bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP2D6 Phenotype and Breast Cancer Outcomes: A Bias Analysis and Meta-Analysis
Authors: MacLehose Richard F. , Ahern Thomas P. , Collin Lindsay J. , Li Aixin , Lash Timothy L. 
Published: November 2024

Abstract

Background:
We evaluated the impact of systematic bias due to loss of heterozygosity (LOH) and incomplete phenotyping in studies examining the relationship between CYP2D6 variants and breast cancer recurrence among women treated with tamoxifen.

Methods:
We performed a systematic review of the literature on tamoxifen, CYP2D6 variants, and breast cancer recurrence. A quantitative bias analysis was performed to adjust for LOH and incomplete phenotyping. Bias-adjusted results were then combined in a meta-analysis.

Results:
Thirty-three studies informed the bias analysis and meta-analysis on CYP2D6 variants and breast cancer recurrence and/or mortality. An unadjusted meta-analysis suggested increased risk of recurrence and/or mortality for poor relative to normal metabolizers [RR = 1.28; 95% simulation interval (SI), 1.04–1.58] with substantial heterogeneity (I2 = 27%; P for heterogeneity = 0.07). Adjusting for LOH and incomplete genotyping resulted in a slight change in the effect estimate and a decrease in heterogeneity (RR = 1.34; 95% SI, 1.10–1.63; I2 = 0%; P for heterogeneity = 0.17). Intermediate metabolizers had a slightly increased risk of recurrence and/or mortality relative to normal metabolizers (RR = 1.15; 95% SI, 1.00–1.34; I2 = 0%; P for heterogeneity = 0.89).

Conclusions:
Adjusting for biases such as LOH and incomplete genotyping reduced observed heterogeneity between studies. Individuals with poor CYP2D6 phenotypes were at increased risk for breast cancer outcomes compared with those with normal phenotypes.

Impact:
Reduction in CYP2D6 activity was associated with an increased risk of breast cancer recurrence and/or mortality, and results underscore the importance of quantitatively adjusting for biases when aggregating study results.
See related In the Spotlight, p. 221
Abstract A012: g3bp1-mediated stress granule formation drives melanoma initiation in zebrafish
Authors: Drake Kyle D , Formato Emily , Zon Leonard 
Published: November 2024

Abstract
Stress granules confer cancer cells the ability to withstand harsh biological conditions and impart tumorigenic translational states through mRNA sequestration. Despite advances in in vitro knowledge, mechanistic understanding of the endogenous influence of stress granules during tumorigenesis in vivo remains understudied. To address this, we use a zebrafish melanoma model where oncogenic human BRAF V600E is driven by the melanocyte master regulator mitfa in a p53 -/- background. Through vector-based genetic engineering, endogenous melanoma induction in these zebrafish can be developmentally staged from single cell to tumor. BRAF V600E ::p53 -/- melanocytes form a cancerized field (CF), from which a subset upregulate the melanocyte master regulator mitfa, creating a cancer precursor zone (CPZ). Transformation of CPZ cells to an embryonic, neural crest-like state facilitates their formation of an early tumor patch that inevitable develops into an overt tumor. Single cell RNAseq analysis of cells representing each melanoma stage showed that CPZ cells upregulate core stress granule markers, including g3bp1, tia1, tia1l, and nufip2. Immunostaining of g3bp1 in CF, CPZ, patch, and tumor cells revealed a significant induction of stress granules from the CF to CPZ transition (2 vs 10 stress granules/cell; N=3; p=0.034) that persists during the patch and tumor stage, indicating cell stress accompanies melanoma initiation and progression. Genetic disruption of g3bp1 through cell autonomous, melanocyte-specific CRISPR editing in zebrafish (N=10-13) causes delayed CPZ onset (P=0.012) and fewer CPZs to form (P=0.021). In turn, g3bp1-edited zebrafish have delayed tumor formation (P=0.026) and develop fewer tumors (P=0.006). To decipher the RNAs sequestered by stress granules during melanomagenesis, we performed RIPseq for G3BP1 in human A375 melanoma cells stressed with sodium arsenite. RNAs significantly bound to G3BP1 upon stress induction include major tumor suppressors, such as CDKN2A, RBM5, BIK, and RHOB. Together, these results suggest that endogenous g3bp1-mediated stress granule formation in melanoma initiating cells is tumorigenic in vivo and operates through the sequestration of tumor suppressive RNAs.
Citation Format: Kyle D Drake, Emily Formato, Leonard Zon. g3bp1-mediated stress granule formation drives melanoma initiation in zebrafish [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A012.
Abstract A016: YBX1 is a negative regulator of post-transcriptional program associated with invasion and metastasis in cSCC
Authors: Sol Stefano , Mandinova Anna , Boncimino Fabiana , Todorova Kristina , Di Cicco Emery , Tebaldi Toma , Bucciarelli Giorgia 
Published: November 2024

