Search Results (25,726)

Background: Aerobic vaginitis (AV) is characterized by dysbiotic vaginal microflora with overgrowth of aerobic pathogens of enteric origin, presence of vaginal inflammation and immature epithelial cells. This study aimed to evaluate, over a period of 10 years, women of reproductive age (non-pregnant and pregnant) as well as menopausal women affected by AV. Methods: We included non-pregnant, pregnant and menopausal women diagnosed with AV over a period of 10 years. Diagnosis of AV was determined according to the criteria proposed by Donders in 2002. The isolated pathogens were identified with the rapid identification system I-dOne (Alifax S.r.l, Polverara, Italy) and the automated system VITEK2 (Biomerieux, Marcy l’Etoile, France), which was used for antimicrobial susceptibility testing. Results: The overall aerobic vaginitis prevalence rate during the studied period was 9.5%. The most common isolated pathogens were Escherichia coli 27.3%, Enterococcus faecalis 25.0%, Streptococcus agalactiae 22.2%, Klebsiella pneumoniae 8.9%, Proteus spp 4.7%, and Staphylococcus aureus 3.5%. E. coli infection significantly increased the odds of mild AV by 1.65 times (p = 0.002) and Proteus species infection was over 6 times more likely to progress to severe disease (p < 0.001). Furthermore, pregnant women were more likely to be infected with E. faecalis (p < 0.001) while menopausal women were diagnosed significantly more with severe AV (p < 0.001) compared to the other groups. Conclusions: The prevalence of aerobic vaginitis in the population studied was in concordance with global rates. Menopausal women displayed increased severe AV cases while, in contrast, mild cases were recorded during pregnancy. The most commonly isolated pathogens were of enteric origin. Full article

Background: Intraductal carcinoma (IDC) and invasive cribriform (Cr) histologic patterns are important adverse morphologies in prostate cancer (PCa) and may influence pretreatment risk stratification. This study evaluated the feasibility of time-dependent diffusion magnetic resonance imaging (t_d-dMRI)-based microstructural mapping for preoperative characterization of these aggressive morphologies. Methods: This retrospective study included 95 men with pathologically confirmed PCa on radical prostatectomy specimens from March 2023 to March 2025. T_d-dMRI was performed using pulsed and oscillating gradient diffusion sequences. Microstructural parameters, including extracellular diffusivity (D_ex), cell diameter (d), intracellular volume fraction (f_in), cellularity, and diffusivities at 0, 17, and 33 Hz (ADC_0Hz, ADC_17Hz, and ADC_33Hz), were estimated using a two-compartment model. Conventional apparent diffusion coefficient (ADC_DWI) values were obtained from standard diffusion-weighted imaging. Parameters were compared between tumors with and without Cr/IDC patterns, and diagnostic performance was assessed using receiver operating characteristic analysis. Pairwise comparisons of AUCs were performed using the DeLong test. Results: Among 95 participants, 62 (65.3%) had Cr/IDC patterns. Compared with Cr/IDC-negative tumors, Cr/IDC-positive tumors showed higher f_in and cellularity (both p < 0.001) and lower ADC_DWI, ADC_0Hz, ADC_17Hz, and ADC_33Hz values (all p < 0.05). D_ex and d did not differ significantly between groups. Among t_d-dMRI-derived parameters, f_in showed the highest diagnostic performance (AUC = 0.757; 95% CI, 0.654–0.860). Conclusions: T_d-dMRI-based microstructural mapping demonstrates promise for characterizing the Cr/IDC morphologies in PCa. Full article

