搜索结果：Journal of translational medicine

We aimed to examine regional differences in the relationship between core clinical features assessed using the Improving the DIAgnosis and Management Of Neurodegenerative Dementias of Lewy body type in the NHS (DIAMOND-Lewy) dementia with Lewy bodies (DLB) Assessment Toolkit and memory service diagnoses of Lewy body dementia (LBD). Secondary analysis of a multicentre observational study. Memory clinics in three sites across England (North East, London and South East) from July 2019 to March 2023. 935 individuals with a new memory service diagnosis of dementia enrolled in the DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND) programme. Core clinical features of DLB were assessed using the DLB Assessment Toolkit. The relationship between core clinical features and memory service diagnosis of LBD was examined using Bayesian probit models. There were higher rates of LBD diagnosis from memory services in the cohort in North East England compared with the London and South East centres (11% vs 4%; risk ratio (RR)=1.72 (1.35-2.08)) and evidence of a regional moderating effect on the relationship between clinical features and LBD diagnosis (RR=1.73 (1.26-2.40)).All core clinical features of DLB were associated with LBD diagnosis in North East England, whereas visual hallucinations were the most influential diagnostic feature in London and the South East (RR=3.18 (2.29-4.02)). Regional differences in LBD diagnosis in UK memory services appear to reflect different rates of recognition of specific LBD clinical features. Routinely using a standardised DLB Assessment Toolkit and improving awareness of non-hallucination features in LBD could help to address this disparity.

Recent advances in Blood-Based Biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer Disease (AD), with plasma p-tau217 emerging as a highly accurate and scalable diagnostic marker of AD pathology. Across multiple analytical platforms, plasma p-tau217 has demonstrated consistently strong diagnostic performance for the detection of amyloid pathology. The interpretation of BBMs in older adults presents unique challenges due to the high prevalence of multimorbidity, chronic kidney disease, polypharmacy and frailty. Although these factors may influence absolute biomarker concentrations, current evidence suggests the diagnostic performance of p-tau217 remains largely preserved across diverse older populations when interpreted appropriately. Frailty may modify the relationship between AD pathology and clinical expression of mild cognitive impairment/dementia and may influence the absolute concentration of BBMs underscoring the importance of contextualising test results within a comprehensive assessment. Importantly, these factors should not preclude a clinical-biological diagnosis of AD. The clinical value of BBMs such as p-tau217 in older adults lies not in their use in isolation, but in their integration with a gerontologically attuned diagnostic pathway. Current evidence and international guidelines support the use of BBMs only in symptomatic older adults presenting to specialist services and not in asymptomatic individuals. This commentary reviews recent advances in BBM performance, emerging clinical guidelines, real-world evidence and potential diagnostic pitfalls relevant to older adults. We propose that incorporating BBMs within a Comprehensive Geriatric Assessment framework offers a pragmatic approach to achieving timely, accurate and equitable clinical-biological diagnosis whilst preserving the holistic, person centred principles of geriatric medicine.

It is widely recognized that dysregulated mineral balance, in the context of disease, has negative health consequences. However, growing evidence shows that imbalances in mineral homeostasis from a sustained high dietary intake of inorganic phosphate/phosphorus (Pi), even when kidney function remains clinically normal, can also cause serious health problems, including bone disease. Western-style diets, which commonly include added Pi salts, contribute significantly to the issue. Despite this, investigations into therapeutic strategies to counter these effects in the absences of disease are limited. This study aimed to determine whether clinically used pharmacologic and nutritional interventions could regulate mineral homeostasis and prevent bone loss while correcting the systemic consequences of chronic high dietary Pi intake. Healthy mice were fed diets with high (HPD), normal (NPD), or low (LPD) levels of Pi additives and constant calcium (Ca). Additional groups were treated with HPD and supplemented with Vitamin D, Lanthanum Carbonate, Cinacalcet, Zoledronic acid, or a strategy of balancing dietary Ca:Pi. The therapies that partially or fully corrected serum Pi levels and homeostatic factors, interestingly, corrected the increase in cortical porosity but did not correct the HPD-induced decrease in cortical or trabecular bone volume. Only Zoledronic acid successfully restored the bone volume lost due to HPD but exacerbated the HPD increase in cortical porosity. Surprisingly, many of the treatments generated an inflammatory response in kidney in the context of HPD, suggesting that they can have harmful side effects in the absence of overt kidney disease. This work advances the understanding of the health impacts of Pi additives which are common in ultra-processed foods and common in the Western style diet. Specifically, the results produce clinically relevant findings that simply controlling serum Pi and/or Ca levels or Pi responsive endocrine factors such as FGF23, PTH, and osteopontin are not sufficient to block the negative impacts of chronic high dietary Pi consumption on the skeleton. Further, therapeutic strategies to control serum Pi have an impact on the kidneys in the context of high dietary Pi intake.

