Search Results (1,263)

Background/Objectives: Carbapenemase-producing Escherichia coli (CP-Ec) has emerged as an important contributor to the global crisis of antimicrobial resistance. Although less prevalent than carbapenemase-producing Klebsiella pneumoniae, CP-Ec exhibits marked genomic plasticity, efficient plasmid-mediated dissemination, and increasing involvement in bloodstream infections. This comprehensive review summarizes the global epidemiology, molecular features, treatment options, clonal structure and transmission dynamics of CP-Ec. Particular attention is given to the expanding repertoire of NDM, OXA-48-like, and KPC carbapenemases and their associated plasmid backbones. Key high-risk clones, including ST410, ST167 and ST131, are highlighted as drivers of international spread. Conclusions and Future Directions: CP-Ec bloodstream infections represent a growing clinical challenge, often associated with severe outcomes and limited therapeutic options, particularly for NDM producers. The emergence of treatment failures with last-resort agents further underscores the need for improved management strategies. Strengthened global surveillance, integration of genomic epidemiology, optimized antimicrobial stewardship, and targeted infection control measures are essential to limit the dissemination of CP-Ec and mitigate its impact on human health. Full article

A decrease in conductivity under illumination, known as negative photoconductivity, has been observed in various semiconductors and is commonly attributed to trapping of excess carriers by deep centers. Here, we demonstrate that negative photoconductivity can instead arise from a rapid increase in carrier scattering in ultranarrow-gap semiconductors with degenerate carrier statistics. This behavior is explained by the combined effects of enhanced optical phonon emission scattering and an increase in effective mass due to band filling. Experimentally, photoconductivity was measured over wide ranges of excitation and temperature in unintentionally doped n-type short-period InAsSb_0.6/InAsSb_0.3 strained-layer superlattices (SLS), relevant for long-wavelength infrared optoelectronic devices. The resistive device impedance, weakly dependent on excess carrier concentration, simplifies broadband impedance matching to low-voltage CMOS driver electronics. At 77 K, 10.6 µm laser excitation led to an initial rise in conductivity, with a decrease observed above 10 W/cm². Full article

Tumor angiogenesis is a critical driver of cancer progression; however, current anti-angiogenic therapies remain limited by resistance and toxicity. Hypoxia within the tumor microenvironment induces hypoxia-inducible factor-1α (HIF-1α), which promotes aberrant angiogenesis by upregulating vascular endothelial growth factor (VEGF) and, subsequently, delta-like ligand 4 (DLL4) in endothelial cells. A systematic screening of flavanone derivatives was performed to identify compounds capable of dual inhibition of HIF-1α and DLL4. Among 16 natural compounds evaluated, isoxanthohumol (IXN), a prenylated flavanone, emerged as the most potent, suppressing both hypoxia-induced HIF-1α accumulation in tumor cells and VEGF-induced DLL4 expression in endothelial cells. IXN markedly inhibited endothelial proliferation, migration, and tube formation in vitro. In a Lewis lung carcinoma (LLC) mouse syngeneic model, IXN monotherapy reduced tumor growth and vessel density. Notably, combination treatment with IXN and anti-PD-1 immunotherapy produced greater anti-tumor effects than either monotherapy. This combination enhanced cytotoxic T cell infiltration into the tumor core, increased granzyme B expression, and induced widespread tumor cell apoptosis, consistent with improved vascular normalization. These findings identify IXN as a promising dual-targeting agent that inhibits both HIF-1α and DLL4 and demonstrate its potential to enhance immune checkpoint blockade. Simultaneous targeting of hypoxia-driven and VEGF-DLL4-mediated angiogenic pathways represents a compelling therapeutic strategy to overcome the limitations of current anti-angiogenic and immunotherapeutic approaches. Full article

