Redox regulation and DNA repair coordination are essential for genomic stability. Peroxiredoxin 1 (PRDX1) is a thiol-dependent peroxidase and a chaperone that protects proteins from excessive oxidation. ATM kinase (Ataxi...Redox regulation and DNA repair coordination are essential for genomic stability. Peroxiredoxin 1 (PRDX1) is a thiol-dependent peroxidase and a chaperone that protects proteins from excessive oxidation. ATM kinase (Ataxia-Telangiectasia Mutated) and the MRN (MRE11-RAD50-NBS1) complex are DNA damage signaling and repair proteins. We previously showed that cells lacking PRDX1 are sensitive to arsenite, a toxic metal that induces DNA single- and double-strand breaks (DSBs). Herein, we showed that PRDX1 interacts with ATM. PRDX1-deleted cells have reduced ATM, MRE11, and RAD50 protein levels, but not NBS1. In control cells treated with arsenite, we observed γH2AX foci formation due to arsenite-induced DSBs, and not from PRDX1-deleted cells. Arsenite caused profound depletion of ATM in PRDX1-deleted cells, suggesting that PRDX1 protects and stabilizes ATM required to form γH2AX foci. Importantly, arsenite pretreatment of PRDX1-deleted cells caused hypersensitivity to chemotherapeutic agents that generate DSBs. Analysis of a clinical cohort of ovarian cancers treated with platinum chemotherapy revealed that tumours with high PRDX1/high ATM or high PRDX1/high MRE11 expression manifested aggressive phenotypes and poor patient survival. The data suggest that PRDX1 can predict responses to chemotherapy, and targeting PRDX1 could be a viable strategy to improve the efficacy of platinum chemotherapy.
Different treatment strategies are required for the non-muscle-invasive, muscle-invasive, and metastatic stages of bladder cancer. Standard treatments include surgery, chemotherapy, and radiation; however, they have thei...Different treatment strategies are required for the non-muscle-invasive, muscle-invasive, and metastatic stages of bladder cancer. Standard treatments include surgery, chemotherapy, and radiation; however, they have their limitations. New discoveries have shown that combining immunotherapy and radiation treatment may improve patient outcomes. Radiation therapy promotes immunogenic cell death, which leads to antigen release and immune cell activation, whereas immunotherapy enhances the immune system's ability to recognize and destroy cancer cells by targeting checkpoint pathways like PD-1/PD-L1 and CTLA-4. This review examines the synergistic mechanisms of diverse modalities, focusing on their capacity to alter the tumor microenvironment and elicit systemic anti-tumor responses, such as the abscopal effect. Key clinical trials, such as BTCRC-GU15-023 and ANZUP, have demonstrated the efficacy and safety of combining these medications. However, difficulties persist, such as overlapping toxicities, unpredictability in patient responses, and a lack of accurate patient selection markers. Large-scale randomized trials are needed in the future to fine-tune treatment procedures, minimize toxicity, and validate predictive biomarkers such as PD-L1 expression and tumor mutation burden. By addressing these hurdles, the combination of radiation treatment and immunotherapy has the potential to change the bladder cancer therapeutic landscape.
BACKGROUND: Circulating tumor DNA (ctDNA) can be used as a tool to detect minimal residual disease (MRD) which can provide important prognostic information in diffuse large B-cell lymphomas (DLBCL). Here, we present an u...BACKGROUND: Circulating tumor DNA (ctDNA) can be used as a tool to detect minimal residual disease (MRD) which can provide important prognostic information in diffuse large B-cell lymphomas (DLBCL). Here, we present an ultra-sensitive MRD assay reliant on Phased Variant Enrichment and Detection Sequencing (PhasED-Seq), which leverages phased variants to detect ctDNA. METHODS: Blank plasma samples were used to assess assay specificity and a limiting dilution series with a DLBCL clinical-contrived sample was performed to assess assay sensitivity and precision. DLBCL plasma patient samples with MRD comparator assay results were tested with PhasED-Seq technology to assess assay accuracy. RESULTS: The assay's false positive rate was 0.24% and the background error rate was 1.95E-08. The limit of detection at 95% detection rate with 120 ng of input DNA was 0.7 parts in 1,000,000 and precision was >96%. Positive percent agreement for the MRD assay was 90.62% (95% CI 74.98%, 98.02%) and negative percent agreement was 77.78% (95% CI 52.73, 93.59) using a single nucleotide variant-based method as reference. CONCLUSIONS: The PhasED-Seq-based MRD assay has strong analytical and clinical performance in B-cell malignancies. Improved ctDNA detection methods such as this may improve patient outcomes through detection of residual disease or early relapse.