Resistance to immune checkpoint blockade substantially limits its clinical efficacy in head and neck squamous cell carcinoma(HNSCC). ZC3H13 is a component of the N6-methyladenosine writer complex, but its roles in HNSCC progression and response to anti-programmed cell death protein 1(anti-PD-1) therapy remain unclear. The expression and clinical relevance of ZC3H13 were evaluated using clinical cohorts and publicly available transcriptomic datasets. Gain- and loss-of-function experiments were performed to determine the effects of ZC3H13 on the malignant phenotypes of HNSCC cells. An epithelial-specific ZC3H13 conditional knockout mouse model of 4-nitroquinoline-1-oxide-induced oral tumorigenesis was used to assess tumor development and responsiveness to anti-PD-1 therapy. N6-methyladenosine modification, RNA stability and functional rescue assays were conducted to investigate the underlying molecular mechanism. ZC3H13 was upregulated in HNSCC and was associated with poor prognosis and a limited response to anti-PD-1 treatment. ZC3H13 promoted the proliferation and invasion of HNSCC cells, whereas epithelial-specific ablation of ZC3H13 suppressed oral tumorigenesis and enhanced the therapeutic efficacy of anti-PD-1 treatment. Mechanistically, ZC3H13 regulated the N6-methyladenosine modification of cyclin D1(CCND1) mRNA and promoted its IGF2BP1-dependent stabilization, thereby contributing to malignant tumor phenotypes and alterations in immunosuppressvie features. The ZC3H13/IGF2BP1/CCND1 regulatory axis contributes to HNSCC progression and resistance to anti-PD-1 therapy. These findings identify ZC3H13 as a potential therapeutic target for improving the efficacy of anti-PD-1 treatment in HNSCC.

Transferability of questionnaires across languages and cultures requires a systematic process to preserve content integrity and ensure validity and reliability. The aim of this study was to translate, culturally adapt and face validate the US-developed patient-reported outcome (PRO) measure 'Type 1 Diabetes and Life' (T1DAL) for use in a Danish population of parents of children under the age of 11 years living with type 1 diabetes. The process followed the 10-step International Society for Pharmacoeconomics and Outcomes Research good practice principles for the translation and cultural adaptation of PRO measures, thereby establishing content validity and cross-cultural validity in accordance with COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) recommendations. Following approval from the developer of the original questionnaire, two independent forward translations were conducted by bilingual native Danish speakers. These translations were then synthesised into a reconciled version, which were then back translated by two bilingual native English speakers. Discrepancies between the original and the reconciled versions were reviewed, leading to small linguistic and cultural adjustments. This process included discussions around the response categories on the Likert-scale and items reflecting the US healthcare context-particularly those related to insurance-dependent access, which are less relevant in Denmark.Cognitive debriefings regarding the updated Danish version with 12 parents resulted in a Danish version demonstrating strong semantic, conceptual and experiential equivalence. Additionally, minor linguistic and cultural adjustments were made to enhance clarity and contextual appropriateness. Cognitive debriefing confirmed the questionnaire's acceptability and comprehensibility across a diverse range of respondents. Applying ISPOR principles emphasised the importance of cultural adaptation that extends beyond linguistic translation to preserve the original questionnaire's integrity and meaningfulness and resulted in a conceptually equivalent and culturally adapted Danish version of the original T1DAL questionnaire, suitable for use in Danish clinical and research settings. H-25016032.