Due to the weak electrical response characteristics of groundwater nitrate contamination, traditional monitoring and remediation assessment methods are limited by low spatiotemporal resolution, high cost, and strong subjectivity. To address this issue, this study proposed an integrated technical framework combining field detection, laboratory-controlled experiments, and remediation process monitoring, aiming to explore the application potential of Electrical Resistivity Tomography (ERT) in nitrate pollution monitoring and remediation evaluation. First, ERT survey lines (L1 and L2) were deployed at a chemical-contaminated site in Luzhou, Sichuan Province, and groundwater samples were collected. Coupled with hydrochemical analysis, the feasibility of ERT for identifying nitrate plumes was verified. Second, a quantitative response model between nitrate concentration and resistivity was established through Miller box experiments, and a multi-line layout was optimized via sand tank experiments to mitigate boundary effects and improve monitoring accuracy. Finally, grouped sand tank experiments involving electroactive bacteria (EAB) and magnetite were conducted. Combined with 16S rRNA sequencing, the coupling mechanism between ERT electrical responses and biogeochemical processes was elucidated. The results showed that the low-resistivity anomaly zones identified by field ERT were accurately consistent with the high-nitrate contamination zones, and Piper diagrams confirmed that nitrate-related ions were the primary cause of the low-resistivity anomalies. The power function quantitative model established by the Miller box experiment (y = 1021.97x^−0.74, R² = 0.9589) enabled the indirect inversion of nitrate concentrations, with a small deviation between theoretical and measured values in the deep layer (16–18 m). The optimized layout of one main and three auxiliary survey lines effectively characterized the spatiotemporal migration of the contamination plume. Under high-water level conditions, the ternary system of nitrate–magnetite–EAB exhibited the strongest low-resistivity response. Microbial analysis indicated that electroactive groups (e.g., Pseudomonas and Flavobacterium) enriched in the EAB group were the core drivers of enhanced electrical conductivity. The integrated ERT monitoring technology system constructed in this study realizes the visual identification of nitrate plumes and dynamic tracking of remediation processes, providing technical support for the precise monitoring and in situ remediation of nitrate contamination in agricultural non-point sources and industrial sites. Full article

Antibiotic resistance gene (ARG) monitoring in environmental systems increasingly relies on DNA-based molecular approaches; however, the extent to which DNA extraction strategies bias downstream resistome interpretation remains insufficiently understood. This study systematically evaluated the effects of single versus successive DNA extraction on DNA recovery, microbial community composition, and the abundance and diversity of 385 genes related to antibiotic resistance including ARGs and mobile genetic elements (MGEs) across three contrasting matrices: water, sediment, and fish intestinal tissue. Successive extraction markedly increased DNA yield and detection of functional genes in water and sediment, particularly for low-abundance and particle-associated taxa. Enhanced recovery resulted in higher richness and abundance of ARGs and MGEs and strengthened correlations between intI1, ARGs, and bacterial taxa, indicating that single-cycle extraction may underestimate resistome magnitude and potential host associations in complex matrices. Conversely, fish intestinal tissue, used here as a representative biological matrix, showed limited benefit or even reduced gene abundance with repeated extraction, likely due to rapid depletion of extractable nucleic acids and DNA degradation. While successive extraction improves recovery efficiency, the potential inclusion of extracellular or relic DNA suggests caution in interpreting inflated ARG abundance. Overall, our findings demonstrate that DNA extraction is a matrix-dependent methodological driver that can reshape both quantitative outcomes and ecological inference. Matrix-specific optimization and careful protocol selection are therefore essential for improving data comparability and minimizing methodological underestimation in environmental resistome assessments. Full article

Objective: This study evaluated the effects of a 12-week High-Intensity Functional Training (HIFT) program combined with thylakoid supplementation on plasma adipo-myokine levels (Decorin, Myostatin, Follistatin, Activin A, and TGF-β1) in men with obesity. Secondary outcomes included anthropometric indices, lipid profiles, and insulin resistance markers. Methods: Sixty men with obesity (age: 27.6 ± 8.4 years; BMI: 32.6 ± 2.6 kg/m²) were randomly assigned to four groups (n = 15 per group): Placebo (PG), Supplement (SG), HIFT + placebo (TPG), and HIFT + supplement (TSG). To ensure robustness against the 27% attrition rate, statistical analyses included both per-protocol and intention-to-treat (ITT) models. HIFT was performed for 3 sessions/week (Borg scale: 15–17). Results: Following Bonferroni correction for multiple endpoints, repeated-measures ANOVA showed significant Time × Group interactions for most adipo-myokines and metabolic markers. Both training groups (TPG and TSG) demonstrated improvements in body composition and insulin sensitivity compared to PG (p < 0.05). While no significant differences were observed between TPG and TSG for systemic metabolic markers, preliminary data suggested that thylakoid supplementation might provide modest complementary modulations in specific myokines (e.g., decorin and follistatin). However, these observed trends did not reach clinical superiority over exercise alone in the broader metabolic profile. Conclusions: Twelve weeks of HIFT is an effective primary driver for modulating the adipo-myokine network in obese men. Although thylakoid supplementation showed potential for selective complementary effects on certain myokines, these findings are exploratory given the small sample size. The clinical significance and long-term complementary value of thylakoid-exercise interactions require further validation in larger, more diverse cohorts. Full article

