity in using live bacteria, our group utilized a less toxic alternative, an FDA-approved Haemophilus influenzae type b vaccine (HibVx) also containing a tetanus toxoid component. To determine the antitumor potential of HibVx, our group used a physiologically relevant murine model, low T cell clone murine PDAC tumor model 641c95 and clinically relevant KPC mice model for PDAC. After tumors were established, animals received three consecutive daily treatments of HibVx via intraperitoneal injection. HibVx-treated animals experienced a dramatic reduction in tumor growth compared to PBS-treated controls (p&amp;lt;0.001). Given that tetanus toxoid is highly immunogenic in nature, changes in intratumoral immune cell populations following HibVx treatments were of great interest. Using flow cytometry analysis, HibVx-treated tumors had a significant increase in natural killer cells compared to control tumors (p&amp;lt;0.05). In addition, HibVx affected myeloid-derived suppressor cell populations (MDSCs), which are heavily implicated in the suppressive nature of PDAC tumors. HibVx also significantly decreased MDSCs within the tumor (p&amp;lt;0.05). In all, these findings position HibVx as an effective immunostimulatory agent that can be used as an alternative to live bacteria-based therapy for the treatment of PDAC. Citation Format: Eileena F. Giurini, Sam G. Pappas, Kajal H. Gupta. The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6637.
Abstract 5837: Aryl hydrocarbon receptor is critical for enzalutamide-resistant prostate cancer growth
Authors: Chia-Hui Chen, Boyang Jason Wu
Journal: Cancer Research (2024)

Abstract Therapy resistance is a ubiquitous and major challenge for curing cancer including prostate cancer. As the most prevalent non-skin cancer for men, prostate cancer is responsible for more than 30,000 deaths annually in the U.S. Despite a favorable prognosis at early stages, prostate cancer progressively develop into an incurable castration-resistant stage (CRPC) where prostate cancer grows in a low-androgen environment. Enzalutamide (ENZ) is the first drug approved by FDA for treating CRPC by inhibiting the residual androgen signaling. While ENZ significantly improves overall survival and quality of life, resistance inevitably develops and greatly limits its benefit. To understand ENZ resistance and identify novel therapeutic targets with the hope of overcoming resistance, we performed RNA-seq to analyze mRNA expression profiles from three ENZ-resistant human CRPC cell lines (C4-2BENZR, CWR-R1ENZR and VCaPENZR) and identified the aryl hydrocarbon receptor (AHR) among the 114 commonly upregulated genes. AHR is a ligand-dependent transcription factor that has been shown to drive disease progression in multiple types of cancer. Stable shRNA-mediated knockdown of AHR substantially decreased growth of ENZ-resistant CRPC cells. Our pilot study also showed that AHR knockdown resulted in fewer and smaller CWR-R1ENZR tumors in a xenograft mouse model. To elucidate the underlying mechanism of AHR-mediated cancer growth, gene set enrichment analysis (GSEA) revealed a declining trend of enrichment of the 114 commonly ENZ-upregulated genes among differentially altered genes upon AHR knockdown in ENZ-resistant cells, suggesting that AHR may act as a master regulator of ENZ resistance. Moreover, we found that the Hallmark androgen response gene set is downregulated in AHR-silenced ENZ-resistant cells, implying a role of AHR in sustaining androgen response for ENZ-resistance. Consistently, we performed AHR ChIP-seq and confirmed that AHR bound to promoter regions of several androgen-regulated genes in CWR-R1ENZR cells. In addition, three peroxisome-related Hallmark gene sets are also negatively enriched in AHR-knockdown cells, which provides a rationale for further exploring a potential AHR-dependent connection of peroxisomal function to ferroptosis as a newly emerging mechanism of action for ENZ. In summary, our study suggests that AHR plays a critical role in maintaining ENZ-resistant CRPC growth with the likely involvement of modulating androgen signaling and ferroptosis susceptibility. Citation Format: Chia-Hui Chen, Boyang Jason Wu. Aryl hydrocarbon receptor is critical for enzalutamide-resistant prostate cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5837.
Abstract 1953: Posttranslational modification in glucocorticoid receptor in treatment resistant prostate cancers
Authors: Surendra Gulla, Ephraim Gardner, Shreya Shyam Sundar, Praveen Jaiswal, Ning Gao, Lynda Bennet, Suzanne Conzen, Remi Adelaiye-Ogala
Journal: Cancer Research (2024)