In the era of immunotherapy, head and neck squamous cell carcinoma (HNSCC) has demonstrated clear benefits from immune-based treatments and is widely regarded as a tumor type with high immunotherapeutic potential. These tumors are characterized by robust and persistent inflammatory responses that actively drive tumor initiation and progression while concurrently shaping their sensitivity or resistance to therapy. Inflammation simultaneously creates therapeutic vulnerabilities and barriers by altering tumor behavior and reprogramming the immune microenvironment. This review examined HNSCC through a tripartite prism of inflammation, immunity, and tumor biology to demonstrate how chronic inflammatory cues rewire immune cells, reshape signaling circuits, and remodel tissue architecture, ultimately altering responses to immunotherapy. We first examined how immune cell reprogramming occurs under inflammatory pressure. Macrophages, regulatory T cells, exhausted CD8+ T cells, and specialized dendritic cell subsets can switch roles-from tumor-clearing sentinels to promoters of tumor growth, stemness, and invasion. This plasticity-sometimes transient, sometimes entrenched-determines whether the immune ecosystem favors elimination or tolerance, and consequently whether immune checkpoint blockade succeeds or fails. Next, we catalogued the inflammation-linked pathways and readouts that capture these state changes. Signaling hubs such as NF-κB/STAT3, IL-6/TNFα, TGF-β, HA-CD44, and PI3K-4EBP1-SOX2 orchestrate the trade-offs between proliferation and invasion and govern cancer stem cell dynamics. Corresponding biomarkers-PD-L1, CD163/CD68 ratios, LAMP3, ALDH/SOX2, Zeb1, Vimentin, and CD44 isoforms-become far more informative when resolved at single-cell and spatial scales, thereby enabling sharper patient stratification. We then mapped the pathological interplay among tumor, stromal, and immune compartments. Extracellular matrix reprogramming, CAF heterogeneity, and the spatial polarity of immune infiltrates generate discrete micro-niches with distinct functional consequences. Spatial profiling can convert static pathology into a dynamic atlas of therapeutic opportunities. Finally, we outlined translational directions. Targeting inflammation and the microenvironment-via TAM reprogramming, cytokine blockade, or STING/CD47 pathway modulation combined with immune checkpoint blockade (ICB)-offers a rational strategy to improve outcomes. Altogether, these strategies point toward an ecology-aware approach to precision immunotherapy for HNSCC-one that reads and reshapes the tumor's inflammatory language rather than ignoring it.

Background: Anxiety and depression are major contributors to mental-health burden and frequently co-occur in clinical practice. In tele-mental health, routinely captured operational variables such as consultation duration, visit frequency, and follow-up cadence may provide clinical digital phenotypes that complement conventional symptom scales. This study aimed to characterize anxiety-depression comorbidity in a large real-world tele-mental health cohort and to determine whether symptom severity was associated with distinct patterns of healthcare utilization. Methods: We conducted a retrospective real-world study of 3467 patients followed in psychiatry and psychology teleconsultations. Patients were classified as anxiety only, depression only, comorbid anxiety-depression, or neither. Symptom severity was categorized as mild, moderate, or severe using validated questionnaire-based measures; to improve comparability across instruments, scores were additionally harmonized using z-score normalization. Associations between anxiety and depression severity within the comorbid subgroup were examined using a chi-square framework. Telehealth utilization endpoints included consultation duration, number of consultations, and inter-visit interval, analysed overall and stratified by sex, age group, and symptom severity. Results: Anxiety and/or depression were present in 61.7% of the cohort (2140/3467), and anxiety-depression comorbidity accounted for 43.8% of all patients (1520/3467), indicating substantial real-world overlap. Within comorbid cases, anxiety and depression severity were strongly coupled, with depression severity varying systematically across anxiety severity strata (chi-square p = 9.88 × 10-102). Compared with isolated anxiety or depression, comorbidity was associated with a more intensive healthcare-utilization profile, characterized by a higher mean number of consultations and shorter inter-visit intervals. Among comorbid patients, females showed greater longitudinal service use than males, with more visits and closer follow-up. Resource use also varied according to symptom burden, mainly in depression, supporting a graded relationship between clinical severity and operational care demand. Conclusions: In this large real-world tele-mental health cohort, anxiety-depression comorbidity was highly prevalent, clinically structured, and associated with distinct and measurable resource-use signatures. These findings highlight the novelty and practical value of integrating symptom severity with operational telehealth data to derive pragmatic digital phenotypes of care intensity. Such phenotypes may support risk stratification, triage, follow-up scheduling, and capacity planning in tele-mental health, with potential translational relevance for broader mental healthcare systems. However, these findings should be considered descriptive and hypothesis-generating and warrant further longitudinal validation in other clinical settings.

