Search Results (243)

Poly(ADP-ribose) polymerase inhibitors (PARPis) have transformed the treatment landscape of homologous recombination-deficient malignancies, particularly BRCA1/2-mutant breast, ovarian, pancreatic, and prostate cancers. In contrast, clinical studies evaluating PARPis in broadly selected colorectal cancer (CRC) patients have yielded disappointing outcomes despite evidence that a subset of CRCs harbor DNA damage response (DDR) defects and homologous recombination deficiency (HRD)-associated mutational signatures. These observations highlight the need for improved patient stratification and the development of strategies to enhance PARPi sensitivity in CRC. In this review, we integrate CRC-specific evidence with mechanistic and preclinical findings from other malignancies and discuss candidate biomarkers associated with PARPi responsiveness, including TP53, RAD51, and MRE11, and examine their potential utility in identifying CRC patient populations most likely to benefit from PARP inhibition. We further summarize therapeutic approaches aimed at inducing “BRCAness” and sensitizing CRC cells to PARPis through epigenetic modulation, targeting cell-cycle checkpoint regulators, inhibiting growth factor signaling pathways, and exploiting metabolic vulnerabilities. Emerging strategies involving polyamine inhibition and modulation of NAD+ metabolism have been specifically highlighted for their potential role in therapeutic response. Collectively, these approaches provide a framework for investigating mechanistically compelling opportunities to overcome intrinsic and acquired resistance to PARPis and expand the clinical utility of DDR-targeted therapies in CRC. A deeper mechanistic understanding of PARPi response and resistance, in addition to extensive investigations in CRC-specific models and molecularly selected clinical cohorts, will facilitate the development of biomarker-driven combination therapies and improve outcomes for patients with CRC. Full article

Germline Whole-Exome Sequencing (WES) has emerged as a powerful genomic approach for investigating Hereditary Cancer predisposition through the comprehensive analysis of coding regions across the genome. Although multigene panels currently represent the standard diagnostic approach for Hereditary Cancer assessment, a substantial proportion of high-risk individuals and families remain molecularly unexplained. In this setting, germline WES may serve as a valuable second-tier strategy by identifying pathogenic variants in genes not routinely included in conventional testing panels and by addressing part of the unresolved “missing heritability” observed across Hereditary Cancer syndromes. Increasing evidence supports its application in hereditary breast and ovarian cancer, Lynch-like syndrome, colorectal polyposis, hereditary diffuse gastric cancer, and ovarian cancer predisposition, where WES has contributed to the identification of additional susceptibility genes and improved molecular characterization. Beyond Hereditary Cancer diagnostics, exome-based approaches have also been explored for tumour profiling, homologous recombination deficiency (HRD) assessment, biomarker discovery, and therapeutic stratification. However, despite its significant potential, the clinical implementation of WES remains challenging because of the high burden of variants of uncertain significance (VUS), difficulties in variant interpretation, incidental findings, and the need for robust functional validation of candidate genes. This review critically examines the current evidence supporting the clinical utility of germline WES in Hereditary Cancer syndromes, focusing on the clinical scenarios in which WES may provide meaningful additional information beyond multigene panels, its diagnostic yield, limitations, and future perspectives in precision oncology. Full article

Background: This study aimed to investigate flow, contact angles and capillary penetration of commercially available endodontic sealers by substrate (human root dentin discs [HRD] and gutta-percha [GP]) and by temperature [room (20 °C), or body (37 °C)]. Methodology: Nine commercially available endodontic sealers were tested using the two-plate method, contact angle calculation (measured on HRD and GP surface—for both temperatures), free-flow, and penetration co-efficiency using a capillary permeability test (in 37 °C). Discs, set-ups and sealers were prepared according to the protocol; specimens were photographed; results were collected; and all recordings were statistically analyzed. Results: The chemical composition of each sealer significantly affected rheological properties even in the same chemical group (p < 0.001). Also, recordings from every test made were also significantly influenced by temperature (p < 0.001). More specifically, the behaviour of sealers under higher temperature proved to be sealer-specific. Conclusions: Within the limitation of this study, it was verified that Endodontic sealers’ rheological properties were affected by the substrate’s composition and temperature. Additionally, body temperature significantly influenced thier performance. Full article

