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Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials. Plasma extracellular vesicles contain quantifiable amounts of TDP-43 and full-length tau, allowing the accurate assessment of pathology in frontotemporal dementia, frontotemporal dementia spectrum disorders and amyotrophic lateral sclerosis.

Current technological advancements in clinical and research settings have permitted a more intensive and comprehensive understanding of Alzheimer’s disease (AD). This development in knowledge regarding AD pathogenesis has been implemented to produce disease-modifying drugs. The potential for accessible and effective therapeutic methods has generated a need for detecting this neurodegenerative disorder during early stages of progression because such remedial effects are more profound when implemented during the initial, prolonged prodromal stages of pathogenesis. The aggregation of amyloid-β (Aβ) and tau isoforms are characteristic of AD; thus, they are considered core candidate biomarkers. However, research attempting to establish the reliability of Aβ and tau as biomarkers has culminated in an amalgamation of contradictory results and theories regarding the biomarker concentrations necessary for an accurate diagnosis. In this review, we consider the capabilities and limitations of fluid biomarkers collected from cerebrospinal fluid, blood, and oral, ocular, and olfactory secretions as diagnostic tools for AD, along with the impact of the integration of these biomarkers in clinical settings. Furthermore, the evolution of diagnostic criteria and novel research findings are discussed. This review is a summary and reflection of the ongoing concerted efforts to establish fluid biomarkers as a diagnostic tool and implement them in diagnostic procedures. Alzheimer’s disease: early diagnostic biomarkers in body fluids Markers from body fluids could help clinicians diagnose Alzheimer’s disease before cognitive decline appears. After numerous setbacks in treating advanced Alzheimer’s, researchers are eager to identify biological indicators that facilitate earlier disease detection and interception. A review by YoungSoo Kim and colleagues at Yonsei University in South Korea, explores the promise of ‘fluid biomarkers,’ which enables diagnosis using cerebrospinal fluid (CSF), blood, oral, ocular, and olfactory fluid samples. Shifts in CSF levels of amyloid beta and tau, two proteins central to Alzheimer’s pathology, can reliably monitor at-risk individuals. Although CSF collection is unpleasant for patients, it remains more promising than blood, where current data for candidate fluid biomarkers are relatively inconclusive. In this review, investigations to discover safer, cheaper, and more reliable diagnostic tools to shift treatment from alleviation to prevention are introduced.

Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²²) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²²). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻⁷). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.

Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans. DPP4 inhibitors are used for the treatment of diabetes, but the impact of DPP4 activity and soluble DPP4 on development of diabetes-associated inflammation remains uncertain. Here the authors study whether DPP4 inhibition controls sDPP4 and inflammatory biomarkers, and demonstrate that DPP4 inhibition is dissociated from changes in inflammation in mice and humans.

Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component). We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariable-adjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform. Separately, the GC -cancer risk association was examined using proportional hazards regression among 109,746 individuals with genetic data and 26,713 diagnosed with cancer. Specific vitamin D binding protein isoform subtypes were delineated and analyzed, including Gc1-1 subtypes (Gc1s-Gc1s, Gc1f-Gc1s, and Gc1f-Gc1f) and Gc2 subtypes (Gc1s-Gc2, Gc1f-Gc2, and Gc2-Gc2). For most cancers, the GC genotype did not modify the risk associations for 25(OH)D; e.g., the OR for high vs. low vitamin D quintile was 1.09 (0.89–1.33) for overall cancer risk among individuals with the Gc1-1 isoform and 1.04 (0.83–1.31) among those with either the Gc1-2 or Gc2-2 isoforms. ORs for high compared to low vitamin D tertile for colorectal, lung, breast, and prostate cancer among those with the Gc1-1 vs. any Gc2 isoforms were, respectively, 0.60 vs. 0.73, 1.96 vs. 1.03, 1.30 vs. 1.18, and 1.19 vs. 1.22 (all p-interaction ≥0.36). However, GC qualitatively modified the vitamin D-bladder cancer risk association: OR = 1.70 (95% CI 0.96–2.98) among those with the Gc1-1 isoform and 0.52 (0.28–0.96) among those with any Gc2 isoforms (p-interaction = 0.03). When modeled without regard for 25(OH)D, Gc isoforms were generally not associated with cancer risk, although melanoma risk was significantly lower among individuals with the “f” subtype of the Gc1-1 isoform, specifically HR = 0.83 (95% CI 0.70–0.98) for Gc1f-1s and 0.67 (0.45–1.00) for Gc1f-1f, compared to individuals with the Gc1s-Gc1s isoform. Vitamin D binding protein genetic isoforms may be associated with melanoma risk but do not modify the association between vitamin D status and cancer, with the possible exception of bladder cancer.

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA111(43):15544–15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.