Digital immunoassay allows for the detection of proteins at fg/mL levels by leveraging the principles of Poisson distribution. Nevertheless, the inherent Poisson noise restricts digital sensitivity to targets exceeding 100 molecules, rendering standard digital assays incapable of detecting targets below this threshold. To overcome this constraint, we introduce an integrated CRISPR/Cas12a-digital immunoassay technology. In this system, the CRISPR/Cas12a machinery first acts as a molecular amplifier, converting each target protein into multiple enzymatic reporters. These enzyme molecules are then individually quantified via a digitized readout system, enabling ultrasensitive protein detection. By harnessing the catalytic amplification of CRISPR/Cas12a, the method achieves detection of proteins at copy numbers below 100, effectively surpassing the conventional sensitivity barrier of digital immunoassays. We validated this approach through highly selective and accurate detection of CD44 protein. A linear response was observed across a concentration range of 0.05 to 5 fg/mL, conforming to the calibration model: P(X > 0) = 0.1191c + 0.0036. The limit of detection was determined to be 0.018 fg/mL, equivalent to approximately 36 molecules of CD44. The method was further applied to quantify CD44 in plasma samples from colorectal cancer patients, demonstrating its strong potential for clinical use in early cancer diagnosis and treatment monitoring.

Acute liver injury (ALI) can rapidly progress to life-threatening acute liver failure. Liver transplantation remains the only definitive treatment, despite critical donor shortages. Macrophage-based therapies have shown promise in ALI but face challenges related to subset imprecision and limited humanized validation. VSIG4 is generally considered a marker of Kupffer cells; however, it is also expressed in monocyte-derived macrophages (MoMFs), and its role remains unclear during ALI. By integrating single-cell RNA sequencing (scRNA-seq) data from human and mouse liver tissues with clinical ALI tissue samples, we elucidated the dynamic changes in VSIG4+ macrophages (VSIG4+ Mφ) within the liver. We developed a reversible immunomagnetic nanoparticle system for the non-destructive isolation of viable VSIG4+ Mφ. The therapeutic efficacy and potential mechanisms of VSIG4+ Mφ were evaluated through tissue and molecular-level analyses in an acetaminophen (APAP)-induced ALI mouse model, as well as in a newly established vascularized human liver organoid ALI and monocyte chemotaxis model. scRNA-seq revealed a previously underrecognized subpopulation of VSIG4+ MoMFs, which increases following ALI, while the number of resident VSIG4+ Kupffer cells decreases significantly. Clinical ALI tissue samples also confirmed the presence of CCR2+VSIG4+ cells in the livers of patients with ALI. In the APAP-induced ALI animal model, adoptive transfer of isolated VSIG4+ MoMFs dramatically decreased serum alanine transaminase, hepatic necrosis, and apoptosis while increasing anti-inflammatory cytokines. In contrast, adoptive transfer of unselected BMDM failed to improve liver injury and instead exacerbated certain pro-inflammatory responses, including elevated TNF-α and reduced CD206 expression. Mechanistically, VSIG4+ MoMFs prevented inflammatory amplification by suppressing NF-κB-dependent CCL2 transcription, thereby disrupting the CCL2-CCR2 chemotactic axis and reducing pro-inflammatory CCR2+ monocyte and macrophage recruitment. We further developed vascularized human liver organoids and APAP-induced hepatocyte injury and monocyte chemotaxis, finding that the chemotaxis-interrupting mechanism was fully recapitulated in the human liver organoid ALI model. This study identifies VSIG4+ MoMFs as a therapeutically viable subset for ALI, with clear superiority over unselected BMDM. By blocking the CCL2-CCR2 inflammatory amplification loop, these cells attenuate liver injury in both mouse and humanized models. These consistent findings provide robust preclinical evidence to support the advancement of VSIG4+ Mφ-based immunotherapies into clinical practice.