The brain maintains homeostasis partially by scavenging waste products. Failure of this function is closely associated with the onset and pathogenesis of various brain diseases, such as Alzheimer’s disease, sleep disorder, and the delay of the reparative process after brain injuries. We recently demonstrated that brain pericytes (BPCs) are sources of lipocalin-type prostaglandin D synthase (L-PGDS), a waste scavenger, in the brain. Based on the above, chemical compounds which promote L-PGDS production could have potential against brain diseases, such as dementia, sleep disorders, and brain injuries. However, the specific chemical compounds that may enhance L-PGDS production in BPCs have not yet been identified. In this study, we explored 158 chemical compounds from FDA-approved drug libraries with these activities. qPCR analysis showed that mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant, can increase L-PGDS expression in BPCs as well as in mouse- (m-BPCs) and human-derived BPCs (h-BPCs) in a dose-dependent manner. Since L-PGDS is a secretory protein, m-BPCs and h-BPCs were treated with various MTZ doses and L-PGDS levels in the culture supernatant were investigated. Western blot analysis showed that L-PGDS levels were significantly increased in a dose-dependent manner in both cell types, indicating that MTZ promoted L-PGDS secretion from m-BPCs and h-BPCs. Thus, MTZ may have the potential to be applied as drug repositioning for various brain diseases other than depression by activating L-PGDS production in BPCs, highlighting the importance of BPCs as the source to maintain brain homeostasis. Full article

Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine. Full article

Background/Objectives: Immune surveillance is increasingly recognized as a modifier of myeloproliferative neoplasm (MPN) initiation and evolution, yet the contribution of the NKG2D receptor and its ligands MICA/MICB to CALR-mutated disease remains unclear. Methods: We performed high-resolution next-generation sequencing genotyping of MICA and MICB in 43 patients with CALR-mutated MPN (WHO 2022 criteria) and compared the allele and haplotype distributions with those of 156 healthy Bulgarian controls and 85 patients with JAK2 V617F-positive MPN. Associations were tested using age- and sex-adjusted additive generalized linear models; bi-locus haplotypes were evaluated using haplotype score methods. In a genotyped subgroup (35 CALR-mutated MPN patients and 105 controls), functional KLRK1 (NKG2D) polymorphisms were analyzed for haplotype-level associations. We also performed 700 ns molecular dynamics simulations of selected MICA variants in complex with NKG2D and reanalyzed publicly available single-cell RNA-sequencing data (GSE117826) and RNA-sequencing data from CRISPR/Cas9-edited CALR-mutant iPSC-derived megakaryocytes to evaluate MICA/MICB expression. Results: MICA*004:001 was significantly associated with CALR-mutated MPN versus controls (p = 0.004; Bonferroni-adjusted p = 0.047), while MICB*008:001 showed only nominal association. Exploratory haplotype analyses identified a MICA*009:01-MICB*004:001 haplotype associated with CALR-mutated status (p = 0.008) and a KLRK1 G-A-G-T haplotype (rs1049174-rs2617160-rs2246809-rs2617170) associated with increased CALR-mutated MPN risk (OR = 3.61; p = 0.029). Transcriptomic reanalysis indicated a higher fraction of CALR-mutant stem and progenitor cells expressing detectable MICA/MICB transcripts, and heterozygous CALR-mutant megakaryocytes exhibited higher MICA expression than the wild type. Conclusions: Together, these data support an exploratory immunogenetic and transcriptomic link between the NKG2D-MICA/MICB axis and CALR-mutated MPN, but direct protein-level and functional studies are required before mechanistic or therapeutic conclusions can be drawn. Full article

TERT, the catalytic subunit of telomerase, is aberrantly activated in most cancers and represents an attractive therapeutic target. However, conventional TERT-targeting strategies, including chemical inhibitors and siRNA, are limited by several issues, such as insufficient efficacy and off-target effects. In this study, we investigated whether dCas9-KRAB-mediated CRISPR interference (CRISPRi) could overcome the limitations by transcriptional repression of TERT without DNA cleavage. We first assessed the efficacy of the dCas9-KRAB system by applying it to H1299 non-small-cell lung cancer cells and observed reduction in TERT expression up to approximately 80% and significant decreases in cell viability and growth. Transcriptome-wide analysis showed limited detectable changes in non-target-gene expression under the conditions tested. Together, the results suggest that dCas9-KRAB-mediated CRISPRi could serve as a proof-of-principle approach for targeted repression of TERT in cancer cells with limited detectable effects on non-target-gene expression. Full article

