Search Results (359)

The ataxia–telangiectasia-mutated (ATM) protein plays a crucial role in the DNA damage response, particularly in the homologous recombination (HR) pathway. This study aimed to assess the impact of deleterious ATM variants on homologous recombination deficiency (HRD) and response to PARP inhibitors (PARPi) in melanoma patients, using a cell line established from melanoma tissue of a patient carrying the c.5979_5983del germline ATM variant. Despite proven loss of heterozygosity, lack of ATM activation, and HRD, our model did not show sensitivity to PARPi. We assessed the potential contribution of the Schlafen family member 11 (SLFN11) helicase, whose expression is inversely correlated with PARPi sensitivity in other cancers, to the observed resistance. The ATM mutant cell line lacked SLFN11 expression and featured hypermethylation-mediated silencing of the SLFN11 promoter. While sensitive to the ATR inhibitor (ATRi), the addition of ATRi to PARPi was unable to overcome the resistance. Our findings suggest that ATM mutational status and HRD alone do not adequately account for variations in sensitivity to PARPi in our model. A comprehensive approach is essential for optimizing the exploitation of DNA repair defects and ultimately improving clinical outcomes for melanoma patients. Full article

Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair (pMMR) and microsatellite stability (MSS) metastatic colorectal cancer (mCRC). Inhibition of vascular endothelial growth factor (VEGF) or cytotoxic chemotherapy can boost immunogenicity and has the potential to upregulate ICI efficacy. Methods: A comprehensive electronic literature search was conducted up to April 2025 to identify randomized controlled trials comparing cytotoxic chemotherapy plus bevacizumab with or without ICI. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival (OS), objective response rate (ORR), and severe adverse events (AEs: grade 3 or more). A meta-analysis was performed using random-effects models to calculate hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: Four studies involving 986 patients (With-ICI group, n = 651; Without-ICI group, n = 335) were included. The meta-analysis demonstrated a significant improvement in PFS in the With-ICI group compared with the Without-ICI group, with an HR of 0.82 (95% CI: 0.70–0.96, p = 0.01) without statistical heterogeneity. No significant improvements were observed between the With- and Without-ICI groups in OS and ORR meta-analyses, but the With-ICI group had a favorable trend in OS. A significant increase in serious AEs was not observed in the With-ICI group. Conclusions: This meta-analysis suggests a potential benefit of adding ICIs to chemotherapy plus bevacizumab in pMMR mCRC; however, the evidence remains preliminary and hypothesis-generating, warranting further investigation in biomarker-driven trials and clarification of long-term outcomes. Full article

Background: Circadian rhythms regulate critical cellular processes, including DNA repair and cell cycle dynamics, potentially influencing the effectiveness of radiotherapy (RT). This study evaluated whether RT timing impacts clinical outcomes and symptom burden in prostate cancer patients. Patients/Methods: This retrospective study (n = 336, median follow-up 55 months) included men who received curative intent external beam RT between 2010 and 2019 (median age 69, 69% black, median PSA 11.3, 40% with Gleason 8–10). Treatment times (TTs) were averaged and analyzed by quartile/median. Outcomes included freedom from biochemical failure (FFBF) and distant metastasis (FFDM), GI and GU toxicity, and quality of life (QOL). Subgroup analyses by race and hormone therapy status were performed. Results: Across the overall cohort, TT was not associated with FFBF or FFDM. However, in white men, earlier TTs were significantly associated with higher 5-year FFBF (89% vs. 67%, p = 0.0139) and FFDM (93% vs. 72%, p = 0.0268). In the multivariate analysis (MVA), TT was not associated with FFBF or FFDM for all men, but in white men, earlier TT was associated with improved FFBF (HR 2.8, p = 0.06) in a model also including risk category (p = 0.21). Overall, no significant differences were observed for grade 2–3+ toxicity and TT. Trends for inferior QOL, and worse grade 2+ (p = 0.2) and 3+ GU toxicity (p = 0.1) were observed for later TTs. In white men, bowel, urinary continence, and irritative/obstructive urinary QOL were worse with later TTs (p < 0.05). Conclusions: TT may influence clinical outcomes and symptom burden, particularly in white men. These findings underscore the potential of chronoradiotherapy as a personalized treatment strategy and highlight the need for prospective trials. Full article

