Search Results (7,909)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because of aggressive tumor biology, pervasive therapeutic resistance, rapid adaptive reprogramming, and a profoundly immunosuppressive tumor microenvironment. This review summarizes recent advances in KRAS-targeted therapies, DNA damage response (DDR)-directed strategies, immune-redirection platforms, and tumor microenvironment modulation. Methods: We conducted a narrative review of peer-reviewed publications, clinical trial reports, trial registries, and selected conference data addressing emerging therapeutic strategies for PDAC. Results: KRAS-targeted therapies, including KRAS G12D-selective and multi-selective RAS(ON) inhibitors, have demonstrated substantial preclinical and emerging clinical activity while revealing diverse mechanisms of adaptive resistance. DDR-directed approaches are expanding beyond BRCA-mutated disease toward functional homologous recombination deficiency, replication stress, and synthetic lethality. In parallel, bispecific antibodies, T-cell engagers, and CAR-T-cell therapies have generated preliminary evidence of antitumor activity, although stromal exclusion, antigen heterogeneity, and immune suppression remain major barriers. These advances indicate that therapeutic resistance in PDAC is a dynamic process involving interconnected oncogenic, genomic, stromal, metabolic, and immune mechanisms. Conclusions: Future progress will require biologically informed treatment frameworks integrating complementary therapeutic modalities according to baseline tumor biology and treatment-induced adaptive states, supported by longitudinal biomarkers and rational clinical trial design. Full article

Background/Objectives: The developmental origins of health and disease (DOHaD) theory suggests that intrauterine and early postnatal life represents a critical window for programming lifelong health trajectories and disease susceptibility in offspring. Maternal nutritional imbalance during this period is closely associated with obstetric complications and an elevated risk of metabolic disorders in children. As central metabolic hubs, mitochondria constitute a critical axis linking adverse in utero exposure to metabolic defects in offspring across generations. Methods: In this narrative review, we searched PubMed and Web of Science (up to 8 July 2026) for English-language literature linking maternal metabolic conditions and mitochondrial dysfunction. We included in vivo, in vitro, and clinical studies, explicitly excluding primary inherited mtDNA mutations and nonnutritional toxicant exposures to isolate nutritional programming effects. Results: Maternal metabolic stress induces multifaceted, tissue-specific mitochondrial alterations in the developing offspring. Rather than a uniform systemic decline, mitochondrial reprogramming exhibits profound spatial and cellular heterogeneity across critical metabolic organs, including the placenta, liver, skeletal muscle, heart, and hypothalamus. These developmental adaptations often manifest as molecular compensations, such as altered mitochondrial dynamics, perturbed biogenesis, and shifted OXPHOS capacity, ultimately leading to functional bioenergetic failure, oxidative stress, and the establishment of insulin resistance. Discussion: Organ-specific mitochondrial dysfunction drives the maternal transmission of metabolic syndrome. Targeting these mechanisms via dietary modifications, exercise, pharmacological agents, and mitochondrial transplantation offers promising strategies to rescue bioenergetics and prevent metabolic diseases in offspring. Full article

Small cell carcinoma of the cervix (SCCC) is a rare yet highly aggressive subtype of cervical cancer (CC), characterized by early invasion, high metastatic potential, frequent recurrence, and extremely poor prognosis, which severely impairs women’s physical and mental health. Currently, high-risk human papillomavirus (hr-HPV, particularly HPV18) infection is recognized as one of the core drivers underlying the initiation and progression of SCCC. Malignant evolution is not triggered by a single infection event but is cooperatively regulated at multiple molecular levels, including HPV genome integration, critical gene mutations, and aberrant activation of multiple signaling pathways. In addition, SCCC exhibits an HPV-independent oncogenic pathway mainly mediated by somatic mutations in tumor protein 53 (TP53) and retinoblastoma 1 (RB1), thus forming a dual pathogenic mechanism. Based on current clinical understanding and molecular mechanisms, this paper reviews the molecular pathogenesis and subtypes of SCCC, reveals the associations between tumor heterogeneity, therapeutic resistance, and metastasis, and proposes potential novel targets for the treatment of SCCC. This study innovatively presents a closed-loop model of two-way empowerment between basic research and clinical application. It emphasizes that basic research should be oriented toward real clinical problems and highlights the reciprocal feedback of clinical practice on basic research, thereby achieving dynamic iteration and collaborative breakthroughs in both fields. Full article

