Search Results (9,687)

Background: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency are key predictive biomarkers for immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). In real-world practice, however, diagnostic pathways often involve heterogeneous testing modalities, which may lead to discordant or inconclusive results. Methods: We conducted a retrospective study of patients with mCRC who underwent at least one MSI/MMR assessment between 2015 and 2025. Diagnostic modalities included IHC, tissue-based and liquid-based MSI testing. A predefined decision algorithm classified results as conclusive or inconclusive; discordant cases underwent adjudication that integrated a pathology review, molecular features, and technical considerations. Patients were ultimately assigned to definitive MSS or definitive MSI groups. Clinical characteristics, treatment patterns, and outcomes—particularly in relation to immunotherapy—were evaluated. Results: Among 727 evaluable patients, the MSI/MMR status was conclusive in 695 (95.6%) and inconclusive in 32 (4.4%). Inconclusive cases resulted from isolated MMR protein loss, heterogeneous or equivocal staining, inter-tumoral discordance, or discrepancies between tissue- and liquid-based assays. After adjudication, 54 patients (7.4%) were classified as definitive MSI and 673 (92.6%) as definitive MSS. Definitive MSI tumors were associated with female sex, right-sided primaries, high-grade histology, nodal involvement, and BRAF V600E mutations. Among the definitive MSI patients, 31 (57.4%) received immunotherapy, achieving a complete response rate of 48.4% and an overall response rate of 71.0%. Median PFS and OS were not reached in the definitive MSI group, whereas definitive MSS patients treated with ICIs experienced significantly poorer outcomes. Conclusive and adjudicated MSI groups demonstrated comparable responses to immunotherapy. Conclusions: In real-world practice, a meaningful proportion (4%) of mCRC patients experience inconclusive MSI/MMR assessment, with important clinical implications. Both technical and biological factors contribute to diagnostic uncertainty. Integrating orthogonal testing modalities and applying structured adjudication improves classification accuracy and ensures appropriate access to immunotherapy. Full article

Unmanned aerial vehicles (UAVs) are increasingly used in precision pest management, yet their performance in operational forest settings remains underexplored. We evaluated the efficacy of SPLAT^® SM-O mating disruptant applied using a UAV at a dosage of 14.8 for control of the spongy moth, Lymantria dispar dispar L. (Lepidoptera: Erebidae). One treatment plot received 11.4 g AI/ha because of a calibration deviation during application. Both treatments reduced trap catches by >90% for 10 weeks following the application, meeting the efficacy requirement set by the USDA’s National Slow the Spread (STS) Program. One year after the application, trap catches continued to be reduced by 28% and 67% in plots treated with 14.8 and 11.4 g AI/ha, respectively. These levels of trap catch reduction in the year of treatment and one year after the treatment application are comparable to those reported following fixed-wing aerial treatments. These results indicate that UAV-applied SPLAT^® SM-O meets STS requirements for operational use and is suitable for integration into the program for treating small or isolated blocks. These findings also have broader implications for the use of unmanned aerial vehicles to deploy SPLAT^® formulations in forest pest management programs. Full article