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic agents. To address this limitation, bioreductive drugs have been developed that become selectively activated in hypoxic environments, providing targeted cytotoxic effects within oxygen-deprived tumor regions. Additionally, the rapid growth of tumors often results in disorganized and inefficient vasculature, further impairing the delivery of oxygen and therapeutic agents. This review explores the molecular mechanisms by which hypoxia disrupts DNA repair and contributes to treatment resistance. It also presents emerging therapeutic strategies aimed at targeting the hypoxic tumor microenvironment to improve treatment efficacy and patient outcomes. Full article

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Acute neutrophil responses following myocardial infarction (MI) play a central role in remodeling, contributing to both repair and potential maladaptive responses. Although prior studies have investigated circulating immune cell indices at a single time point during hospitalization for MI, limited data exist on acute intra-individual changes in circulating immune profiles during evolving MI. We analyzed clinical measurements, such as the count and proportion of immune cell components in a serial complete blood count, with differential tests conducted for patients hospitalized with ST-elevation MI (STEMI) in various hospitals in the Northwestern Medicine system from 1 January 2002 to 1 August 2024. Patients with STEMI diagnosis, troponin peaks ≥ 5 ng/mL, and cell count and proportion data prior to the troponin peak and within 24 h after the troponin peak were included. Primary analyses investigated the associations between the troponin peak and peri-STEMI changes in immune cell subsets. Multivariable-adjusted Cox models were used to investigate associations between these peri-STEMI immune cell changes and mortality at 1 year and 3 years. Among the 694 STEMI patients meeting the inclusion criteria, a higher troponin peak was associated with a modest peri-MI increase in neutrophil proportion. Higher adjusted peri-STEMI increases in neutrophil count and proportion were strongly associated with mortality at one and three years [hazard ratio (HR) = 1.31 (95% confidence interval (CI) 1.15–1.49) and HR = 1.27 (95% CI 1.14–1.45) per 1000 cells/μL absolute neutrophil increase, respectively]. Individuals with higher STEMI-related neutrophil increases had higher mortality at one year and three years, independent of the extent of troponin elevation. Full article

Epigenetic modifications are heritable, reversible alterations that causally reshape chromatin architecture and thereby influence DNA repair without changing nucleotide sequence. DNA methylation, histone modifications and non-coding RNAs profoundly influence DNA repair mechanisms and genomic stability. Aberrant epigenetic patterns in cancer compromise DNA damage recognition and repair, therefore impairing homologous recombination (HR), non-homologous end joining (NHEJ), and base excision repair (BER) by suppressing key repair genes and lowering access to repair sites. Then it is dissected how loss-of-function mutations in Switch/Sucrose non-fermentable, imitation switch and CHD (Chromodomain helicase DNA-binding) chromatin-remodeling complexes impair nucleosome repositioning, preventing effective damage sensing and assembly of repair machinery. Non-coding RNAs contribute to epigenetic silencing at DNA break sites, exacerbating repair deficiencies. This review evaluates recent advances concerning epigenetic dysfunction and DNA repair impairment. It is also highlighted that nanoparticle-mediated delivery strategies are designed to overcome pharmacologic resistance. It is presented how epigenetic dysregulation of DNA repair can guide more effective and drug-resistant cancer therapies. Full article

Alterations in the PTEN tumor suppressor gene are common in prostate cancer. They have been associated with a more aggressive disease and poor outcomes and potential benefit of targeted therapies. The purpose of this work is to study the clinical and transcriptional landscapes associated to low PTEN mRNA expression in metastatic hormone-sensitive prostate cancer (mHSPC) patients. A multicenter biomarker ambispective study was performed in mHSPC patients. PTEN mRNA expression was assessed by nCounter in formalin-fixed paraffin-embedded tumor samples. PTEN_low status was defined by a previously validated cut-off and was correlated with castration-resistant prostate cancer (CRPC)-free survival (CRPC-FS) (primary endpoint) and overall survival (OS). RNA-Seq was performed to molecularly characterize PTEN_low vs. PTEN_wt tumors. A total of 380 patients were included, 350 eligible. PTEN_low was observed in 28.2% of patients and was independently associated with shorter CRPC-FS (HR 1.6, 95% CI 1.2–2.1, p = 0.002) and OS (HR 1.5, 95% CI 1.1–2, p = 0.014). PTEN_low tumors showed overexpression of neuroendocrine, cell cycle, and DNA repair gene signatures, reduced expression of the androgen receptor pathway, and a distinct immune microenvironment. Using microarray data from the CHAARTED trial, we developed a PTEN-low related signature, independently associated with CRPC-FS (HR 1.5, 95% CI 1–2.3, p = 0.036) and OS (HR 1.9, C1 1.2–2.9, p = 0.005), and identified targets for potential therapies in PTEN-altered tumors. We conclude that PTEN_low correlates with an aggressive clinical outcome in mHSPC patients and is associated with a unique transcriptional profile. These findings further support the investigation of novel therapeutic strategies for patients with PTEN alterations. Full article