The dynamics of cell surface marker expression on systemic neutrophils provide valuable insights into the post-traumatic immune response. Recent advances in point-of-care (PoC) technologies allow for rapid on-site neutrophil analysis. The current study aimed to proof, if results of PoC measurements are comparable between two study centers. A well-established laboratory protocol for fully automated PoC flowcytometry analysis of neutrophils was applied inside the trauma bay of two level 1 trauma centers. We analyzed the neutrophil surface patterns CD16, CD11b, CD62L, CD10 and CD64 and compared the results between two centers both in heathy controls and patients. 28 Polytrauma patients were included. The measurements at both centers revealed similar results with respect to the expression neutrophil activation markers in patients with different trauma severities. Particularly the expression of CD16, CD11b and CD10 were very comparable between both centers in both healthy controls and trauma patients. This study demonstrates the successful implementation of a fully automated PoC neutrophil analysis infrastructure from one trauma center to another facilitating multicenter flow cytometry studies. This paves the way for advanced immune monitoring that could significantly improve personalized clinical decision-making.

Tumor-immune cell interactions critically contribute to the progression of non-small cell lung cancer (NSCLC). In this study, we investigated the role of WNT1-inducible signaling pathway protein 3 (WISP-3) in regulating tumor cell adhesion and the underlying molecular mechanisms in lung adenocarcinoma cells. Treatment with recombinant WISP-3 significantly increased intercellular adhesion molecule-4 (ICAM-4) expression at both mRNA and protein levels in A549 and H1299 cells in a dose-dependent manner. Consistently, WISP-3 enhanced tumor-monocyte adhesion, indicating its involvement in tumor-immune cell interactions. Mechanistically, WISP-3 stimulated rapid activation of the MEK/ERK signaling cascade, as demonstrated by increased phosphorylation of MEK and ERK. Pharmacological inhibition of MEK using PD98059 or U0126, as well as direct inhibition of ERK with SCH772984, markedly attenuated WISP-3-induced ICAM-4 expression and THP-1 adhesion. These findings were further supported by siRNA-mediated knockdown of MEK or ERK, confirming the essential role of this pathway. In addition, WISP-3 suppressed the expression of hsa-miR-12131, which was identified as a negative regulator of ICAM-4. Restoration of hsa-miR-12131 significantly reduced ICAM-4 expression and impaired tumor-monocyte adhesion, indicating that miR-12131 functions downstream of MEK/ERK signaling. Collectively, these results demonstrate that WISP-3 promotes ICAM-4-dependent monocyte adhesion through activation of the MEK/ERK pathway and subsequent suppression of hsa-miR-12131. This WISP-3/MEK/ERK/miR-12131/ICAM-4 axis provides new insight into tumor-immune interactions in NSCLC and highlights potential therapeutic targets.

Anemia is a common and debilitating complication of chronic kidney disease (CKD), but its pathogenesis remains incompletely understood. Endostatin, an anti-angiogenic peptide that is elevated in CKD, may impair erythropoiesis through vascular dysfunction. We investigated the relationship between circulating endostatin and both prevalent and incident anemia in older adults, as well as whether kidney function modified this association. We analyzed data from 2,008 participants aged ≥ 75 years enrolled in the Screening for CKD among Older People across Europe (SCOPE) prospective cohort. Cross-sectional associations between standardized log-transformed endostatin and hemoglobin levels or prevalent anemia were assessed using linear and logistic regression, respectively. Dose-response relationships were explored across endostatin tertiles. Longitudinal analyses included 1,394 non-anemic individuals followed for two years; incident anemia was assessed using Fine-Gray competing risk models, with death treated as a competing event. Models were progressively adjusted for demographics, comorbidities, kidney function, iron status, medications, and baseline hemoglobin. Sensitivity analyses included Winsorization and subgroup interaction testing. At baseline, 405 participants (20.2%) had anemia. Higher endostatin levels were independently associated with lower hemoglobin levels (β -0.21, 95% CI -0.28 to -0.14) and higher odds of prevalent anemia (OR, 95% CI: 1.38, 1.18-1.62). During follow-up, 159 of 1,394 participants (11.4%) developed anemia; higher endostatin levels predicted incident anemia (sHR, 95% CI: 1.40, 1.17-1.69), with more than a twofold higher risk in the highest tertile. Associations were stronger among patients with CKD and were significantly modified by eGFR, advanced age, and the absence of diabetes. These findings suggest that vascular dysfunction may contribute to anemia in older adults and identify endostatin as a potential biomarker of the risk of anemia, particularly among individuals with CKD.