Human immunodeficiency virus type 1 exhibits extensive genetic diversity, which has important implications for molecular epidemiology, recombinant-pattern assessment, and antiretroviral resistance surveillance. In Mexico, HIV-1 molecular surveillance has historically relied mainly on partial pol gene sequencing, limiting the ability to compare lineage assignments across gag, pol, and env regions. We analyzed plasma samples from 40 treatment-naïve adults receiving care at a tertiary-care hospital in Mexico using a commercial amplicon-based multiregion HIV-1 genomic sequencing workflow. DeepChek^® was used as the primary workflow for read processing, mutation calling, region-level subtype assignment, and antiretroviral resistance interpretation. Resistance interpretation was restricted to antiretroviral target regions with sufficient coverage, mainly reverse transcriptase, protease, integrase, and capsid, when available. Drug resistance mutations were identified in 6/40 participants (15.0%) when mutation-level resistance findings in RT, PR, and IN were considered; one additional sample showed a capsid inhibitor-nonsusceptible NGS call. NNRTI-associated findings were identified in 2/40 patients (5.0%), whereas NRTI- and PI-associated findings were identified in 1/40 patients (2.5%). Accessory or secondary INSTI-associated substitutions were detected in 2/40 patients (5.0%). Region-level subtype analysis revealed frequent discordant assignments across amplified segments, which is consistent with complex mosaic profiles; however, these findings are interpreted as region-level subtypes and recombinant-pattern assignments rather than continuous whole-genome recombination maps. One sample had insufficient RT/PROT/INT coverage for drug resistance interpretation in the complete DeepChek report and was retained only for regions meeting quality thresholds. These findings support the value of multiregion HIV-1 sequencing for local molecular surveillance while emphasizing the need for transparent region-level coverage reporting, cautious interpretation of recombinant-pattern calls, and transparent repository reporting. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer’s disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders. Full article

Antimicrobial resistance (AMR) is a growing global public health challenge. Its development is strongly associated with the inappropriate and excessive use of antimicrobial agents, leading to reduced treatment effectiveness, limited availability of therapeutic options, constraints on medical procedures, and an increasing economic burden. This narrative review synthesizes current knowledge on antibiotic-resistant bacteria detected in airborne samples from healthcare environments and examines their reported resistance profiles. The review focused on the bacterial species identified, methods used for antimicrobial susceptibility assessment, types of healthcare facilities investigated, and environmental and behavioral factors influencing the occurrence and dissemination of airborne antibiotic-resistant bacteria. The clinical relevance of the reported pathogens was discussed in the context of the WHO Bacterial Priority Pathogens List (BPPL), while the WHO AWaRe classification and TrACSS framework were used as complementary interpretative tools to contextualize resistance patterns and their implications for antimicrobial stewardship and AMR surveillance. The reviewed studies showed that airborne bacterial communities in healthcare settings were dominated by Gram-positive bacteria, particularly Staphylococcus spp. and Bacillus spp., while clinically relevant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Acinetobacter baumannii were also frequently detected. Resistance to β-lactam antibiotics was the most frequently reported resistance pattern. Considerable heterogeneity in sampling strategies, antimicrobial susceptibility testing methods, and interpretive criteria limited direct comparison among studies. The findings highlight the need for standardized monitoring methods, long-term surveillance, and integrated environmental and clinical research to support infection prevention strategies and mitigate antimicrobial resistance. Full article

Sewage sludge management is increasingly shifting from a liability-focused “treat-and-dispose” approach toward resource recovery, where digestion residues and their liquid fractions are treated as secondary feedstocks for nutrient, water, and energy recovery. In Europe, the recast Urban Wastewater Treatment Directive strengthens performance and monitoring requirements and reinforces the need for efficient sludge treatment and downstream valorization routes. This review synthesizes evidence on how pretreatment-induced changes in digestate properties translate into membrane performance outcomes and maps practical design implications for selecting pretreatment-membrane trains for nutrient recovery and reclaimed water production. Pressure-driven membrane methods (MF/UF/NF/RO), together with membrane distillation and electrodialysis, are central candidates for producing clarified water streams and concentrating nutrients; however, their performance is governed by digestate rheology, colloidal stability, and the composition of soluble microbial products and inorganic ions, which collectively shape fouling and scaling risks. Pretreatments such as thermal hydrolysis and microwave conditioning can modify floc structure and solubilize organics, with potential benefits for dewaterability and mass transfer, but can also shift particle size distributions toward fines and increase fouling propensity if not coupled with appropriate solid–liquid separation and conservative flux control. Emphasis is placed on mechanisms and operational trade-offs rather than single-point performance claims, highlighting where evidence is robust and where further comparability and full-scale validation remain necessary. Full article