Background: Antibiotic resistance in Helicobacter pylori is steadily increasing, rendering the treatment of related gastroduodenal diseases increasingly difficult. Lefamulin is a new broad-spectrum antibacterial in the pleuromutilin class, acting by suppressing bacterial protein synthesis. It has the advantages of its unique “induced-fit” mechanism, a low frequency of spontaneous mutations, stepwise development of resistance, stability in acidic environments, and potential for additive or synergistic activity when combined with certain other antibiotics against various facultative anaerobes, including multidrug-resistant isolates. Methods: We investigated, for the first time to the best of our knowledge, the activity of lefamulin against 91 clinical H. pylori isolates from symptomatic adult patients using MIC test strips. Results: Overall, lefamulin MICs₅₀ and MICs₉₀ were 0.25 and 2 mg/L versus 4 and ≥256 mg/L for clarithromycin, and 0.75 and ≥32 mg/L, respectively, for levofloxacin. Lefamulin MICs₅₀ and MICs₉₀ were 0.5 mg/L and 4 mg/L against the 61 clarithromycin-resistant (MICs, >0.25 mg/L) isolates, 0.25 and 0.75 mg/L against the 40 levofloxacin-resistant (MICs, >1 mg/L) isolates, and 0.38 mg/L and 0.75 mg/L, respectively, against the 28 isolates resistant to both agents. Conclusions: Briefly, the new pleuromutilin antibiotic outperformed in vitro both clarithromycin and levofloxacin against H. pylori isolates. Its potential usefulness in treating H. pylori infections resistant to macrolides and fluoroquinolones, and especially those with dual resistance, justifies further investigation. However, some precautions should also be considered. The use of the novel antibiotic lefamulin may offer benefits for H. pylori eradication if our results are confirmed in subsequent studies, including clinical trials. Full article

Background: Founder mutations in MYBPC3 may contribute substantially to the genetic burden of hypertrophic cardiomyopathy (HCM) and provide important insights into genotype–phenotype correlations and population-specific disease mechanisms. In this study, we investigated two recurrent canonical splice-site variants, MYBPC3 c.1458-1G>A and c.3331-1G>A, identified in patients with HCM from the Emilia-Romagna region of Northern Italy. Methods: Ninety-one unrelated patients with HCM carrying either MYBPC3c.1458-1G>A or c.3331-1G>A were analyzed. Haplotype reconstruction was performed to assess a possible founder effect and estimate the approximate age of the shared ancestral allele. Functional characterization was carried out by RNA sequencing of myocardial tissue to evaluate the impact of the variants on splicing. Clinical and phenotypic data were compared with those of carriers of other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Results: Both variants, classified as pathogenic according to ACMG criteria, shared a conserved variant-specific core haplotype. Founder age was estimated at approximately 10.5 generations (~262 years), consistent with a regional founder effect. RNA sequencing demonstrated aberrant splicing for both variants, resulting in premature termination codons and presumably subsequent nonsense-mediated mRNA decay. Clinically, carriers showed delayed disease onset, with a mean onset in the fifth decade of life, and a comparatively milder phenotype, including a lower incidence of sudden cardiac death, than patients carrying other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Both variants exhibited partial penetrance (approximately 63–67%) and age-dependent variable expressivity. Conclusions:MYBPC3 c.1458-1G>A and c.3331-1G>A represent novel founder alleles associated with HCM in Northern Italy. Identification of these locally prevalent variants improves molecular diagnosis, family screening, and supports the development of variant-targeted therapeutic approaches. Full article

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) evolution has been marked by the rapid accumulation of mutations, among which cytosine-to-uracil (C-to-U) transitions represent a major proportion of observed genomic changes. These mutations have been proposed to result from the activity of host APOBEC3 cytidine deaminases, innate immune enzymes capable of editing viral RNA. However, the molecular mechanisms underlying APOBEC3 involvement in SARS-CoV-2 biology remain poorly understood. Here, we systematically investigated physical interactions between APOBEC family members and the SARS-CoV-2 proteins using a Gaussia princeps protein complementation assay. Screening of APOBEC family proteins against the viral proteome identified specific interactions between APOBEC3G (A3G) and APOBEC3H (A3H) with the viral nucleocapsid (N) protein. These interactions were validated by co-immunoprecipitation and were found to be conserved across nucleocapsid proteins from all seven human coronaviruses, suggesting conserved structural determinants. Mechanistic analyses revealed that the RNA-binding and oligomerization capacities of A3G and A3H are key for their interaction with the SARS-CoV-2 nucleocapsid. Mapping experiments further showed that the C-terminal domain of N constitutes the minimal interacting region, with stronger binding observed in larger constructs encompassing adjacent regions, indicating cooperative stabilization. Further work will be needed to determine whether A3G and/or A3H can restrict viral replication and whether their interaction with the nucleocapsid allows them to access and mutate the viral genome. Full article