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability, inflammation, and epithelial injury, leading to discomfort and visual disturbance. Current treatments remain limited in efficacy and safety. A heparin-like glycosaminoglycan purified from the snail mucus of Achatina fulica (AFG) exhibits potential regenerative and anti-inflammatory properties. This study aimed to evaluate the therapeutic effectiveness and mechanism of AFG in DED. The effects of AFG on human corneal epithelial (HCE) cells were assessed by cell viability, proliferation, migration, and qRT-PCR analyses of proliferation- and mucin-related genes. In vivo, a benzalkonium chloride (BAC)-induced murine model of DED was used to evaluate corneal integrity, tear production, histological changes, inflammatory infiltration, and molecular expression following topical AFG treatment. Gene and protein expression levels were examined using qRT-PCR, western blotting, and immunofluorescence. AFG showed no cytotoxicity toward HCE cells and significantly enhanced their proliferation and migration by upregulating K14, KI67, P63, MUC1, and MUC4. In the DED mouse model, topical AFG treatment markedly improved corneal integrity, increased tear secretion, and restored epithelial structure. AFG upregulated the expression of epithelial differentiation and repair markers (K12, K14, PAX6) while downregulating inflammatory genes (IL-1β, TNF-α, IL-6, MMP-9, CD45) and reducing macrophage infiltration. These effects collectively promoted corneal epithelial regeneration and tear film stabilization. AFG alleviates dry eye disease by enhancing corneal epithelial proliferation, promoting mucin secretion, and suppressing inflammation. Its heparin-like glycosaminoglycan structure enables biocompatible and multifunctional activity, highlighting AFG as a promising candidate for topical therapy in corneal repair and dry eye management.

Oral squamous cell carcinoma (OSCC) is frequently associated with severe nociceptive and neuropathic pain that adversely affects patient quality of life, functional capacity, psychological well-being, and prognosis. Pain in OSCC is increasingly recognized not only as a clinical symptom but also as a dynamic indicator of tumor progression and neuroinflammatory activity. This review summarizes the epidemiological, molecular, neurobiological, and clinical mechanisms underlying OSCC-associated pain and discusses current and emerging approaches for mechanism-based multimodal pain management. Recent evidence demonstrates that tumor-nerve interactions, perineural invasion, inflammatory cytokines, and peripheral and central sensitization play central roles in the pathogenesis of OSCC pain. Molecular alterations involving TP53 mutations, EGFR overexpression, and PI3K/AKT/mTOR pathway activation contribute to inflammatory signaling, neural remodeling, and nociceptive sensitization within the tumor microenvironment. Advances in salivary biomarkers, liquid biopsy approaches, artificial intelligence-assisted pain assessment, and organoid-based translational models are improving the understanding of cancer pain biology and supporting the development of precision analgesia and individualized therapeutic strategies. OSCC-associated pain is a complex and multidimensional phenomenon closely linked to tumor aggressiveness, neuroinflammation, and disease progression. Effective pain management requires mechanism-based multimodal approaches integrating pharmacological, rehabilitative, interventional, and tumor-directed therapies. Emerging precision medicine strategies, combined with equitable access to supportive care, have the potential to improve pain control, treatment outcomes, patient dignity, and overall quality of life in individuals with OSCC.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, particularly in advanced or metastatic disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway mediates cytokine-driven signaling, and its persistent activation contributes to tumor growth, invasion, immune escape, and therapeutic resistance. Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of cytokine and growth factor signaling, especially the IL-6/JAK/STAT3 axis. This review summarizes the structure and physiological functions of SOCS3 and discusses its dysregulation in CRC initiation, progression, metastasis, prognosis, and treatment response. Current evidence indicates that SOCS3 is frequently downregulated in CRC through promoter methylation and post-transcriptional regulation by oncogenic microRNAs, leading to sustained STAT3 activation, increased proliferation, reduced apoptosis, and enhanced invasiveness. SOCS3 also interacts with MEK/ERK and PI3K/AKT signaling and influences the tumor microenvironment by regulating T-cell balance, PD-L1 expression, and macrophage activity. Clinically, reduced SOCS3 expression has been associated with lymph node metastasis, advanced TNM stage, and poorer prognosis, whereas higher SOCS3 levels may correlate with improved outcomes and chemosensitivity. Emerging therapeutic strategies include epigenetic modulation, JAK/STAT pathway inhibition, regulation of IL-6 signaling in adoptive T-cell therapy, AhR/IL-22 modulation, and FXR activation. Further translational studies are needed to validate SOCS3 as a biomarker and therapeutic target in CRC.