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, and progressive neurodegeneration. While there is a small component of genetic susceptibility to MS risk, environmental factors, including infectious exposures, are gaining increased recognition as playing a critical role in MS initiation and progression. Viral infections, especially by Epstein–Barr virus (EBV), have emerged as strong candidates and triggers of MS symptoms, through antibody-mediated molecular mimicry and B-cell dysregulation. In contrast, parasitic infections, including helminths and select protozoa, appear to exert neuroprotective effects by skewing immune responses toward regulation and tolerance. In this review, we examine antibody-driven mechanisms by which viral pathogens promote autoimmunity in MS and contrast these with parasite-induced immunoregulatory pathways that suppress pathogenic inflammation. We further discuss diagnostic and therapeutic implications, highlighting how insights from infectious immunology may inform novel strategies for MS treatment. Full article

Background/Objectives: Alzheimer’s disease (AD) disproportionately affects women, who account for nearly two-thirds of affected individuals worldwide. This sex imbalance cannot be explained by longevity alone and likely reflects complex interactions among biological sex, endocrine aging, genetic susceptibility, and brain-specific mechanisms of vulnerability. Neuroimaging has played a pivotal role in characterizing these sex-related differences in vivo, enabling the assessment of amyloid-β deposition, tau propagation, neurodegeneration, cerebral glucose metabolism, and network reorganization. This invited review examines AD through a rigorously sex-specific neuroimaging perspective, with particular emphasis on implications for women’s brain health. Methods: We integrated evidence from structural MRI, FDG-PET, amyloid-PET, tau-PET, estrogen receptor PET, diffusion MRI, and fluid biomarkers, together with epidemiological, molecular, genetic, and endocrine studies. The review focuses on female-specific trajectories of AD initiation and progression, highlighting the contribution of neuroendocrine aging, menopause, metabolic dysfunction, and sex-modulated genetic risk factors. Results: Available evidence indicates that women exhibit distinct biological and neuroimaging signatures across the AD continuum. Menopause emerges as a critical neuroendocrine transition associated with metabolic decline, altered brain connectivity, increased amyloid and tau vulnerability, and progressive neurodegeneration. Female-specific patterns of tau propagation and sex-dependent interactions with genetic risk factors further contribute to differential disease trajectories. Advanced multimodal neuroimaging approaches have substantially improved the characterization of these mechanisms and their relationship with cognitive decline and clinical progression. Conclusions: A sex-specific neuroimaging framework is essential to improve understanding of AD pathophysiology and to advance precision medicine approaches tailored to women’s brain health. Recognition of endocrine aging and female-specific biological vulnerability may inform earlier identification of at-risk individuals and the development of targeted prevention and treatment strategies. Future research should prioritize sex-aware longitudinal studies and multimodal biomarker integration to optimize personalized interventions in AD. Full article

Lateral femoral neck and peritrochanteric fractures are common and clinically challenging injuries, particularly in the elderly population, with significant implications for morbidity, mortality, and functional recovery. Traditional classification systems are widely used to guide treatment, yet their reproducibility and clinical applicability remain debated. Increasing attention has been directed toward trabecular architecture and its role in fracture behavior and reduction strategies. This review aims to summarize current evidence on classification systems, trabecular-based fracture patterns, pre-operative reduction techniques, and fixation strategies. A narrative review was conducted using PubMed/MEDLINE, Embase, and Scopus databases up to May 2026. Original studies, reviews, and biomechanical investigations focusing on proximal femur fracture classification, reliability, trabecular alignment, reduction techniques, and fixation methods were included. Data were qualitatively analyzed, with emphasis on interobserver reliability, biomechanical implications, and clinical outcomes. Conventional classification systems, including anatomical, Evans–Jensen, and AO/OTA frameworks, demonstrated variable and generally moderate reproducibility, with reported interobserver agreement ranging from approximately κ = 0.30 to 0.60. Emerging evidence highlights the importance of trabecular architecture, distinguishing intradigital fractures—confined within trabecular pathways and relatively stable—from extradigital fractures, which disrupt load-bearing structures and are associated with increased mechanical instability and higher failure rates. Biomechanical and clinical studies indicate that inadequate reduction with trabecular misalignment significantly increases the risk of varus collapse and implant cut-out. Reduction strategies tailored to fracture pattern, such as internal rotation for intradigital fractures and external or combined maneuvers for extradigital patterns, improve alignment and load transfer. In terms of fixation, dynamic hip screws remain effective in stable fractures, whereas cephalomedullary nails demonstrate superior performance in unstable patterns, with lower reoperation rates reported (approximately 5–8% vs. 10–15%). Management of lateral femoral neck and peritrochanteric fractures should extend beyond traditional classification systems to incorporate trabecular biomechanics. Restoration of trabecular alignment, alongside established parameters such as neck–shaft angle and tip–apex distance, is critical for optimizing outcomes. Further prospective studies are needed to validate trabecular-based classifications and standardize reduction strategies. Full article