The myocyte enhancer factor 2 (MEF2) transcription factor family plays crucial roles in differentiation, lineage specification, stress responses, and tissue homeostasis. Recent investigations have shown that the dysregulation of MEF2A, MEF2B, MEF2C, and MEF2D is associated with tumorigenesis, tumor progression, and adverse clinicopathological features in several cancers. MEF2B has a particularly important role in B-cell malignancies, where recurrent mutations deregulate BCL6 and promote lymphoma progression. MEF2A, MEF2C, and MEF2D also regulate malignant phenotypes, including proliferation, migration, invasion, apoptosis, drug resistance, angiogenesis, inflammation, and immune evasion, by the mechanism of regulating cell-cycle regulators, apoptosis-related genes, EMT-related genes, and other transcriptional programs. This review summarizes the mechanisms by which MEF2 family members contribute to tumor initiation and progression, with added emphasis on MEF2B mutations and MEF2D fusions. We also discuss clinical associations with overall survival and recurrence in solid tumors and hematologic malignancies. Because MEF2 proteins are transcription factors with broad physiological functions, we evaluate therapeutic strategies: RNA interference, genetic perturbation, small molecules that alter MEF2-dependent transcription, and PROTAC or oligonucleotide-PROTAC. These platforms remain promising but require MEF2-specific validation, tumor-selective delivery, and careful toxicity assessment. Full article

Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers. Full article

Wheat Fusarium head blight (FHB) is a globally prevalent and destructive fungal disease predominantly caused by Fusarium graminearum. Pydiflumetofen, a novel succinate dehydrogenase inhibitor (SDHI) fungicide, exhibits strong inhibitory activity against F. graminearum; however, the molecular regulatory mechanisms underlying the field-developed resistance in this pathogen remain poorly defined. In the present study, a field-evolved resistant isolate W24-039 and a sensitive isolate W24-016 were subjected to multi-omics analysis. The sequencing results identified compound mutations C89S/A93V in SdhC2, and A21T/S30F in SdhD of the resistant strain, which confer stable fungicide resistance without any detectable fitness costs. Physiological tests revealed that these target mutations sustain the homeostasis of succinate dehydrogenase (SDH) activity and intracellular ATP production. Following pydiflumetofen treatment, the sensitive isolate displayed remarkable declines in SDH activity, intracellular ATP content and deoxynivalenol (DON) biosynthesis, accompanied by markedly elevated cell membrane permeability. Transcriptomic sequencing uncovered 2221 differentially expressed genes (DEGs) in the sensitive strain under fungicide stress, and 2566 DEGs in the resistant isolate under the same conditions. The genes associated with detoxification and drug efflux, including cytochrome P450, glutathione S-transferase (GST), ABC and MFS transporters, were significantly upregulated in the resistant isolate. Metabolomic analysis indicated that differential metabolites were mainly enriched in the tricarboxylic acid (TCA) cycle, amino acid metabolism and membrane lipid biosynthesis pathways. The resistant strain maintained intact TCA cycle operation and accumulated high levels of pivotal metabolites such as phosphatidylcholine, unsaturated fatty acids and reduced glutathione. Integrated multi-omics analysis verified that the ABC transporter and glutathione metabolism pathways serve as core regulatory modules governing fungicide resistance. Collectively, F. graminearum develops resistance via the synergistic effects of SDH compound mutations, enhanced detoxification and efflux, and global metabolic remodeling, demonstrating that target-site mutation alone is not the sole driver of resistance, which is instead controlled by an intricate regulatory network involving multiple coordinated pathways. This study systematically characterizes the resistance regulatory network of F. graminearum against pydiflumetofen, and provides theoretical guidance for the rational application and sustainable field resistance management of this fungicide. Full article