Background: Breast cancer (BC) is the most common cancer in women worldwide. Much progress has been made to improve treatment options for patients suffering from the disease, including a novel therapy—Poly (ADP-ribose) polymerase inhibitor (PARPi) that specifically targets tumors with deficiencies in the Homologous Recombination (HR) DNA repair pathway. To benefit better from conventional therapy, many patients seek alternative supplementation, with 20–30% of cancer patients using herbal medication on top of their regular treatment. An example of such easily available over-the-counter supplements is curcumin, a natural compound derived from turmeric (Curcuma longa). Various studies reported the potential HR deficiency (HRD) inducing effect of curcumin in cancer cells. Methods: Eight BrC and three normal cell lines and a BrC PDX model were used to evaluate the effect of curcumin on RAD51 ionizing radiation-induced focus (IRIF) formation. Three breast BrC cell lines underwent further analysis using the BRCA2 Western blot technique. To assess cell survival after treatment with curcumin and/or PARPi, a clonogenic survival assay was performed on both normal and cancerous cell lines. Results: Curcumin treatment led to a reduction in RAD51 IRIF formation capacity across all tested models. A decrease in BRCA2 levels was observed in the tested cell lines. Our findings demonstrate that HRD can be induced in both cancerous and normal cells, suggesting that curcumin treatment may increase the risk of toxicity when combined with PARPi therapy. Conclusions: The use of curcumin in combination with certain anti-cancer treatments should not be implemented without extensive monitoring for deleterious side effects. Full article

GEN1 is implicated in DNA damage repair, as are several other breast cancer susceptibility genes, and is included in several comprehensive next-generation sequencing (NGS) testing panels. To investigate the possible association of GEN1 variants with breast cancer risk, we sequenced this gene in 617 Polish women with hereditary breast cancer (HBC) and 300 Polish cancer-free controls. No protein-truncating variants were detected in the conserved part of GEN1 (first 480 codons). Two frameshift variants were detected in the last exon of GEN1: c.2515_2519delAAGTT (p.Lys839Glufs*2) and c.1929_1932delAAAG (p.Lys645Cysfs*29). The p.Lys839Glufs*2 variant was detected in 21.1% of 617 HBC cases and 18.4% of 300 controls (p = 0.38). The p.Lys645Cysfs*29 variant was rare, seen in 0.6% of 617 HBC cases and 0.3% of 300 controls. The variant was then detected in 38 (0.24%) of 15,930 unselected breast cancer cases and 8 (0.17%) of 4702 cancer-free female controls from Poland (OR = 1.40, p = 0.49). Clinical characteristics of breast tumors in the 38 carriers of p.Lys645Cysfs*29 and 15,892 non-carriers were similar. Survival was similar among variant carriers and non-carriers (the age-adjusted HR = 0.87, p = 0.76). The wild-type GEN1 allele was retained in all five breast cancers of carriers of p.Lys645Cysfs*29. No cancer type was more frequent in the relatives of 35 p.Lys645Cysfs*29 variant carriers compared to the relatives of 14,592 non-carriers. We conclude that GEN1 is unlikely to be a high or moderate-risk breast cancer susceptibility gene. Our study has clinical implications for genetic counseling and suggests that GEN1 changes should be reclassified as variants of uncertain significance (VUS) when they are detected in clinical testing panels. Full article

Hereditary breast and ovarian cancer (HBOC) syndrome is primarily associated with mutations in BRCA1 and BRCA2, but increasing evidence links it to other malignancies, including male breast, prostate, and pancreatic cancers. Advances in genetic testing have led to the use of multigene panels, revealing that additional genes contribute to HBOC risk. We tested 280 patients with suspected HBOC using a multigene panel including BRCA1, BRCA2, and other genes involved in homologous recombination (HR) and additional DNA repair mechanisms. Variants were classified as pathogenic variants (PVs), variants of uncertain significance (VUS), or novel. In silico tools were used to predict the clinical relevance of VUS and novel variants. The clinical phenotype of families carrying a PV was evaluated. PVs were identified in 19.3% of patients: 8.9% in BRCA1/2 and 10.4% in other genes, mainly CHEK2, ATM, PALB2, and BRIP1. An additional 1.8% of cases harbored likely pathogenic VUS or novel variants according to bioinformatic prediction. Breast and ovarian cancer were the most frequent malignancies in our population, both in the BRCA group and in those with PVs in other susceptibility genes. Broad genetic testing beyond BRCA improves HBOC diagnostics, supports identification of at-risk families, and enables more personalized surveillance and treatment. Full article