As global ecosystems and food systems face unprecedented anthropogenic and climatic challenges, there is a demand for an integrated understanding of biological systems. Proteomics has emerged as a definitive approach offering a direct view of the molecular phenotype, yet it is traditionally separated into plant and animal disciplines. With recent advances in mass spectrometry (MS) and bioinformatics tools, this prospective review proposes that combining a One Health proteomics approach with deep-learning data analysis can revolutionize global food security, animal productivity, and ecosystem health by uncovering proteoform signatures that drive resilience across life. The potential of a unified One Health proteomic framework, highlighting major developments, including 4D proteomics, Data-Independent Acquisition (DIA), and single-cell resolution, and emphasizes their capacity to resolve the complex proteoform landscape across kingdoms. Review emphasizes the applications of proteogenomics as a cross-disciplinary tool to improve genome annotations, explain evolutionary differences, discover biomarkers in animals and resolve complex signaling networks in plants under stress. Nevertheless, contemporary proteogenomics methods still show limitations in their ability to comprehensively resolve proteoforms due to the fact that the use of peptide-based approaches makes it difficult to fully appreciate the post-translational modifications specific to each protein isoform. We show that One Health proteomics will provide a transformative roadmap for deciphering the functional proteoform signatures that underpin resilience across the tree of life. Full article

Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation and survival of neoplastic plasma cells (PCs) within the bone marrow (BM), where disease progression is critically supported by interactions with the BM tumor microenvironment (TME). Despite significant advances in therapeutic strategies, MM remains incurable, underscoring the need for improved preclinical models to better understand the disease biology and therapeutic response. This review summarizes current and emerging MM treatment approaches and critically examines the development of models designed to more accurately recapitulate interactions between MM-PCs and the surrounding BM niche. We describe established and emerging modeling platforms, with emphasis on advanced three-dimensional (3D) culture systems and highlight their unique contributions to the preclinical assessment of both existing and novel therapies. The advantages of 3D models, including in vitro and in silico systems, over traditional two-dimensional (2D) models are discussed, alongside a comparative evaluation of scaffold-free and scaffold-based approaches. In addition, the benefits and recent advances in the customization of BM niche simulation using microfluidic technologies and organ-on-a-chip platforms are reviewed. The application of 3D models in MM research is increasingly enabling the study of disease pathogenesis, progression, drug resistance and precision-medicine approaches (informed by biomarker discovery). Although standardized preclinical approaches for evaluating MM therapeutics are currently lacking, the growing imperative to reduce reliance on preclinical animal models highlights the importance of alternate systems. Consequently, the development and adoption of physiologically relevant models that accurately recapitulate MM-PC interactions with the BM TME will be critical for advancing future therapeutic strategies in MM. Full article

Background/Objectives: The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. Cancers with reduced MRE11 expression have been suggested to be more sensitive to radio-chemotherapy and may be subject to synthetic lethality. The aim of this study was to assess the prevalence of MRE11 deficiency and the potential role and clinical significance of elevated and/or reduced MRE11 expression in human cancer. Methods: A tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed for MRE11 by immunohistochemistry. Results: In normal tissues, strong nuclear MRE11 staining occurred in almost all cell types. In cancers, nuclear MRE11 staining was strong in 11,797 (91.0%), moderate in 1018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4%) of 12,956 informative tumor samples. Only six tumor entities had more than one MRE11-deficient cases including hepatocellular carcinoma (9 of 193), intestinal type gastric adenocarcinoma (4 of 208), endometrioid endometrial carcinoma (5 of 268), pulmonary adenocarcinoma (2 of 165), colorectal adenocarcinoma (CRC, 16 of 2183), and clear cell renal cell carcinoma (ccRCC, 7 of 1011). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC and in gastric adenocarcinoma (p < 0.0001 each), advanced pT stage (p = 0.0003) and L1 status (p = 0.0019) in testicular seminoma, high grade (p < 0.05), advanced pT (p < 0.0001), and high UICC stage (p = 0.0014) in ccRCC, advanced pT stage in high-grade serous ovarian carcinoma (p = 0.0396), and nodal metastases in papillary thyroid cancer (p = 0.0332). Conclusions: MRE11 is highly expressed in most cancers. Reduced MRE11 expression is associated with aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored. Full article