Background/Objectives: Symmetrical dual-site acetylcholinesterase (AChE) inhibitors offer a compelling strategy to mitigate mutational drug resistance, yet static modeling fails to capture induced-fit dynamics under mutational stress. Methods: Here, a 100,000-compound virtual library was filtered using a machine learning-based QSAR classification pipeline. A strict, empirically calibrated Jaccard applicability domain filter (AD = 0.823) eliminated topological anomalies, yielding a robust cross-validation accuracy (ROC-AUC: 0.80 ± 0.05; independent test MCC: 0.61). Multi-parameter ADMET and shape screening prioritized unique chemotypes to probe the 20 Å enzyme gorge. All-atom explicit-solvent molecular dynamics simulations were coupled with 150 ns enhanced-sampling Metadynamics along two orthogonal collective variables (gorge depth and ligand orientation) to map out the free energy surfaces under mutational stress. Results: Symmetrical probes suffered catastrophic unbinding upon anchor loss. Conversely, the symmetrical core of Lead Compound 1631 demonstrated extraordinary structural resilience. In silico site-directed mutagenesis (W86A and W286A) triggered a thermodynamic locking effect; the W86A mutant forced the complex into a deeper energetic well (ΔG_min = 9.23 ± 1.98 kJ/mol) than the wild-type state (5.26 ± 1.69 kJ/mol). MM/GBSA decomposition confirmed an active electrostatic-solvation compensation mechanism along a “solvation see-saw” diagonal (ΔΔG_total = +1.59 kcal/mol). Finally, Dynamic Cross-Correlation Matrix analysis quantified a mechanical inversion of the CAS-PAS axis into an anti-correlated clamping mode (−0.04) that locked the ligand bridge in place. Conclusions: These results demonstrate that symmetrical dual-site targeting, combined with dynamic thermodynamic locking, provides a resilient framework to overcome mutational resistance in AChE inhibitors. Full article

Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disorder caused by mutations in the SMPD1 gene, resulting in sphingomyelin accumulation. With a birth prevalence of 0.25–0.6 per 100,000, it is more prevalent in Ashkenazi Jewish and Middle Eastern populations. The disease features a clinical spectrum ranging from severe, early-onset neurodegeneration (infantile neurovisceral ASMD) to chronic, non-neurological visceral involvement (chronic visceral ASMD) and intermediate forms (chronic neurovisceral ASMD). The chronic visceral form is characterized by liver dysfunction, respiratory symptoms, and hepatosplenomegaly, which can lead to secondary thrombocytopenia. The majority of patients exhibit thrombocytopenia and/or mild bleeding manifestations, most commonly easy bruising and epistaxis, whereas clinically significant bleeding events, including gastrointestinal or variceal hemorrhage, occur less frequently. Systematic platelet-function studies in patients with ASMD are currently lacking. Evidence retrieved from biological models indicates that ASMD contributes to platelet dysfunction, including impaired secretion and thrombin generation, mediated by complex pathological mechanisms. These findings underscore the importance of hematological monitoring and further research in patients with this condition and could potentially offer new therapeutic possibilities. Full article

The efficiency of ammunition support operations in the aircraft carrier intermediate ordnance staging deck is critical to sortie generation rates in naval aviation, yet joint scheduling and personnel allocation in this multistage, resource-constrained environment remains a challenging bi-objective optimization problem. This study develops a framework integrating an improved Nondominated Sorting Genetic Algorithm II (NSGA-II) with a marginal-benefit-based iterative feedback mechanism. The intermediate ordnance staging deck support process is decomposed into individual ammunition processing stations and formulated as a processflow model incorporating operation sequencing and personnel specialization constraints. A constraint decision model then dynamically reconciles the minimization of total makespan and personnel workload equilibrium through iterative marginal-benefit comparison across support teams. The NSGA-II is enhanced with an adaptive crossover-mutation mechanism and an improved elitism preservation strategy to strengthen global search capability. Validation on a typical carrier intermediate ordnance staging deck scenario demonstrates that the improved NSGA-II outperforms the conventional NSGA-II in convergence speed and Pareto front quality. Under the optimized configuration, the total makespan remains 3600 s with a workload balance metric of 1075 even as ammunition quantity doubles from two to four units. The proposed framework offers practical decision support for carrier ammunition operations and extends to other resource-constrained multi-objective scheduling domains. Full article