FGFR4 signaling is an essential driver in hepatocellular carcinoma. However, traditional screening is often time-consuming, highlighting a need for efficient strategies to identify covalent chemotypes and accelerate FGFR4 drug discovery. We established an integrated AI-driven virtual screening framework to discover FGFR4 covalent inhibitors. The theoretical predictions were evaluated through a biochemical pipeline, encompassing in vitro FGFR4 kinase assays, immunoblotting of intracellular signaling cascades, and bottom-up LC-MS/MS peptide mapping. Biological validation of the computational predictions identified five distinct chemical scaffolds (hits 1, 2, 5, 7, and 8) exhibiting antiproliferative activity. The two most active candidates, hit 1 and hit 2, were selected for further mechanistic profiling. These compounds demonstrated dose-dependent FGFR4 kinase inhibition with IC50 values of 1.06 μM and 3.57 μM, respectively. Cellular assays revealed that both compounds attenuate FGFR4 autophosphorylation and its downstream FRS2/ERK1/2 signaling cascade without inducing non-specific protein degradation. Furthermore, bottom-up LC-MS/MS peptide mapping provided direct structural evidence that hit 1 and hit 2 engage the target cysteine residue via a Michael addition mechanism. Our AI-guided computational workflow identified multiple covalent FGFR4 inhibitors with measurable biological activity. Hit 1 and hit 2 represent structurally characterized covalent scaffolds. This study provides chemical starting points for targeted HCC therapy and demonstrates the integration of theoretical prediction and experimental validation in covalent drug discovery.

Background and Objectives: Malnutrition and frailty affect 30-55% of intensive care unit (ICU) patients, yet formal nutritional screening remains inconsistently implemented in routine ICU admission workflows. The APACHE II score, the standard measure of acute physiological severity, does not capture pre-existing nutritional status or functional reserve. The Norton scale, routinely recorded by nursing staff for pressure-ulcer screening, could serve as a pragmatic proxy for the nutritional-functional axis. We assessed its independent prognostic value at admission for in-hospital and post-ICU mortality. Materials and Methods: Retrospective cohort study of 5775 consecutive adult patients admitted to a Spanish tertiary polyvalent ICU between 2012 and 2019, with APACHE II and Norton scores recorded at admission. The Norton was analysed as continuous and categorised (minimal >14, medium 13-14, high 10-12, very high 5-9). Discrimination was assessed by AUC and DeLong's test, predictive improvement by IDI and NRI, and internal validity by bootstrap resampling (B = 200). Results: Hospital mortality was 12.8% (n = 738), rising from 7.7% in patients with minimal-risk Norton to 34.5% in very high risk. After adjustment for APACHE II, each additional Norton point reduced the odds of death by 7.7% (adjusted OR = 0.923; 95% CI 0.903-0.943). Adding the Norton to APACHE II improved discrimination (AUC 0.865 → 0.872; DeLong p = 0.003; IDI = 0.011; continuous NRI = 0.30). In the highest APACHE II quartile, the absolute mortality difference between minimal and very high Norton categories reached 23.2 percentage points. The Norton's prognostic effect was approximately twice as large for post-ICU mortality (ΔAUC +0.011) as for overall in-hospital mortality (ΔAUC +0.006). Conclusions: The Norton scale at admission improves the prognostic capacity of APACHE II in critically ill patients, particularly for post-ICU mortality. Its widespread availability without additional patient-level data collection positions it as a pragmatic candidate for routine prognostic assessment and for guiding targeted nutritional screening.