The use of insect-based protein sources in aquaculture is gaining increasing attention with Hermetia illucens (black soldier fly, BSF) larvae meal representing a promising substitute to fishmeal (FM). This study evaluated the effect of partial dietary inclusion of BSF meal (BSF0, BSF2.5, BSF5, BSF10%) on the volatilome of rainbow trout (Oncorhynchus mykiss) fillets, before and after cooking, using gas chromatography–mass spectrometry (GC–MS) and a metal oxide sensor-(MOX)-based device. Fish were fed diets with increasing BSF inclusion, and both raw and cooked fillets were analyzed to assess changes in volatile organic compounds (VOCs). GC–MS enabled the identification and semi-quantitative analysis of VOC classes, while MOX sensor responses were processed using Linear Discriminant Analysis (LDA) to assess discrimination among dietary treatments. Results showed that BSF inclusion influenced the volatile profile, with clearer separation at higher inclusion levels (BSF5–BSF10%), especially in cooked fillets. Thermal processing enhanced these differences. GC–MS analysis revealed a reduction in aldehydes and ketones and an increase in carboxylic acids with higher BSF inclusion. Key compounds such as hexanal and heptanal decreased, indicating changes in lipid-derived volatile pathways. Overall, the integration of GC–MS and MOX sensors proved effective in detecting diet-induced changes, supporting their application as effective and reliable tools for quality assessment in aquaculture products, with potential implications for sensory quality that should be further confirmed through dedicated sensory studies. Full article

Background/Objectives: Although vitamin K has been implicated in osteoarthritis pathophysiology, the specific effects of vitamin K2 (menaquinone) on cartilage degeneration remain poorly characterized. This study aimed to investigate the effect of oral vitamin K2 supplementation in a monosodium iodoacetate-induced osteoarthritis model. Methods: Twenty-four male Sprague Dawley rats were included in the study and divided into 3 equal groups: sham group, control (osteoarthritis) group, and treatment group. Saline was applied to the right knee of the sham group, and MIA was applied intra-articularly to the right knee of the control and treatment groups to create an osteoarthritis model. Rats in the treatment group were given 8 micrograms (μg)/day of vitamin K2 orally in addition to the standard diet. After 28 days of follow-up, all rats were euthanized. The right knee articular cartilage was examined histologically with Hematoxylin–Eosin and Safranin O and immunohistochemically with type II collagen alpha 1 and Matrix Metalloproteinase-13. Results: Histological evaluation demonstrated significantly lower Mankin scores in the treatment group (4.25 ± 0.83) compared with the control group (11.10 ± 0.83). Immunohistochemical analysis showed more intense type II collagen staining and reduced matrix metalloproteinase-13 staining in the treatment group relative to the control group. Conclusions: Oral vitamin K2 administration was associated with reduced cartilage degeneration and improved matrix preservation at the 28-day endpoint in an induced MIA osteoarthritis rat model. Full article

