Publications by authors named "McGrail D"
Therapeutic strategies targeting the DNA damage response, such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have revolutionized cancer treatment in tumors deficient in homologous recombination (HR). However, overcoming innate and acquired resistance to PARPi remains a significant challenge. Here, we employ a genome-wide CRISPR knockout screen and discover that the depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARPi in HR-proficient ovarian cancer cells.
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- Researchers suggest a new network-based method to identify immunomodulatory genetic variants linked to COVID-19 by analyzing protein interaction networks.
- They discovered that variants affecting specific protein interactions can significantly impact immune response, even if they don't reach usual statistical significance in genome-wide studies.
- Their findings highlight the importance of myeloid and T cell subsets in the immune response and point out a specific variant that disrupts a key protein interaction related to interferon signaling.
Transcutaneous aortic valve replacement (TAVR) has evolved from a complex procedure meant only for patients at prohibitive risk for surgery to a commonly performed procedure across a wide variety of clinical scenarios including the treatment of failed aortic valve bioprosthesis. Annuloplasty rings in the aortic position such as HAART 300 (Biostable Science and Engineering) have been introduced in the management of native aortic regurgitation. Percutaneous management of failed bioprosthesis rings in the aortic position has not been widely described.
View Article and Find Full Text PDFPurpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.
Experimental Design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models.
Article Synopsis
- Pharmacological inhibition of ATR (Ataxia Telangiectasia and Rad3-related protein) is showing promise for cancer treatment by targeting DNA damage repair pathways, helping to overcome resistance to therapies, and boosting anti-tumor immunity.
- Multiple novel ATR inhibitors are currently being tested in clinical trials across various solid tumors, with some reaching phase III trials, but more research is needed to understand their interactions with DNA repair and the immune system.
- Key challenges in developing ATR inhibitors include improving their effectiveness, identifying the right patient populations through predictive biomarkers, and creating effective drug combinations to maximize therapeutic benefits.
Article Synopsis
- The study aims to identify host anti-viral factors that can help control SARS-CoV-2 infection, which have been overlooked in previous research focused mainly on pro-viral factors.* -
- Using a genome-wide CRISPR dropout screen, the researchers found several underappreciated host factors, such as components of V-ATPases, ESCRT, and N-glycosylation pathways, which affect viral entry and replication.* -
- Key findings include the identification of the cohesin complex as an anti-viral pathway and the transcription factor KLF5, which is linked to severe COVID-19 symptoms, shedding light on the genetic and molecular interactions that influence the severity of the disease.*
Article Synopsis
- Inactivating TP53 mutations disrupt p53 function and can lead to gain-of-function (GOF) activities of mutant p53 proteins, which contribute to tumor growth and spread.
- The study reveals that GOF mutp53 interacts with components of the minichromosome maintenance complex (MCMs), causing replication stress and chromosomal instability (CIN), which intensifies cancer cell behavior.
- This interaction triggers a series of signaling pathways, including cGAS-STING-NC-NF-κB, that promote tumor metastasis and create an immunosuppressive tumor environment by dampening interferon responses and enhancing inflammation-related gene expression.
Article Synopsis
- Some types of cancers have problems with proteins that are supposed to help with DNA, and this can make them grow badly.
- Researchers tested different cancer cells by blocking certain proteins (PRMT1, PRMT4, and PRMT5) and found this stopped a key protein (ATR) from working properly.
- Combining the blockage of PRMT5 with a type of cancer treatment (PARP inhibitors) was found to help fight tumors without being too harmful to healthy cells.
Article Synopsis
- B7-H4 (VTCN1) is a protein that is highly expressed in various cancers, and this study focuses on its expression in salivary gland carcinomas (SGC) to evaluate its role as a potential prognostic marker.
- The analysis of 340 tumors showed that B7-H4 expression was particularly prevalent in adenoid cystic carcinomas (ACC) and correlated with specific clinical characteristics, indicating its potential to help predict patient outcomes, especially in ACC cases.
- However, high B7-H4 expression was not found to be prognostic in non-ACC salivary gland tumors, suggesting that its therapeutic implications may be more relevant for certain types, particularly solid ACC.
Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%-20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes.
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- Immune checkpoint blockade (ICB) has changed cancer treatment, but it's not very effective for most breast cancer patients, leading to a need for better strategies.
- The study explored how increasing cytosolic single-stranded DNA (ssDNA) in tumors through genetic silencing improves the immune response and ICB effectiveness in triple negative breast cancer models.
- Results showed that accumulating cytosolic ssDNA enhances tumor immunogenicity and could be a new approach to boost ICB efficacy with fewer side effects, particularly by using the cytosolic ssDNA inducer CEP-701.
Article Synopsis
- * Study of 166 FOs in HeLa cells showed that 58% could form these condensates, indicating distinct physical and chemical properties based on their cellular roles and functions.