Carboplatin/paclitaxel (CP) chemotherapy is the cornerstone of therapy for advanced stage ovarian cancer (OC). However, despite initial sensitivity, this regimen cannot avoid the emergence of resistance. Ixabepilone ± bevacizumab (IB) is a combination recently added to NCCN guidelines for the treatment of platinum-resistant OC. It would be desirable to identify biomarkers able to differentiate patients who are resistant to CP and IB, and biomarkers that identify which patients may benefit from IB treatment. We analyzed whole-exome-sequencing (WES) data from 49 OC patients exposed to CP, including 28 platinum-sensitive vs. 21 platinum-resistant, and 31 additional platinum-resistant patients, including 16 responders (i.e., CR/PR) vs. 15 non-responders (SD/PD) to ixabepilone ± bevacizumab. Comprehensive genetic analyses were performed to identify alterations correlated with resistance to CP and IB. WES analysis of CP responders vs. non-responders revealed differences in HRD-signatures (p < 0.05), OS (p < 0.005) and gain/loss-of-function in multiple genes associated with tumor growth/progression including but not limited to ACVR2A, INHBA, MAP3K7, ATG5, SGK1, FYN, RSPO3, NOD1 and LRRK2. WES analysis of platinum-resistant IB-treated patients revealed additional nominally significant genes and deranged pathways including gains in the DROSHA and SDHA genes in responders vs. non-responders (p < 0.05). Patients harboring HRD-signatures showed significantly higher sensitivity to CP and prolonged survival compared to HRD-negative patients. Alterations in genes associated with tumor growth/progression correlated with resistance to CP regimen and may represent novel “druggable” candidate biomarkers for the targeted treatment of CP/IB-resistant patients. Further validation in independent cohorts and preclinical experiments in CP/IB-resistant models are warranted to establish the clinical utility of these findings. Full article

Rhizogenic Agrobacterium (Rhizobium) spp. are causative agents of hairy root disease (HRD), a major threat to hydroponic crop production worldwide. The use of specific bacteriophages is considered a prospective approach to control the development of HRD in greenhouses. A combination of diverse bacteriophages is a key step to overcome potential phage resistance in the pathogen. In this study, a novel lytic bacteriophage, named Miki, was identified and characterized for its antibacterial potential against a rhizogenic Agrobacterium sp. strain circulating in greenhouses in Central Russia. High-throughput sequencing revealed a 63,458 bp double-stranded DNA genome (G + C content 53%), with 117 predicted coding sequences, considering Miki as a lytic candidate phage for plant protection. Electron microscopy of phage Miki shows a morphology unusual for Agrobacterium phages, and phylogenetic analysis attributes it as a representative of a previously undescribed taxon at least at the genus level. The paper presents a detailed analysis of the genome and structural proteome of phage Miki, including in silico predictions and modeling of receptor-binding proteins, including central and proximal fibers resembling the adsorption apparatus of Escherichia phage T5. Full article

Background/Objectives: First-line maintenance is established in advanced epithelial ovarian cancer (AEOC), but management remains uncertain for patients without a BRCA mutation or homologous recombination deficiency (HRD)-positive disease. We assessed real-world use of bevacizumab, poly(ADP-ribose) polymerase (PARP) inhibitors and active surveillance in France (FR), Germany (DE), Italy (IT), Spain (ES) and the United Kingdom (UK). Methods: Anonymised physician-reported charts were analysed from a retrospective, non-interventional online survey conducted by AplusA Healthcare Marketing Research. Eligible patients had stage III–IV AEOC, no known BRCA-mutated or HRD-positive disease, no progression after first-line platinum chemotherapy, and started maintenance therapy or active surveillance between November 2024 and March 2026. Treatment allocation was compared by chi-square testing. Multinomial logistic regression assessed whether country remained associated with strategy after adjustment for clinical and disease characteristics. Results: Among 3293 patients, 1295 (39.3%) received bevacizumab, 1087 (33.0%) niraparib, 158 (4.8%) rucaparib, 477 (14.5%) active surveillance and 276 (8.4%) other therapy. Treatment allocation differed by country (χ² = 725.4, df = 16, p < 0.001). Bevacizumab was most frequent in FR and least frequent in the UK; niraparib was most frequent in ES and the UK; active surveillance was most common in the UK and IT. In the adjusted model, country was the strongest factor associated with strategy (likelihood-ratio χ² = 550.1, df = 8, p < 0.001). Conclusions: First-line maintenance practice in AEOC without an actionable BRCA/HRD biomarker varies substantially across European countries. These differences may partly reflect national access, reimbursement, clinical practice and other unmeasured country-level factors. Outcome-based real-world studies are needed to clarify the best strategy. Full article