Sjögren’s disease (SjD) remains one of the few major systemic autoimmune diseases without an approved disease-modifying therapy, despite decades of pathogenic insight and several randomised trials. We contend that these repeated failures reflect not intrinsic therapeutic refractoriness, but trial designs insufficiently aligned with the underlying biological heterogeneity of SjD. We propose a tripartite framework in which SjD is organised around three dominant biological axes: an interferon-driven systemic axis, a B-cell/lymphoproliferative axis, and a symptom/fibro-structural axis. Each axis carries its own characteristic biomarkers, histopathology, prognostic features, candidate endpoints, and therapeutic targets, and each implies a distinct trial enrolment strategy. Recent positive trials—phase III for ianalumab in NEPTUNUS-1/2, phase 2b for iscalimab in TWINSS, phase 2 for nipocalimab in DAHLIAS, and phase 2 for dazodalibep in a phenotype-defined symptom-dominant cohort—illustrate that meaningful clinical benefit becomes detectable once stratification is aligned to biology. By integrating molecular endotypes, validated biomarkers, composite endpoints, and phenotype-matched therapies onto a single explicit architecture, SjD shifts from a recurring example of translational failure to a model for precision medicine in heterogeneous autoimmune disease. The central message is that SjD may be less intrinsically treatment-resistant than it has historically been treatment-mistargeted. Full article

Liver-on-a-chip (LoC) platforms offer promising alternatives to conventional in vitro and animal models for studying hepatic function and drug response; however, wide variability in cell sources, seeding strategies, extracellular matrices (ECMs), and functional assays limits reproducibility. This study reviews reported 2D and 3D LoC systems to identify commonly used liver cell types, seeding densities, ECM materials, and albumin/urea assay methods. Immortalised HepG2-based models dominate current platforms, with optimal seeding densities typically ranging from ~3 × 10⁶ cells/mL in 2D systems and 0.5–5 × 10⁶ cells/mL in 3D constructs. Collagen I, alone or combined with Matrigel, emerged as the most frequently adopted ECM. Functional assessment across studies highlighted albumin and urea as robust markers, with Abcam ELISA and QuantiChrom DIUR assays providing suitable sensitivity for microfluidic sample volumes. Collectively, this work establishes practical benchmarks for hepatic cell selection, seeding parameters, ECM choice, and assay selection, supporting more standardised and reproducible LoC development. Full article