Abstract
Y-box binding protein 1 (YB-1), which is encoded by YBX1 gene, is a multifunctional cold-shock protein that binds both DNA and RNA to orchestrate transcription as well as RNA processing and translation. Recently, we demonstrated that YBX1 is a post-transcriptional effector required for the maintenance of epidermal homeostasis. Although it was well known that YBX1 plays prominent pro-oncogenic roles in malignant transformation and cell invasion in a wide variety of cancers, the role of YBX1 in cutaneous squamous cell carcinoma (SCC) is poorly understood. Here, we report that YBX1 protein level is higher in SCC tumor compared with non-neoplastic skin, but it goes down during tumor progression, in invasive and metastatic states. Indeed, both in vitro and in vivo experiments show that YBX1 acts as an antagonist of SCC progression, inhibiting its migration, invasiveness and metastasis. YBX1 is predominantly found in the cytoplasm of SCC cells. Therefore, we focused on the role of YBX1 as a posttranscriptional regulator and performed an eCLIP-seq (crosslinking immunoprecipitation sequencing) to identify its direct RNA targets. We found that YBX1 binds pro-invasive RNA associated with cell-cell and cell-matrix adhesions. From the integration of eCLIP-seq data with RNA-Bisulfite Seq data, an increased number of m5C modifications was observed to be located within the 3'UTR and CDS of tumor-enriched YBX1 target regions. Upon silencing of YBX1, polysome fractionation analysis revealed that YBX1 KD regulates targets involved in cancer motility, revealing that the loss of function of YBX1 promotes migration and invasion at the post-transcriptional
Citation Format: Stefano Sol, Anna Mandinova, Fabiana Boncimino, Kristina Todorova, Emery Di Cicco, Toma Tebaldi, Giorgia Bucciarelli. YBX1 is a negative regulator of post-transcriptional program associated with invasion and metastasis in cSCC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A016.
Abstract A019: Identification and Genomic Analysis of miRNA-mRNA Binding Site SNPs in Hepatitis C Virus-Associated Hepatocellular Carcinoma
Authors: Butt Azeem M , Qamar Anum , Siddique Shafiqa 
Published: November 2024