Breast cancer (BC) is the most frequently diagnosed malignancy and generally the leading cause of cancer-related mortality among women worldwide. Molecular targeted therapies, including endocrine treatment for hormone-responsive tumors, anti-HER2 agents for HER2-positive tumors and PARP inhibitors (PARPis) for homologous recombination-deficient (HRD) tumors, have significantly improved patient outcomes, but several clinical challenges are still open. The development of acquired resistance strongly limits the long-term efficacy of current treatment strategies, underscoring the necessity to identify novel therapeutic approaches for breast cancer therapy. In this review, we summarize and discuss recently investigated natural compounds with anti-breast cancer activity, ranging from polyphenols, terpenoids, alkaloids, sulfur-containing compounds and the emerging plant-derived extracellular vesicles. We focus on their ability to induce DNA damage or oxidative stress, modulating the DNA damage response (DDR) and interfering with key oncogenic signaling pathways. We also discuss the potential of these compounds to enhance the efficacy of conventional therapies, thereby offering a promising role in overcoming clinical resistance. Despite clinical relevance remains under development and further studies are required; many of the natural compounds examined here appear to effectively target DDR signaling and oncogenic pathways, supporting their potential use in breast cancer therapy. Full article

AI-enabled simulation platforms are increasingly used for talent development, offering scalable, low-risk practice and algorithmic feedback for interpersonal HR capabilities such as difficult conversations, negotiation, and consultation. Yet HRD evaluation cautions that within-platform improvement may not transfer to authentic interactions once dashboards and metrics disappear. We conceptualize AI-enabled simulation training as metricized scaffolding and integrate scaffolding theory with exploration–exploitation learning dynamics to explain when algorithmic supports fade into self-regulation rather than produce metric adaptation (score chasing). We introduce Algorithmic Feedback Literacy (AFL)—learners’ capability to interpret algorithmic feedback, calibrate its authority, and translate cues into portable self-scaffolds—as a mechanism linking metricized practice to transfer. We test this model in an AI-enabled virtual internship and career development program that combines repeated simulation attempts with an authentic consultation assessment. Using platform traces (592 attempts nested within 90 learners), instructor-rated consultation performance as a transfer outcome, and 102 learner reflections, we examine how distributed practice span and practice dose related to simulation gains and transfer, and how consultation complexity changes, which interactional behaviors predicted success. Distributed practice span predicted transfer beyond within-platform gains, while practice dose operated primarily through measurable simulation improvement. Complexity shifted performance relevance toward governance and boundary-setting behaviors. Qualitative evidence identified two developmental pathways: productive internalization, where learners converted metric cues into routines and mode-switching strategies, and metric adaptation, where learners optimized scores without internalizing broader professional judgment. We discuss design implications for AI-enabled HRD and retention-oriented capability building: cultivate AFL through transparency and calibration supports, design for deliberate fading, and pair metricized refinement with authentic assessments to strengthen transfer. Full article

Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in tumors carrying BRCA1/2 pathogenic variants (PVs) through the mechanism of synthetic lethality. PVs in other homologous recombination (HR) genes may also impair homologous recombination repair and confer sensitivity to PARPis; however, their predictive value remains uncertain and appears to vary according to the affected gene and tumor type. We review and critically discuss the current evidence regarding the predictive value of non-BRCA HR gene pathogenic variants as biomarkers of PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers. A narrative review was conducted between October 2023 and December 2025, first identifying pivotal clinical trials of PARP inhibitors across ovarian, breast, prostate, and pancreatic cancers, followed by a targeted search of PubMed, Embase, Web of Science, and Google Scholar for relevant preclinical and clinical studies. Seventeen clinical studies and multiple preclinical reports were analyzed regarding genomic frequency, HRD association, and treatment response. Preclinical studies consistently demonstrated increased PARPi sensitivity in models with alterations in several non-BRCA HR genes. Clinical evidence, however, was heterogeneous. PALB2 demonstrated the strongest and most consistent association with PARPi benefit across tumor types, while RAD51C and RAD51D also showed clinically meaningful activity, particularly in ovarian cancer. In contrast, evidence supporting PARPi sensitivity in tumors harboring ATM, CHEK2, CDK12, and several other HR gene alterations remained limited or inconsistent. Differences in gene function, biallelic inactivation, variant type, and current limitations of HRD companion diagnostic assays likely contribute to the observed variability in clinical response. Non-BRCA HR gene alterations represent promising predictive biomarkers for PARPi therapy but should not be considered a homogeneous group. Future biomarker-driven studies integrating comprehensive genomic profiling and functional assessment of homologous recombination deficiency are needed to refine patient selection and optimize the clinical application of PARPis beyond BRCA1/2-associated cancers. Full article