BACKGROUND: Breast cancer is a type of cancer that can affect both males and females, but it is widespread among women. Blood types may be associated with breast cancer, as many studies have reported on this relationship...BACKGROUND: Breast cancer is a type of cancer that can affect both males and females, but it is widespread among women. Blood types may be associated with breast cancer, as many studies have reported on this relationship but rarely described it. The primary objective of our research is to summarize and analyze the available evidence to produce comprehensive and accurate information that can be used to make evidence-based decisions. METHODS: Researchers searched for studies on breast cancer patients and ABO blood groups across four major databases: PubMed, Scopus, Web of Science, and Google. The outcomes of the studies were presented as a relative risk and odds ratio with a 95% confidence interval. RESULTS: Twenty-nine case-control studies with 13029 breast cancer patients. Blood type A was the most common blood type among patients. For blood type A, there was an association with breast cancer (OR = 1.18, 95% CI: 1.03-1.36). Blood types B, AB, and Rh factor showed no significant association with breast cancer (OR = 0.97, 95% CI: 0.86-1.11, OR = 1.05, 95% CI: 0.89-1.25, and OR = 1.14, 95% CI: 0.81-1.60 respectively) in compare to blood type A. CONCLUSIONS: This study highlights the potential of blood type A as a risk factor for breast cancer compared to blood type O. This relationship was insignificant for blood types B, AB, or Rh. Further studies are needed to understand the mechanisms behind the blood type and breast cancer correlation.
N6-methyladenosine (m6A), one of the most prominent and reversible internal modifications of eukaryotic RNAs, has emerged as a critical regulator of gene expression in various cancers including oral squamous cell carcino...N6-methyladenosine (m6A), one of the most prominent and reversible internal modifications of eukaryotic RNAs, has emerged as a critical regulator of gene expression in various cancers including oral squamous cell carcinoma (OSCC), wherein it shapes the tumor-specific epitranscriptomic gene-regulatory networks. METTL3, the primary m6A RNA methyltransferase, is significantly upregulated in OSCC cells leading to increased global m6A levels. Interestingly, METTL3 positively regulates miRNA biogenesis by modulating the processing of primary miRNAs in a m6A-dependent manner. We identified miR-146a-5p, an oncogenic miRNA as one of the METTL3-regulated miRNAs in OSCC. METTL3-depletion or inhibition of its catalytic activity leads to a reduction of miR-146a-5p and an appreciable accumulation of primary miR-146a in OSCC cells. Functional assays examining the effects of miR-146a-5p inhibition or overexpression confirm its oncogenic role in OSCC pathophysiology. Further, SMAD4, a central transducer in TGF-β signaling, was identified as a miR-146a-5p target. In OSCC cells, SMAD4-depletion exacerbates the oncogenic traits, whereas its overexpression exerts the opposite effect. Additionally, METTL3-depletion dysregulates SMAD4-regulated genes suggesting its potential involvement in SMAD4-dependent TGF-β signaling. Taken together, we report that METTL3, an oncogene regulates the expression of SMAD4, a tumor-suppressor via miR-146a-5p, thus unveiling a novel regulatory axis of METTL3/miR-146a-5p/SMAD4 in OSCC, which can potentially have therapeutic implications.