Chronic Kidney Disease (CKD) and Colorectal Cancer (CRC) share a profound epidemiological link, supported by Mendelian randomization studies suggesting causality. This review articulates a refined Gut–Kidney Axis, focusing on the pathophysiology of indole-derived uremic toxins. CKD-induced dysbiosis drives hepatic synthesis and systemic accumulation of indoxyl sulfate, which is proposed to promote carcinogenesis via Aryl Hydrocarbon Receptor (AhR) and Akt signaling, ultimately upregulating c-Myc and EGFR. We propose a two-compartment model: while systemic indoxyl sulfate reflects the total gut indole pool (mainly from planktonic bacteria), adherent bacteria like Fusobacterium nucleatum may create high-concentration indole hotspots within the tumor microenvironment. Clinically, we advocate for protein-independent DNA methylation biomarkers (SEPT9, SDC2) to avoid renal confounding. Furthermore, we propose a novel diagnostic panel integrating serum indoxyl sulfate (systemic load) and urinary indoxyl sulfate (gut production) to guide therapy. Therapeutically, targeting upstream drivers (AhR/Akt) may bypass resistance to anti-EGFR therapies in KRAS-mutated tumors. We also discuss the repurposing of the oral adsorbent AST-120 and emerging bacteriophage therapies as strategies to disrupt this oncogenic axis. This review offers a comprehensive framework for stratified management of CKD-associated CRC. Full article

Pancreatic cancer (PC) is one of the most lethal malignancies worldwide, characterized by late diagnosis, aggressive progression, and limited responsiveness to current therapeutic strategies. Although extensive genomic analyses have identified key driver protein-coding genes (PCGs), therapeutic approaches targeting individual genes have shown limited clinical benefit. This limitation highlights the molecular complexity of PC, where tumor progression is governed by regulatory networks that extend beyond genetic alterations. Non-coding RNAs (ncRNAs), which constitute nearly 98% of the human genome, have emerged as regulators of gene expression in cancer. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate oncogenic processes, including aberrant signaling activation, tumor microenvironment remodeling, epithelial–mesenchymal transition, immune evasion, and resistance. Beyond their independent functions, lncRNAs, miRNAs, and mRNAs form an integrated regulatory network known as the lncRNA–miRNA–mRNA TRIAD, enabling control of gene expression. Such network-based regulation provides a framework for multi-target therapeutic strategies. Moreover, the rapid responsiveness and disease-specific expression patterns of ncRNAs suggest strong potential as diagnostic and prognostic biomarkers in PC, where early detection remains challenging. This review summarizes the regulatory roles of PCGs, miRNAs, and lncRNAs in PC and highlights the lncRNA–miRNA–mRNA TRIAD as a framework for understanding gene regulatory networks. Full article

Epithelial-mesenchymal transition (EMT) is a key driver of invasion, metastasis, and treatment resistance in gastric cancer, yet its post-transcriptional regulation by microRNAs (miRNAs) is not fully delineated. We performed a structured literature search in PubMed, Web of Science, and Scopus for studies evaluating miRNAs in relation to EMT in gastric cancer and synthesised tumor-intrinsic, microenvironmental, and circulating EMT-related miRNA networks. Downregulated, predominantly tumor-suppressive miRNAs, including miR-34a, miR-200 family, miR-148a, miR-204, miR-30a, miR-101, miR-218, miR-26a, miR-375, miR-506, and others, converge on EMT transcription factors and pathways such as ZEB1/2, Snail, TGF-β/SMAD, Wnt/β-catenin, c-Met, and PI3K/AKT, and their restoration reverses EMT phenotypes in preclinical models. Upregulated oncomiRs, such as miR-21, miR-17-5p, miR-106b-5p, miR-23a, miR-130a-3p, miR-196a-5p, miR-181a, miR-616-3p, miR-301a-3p, miR-150, miR-27a-3p and miR-192/215, target tumor suppressors and reinforce these pathways. Cancer-associated fibroblast, macrophage, neutrophil, and natural killer cell-derived miRNAs, together with systemic indices such as the neutrophil-to-lymphocyte ratio and mediators like FAM3C, add microenvironmental layers of EMT regulation. Several EMT-related miRNAs show consistent associations with invasion, metastasis, peritoneal dissemination, prognosis, and chemoresistance, and many are detectable in circulation. Overall, EMT-related miRNAs orchestrate gastric cancer cell plasticity and tumor-microenvironment crosstalk and represent promising biomarker and therapeutic candidates that warrant validation in prospective, subtype-stratified, and translational studies. Full article