Triple-negative breast cancer (TNBC) lacking androgen receptor (AR) expression defines quadruple-negative breast cancer (QNBC), which is characterized by younger age at diagnosis, high Ki-67 index, and high genomic instability, however a comprehensive description of the genomic characteristics remains poorly defined. A total of 54 TNBC cases were categorized as TNBC with 100% AR expression (TNBC AR-100%) or QNBC, TNBC with 0% AR expression (TNBC AR-0%). Clinical, molecular, and genomic parameters, specifically pathogenic/likely pathogenic (P/LP) variants in homologous recombination repair (HRR) and cancer-related pathways were measured and analyzed. The QNBC cohort exhibited a high homologous recombination deficiency (HRD) score and a greater overall incidence of copy number variants (CNVs). QNBC harbored a higher mutation rate in TP53 and MYC signaling pathway than TNBC AR-100% tumors. P/LP variants corresponding to the HRR, PI3K/AKT, and RTK/RAS pathways were exclusively identified in QNBC. These results suggest that, at both molecular and genomic levels, the two groups are distinct, holding QNBC tumors more aggressive characteristics, genomic instability, and particular impairments in HRR and cancer-related pathways. In terms of actionability, these differences could potentially be leveraged through different combinations of therapies. Full article

DNA double-strand breaks (DSBs), caused by various endogenous and exogenous factors, pose a significant threat to genomic stability. Several conserved repair pathways address DSBs, with homologous recombination (HR) being the only mechanism capable of accurately restoring the original DNA sequence. The BRCA1 gene plays a critical role in HR and is involved in maintaining genomic stability, cell cycle regulation, transcription, and tumor angiogenesis. Germline mutations in BRCA1 are strongly associated with increased risks of breast, ovarian, and other cancers. Dysfunction of BRCA1 leads to homologous recombination deficiency (HRD), forcing cells to rely on error-prone repair pathways, which promotes genomic instability and tumorigenesis. Besides hereditary mutations, HRD can also arise in sporadic cancers through epigenetic mechanisms such as promoter hypermethylation and reduced BRCA1 expression. Although BRCA1 deficiency is uncommon in lung cancer, BRCA1 status is considered a potential biomarker for sensitivity to platinum-based chemotherapy and other cytotoxic agents used in lung cancer treatment. However, the impact of BRCA1 on treatment response and prognosis in lung cancer remains controversial and not fully understood. This review summarizes current evidence on the role of BRCA1 in modulating chemotherapy response and disease outcomes in lung cancer patients, highlighting its potential as a biomarker for personalized therapy selection. Thus, in this context, the key unresolved issues critical for the development of personalized treatment strategies for lung cancer associated with BRCA1 alterations include the identification of molecular biomarkers most reliably associated with tumor sensitivity to chemotherapy. In addition, the development of methods for identifying patients with homologous recombination deficiency specifically in lung tumors appears to be of considerable importance, as does a better understanding of how the biological and therapeutic implications of BRCA1-related parameters in lung cancer differ from those observed in other tumor types. Addressing these challenges could substantially improve the efficacy of chemotherapy and patient outcomes, while also expanding the opportunities for a personalized approach to treatment selection in patients with lung cancer. Full article