Host immunosurveillance is an important factor in the progression of high-grade squamous intraepithelial lesions (HSIL) into high-risk human papillomavirus (HR-HPV)-related squamous cell carcinoma. Immune escape by forkh...Host immunosurveillance is an important factor in the progression of high-grade squamous intraepithelial lesions (HSIL) into high-risk human papillomavirus (HR-HPV)-related squamous cell carcinoma. Immune escape by forkhead box protein P3 (FOXP3+) immunoregulatory T cells and the programmed death-ligand 1 (PD1/PD-L1) axis, mechanisms best described in the context of invasive neoplasms, may play a role in the evolution of pre-malignant lesions. This morphological study aimed to characterize the inflammatory response and expression of FOXP3 and PD-L1 in anal, vulvar, and penile HSILs and compare them with those in low-grade SILs co-infected with HR-HPV (LSIL). The study group comprised 157 samples from 95 male and 55 female patients (median age = 35.5 years), including 122 HSILs and 35 LSILs. Dense inflammatory infiltrates and high counts of FOXP3 cells were significantly more frequent in patients with HSILs than in those with LSILs ( = 0.04 and 0.02, respectively). HSILs also exhibited higher PD-L1 expression ( < 0.01 and < 0.01 for the SP142 and 22C3 clones, respectively), based on the Poisson generalized linear model. In addition, concordant higher PD-L1 expression was observed in cases with a greater number of FOXP3+ cells ( < 0.05). Our findings indicate a putative role of transcriptionally active HR-HPV in evoking an inflammatory response and immune evasion in the early phases of carcinogenesis in a subset of non-cervical anogenital HSILs.
The polymorphic genes PTGS1 and PTGS2 encode cyclooxygenases COX-1 and COX-2, respectively. Overexpression of these cyclooxygenases is linked to inflammation and neoplasms. This study investigated the potential associati...The polymorphic genes PTGS1 and PTGS2 encode cyclooxygenases COX-1 and COX-2, respectively. Overexpression of these cyclooxygenases is linked to inflammation and neoplasms. This study investigated the potential association between the single nucleotide polymorphism (SNP) -842A>G (rs10306114) of the PTGS1 gene and SNP-765G>C (rs20417) of the PTGS2 gene with prostate cancer (PCa) and benign prostate hyperplasia (BPH). Blood leucocyte DNA from 56 healthy individuals, 61 individuals with PCa, and 51 individuals with BPH were genotyped using the PCR-RFLP method. Associations were inferred by calculating odds ratios (OR) and relative risks (RR) of genotype distributions and allele frequencies. The genotypes for both SNPs were in Hardy-Weinberg equilibrium for all groups. No significant association was observed between the A or G alleles or the AA, AG, or GG genotypes of the SNP-842A>G of the PTGS1 gene and prostatic diseases. However, the C allele of SNP-765G>C of the PTGS2 gene was significantly associated with an increased risk of BPH (OR = 2.30, -value = 0.01). Differences in the ratios of GG/GC and GG/(GC+CC) genotypes also suggested a potential association between the C allele and PCa (-value <0.1), and the combined affected (PCa+BPH) group (-value <0.04). The small sample size and sampling from one ethnic group are limitations of this study.
Recent advances in deep learning models have transformed medical imaging analysis, particularly in radiology. This editorial outlines how uncertainty quantification through embedding-based approaches enhances diagnostic...Recent advances in deep learning models have transformed medical imaging analysis, particularly in radiology. This editorial outlines how uncertainty quantification through embedding-based approaches enhances diagnostic accuracy and reliability in hepatobiliary imaging, with a specific focus on oncological conditions and early detection of precancerous lesions. We explore modern architectures like the Anisotropic Hybrid Network (AHUNet), which leverages both 2D imaging and 3D volumetric data through innovative convolutional approaches. We consider the implications for quality assurance in radiological practice and discuss recent clinical applications.