Abstract
Hepatitis C virus (HCV) infection is a major risk factor for hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths globally. MicroRNAs (miRNAs) play critical roles in gene regulation, and single nucleotide polymorphisms (SNPs) within miRNA binding sites can disrupt this regulation, potentially influencing HCC pathogenesis. The present study aims to identify and characterize SNPs within miRNA binding sites of genes associated with HCV- induced HCC (HCV-HCC). A comprehensive bioinformatics analysis workflow was devised. HCV-specific differentially expressed (DE) miRNAs and mRNAs were extracted from literature and databases. SNPs in the 3' UTRs of HCV-HCC genes were identified, and their impact on miRNA binding was predicted using PoymiRTS and TargetScan. RNAhybrid was used to estimate minimum folding energy (MFE) differences (ΔMFE) between mutant and wild types. Functional enrichment analysis was conducted to elucidate the biological processes affected by these SNPs. Our analysis revealed several significant alterations in miRNA-mRNA binding pairs due to SNPs within genes associated with HCV-HCC. For instance, among the downregulated genes in HCV-HCC, the SNP in CTSB (rs3088245; 193T&gt;C) predicted to increase the stability of the miR-27b - CTSB duplex (ΔMFE: 1.4), suggesting enhanced binding and potentially improved repression of CTSB. Conversely, the SNP in EGR2 (rs61865883; 287 T&gt;A) decreased the stability of the miR-140-5p - EGR2 mRNA interaction (ΔMFE: -1.9), suggesting a weaker binding affinity and potentially reduced repression of EGR2 expression. Considering the tumor suppressor role of EGR2, presence of this SNP is likely to reflect good prognosis. For the upregulated gene oncogene, XIAP, the SNP (rs6648556; 5892 T&gt;C) is predicted to enhance the binding of miR- 200c (ΔMFE: 1.5), likely resulting in increased suppression of XIAP expression in patients carrying this SNP and improved prognosis. Our study emphasizes the importance of considering genetic variations in miRNA binding sites in the context of HCV-HCC. These SNPs may serve as genetic modifiers influencing disease susceptibility and progression. Further experimental studies are warranted to explore their potential as therapeutic agents and predictors of prognosis in HCV-HCC patients.
Citation Format: Azeem M Butt, Anum Qamar, Shafiqa Siddique. Identification and Genomic Analysis of miRNA-mRNA Binding Site SNPs in Hepatitis C Virus-Associated Hepatocellular Carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A019.
Abstract I004: Systematic Discovery and Annotation of Cancer Emergent Orphan non-coding RNAs in human Cancers
Authors: Goodarzi Hani 
Published: November 2024

Abstract
We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic search to annotate and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen.
Citation Format: Hani Goodarzi. Systematic Discovery and Annotation of Cancer Emergent Orphan non-coding RNAs in human Cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I004.
Abstract PR001: Targeting mRNA methyltransferase in RNA-dependent DNA repair in cancer therapy
Authors: Lan Li 
Published: November 2024

Abstract
The treatment of many solid tumors presents significant challenges with chemotherapy, radiation therapy, and the limited effectiveness of immunotherapy. Targeted therapy offers a promising approach, yet the lack of validated targets limits its applicability across the spectrum of solid tumors. Our past studies have revealed that an R-loop and mRNA-dependent DNA repair (RDDR) pathway, induced by damage at the transcribed regions of the genome, contributes to cell survival and drug resistance in cancer cells. This is particularly due to the high levels of transcription and DNA damage in these cells. We identified the RNA methyltransferase TRDMT1 as the primary modifier of mRNA methyl-5-cytosine in the RDDR pathway. Overcoming technical difficulties in monitoring RNA modifications, we developed the first TRDMT1 inhibitor (TRDMT1i) using in-house built cell-based and in vitro assays. We have identified highly potent and specific lead compounds that significantly reduce TRDMT1 activity at nanomolar concentrations. Our current lead TRDMT1 inhibitors meets most of the criteria that are required for optimal lead. Initial assessments involving the screening of normal and cancer cell lines, xenograft models, and patient specimens indicate that TRDMT1i sensitizes tumors with genomic instability when used as monotherapy. We aim to develop TRDMT1i as an investigational new drug (IND) for future clinical trials, initially targeting ovarian cancer as a monotherapy or in combination therapy for first-line maintenance and systematic therapy. Our goal is to pioneer the discovery of the RDDR pathway, leading to the development of innovative platforms and next-generation medications to revolutionize the targeting of mRNA modifications in cancer treatment.
Citation Format: Li Lan. Targeting mRNA methyltransferase in RNA-dependent DNA repair in cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR001.
Abstract PR003: Preventing and treating HPV-related Cancer with mRNA Therapy Expressing A DC-targeting Antigen
Authors: Jia William 
Published: November 2024