Phosphorus magnetic resonance spectroscopy (31P-MRS) enables noninvasive measurement of brain metabolism, yet its reproducibility in clinical settings remains unclear. We systematically assessed intrasession and intersession variability as well as interindividual differences of key phosphorus metabolites at 3 T in healthy individuals and persons with Parkinson's disease under various experimental conditions. Intersession variability, as measured by coefficients of variation (CoVs) increased notably for longer scan intervals (~1 year), and metabolite ratios from well-resolved spectral signals (i.e., adenosine triphosphate [ATP], phosphocreatine [PCr], and intracellular inorganic phosphate [Pi]) exhibited consistently higher stability compared with ratios calculated from metabolite signals overlapping on the spectrum (e.g., total nicotinamide adenine dinucleotide [tNAD], as well as phosphate monoesters [PMEs] and phosphate diesters [PDEs]). Test-retest variability ranged from ~5 to 25 CoV%, where PCr, ATP-α, and ATP-γ were the most stable while glycerophosphocholine (GPC), glycerophosphoethanolamine (GPE), phosphoethanolamine (PE), and tNAD varied considerably. Interindividual variability was found to be higher than intraindividual variability for all metabolite ratios, ranging from ~9 to 33 CoV%. By systematically quantifying intraindividual and interindividual variability, as well as providing explicit sample size recommendations, this study facilitates more reliable longitudinal and cross-sectional clinical trials and translational studies of brain metabolism featuring 31P-MRS.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, multi-systemic condition that has gained renewed global attention due to its clinical overlap with the growing population of long COVID patients. Despite ongoing efforts to characterize the disease, definitive diagnostic molecular markers are yet to be fully established, posing challenges in clinically differentiating from idiopathic chronic fatigue (ICF) and depression (Dep). This study aimed to identify circulating extracellular vesicles (EVs)-associated microRNAs (miRNAs) that serve as both diagnostic signatures and windows into the disease's underlying pathophysiology. Circulating EVs from ME/CFS (n = 6), ICF (n = 6), and depression (n = 8) patients were analyzed using flow cytometry, nano-tracking analysis, and comprehensive miRNA analysis. Differentially expressed miRNAs were analyzed using KEGG pathway enrichment to identify ME/CFS-specific signatures. Key candidate biomarkers were further validated in an additional healthy control (HC) cohort (n = 4). ME/CFS-EVs exhibited a unique subpopulation with high calcein intensity and larger diameters. Initial global miRNA profiling (Volcano plot) identified miR-21-5p, let-7f-5p, miR-26b-5p, and miR-20a-5p as significantly dysregulated EV-miRNAs in ME/CFS compared to ICF and Dep. To explore systemic pathophysiology, we identified a 114 EV-miRNA signature that achieved 87.0 ± 4.8% sensitivity and 93.7 ± 2.4% specificity within repeated cross-validation of the discovery cohort. After adjusting for covariates, 91 miRNAs remained significant; pathway analysis of the 62 up-regulated EV-miRNAs revealed significant enrichment in neuro-systemic axes, encompassing cellular structural integrity (focal adhesion), core signaling hubs (PI3K-Akt), and systemic homeostasis (such as insulin signaling and endocrine functions). Preliminary evaluation confirmed that these target EV-miRNAs remained at minimal or undetectable levels in the HC group. A 62 EV-miRNA signature provides insight into the interconnected neuro-systemic pathways disrupted in ME/CFS, particularly those governing neuronal connectivity and cellular scaffolding. Within this candidate EV-miRNA signature, the top-ranked miRNAs-miR-21-5p, let-7f-5p, miR-26b-5p, and miR-20a-5p-emerge as potential candidate biomarkers whose specific elevation was not shared by HC. These findings establish a valuable framework for targeted diagnosis and enhance our understanding of the molecular pathways involved in synaptic and structural alterations in ME/CFS.