Glioblastoma remains a lethal brain tumor in adults with limited therapeutic options. TIC10/ONC201, a first-in-class imipridone we discovered, achieved meaningful therapeutic effects in phase I/II trials in patients with...Glioblastoma remains a lethal brain tumor in adults with limited therapeutic options. TIC10/ONC201, a first-in-class imipridone we discovered, achieved meaningful therapeutic effects in phase I/II trials in patients with diffuse gliomas (DG's) harboring H3K27M mutations, and currently the drug is in randomized phase III testing (ACTION trial; NCT05580562). ONC201 targets mitochondrial protease ClpP to disrupt oxidative phosphorylation and trigger the integrated stress response (ISR), TRAIL/DR5, and tumor cell death. While ONC201 and its analog ONC206 are undergoing clinical trials as single agents, there is limited information on their interactions with stand-of-care therapy. We show that ONC201 and ONC206 synergize with temozolomide (TMZ) and Radiotherapy (RT). ONC201 enhances TMZ- or RT-induced apoptosis, ISR and cytotoxicity. ClpP-silencing suppresses ONC201-induced cytotoxicity but not TMZ. Both ONC201 and ONC206 reduce expression of TMZ-resistance mediator MGMT observed in H3K27M-mutated DG cells following treatment with imipridones+TMZ. Cytokine profiling indicates distinct effects of ONC201 relative to TMZ treatment. These results suggest mechanisms underlying ONC201's anti-tumoral activity are distinct from those associated with TMZ or RT with potential for synergy between these three treatments. Triple ONC201+RT+TMZ (IRT) therapy prolonged median survival to 123 days with tail on survival curve (3-of-7 mice alive beyond 200-days) in orthotopic U251 GBM model versus ONC201 (44-days; = 0.000197), RT (63-days; = 0.0012), TMZ (78-days; = 0.0354), ONC201+RT (55-days; = 0.0004), ONC201+TMZ (80-days; = 0.0041) and RT+TMZ (103-days; > 0.05). By 231-days, the only surviving mice were in IRT group. Our results support investigation of ONC201/ONC206 in combination with RT/TMZ (IRT) in GBM or H3K27M mutated DG therapy.
Overexpression of the H3K36 histone methyltransferase NSD2 in t(4;14) multiple myeloma (MM) is an early, oncogenic event, and understanding its impact on genomic organisation and expression is relevant to understanding M...Overexpression of the H3K36 histone methyltransferase NSD2 in t(4;14) multiple myeloma (MM) is an early, oncogenic event, and understanding its impact on genomic organisation and expression is relevant to understanding MM biology. We performed epigenetic, transcriptional and phenotypic profiling of the t(4;14) KMS11 myeloma cell line and its isogenic translocation knock out (TKO) to characterise the sequelae of NSD2 overexpression. We found a marked global impact of NSD2 on gene expression and DNA organisation implicating cell identity genes; notably the early lymphocyte regulator, LAIR1 and MM cell surface markers, including CD38, a classical marker of plasma cells which was reduced in TKO cells. Plasma cell transcription factors such as PRDM1, IRF4 and XBP1 were unaffected, suggesting a downstream direct gene effect of NSD2 on cell identity. Changes in cell surface markers suggest an altered surface immunophenotype. Our findings suggest a role for NSD2 in maintaining MM cell identity, with potential implications for future therapeutic strategies based on targeting of NSD2.
Retinoic acid (RA), an embryonic morphogen, is used in cancer differentiation therapy, causing extensive gene expression changes leading to cell differentiation. This study reveals that the expression of the Src-family k...Retinoic acid (RA), an embryonic morphogen, is used in cancer differentiation therapy, causing extensive gene expression changes leading to cell differentiation. This study reveals that the expression of the Src-family kinase (SFK), FGR, alone can induce cell differentiation similar to RA. Traditionally, RA's mechanism involves transcriptional activation via RAR/RXR(Retinoic Acid Receptor/Retinoid X Receptor) nuclear receptors. In the HL-60 human myelo-monocytic leukemia model, an actively proliferating phenotypically immature, lineage bipotent NCI-60 cell line. RA promotes myeloid lineage selection and maturation with G1/0 growth inhibition. This study finds that FGR expression alone is sufficient to induce differentiation, marked by CD38, CD11b, ROS, and p27(kip1) expression, characteristic of mature myeloid cells. To understand the mechanism, signaling attributes promoting RA-induced differentiation were analyzed. RA induces FGR expression, which activates a novel cytosolic macromolecular signaling complex(signalsome) driving differentiation. RA increases the abundance, associations, and phosphorylation of signalsome components, including RAF, LYN, FGR, SLP-76, and CBL, which appear as nodes in the signalsome. These traditionally cytosolic signaling molecules go into the nucleus. RAF complexes with a retinoic acid-response element (RARE) in the blr1 gene promoter, where the induced BLR1 expression is essential for RA-induced differentiation. We find now that FGR expression mimics RA's enhancement of signalsome nodes, RAF expression, and phosphorylation, leading to BLR1 expression. Notably, FGR induces the expression of genes targeted by RAR/RXR, such as cd38 and blr1, even without RA. Thus, FGR triggers signaling events and phenotypic shifts characteristic of RA. This finding represents a paradigm shift, given FGR's historical role as a pro-proliferation oncogene.