- * Machine learning methods predicted that out of ~3000 additional FOs, 67% are likely to form condensates, suggesting significant implications for their roles in gene expression and cell signaling.
Article Synopsis
- Malignant pleural mesothelioma (MPM) has a poor prognosis despite treatment advancements, and patient selection for surgery often uses both objective and subjective criteria.
- The study analyzed 99 MPM patients who received neoadjuvant therapy and underwent macroscopic complete resection, assessing factors affecting overall survival (OS).
- Findings indicated that poor response to neoadjuvant therapy and non-epithelioid histology significantly reduced OS, stressing the need for personalized treatment discussions for affected patients.
Article Synopsis
- Glioblastoma stem cell-like cells (GSCs) are crucial for the growth and resistance of glioblastoma (GBM), and long noncoding RNAs (lncRNAs) play a significant but under-researched role in this context.
- A study identified a specific lncRNA that, when depleted, reduces the proliferation and self-renewal of GSCs, leading to longer survival in GBM models and increased sensitivity to radiation therapy.
- The research also revealed that this lncRNA interacts with YBX1 to stabilize mRNA of key regulators, creating a loop that promotes GSC malignancy and suggests that targeting the lncRNA/YBX1 axis could enhance GBM treatments.
Article Synopsis
- The study investigates how the loss of SETD2, a protein related to DNA damage response, affects kidney cancer (RCC) patient responses to immune checkpoint blockade (ICB) therapy.
- It finds that SETD2 loss leads to increased activation of a specific immune signaling pathway, which allows for better immune response when combined with ATR inhibitors, making the cancer more susceptible to treatment.
- The research suggests that patients with RCC who have SETD2 mutations may benefit from combining ATR inhibition with ICB therapy for improved outcomes.
Article Synopsis
- - The study investigates the tumor microenvironment (TME) of adenoid cystic carcinoma (ACC), a type of cancer with no effective systemic treatment for its metastatic form, distinguishing between two molecular subtypes: ACC-I and ACC-II, with varying prognoses and therapeutic vulnerabilities.
- - Using RNA-sequencing and advanced imaging techniques, researchers found that most ACC tumors are immunologically "cold" and that ACC-I tumors, associated with poor prognosis, have more immune cells but are confined to the stroma, indicating an immune-excluded TME.
- - The research highlights the overexpression of the immune checkpoint B7-H4 in ACC-I tumors, which correlates with worse survival outcomes, suggesting that targeting B7-H4 could
Background: While immune-cell infiltrated tumors, such as human papillomavirus positive (HPV+) ororpharyngeal squamous cell carcinomas (OPSCC) have been associated with an improved clinical prognosis, there is evidence to suggest that OPSCCs are also subjected to increased immunoregulatory influence. The objective of this study was to assess whether patients with clinically aggressive OPSCC have a distinct immunosuppressive immune signature in the primary tumor.
Methods: This retrospective case-control study analyzed 37 pre-treatment tissue samples from HPV+ and HPV-negative OPSCC patients treated at a single institution.
Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance.
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- Genetic screens using single-cell CRISPR technology (scCRISPR) are being developed to improve cancer treatment through immune-related studies involving various cell types.
- The study integrates two scCRISPR platforms, Perturb-seq and CROP-seq, to refine experimental conditions and data analysis for better alignment between high-throughput results and individual experiments.
- Findings indicate that scCRISPR platforms not only analyze gene expression and their effects in single cells but also help understand how tumor-related factors interact with T cell activity, offering insights that traditional bulk RNA-seq cannot provide.
Article Synopsis
- Somatic mutations play a crucial role in cancer development, with many known driver mutations found in protein coding regions, but the impact of mutations in miRNAs and their binding sites is poorly understood.
- This study created cancer-specific miRNA regulatory networks for 30 cancer types, analyzing over 3.5 million mutations and revealing that mutations in miRNAs often occur alongside mutations in their target genes, influencing gene expression.
- The findings highlight 148 potential driver mutations that disrupt miRNA networks, suggesting that downregulated targets in 3' UTRs may act as tumor suppressors, and they introduce a web portal (mGI-map) to help researchers explore this data for future biomarker and drug development.
Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models.
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- * A novel integration approach using the shared nearest neighbors algorithm was developed, enabling the creation of a comprehensive network from immunogenomic data of non-small-cell lung cancer patients.
- * This new approach surpassed traditional networks in identifying established and novel interactions, revealing significant insights related to patient recurrence and the TP53 oncogenotype.
Unlabelled: Multicellularity was a watershed development in evolution. However, it also meant that individual cells could escape regulatory mechanisms that restrict proliferation at a severe cost to the organism: cancer. From the standpoint of cellular organization, evolutionary complexity scales to organize different molecules within the intracellular milieu.
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