Introduction: A major health issue in individuals living at high-altitude regions is an increase in the number of red blood cells (RBCs). This condition generates a series of physiological alterations including the nervous system, where damage can occur due to increased blood viscosity. This increased viscosity, in turn, could compromise oxygen uptake, potentially linked to a degree of cognitive impairment. Objective: To determine the association between exposure to chronic hypoxia and sleep quality with the degree of cognitive impairment in a young adult population residing at different altitude levels. Methodology: A cross-sectional study was conducted with 200 apparently healthy subjects (aged 21–26 years) permanently residing in four Peruvian cities: Lima (154 m), Arequipa (2335 m), Puno (3820 m), and La Rinconada (5100 m) (n = 50 per location). Physiological profiles (SpO₂, blood pressure, heart rate, hemoglobin, and hematocrit) were measured. Cognitive impairment and sleep quality were evaluated using the Montreal Cognitive Assessment (MoCA) and the Pittsburgh Sleep Quality Index (PSQI). Sex-stratified hierarchical multiple linear regression models with bootstrapping were utilized for independent correlation analysis. Results: Hemoglobin levels gradually increased with altitude, peaking at 19.47 ± 3.01 g/dL in La Rinconada, while SpO₂ decreased to 81.64%. Moderate-to-severe cognitive impairment was exclusively restricted to the extreme altitude population of La Rinconada, where only 10% of subjects remained unaffected. In the sex-stratified multivariate regression, residency in La Rinconada initially served as a robust negative predictor of MoCA scores among women (β = −5.52, p < 0.001); however, this geographical effect lost statistical significance after adjusting for biological variables in Model 2 (β = −4.72, p = 0.178). In the fully adjusted models, neither individual hemoglobin levels nor SpO₂ fluctuations displayed an independent linear association with cognitive performance in either sex (p > 0.05). Sleep quality was poor across cohorts but showed no significant association with cognitive impairment (p = 0.174). Conclusions: Chronic exposure to severe hypoxia (>5000 m) is associated with a greater presence of cognitive impairment, which is largely accounted for by individual physiological adaptations rather than isolated, linear effects of independent hematological or subjective sleep parameters. Full article

Human papillomavirus type 53 (HPV53) is one of the most prevalent HPV genotypes in China, frequently detected in cervical intraepithelial neoplasia and cervical cancer, yet remains outside the coverage of all currently available prophylactic vaccines and is relatively understudied. This study performed a comprehensive analysis of HPV53 clinical infection profiles, genomic diversity, and T-cell epitopes to inform therapeutic vaccine development. Clinical analysis of 158 HPV53-positive patients showed that infections were most prevalent in women aged 40–59 years, with persistent infection identified in 13.3% participants and a subset of cases associated with cervical lesions. Genomic analysis of 134 HPV53 isolates identified four lineages (A-D, with lineage D further subdivided into four sublineages, and an overall nucleotide variability of 4.4%. E2 was the most variable protein while E7 was the most conserved. Immunoinformatic prediction identified 176 HLA class I-restricted T-cell epitopes across E6, E7, E1, and E2, from which 20 candidates were selected for experimental validation. Ten demonstrated strong HLA binding affinity in vitro, and murine immunization identified a E6 peptide VYNFAYTDL as an immunodominant epitope. Three validated epitopes exhibited sequence overlap with 12 to 13 of other 13 high-risk HPV genotypes, suggesting their potential as broadly cross-reactive targets. These findings clarify the genomic diversity and immunogenic epitope landscape of HPV53, providing a foundation for the rational design of therapeutic vaccines. Full article

Organ failure remains one of the foremost medical and socioeconomic challenges of the twenty-first century, with global transplant waiting lists far exceeding the supply of donor organs. Chronic supportive therapies sustain life but do not restore organ function, underscoring an urgent need for curative alternatives. Bioartificial organs represent a major frontier in organ replacement, driven by converging advances in cell biology, biomaterials science, and bioengineering. By integrating living cells or biologically derived matrices with engineered devices or scaffolds, these systems aim to restore functions that purely mechanical supports cannot reproduce. This review examines the principal technological platforms underpinning the field, including cell encapsulation, decellularization and recellularization, three-dimensional bioprinting, organoids, organ-on-chip systems, and xenotransplantation, and discusses their application to kidney, liver, heart, pancreas, and lung replacement. Across organ systems, progress is advancing from experimental proof-of-concept toward modular and increasingly translational platforms, although whole-organ bioengineering remains largely preclinical for the most structurally complex targets. The major unresolved barriers include vascularization, immune compatibility, scalable cell manufacturing, durable function, and stable integration between biological and engineered components. Overall, bioartificial organ engineering is evolving toward clinically relevant therapeutic strategies capable of complementing, bridging, or eventually reducing dependence on donor-organ transplantation. Full article

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance. Full article