Abstract
Persistent human papillomavirus (HPV) infection is linked to several malignancies, highlighting the need for effective therapeutic vaccines. In this study, we tested a lipid nanoparticle-encapsulated mRNA vaccine expressing tHA-mE7-mE6. By mutating the E6 and E7 proteins to reduce their tumorigenicity and fusing them with a truncated influenza hemagglutinin protein (tHA) for better antigen uptake, we improved the vaccine’s efficacy. The tHA-mE7-mE6 mRNA vaccine showed superior results compared to mE7-mE6 mRNA, achieving complete tumor regression and preventing new tumors in an E6 and E7 positive model. It elicited a strong CD8+ T-cell response, with antigen-specific CD8+ T-cells found in the spleen, blood, and tumors. Additionally, the therapy increased DC and NK cell infiltration into tumors. Overall, this study demonstrates that the tHA-mE7-mE6 mRNA vaccine induces a potent anti-tumor immune response, showing promise for treating HPV-induced cancers and preventing recurrence.
Citation Format: William Jia. Preventing and treating HPV-related Cancer with mRNA Therapy Expressing A DC-targeting Antigen [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR003.
Abstract PR014: PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth
Authors: Yi Hyerim , Zhang Shu , Jones Matthew G , Belk Julia A , Swinderman Jason , Shi Quanming , Curtis Ellis J , Kanakaveti Vishnu P , Mischel Paul S , Chang Howard Y 
Published: November 2024

Abstract
Extrachromosomal DNA (ecDNA), highly amplified circular DNA, is widespread in human cancers and serves as a primary location for oncogene amplification. Due to its dynamic structural rearrangement and asymmetric inheritance during cell division, ecDNA increases tumor genome complexity, contributing to drug resistance and shortened patient survival. Here, we show that ecDNA-mediated genomic amplification is highly associated with transcript fusion events, which are prevalent in cancer and often lead to tumor development. We discovered that transcripts with the highest fusion events originate from genes amplified on ecDNA across ecDNA(+) cell lines. Notably, PVT1 (Plasmacytoma Variant Translocation 1) long noncoding RNA, which is known to be a hotspot for chromosomal translocation, is the most frequently fused RNA species in MYC/PVT1-amplified ecDNA(+) cancer cells. Exon 1 of PVT1 is the predominant fusion partner and confers RNA stability, increasing the RNA abundance of the partner oncogene. Using a model cell line with PVT1-MYC fusion on ecDNA, we found that RNA expression of PVT1-MYC increases in vivo in an ecDNA-dependent manner, while canonical MYC does not show a prominent increase. Additionally, ectopic expression of PVT1- MYC in MYC-depleted cancer cells provides higher rescue efficiency than canonical MYC. In contrast, a PVT1-MYC mutant that is unable to enhance RNA stability fails to rescue, highlighting the functional significance of PVT1-mediated RNA stabilization in cancer. This study unveils the link between PVT1 fusion and ecDNA in cancer, providing insights for developing diagnostic and therapeutic approaches tailored to target ecDNA.
Citation Format: Hyerim Yi, Shu Zhang, Matthew G Jones, Julia A Belk, Jason Swinderman, Quanming Shi, Ellis J Curtis, Vishnu P Kanakaveti, Paul S Mischel, Howard Y Chang. PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR014.
Abstract 4138545: Mitral Valve Replacement is associated with favourable Functional and Clinical Outcome as compared with Restrictive Mitral Annuloplasty in Patients with Severe Ischemic Mitral Regurgitation. A prospective longitudinal analysis
Authors: Fino Carlo , D'Alonzo Michele , iacovoni attilio , Maccarana Agnese , Magne Julien , Pibarot Philippe , Merlo Maurizio , terzi amedeo , SENNI MICHELE , Bichi Samuele , Simon Caterina , BELLAVIA DIEGO 
Published: November 2024

Background:
Restrictive mitral annuloplasty (RMA) and chordal-sparing mitral valve replacement (MVR) are common options for treatment of chronic severe ischemic mitral regurgitation.

Research question:
in patients with severe ischemic mitral regurgitation the most effective surgical approach remains controversial

Aim:
to test whether MVR provides superior clinical and functional outcomes compared with RMA.

Methods:
a prospective longitudinal analysis on 187 patients (age: 66 ± 9 year; EF:35 ± 8 %) undergoing MVR or RMA and CABG for severe ischemic mitral regurgitation. Six-minute walking test and echocardiography were performed at preoperative baseline, at 1 year and at a median FU of 5 year (interquartile range: 2.9). Brain natriuretic peptide levels were also obtained. Mitral regurgitation was defined through a comprehensive and integrative approach. Recurrent mitral regurgitation was defined as a vena contracta ≥ 3 mm at follow-up, in patients with no persistent regurgitation at discharge.