Gene expression analyses of postmortem brains have identified hundreds of dysregulated genes in schizophrenia (SCZ) and bipolar disorder (BD). Lactate accumulation and reduced brain pH are also consistently reported in these disorders. As increased TGFB expression has been implicated in major psychiatric diseases and lactic acid induces TGFB2 upregulation in metabolic diseases, we hypothesized that lactate-induced brain acidosis may drive widespread gene dysregulation through TGFB2 activation. In our previous microarray studies, increased TGFB2 expression was observed in postmortem brains of SCZ and BD patients, while pathway analyses suggested a key role for TGFB2 in the dysregulation of other genes, particularly astrocytic genes. TGFB2 itself also exhibited promoter DNA hypomethylation in postmortem brains of these patients. Here, while brain pH was lower in SCZ and BD patients, we investigated the effects of pH alteration on the expression and promoter DNA methylation of TGFB2 and TGFB2-correlated genes in iPSC-derived neurons, astrocytes, and brain organoids (brainoids). Cultures were treated with lactic acid, HCl, bicarbonate, or NaOH to alter culture medium pH by ±0.4 units, and gene expression and promoter DNA methylation were evaluated by qPCR analyses. In our reanalysis of postmortem brain microarray data, nearly 80% of dysregulated genes, together with TGFB2, exhibited inverse correlations with brain pH. Lactic acid treatment induced increased expression and promoter DNA hypomethylation of TGFB2 and several correlated genes in astrocytes and brainoids, whereas bicarbonate and NaOH treatments showed opposite effects. These findings suggest that lactate-mediated brain acidosis may contribute to TGFB2 upregulation and widespread gene dysregulation implicated in SCZ and BD pathogenesis. Therapeutic interventions targeting lactic acid accumulation or TGFB2 hyperexpression may mitigate disease-associated brain gene dysregulation. Full article

Triple-positive breast cancer (TPBC) is characterized by the overexpression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making its management a therapeutic challenge. Despite the availability of targeted therapies, patients with TPBC often experience recurrence and poor clinical outcomes due to intrinsic and acquired resistance mechanisms. This review summarizes current therapeutic approaches and their limitations, highlights the molecular mechanisms underlying treatment resistance and recurrence, and explores opportunities for drug repurposing, particularly involving multi-target inhibitors. Special emphasis is placed on the interaction between hormone receptor and growth factor receptor pathways, compensatory signaling mechanisms, and predictive biomarkers of recurrence. Furthermore, emerging strategies for drug repurposing using clinically available drugs are analyzed, including in silico, in vitro, and clinical trial evidence, along with their translational implications. Finally, we conclude that drug repurposing and multi-target approaches offer a compelling rationale for the development of novel therapeutic strategies in triple-positive breast cancer. However, their clinical utility remains to be validated through appropriately designed experimental and clinical studies before their impact on recurrence outcomes can be established. Full article

Kidney transplantation is the treatment of choice for end-stage renal disease, although delayed graft function remains a frequent early complication with important clinical implications. Because early graft recovery depends on adequate perfusion, careful perioperative volume assessment and hemodynamic optimization are essential. Conventional markers such as interdialytic weight gain and estimated dry weight provide only indirect information on intravascular volume and may lead to pre-transplant misclassification of volume status. Complementary tools, including bioimpedance, natriuretic peptides, and congestion-focused ultrasound, may improve characterization of fluid distribution and hemodynamic stress, but none reliably define effective graft perfusion. Pressure-based parameters remain central to perioperative management; however, mean arterial pressure reflects systemic perfusion pressure and may be preserved despite reduced renal blood flow. Central venous pressure is an imprecise surrogate of intravascular volume and fluid responsiveness, with inconsistent associations with clinical outcomes across studies. In this context, flow-guided strategies based on dynamic indices of fluid responsiveness provide a more direct assessment of circulatory adequacy and have been associated, in selected studies, with improved early graft outcomes. Overall, the evidence supports a multimodal approach integrating volume assessment tools with pressure- and flow-oriented monitoring to optimize graft perfusion and early transplant outcomes. Full article