Background: Previous studies reported a protective effect of type 2 diabetes on the progression of aortic aneurysms. We aimed to investigate whether this paradoxical phenomenon remained in patients with diabetes undergoing repair of ruptured aortic aneurysms. Methods: Data from the US Nationwide Readmission Database from 2016 to 2019 were analyzed. Patients admitted for surgical repair of ruptured abdominal or thoracic aortic aneurysms were included. Patients discharged alive were followed for 30 days. The co-primary outcomes were in-hospital and 30-day mortality. Results: A total of 9858 patients hospitalized for surgical repair of ruptured abdominal or thoracic aortic aneurysm were included, of whom 16.4% had diabetes. A lower adjusted risk of in-hospital mortality in abdominal and thoracic aneurysms was observed in diabetes patients (aOR = 0.76 [0.67–0.87], 0.61 [0.46–0.810], respectively). However, atrial fibrillation and acute renal failure were more likely to occur in the presence of diabetes (aOR = 1.25 [1.11–1.42]; 1.17 [1.05–1.32], respectively). Within 30 days, diabetes was not associated with a difference in the incidence of mortality or readmission (aHR = 1.47 [95% CI 0.98–2.22]; 1.15 [95% CI 0.99–1.34], respectively). Cardiovascular system-related pathologies were the most prevalent etiologies in all readmitted patients. Infections were more likely to occur in the diabetes group (16.0% vs. 11.0%, respectively, p = 0.042). Conclusions: The paradoxical effect of diabetes is also observed in ruptured aneurysms treated surgically, as type 2 diabetes patients have a lower in-hospital mortality. However, this protective effect does not extend to 30-day readmission or survival. Full article

Trichomonas vaginalis, the protozoan responsible for trichomoniasis, encounters fluctuating levels of metal cations in the male urogenital tract, notably zinc (Zn²⁺) and cadmium (Cd²⁺), which may induce genotoxic stress. While zinc is a key physiological component of the male reproductive tract, both Zn²⁺ and Cd²⁺ can become genotoxic at elevated concentrations. However, their effect on DNA repair mechanisms in T. vaginalis remains poorly understood. This study characterizes, for the first time, the expression and modulation of the recombinase TvRAD51, a homologous recombination (HR) key enzyme, in response to UV irradiation and sublethal concentrations of Zn²⁺ (1.6 mM) and Cd²⁺ (0.1 mM). In silico analyses confirmed the presence and conserved structure of the tvrad51 gene and its interaction with HR-related proteins, such as TvBLM and TvBRCA2. Quantitative RT-PCR, Western blot, and immunofluorescence assays revealed that TvRAD51 is upregulated at both transcript and protein levels following UV- and cation-induced DNA damage, with distinct temporal expression patterns for Zn²⁺ and Cd²⁺ exposure. Notably, TvRAD51 showed nuclear localization at early time points post-exposure, suggesting active participation in DNA repair processes. These findings demonstrate that TvRAD51 is a central component of the genotoxic stress response in T. vaginalis, potentially contributing to parasite survival and adaptation in hostile environments through homologous recombination repair pathways. Full article

Background: Deinococcus radiodurans, renowned for its exceptional resistance to radiation, provides a robust model for elucidating cellular stress responses and DNA repair mechanisms. Previous studies have established PprI as a key regulator contributing to radiation resistance through its involvement in DNA damage repair pathways, oxidative stress response, and metabolic regulation. Methods: Building upon these foundations, our study employs label-free quantitative (LFQ) proteomics coupled with high-resolution mass spectrometry to systematically map pprI deletion protein networks by comparing the global proteomic profiles of pprI knockout and wild-type D. radiodurans strains. Results: Under stringent screening criteria, we identified 719 significantly higher and 281 significantly lower abundant proteins in the knockout strain compared to wild-type strains. Functional analysis revealed that PprI deficiency disrupts homologous recombination (HR) repair, activates nucleotide excision repair (NER) and base excision repair (BER) as a compensatory mechanism, and impairs Mn/Fe homeostasis and carotenoid biosynthesis, leading to increased oxidative stress. Furthermore, PprI deficiency induces significant metabolic reprogramming, including impaired purine synthesis, compromised cell wall integrity, etc. Conclusions: These proteomic findings delineate the extensive regulatory network influenced by PprI, revealing coordinated perturbations across multiple stress response systems when PprI is absent. Full article