The primary outcome was a 5-year composite of all-cause mortality and rehospitalization for heart failure.
Survival analysis was performed with Kaplan-Meier method. Cox regression analysis was used to verify any independent predictor of composite end-point

Results:
Baseline preoperative data were similar between the two group. Mitral valve replacement was performed in 49% of patients (n=92) and RMA in 51 % (n=95).

At 5 year patients referred to prostheses showed significant improvement in six-minute walking test as compared to RMA (MVR: 290 ± 70 meters vs MRA: 165± 56 meters) (p > 0.01) (
Figure 1
). The brain natriuretic peptide values did not differ between the two group at 1 year whereas were significantly lower in the MVR group at 5 years (MVR: 135 pg/ml; interquartile range:100 vs RMA: 486 pg/ml; interquartile range: 68 (p<0.01) (
Figure 2
). At 5 years freedom from all-cause death and rehospitalization for heart failure was higher in the MVR group as compared to RMA (84 ±8.9% vs 61 ±12%, p<0.01) (
Figure 3
). According to the Cox analysis recurrent mitral regurgitation was found to be a predictor of clinical outcome (HR:5.4, 95% CI:1.3-23.2, p= 0.023).

Conclusions:
In patients with severe ischemic mitral regurgitation referred for surgery, chordal- sparing MVR and CABG may improve functional capacity, clinical outcome and brain natriuretic peptide levels, compared with RMA and CABG. The impact of these findings remains to be defined by larger studies on longer term
Abstract 4142376: Impact of Atrial Fibrillation on Outcomes in Patients with Esophageal Cancer Receiving Neoadjuvant Chemoradiation
Authors: Sivamurugan Aravinthasamy , Grewal Udhayvir 
Published: November 2024

Limited data indicate an elevated risk of atrial fibrillation (AF) after neoadjuvant chemoradiation in esophageal cancer however the role of AF as an independent predictor of outcomes post-esophagectomy remains under-studied. We sought to the impact of AF on overall outcomes of patients undergoing neoadjuvant chemoradiation and esophagectomy, with or without adjuvant nivolumab.
The global TriNetX database was used to identify patients (based on ICD-10 codes) with esophageal squamous cell carcinoma or adenocarcinoma who received neoadjuvant chemoradiation with carboplatin and paclitaxel and subsequently underwent esophagectomy between 2009 and 2024. Patients who received adjuvant nivolumab were analyzed separately. Patients who developed AF were compared with patients who did not using propensity score matching (PSM) based on age, race, BMI, and multiple comorbidities. Outcomes over a 5-year period were mortality, ischemic stroke, and use of anticoagulation. Odds ratios with 95% confidence intervals were generated with generalized linear mixed modeling and a p value of <0.05 was considered statistically significant.
A total of 1007 patients were identified, of these 186 (18.5%) developed AF after esophagectomy. PSM yielded 94 pairs for patients without adjuvant nivolumab. In this group, mortality was not significantly higher in patients with AF [OR=1.409 (0.793-2.504), p=0.242]. Incidence of stroke was equivalent between patients with and without AF [OR=1 (0.396-2.528), p = 1], despite significantly higher use of anticoagulation in the AF group [OR= 2.004 (1.071-3.749), p<0.028]. PSM for patients receiving adjuvant nivolumab yielded 68 pairs. In this cohort, AF was not associated with a significant difference in mortality [1.86 (0.843, 3.870), p = 0.126]. Incidence of stroke was significantly higher in patients with AF [Risk difference = 0.147 (0.063, 0.231) p = 0.0001], however anticoagulation use was not significantly higher in the AF group [1.944 (0.862, 4.384), p = 0.106].
The current analysis highlights a high incidence of AF after neoadjuvant chemoradiation in esophageal cancer. However, despite rigorous vetting with PSM, we found no difference in mortality associated with AF both among patients who received or did not receive adjuvant nivolumab. Diligent use of anticoagulation is required among patients with AF post-esophagectomy due to an increased risk of stroke. These findings merit confirmation in a large prospective cohort.