High Mobility Group ^{Box 1} (HMGB1) and S100 proteins are major ligands of Receptor for Advanced Glycation End-products (RAGE) and have causal roles in endometriosis lesions. Yet the AGE–RAGE pathway that unifies Advanced Glycation End-products (AGEs) with these ligands has not been assessed in endometriosis. In diabetes, atherosclerosis, and chronic kidney disease, AGE–RAGE links insulin resistance and oxidative stress to inflammation, fibrosis, and organ harm. Endometriosis shares key drivers of AGE accumulation, including insulin resistance, oxidative stress, and chronic inflammation. Endometriosis is also linked to higher vascular risk and arterial stiffness. We asked whether AGE–RAGE could bridge metabolic stress to pelvic lesions and systemic risk. We did a focused review of mechanisms and an evidence map of studies on AGEs, RAGE, or known RAGE ligands in endometriosis. We grouped findings as most consistent with a driver, amplifier, consequence, or parallel role. We included 29 studies across human samples, cell systems, and animal models. Few studies measured AGE adducts directly. Most work tracked RAGE ligands (mainly HMGB1 and S100 proteins) and downstream immune and angiogenic programs. Across models, this pattern fits best with a self-reinforcing loop after lesions form. RAGE expression often aligned with lesion remodeling, especially fibrosis. Blood and skin readouts of AGE burden were mixed and varied by cohort and sample type. A central gap is receptor proof. Many models point to shared Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB) signaling, but few test RAGE dependence. Overall, current evidence supports AGE–RAGE as a disease-amplifying loop involved in chronic inflammation and fibrosis rather than an initiating trigger. Its effects likely vary by stage and site. Priorities now include direct lesion AGE measurement, paired systemic–pelvic sampling over time, receptor-level studies, and trials testing diet or drug interventions against clear endpoints. Outcomes could include fibrosis, angiogenesis, immune state, pain, and oocyte and follicle function. Full article

Lennox–Gastaut syndrome (LGS) is a rare and severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, mandatory tonic seizures, cognitive and behavioral impairment, and distinctive electroencephalographic features, including slow spike–wave discharges and generalized paroxysmal fast activity. Despite decades of therapeutic advances, LGS remains associated with profound lifelong disability and the absence of a single disease-defining molecular mechanism. Recent advances in genetics, neurophysiology, and network neuroscience have reframed LGS as a convergent network encephalopathy, in which diverse genetic, structural, metabolic, immune, and acquired insults funnel into shared molecular hubs, leading to thalamocortical network dysfunction. This framework helps explain the limited efficacy of purely syndrome-based treatments. This review synthesizes current evidence on electroclinical phenotyping, molecular and network pathogenesis, and contemporary diagnostic workflows and proposes a molecule-to-precision-therapy framework for LGS. We critically appraise pharmacologic, dietary, surgical, and neuromodulatory therapies, emphasizing drop seizures as a major driver of morbidity. Among available treatments, cannabidiol shows the most consistent and clinically meaningful efficacy for drop seizures, with benefits extending beyond seizure counts to seizure-free days and caregiver-relevant outcomes. Finally, we highlight key gaps and future directions, including etiology-stratified trials, network-guided interventions, and outcome measures that capture long-term developmental and quality-of-life impacts. Full article

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particularly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to a pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a subpopulation of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The goal of this review is the following: (i) comprehensively examine the multifaceted nature of oncofetal reprogramming; (ii) elucidate its underlying molecular mechanisms, including its regulators and effectors; and (iii) evaluate its consequences for the therapeutic response in different cancer types. We comprehensively integrate the latest findings from colorectal, breast, lung, liver, and other cancers to provide a detailed understanding of how oncofetal programs interfere with tumor response to treatment. Among the candidates, YAP1 and AP-1 have emerged as central transcriptional drivers of this reprogramming process, especially in colorectal and breast cancers. We also explore the distinct expression patterns of oncofetal genes across different tumor types and how these patterns correlate with treatment outcomes and patient survival. Lastly, we propose a dual-targeting therapeutic strategy that simultaneously targets both cancer stem cells and oncofetal-reprogrammed populations as a more effective approach to overcome resistance and limit recurrence. Full article

Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. This molecular phenotype narrows the availability of targeted therapies and contributes to high rates of early relapse, therapeutic resistance, and poor clinical outcomes. Mounting evidence pinpoints the tumor microenvironment (TME) as a central driver of TNBC progression, immune evasion, and resistance to treatment. The TME encompasses a complex and dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that collectively shape tumor behavior and influence therapeutic response. Notably, TNBC often displays an immunologically active microenvironment, marked by high levels of tumor-infiltrating lymphocytes and immune checkpoint expression, opening a window for immune-based therapeutic strategies. This narrative review summarizes current knowledge on the cellular, molecular, and structural features of the TNBC tumor microenvironment, with particular focus on immunosuppressive mechanisms mediated by tumor-associated macrophages, myeloid-derived suppressor cells, cancer-associated fibroblasts, and dysfunctional T cells. We describe the clinical development and therapeutic impact of monoclonal antibodies, including immune checkpoint inhibitors and antibody–drug conjugates. Additionally, we discuss strategies aimed at modulating the TME to enhance monoclonal antibody efficacy, including immune cell reprogramming, extracellular matrix remodeling, cytokine/chemokine blockade, and combination treatment strategies. Finally, we highlight the role of biomarker-driven patient stratification and personalized therapeutic strategies, addressing current challenges and future directions in TME-targeted drug development. Together, these insights underscore the potential of integrating immune modulation and monoclonal antibody-based therapies to improve outcomes for TNBC patients. Full article

Poorly differentiated gastric carcinoma (PGC) is aggressive, yet subtype-specific genomics are under-characterized. We queried AACR Project GENIE^® (cBioPortal v18.0-public; 12 August 2025) for PGC and analyzed somatic alterations from targeted panels (depth ≥ 100×; variant allele frequency ≥ 5%). Mutation and copy number frequencies were summarized, co-occurrence and exclusivity were tested, and primary versus metastatic tumors were compared using chi-square with Benjamini–Hochberg correction. The cohort included 189 tumors from 188 patients (71% primary; 25% metastatic), with primary and metastatic tumor samples being collected from different patients. Recurrently mutated genes were TP53 (48.7%), CDH1 (31.2%), ARID1A (21.2%), KMT2C (8.5%), and POLD1 (7.4%); additional alterations involved ERBB3, KMT2D, KEL, CDKN2A, and FAT1 (≈1–7%). Amplifications in CCNE1 (8.2%) and FGFR2 (7.6%) were common, alongside gains in MET, MYC, KRAS, and ERBB2 and losses in CDKN2A/CDKN2B, CDH1, and PTEN. Significant co-occurrence was observed for POLD1–KMT2D (p < 0.001), POLD1–ARID1A (p < 0.001), and ARID1A–KMT2D (p < 0.001), while TP53 was mutually exclusive with ARID1A (p = 0.029) and CDH1 (p = 0.041). CDH1 (48.9% vs. 29.6%; p = 0.021) and MLH1 (8.5% vs. 1.5%; p = 0.040) were enriched in metastases, and CCNE1 alterations showed female predominance (p = 2.83 × 10⁻⁴). Several “primary-only” findings likely reflect small denominators and require replication. PGC demonstrates a mutational framework dominated by TP53, CDH1, ARID1A, and recurrent CCNE1/FGFR2 amplifications, underscoring dysregulation of cell cycle and chromatin-remodeling pathways as key drivers. Co-occurrence of POLD1, ARID1A, and KMT2D suggests coordinated disruption of DNA repair and epigenetic regulation, whereas mutual exclusivity of TP53, ARID1A, and CDH1 indicates distinct tumorigenic routes. Metastatic enrichment of CDH1 and MLH1 supports their roles in invasion and therapeutic resistance. Together, these findings highlight candidate biomarkers and actionable pathways warranting validation in larger, multi-omic cohorts to refine precision treatment strategies for this aggressive gastric cancer subtype. Full article

Insulin resistance (IR) is a central driver of cardiometabolic disease and an increasingly recognized modifier of inflammatory and vascular pathology. Beyond impaired glucose homeostasis, IR emerges from chronic, metabolically induced inflammation (“meta-inflammation”) and convergent cellular stress programs that propagate across tissues and organ systems, ultimately shaping endothelial dysfunction, atherogenesis, and cardiometabolic complications. Here, we synthesize multilevel links between insulin receptor signaling, intracellular stress modules (oxidative, endoplasmic reticulum, inflammatory, and fibrotic pathways), tissue-level dysfunction, and systemic inflammatory amplification. This work is a conceptual narrative review informed by targeted database searches and citation tracking, with explicit separation of mechanistic/experimental evidence from human observational and interventional data; causal inferences are framed primarily on mechanistic and interventional findings, whereas associative statements are reserved for observational evidence. We propose an integrative framework in which stress-response pathways are context-dependent and become maladaptive when chronically activated under nutrient excess and persistent inflammatory cues, generating self-reinforcing loops between IR and inflammation that accelerate vascular injury. This framework highlights points of convergence that can guide mechanistic prioritization and translational hypothesis testing. Full article