Abstract Prostate Cancer (PCa) remains the most common cancer in men in the United States and the second leading cause of cancer-related death in men. An evolving concept that contributes to our understanding of resistance to androgen deprivation therapy (ADT) and AR antagonists in advanced PCa is the ability of cells to turn on compensatory hormone receptor signaling for survival. Preclinical and clinical studies demonstrate that induction of glucocorticoid receptor (GR) expression confers resistance to AR-targeted therapy. Previous studies from our lab demonstrated that the inhibition of AKT signaling blocks pro-oncogenic GR activity and overcomes resistance to AR-targeted therapy. AKT1 is predicted to phosphorylate GR at s134, however, the implications of pGR(s134) in advanced PCa remains unclear. Although ligands (e.g., Dex) activates GR, we have found GR activation modulated by post-translational modification (PTM) and persistent in treatment resistant PCa. Therefore, we hypothesize pro-oncogenic GR activation through AKT1-induced PTM. The rationale is that by inhibiting AKT signaling, we block residual GR signaling that can potentially drive lethal prostate cancers and consequently be re-sensitized to the standard of care. We validated our findings by Western blot analysis, we used an AKT1-specific inhibitor (AKT1i) and observed decreased AKT1 activity and decreased pGR(s134) without affecting total GR protein expression. Functional studies using shRNA against AKT1 showed reduced pGR(s134) expression without affecting the total GR expression Our preliminary data suggests that pro-oncogenic GR activity is modulated through the phosphorylation of GR on s134 by AKT1. Citation Format: Surendra Gulla, Ephraim Gardner, Shreya Shyam Sundar, Praveen Jaiswal, Ning Gao, Lynda Bennet, Suzanne Conzen, Remi Adelaiye-Ogala. Posttranslational modification in glucocorticoid receptor in treatment resistant prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1953.
Abstract 5818: Differentiation of human papillomavirus-positive head and neck squamous cell carcinoma cells
Authors: Sarah Gendreizig, Laura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez, Harkiren Pabla, Frank Brasch, Germaine Escames, Tobias Busche, Holger Sudhoff, Lars U. Scholtz, Ingo Todt, Felix Oppel
Journal: Cancer Research (2024)

Abstract Head and neck squamous cell carcinoma (HNSCC) represents a highly malignant disease and death rates remain at approximately 50% for decades. Thus, new tumor-targeting treatment strategies are desperately needed. In a previous study, we dissected human papillomavirus (HPV)-negative HNSCC cell differentiation via cornification and detected an epigenetically determined loss of cell malignancy. Analyzing the mechanisms underlying the differentiation of HNSCC cells may identify targets for anti-tumor therapy. Using patient-derived tumor cells, we created an HNSCC differentiation model in HPV+ tumor cells. Similar to HPV- cells, we observed a loss of malignant characteristics in HPV+ cell cultures in differentiating cell culture conditions including irregular enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. Even though cornification was detected in HPV+ tumor cell cultures and HPV+ FFPE tumor tissue sections, cornification was not induced during HPV+ cell differentiation. Instead, RNA-seq and subsequent Gene Ontology analysis showed myocyte-like differentiation with upregulation of markers of myofibril assembly including TPM1, TAGLN, and ACTA1. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers, reminiscent of myoblast-lineage cells. Moreover, multi-marker immunofluorescence analysis of HPV+ tumor tissue sections revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like differentiation observed in vitro also occurred in human tissue. Normal tissue displayed a co-expression of TPM1, TAGLN, and ACTA1 in differentiating keratinocytes between the basal cell layer and the fully differentiated corneocytes. This shows that the expression of myocyte-lineage markers is reflected in differentiating non-malignant mucosal tissue. Our study suggests that the targeted differentiation of tumor cells might be therapeutically valuable in HPV+ HNSCCs as well. Citation Format: Sarah Gendreizig, Laura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez, Harkiren Pabla, Frank Brasch, Germaine Escames, Tobias Busche, Holger Sudhoff, Lars U. Scholtz, Ingo Todt, Felix Oppel. Differentiation of human papillomavirus-positive head and neck squamous cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5818.