Background/Objectives: Biallelic mutations of NLRP7, a maternal-effect gene encoding a key component of the subcortical maternal complex, are the major monogenic cause of recurrent hydatidiform mole (RHM) and confer a substantial lifetime risk of gestational trophoblastic neoplasia (GTN), including choriocarcinoma. Although oocyte donation is currently the standard reproductive option, anecdotal live births from autologous oocytes in carriers of specific missense variants raise mechanistic and clinical questions that have not been integrated. We aimed to synthesize the current understanding of NLRP7 biology, oncogenic mechanisms in GTN, and genotype-stratified reproductive outcomes, and to propose a genetic permissiveness framework that links cancer surveillance with reproductive decision-making. We also place this monogenic disease in an epidemiological context, given the marked geographical variation in molar pregnancy incidence. Methods: PubMed, Embase and Web of Science were searched from January 2006 to December 2025 using terms related to NLRP7, hydatidiform mole, GTN, choriocarcinoma, maternal-effect genes, genomic imprinting, and assisted reproduction. Original studies, case series, expert consensus statements, and reviews were included. Results: NLRP7 loss disrupts subcortical maternal complex assembly, maternal-DMR methylation, trophoblast differentiation, and HLA-C-dependent immune privilege; in choriocarcinoma, NLRP7 is conversely reported to be up-regulated, where it has been implicated in tumor proliferation and immune evasion through inflammasome-independent pathways. Genetic permissiveness for autologous-oocyte pregnancy is mutation-type dependent: complete loss-of-function variants confer near-zero permissiveness, whereas missense variants with retained partial function may permit rare normal pregnancies. Conclusions: A genetic-permissiveness framework integrating variant-level functional data, GTN risk, and reproductive priorities can support shared decision-making in this rare but high-stakes clinical scenario, and it identifies clear directions for future translational research. We emphasize, however, that this framework has not been prospectively validated and should be regarded as hypothesis-generating rather than as a clinically established decision-making model. Recognizing the biallelic NLRP7 mutation as a heritable cancer-predisposition state further supports genotype-informed, risk-stratified oncological surveillance. Full article

Epidermal growth factor receptor (EGFR) mutations drive hepatocellular carcinoma (HCC) progression, and the T790M gatekeeper substitution is the predominant mechanism of acquired resistance to EGFR-targeted therapies. Herein, we present multiscale quantum-classical in silico predictions of Phyllanthus niruri phytochemicals as non-covalent EGFR T790M binders, employing molecular docking, 100 ns molecular dynamics, MM-PBSA/MM-GBSA, per-residue decomposition, PCA/LDA, DFT at B3LYP-D3(BJ)/def2-TZVP, and comparative wild-type EGFR simulations. Five phytochemicals exhibited computationally predicted binding affinities against EGFR T790M exceeding the non-covalent binding component of osimertinib (−25.74 kcal/mol): corilagin (−53.71 ± 5.05 kcal/mol), eriodictyol-7-rhamnopyranoside (−44.35 ± 4.51 kcal/mol), isoquercetin (−44.23 ± 2.92 kcal/mol), rutin (−42.15 ± 4.50 kcal/mol), and kaempferol-4-rhamnoside (−41.68 ± 3.69 kcal/mol). Wild-type EGFR simulations (PDB 1M17) yielded a selectivity index (IS) of 2.76 for corilagin (<!-- MathType@Translator@5@5@MathML2 (no namespace).tdl@MathML 2.0 (no namespace)@ --> Full article

Cyclin-dependent kinase 4/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform “class effect.” In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g., RB1 loss, CDK6 amplification) and bypass-driven (e.g., ESR1 mutations, PI3K/AKT pathway activation, APOBEC3-mediated mutagenesis). Distinguishing between these classes helps in the design of rational sequencing algorithms and combinatorial regimens. Emerging strategies, such as next-generation protein degraders, oral selective estrogen receptor degraders, antibody–drug conjugates, and inhibition of autophagy, are promising methods for overcoming resistance. Moving forward, the greatest need in breast cancer treatment will be not simply developing additional agents but using current therapies more intelligently by refining biomarker-guided patient selection, tailoring treatment duration, and ensuring broad global access. Full article