Triple-negative breast cancer (TNBC), particularly when associated with breast cancer susceptibility gene 1/2 (BRCA1/2) alterations or homologous recombination deficiency (HRD), remains therapeutically challenging because DNA repair vulnerabilities coexist with molecular heterogeneity, resistance, and toxicity constraints. This narrative review synthesizes mechanistic, preclinical, clinical, and translational evidence on DNA damage response (DDR)-targeted and synthetic lethality-based strategies in TNBC. We summarize TNBC biological heterogeneity, current biomarker-guided treatment options, mechanisms of poly(ADP-ribose) polymerase (PARP) inhibition and resistance, and emerging DDR targets, including ataxia telangiectasia and Rad3-related/checkpoint kinase 1 (ATR/CHK1), WEE1, DNA-dependent protein kinase (DNA-PK), RAD51, DNA polymerase theta (POLQ), neddylation-related pathways, and targeted protein degradation. The review highlights that PARP inhibitors and platinum agents provide clinically validated examples of exploiting HRD in selected populations, whereas most next-generation DDR inhibitors remain preclinical, investigational, or in early clinical trials. Resistance mechanisms, including BRCA reversion, homologous recombination restoration, replication fork stabilization, and checkpoint adaptation, limit durable benefit. Safety, target selectivity, overlapping toxicities, and the lack of standardized functional biomarkers further constrain translation. Future progress will require prospective biomarker validation, dynamic HRD assessment, rational scheduling of combinations, and medicinal chemistry approaches that improve therapeutic index rather than a broad application of DDR inhibition across all TNBC. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP), particularly PARP-1, is overexpressed in prostate cancer and linked to poor prognosis. PARP inhibitors show efficacy in homologous recombination deficiency (HRD)-positive tumors, but 30–70% of patients develop resistance, often due to low PARP expression. Tissue biopsies have limitations in assessing PARP levels, highlighting the need for noninvasive imaging tools. This study aimed to develop a novel [⁶⁸Ga]Ga-PARP-targeted radiotracer for prostate cancer visualization and therapy monitoring, with potential implications for targeted radionuclide therapy. Methods: PET/CT imaging was conducted in 22RV1 prostate cancer xenograft-bearing mice using the [⁶⁸Ga]Ga-FL9-7 probe. Imaging was performed at 1, 2, and 3 h post-injection. Standardized uptake values (SUV) were quantified to evaluate tumor and organ uptake, and tumor-to-normal tissue (T/NT) contrast ratios were calculated. Results: [⁶⁸Ga]Ga-FL9-7 rapidly accumulated in tumors, with optimal imaging contrast achieved at 3 h post-injection. Normal organ uptake (e.g., kidneys) peaked at 1 h and subsequently declined, while tumor uptake increased over time. This differential clearance and retention resulted in the highest T/NT ratio at the 3 h time point. Conclusions: The [⁶⁸Ga]Ga-FL9-7 probe enables effective noninvasive visualization of PARP-1 expression in prostate cancer, demonstrating clinical potential for tumor localization and monitoring of PARP-targeted therapies. This work also lays the groundwork for further development of PARP-targeted radionuclide therapy strategies. Full article

Background/Objectives: Homologous recombination deficiency (HRD) is a predictive biomarker in high-grade serous ovarian carcinoma for platinum-based chemotherapy and PARP inhibitors. The implementation of HRD testing in routine diagnostics has generated multiple commercial assays that differ in genomic targets, bioinformatic analysis, and HRD scoring strategies. We aimed to assess the analytical performance and feasibility of a locally semi-automated workflow based on the Agilent SureSelect CD HRR17 panel with SeqOne/SomaHRD analysis, and to compare it with established commercial HRD assays currently used in routine clinical practice: Myriad MyChoice CDx and SOPHiA DDM Dx HRD Solution. Methods: Thirty high-grade serous ovarian carcinoma cases diagnosed between 2019 and 2023 were retrospectively analyzed. HRD status was assessed with the Agilent-SeqOne workflow and compared with Myriad (n = 12) and SOPHiA (n = 18). Concordance and correlation between genomic instability metrics were evaluated. Results: The Agilent/SeqOne workflow showed high concordance with both comparison workflows. Genomic instability metrics strongly correlated across assays (R² up to 0.96). A lower proportion of inconclusive classifications was observed with the Agilent/SeqOne workflow. Discordances were mainly observed in borderline cases near classification thresholds. Variant detection was highly concordant within shared genomic regions. Conclusions: The locally semi-automated HRD workflow demonstrated high analytical concordance with established commercial assays in evaluable cases. Operational advantages related to workflow flexibility and local reanalysis support its potential implementation in routine molecular diagnostics. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article