Background Glucocorticoid (GC) signaling plays a crucial role in immune regulation during critical illness, but cell-specific responses remain poorly understood. While previous studies have predominantly examined glucocorticoid receptor (GCR)-α and GCR-β, the roles of alternative isoforms (GCR-γ, GCR-P) and the downstream effectors GC-induced leucine zipper (GILZ) and dual-specific phosphatase 1 (DUSP1) across different immune cell populations in critical illness remain unexplored. Methods In this prospective, observational study, we enrolled 43 critically ill patients and 25 healthy controls. Longitudinal blood samples were collected at ICU admission (24–48 h) and days 4 (4d), 8 (8d), and 14 (14d). We quantified the mRNA expression of four GCR variants (GCR-α, GCR-β, GCR-γ, and GCR-P) and GC downstream targets (GILZ and DUSP1) in isolated polymorphonuclear cells (PMNs) and peripheral blood mononuclear cells (PBMCs) via RT‒PCR. Serum cortisol, adrenocorticotropic hormone (ACTH), and cytokines (interleukin (IL)-6 and IL-10) were measured concurrently. Statistical analyses included mixed-effects modeling to assess temporal and cell-specific patterns. Results PMNs exhibited sustained downregulation of GCR-α, GCR-β, and GCR-γ, with preserved GILZ expression, while GCR-P remained stable. In PBMCs, GCR-α, GCR-β, GCR-γ, and GILZ levels showed no significant changes compared to controls, yet GCR-P was upregulated. DUSP1 was downregulated in PMNs and elevated in PBMCs. Negative correlations emerged between IL-6 and both GILZ and DUSP1. All expression patterns remained stable across time points in the subset of patients who completed the 2-week study despite dynamic ACTH changes and persistently elevated cortisol. Conclusions PMNs show reduced GCR-α/β/γ with preserved GILZ, while PBMCs maintain GCR-α/β/γ but upregulate GCR-P and DUSP1. These findings highlight divergent GC responsiveness between innate and adaptive immune cells, with implications for cortisol’s role in immune regulation during critical illness and may reflect cell-specific effects driven by changes in glucocorticoid receptor signaling.

Background/Objectives: Blood flows through the body and reaches all tissues, contributing to homeostasis and physiological functions. Providing information and understanding on how the transcriptome of whole blood behaves in response to physiological or pathological stimuli is critical. Methods: We collected blood from four healthy individuals and performed long-read RNA sequencing (lrRNA-seq) for the precise identification and expression quantification of RNA variants. Moreover, we compared two genome references: the Genome Reference Consortium Human Build 38 (GRCh38) and the Telomere-to-Telomere (T2T) assembly of the CHM13 cell line (T2T-CHM13). Results: With GRCh38, we could identify an average of about 46,000 genes, 1.3-fold more genes than T2T-CHM13. Similarly, we identified about 185,000 isoforms with GRCh38 and 140,000 with T2T-CHM13, finding similar differences for full splice match (FSM) and incomplete splice match (ISM) transcript isoforms. There were about 90,000 novel isoforms for GRCh38 and 70,000 for T2T-CHM13, 47% and 50% of the total number of identified isoforms, respectively. Differences in isoform numbers between GRCh38 and T2T-CHM13 were identified for the subcategories “Genic Genomic”, “Intergenic”, and “Genic Intron”. Using GRCh38, we generally identified a higher number of non-coding isoforms, as well as a higher number of isoforms aligning within intron and intergenic regions. Nonetheless, GRCh38 might incur false positive results, and T2T-CHM13 is likely more accurate for genome sequences in the repetitive regions. Conclusions: LrRNA-seq is a valid method for the identification of novel isoforms in blood, and this study is a first step toward the creation of a comprehensive database of the structure and expression of transcript isoforms for optimized predictive medicine.

The autosomal dominantly inherited east Texas bleeding disorder is linked to an A2440G variant in exon 13 of the F5 gene. Affected individuals have normal levels of coagulation factor V (FV) activity, but demonstrate inhibition of global coagulation tests. We demonstrated that the A2440G mutation causes upregulation of an alternatively spliced F5 transcript that results in an in-frame deletion of 702 amino acids of the large activation fragment, the B domain. The approximately 250-kDa FV isoform (FV-short), which can be fully activated by thrombin, is present in all A2440G carriers' plasma (n = 16). FV-short inhibits coagulation through an indirect mechanism by forming a complex with tissue factor pathway inhibitor-α (TFPIα), resulting in an approximately 10-fold increase in plasma TFPIα, suggesting that the TFPIα:FV-short complexes are retained in circulation. The TFPIα:FV-short complexes efficiently inhibit thrombin generation of both intrinsic and extrinsic coagulation pathways. These data demonstrate that the east Texas bleeding disorder-associated F5(A2440G) leads to the formation of the TFPIα:FV-short complex, which inhibits activation and propagation of coagulation.

Serum adiponectin levels are decreased in patients with cerebral infarction. Adiponectin in circulation exists in three isoforms: high molecular weight (HMW), medium molecular weight (MMW), and low molecular weight (LMW) adiponectin. We measured serum levels of total adiponectin and adiponectin multimers (HMW, MMW, and LMW) in patients with cerebral infarction and compared the serum levels of the three adiponectin multimers in stroke subtypes. We also evaluated the clinical value of adiponectin multimer levels as a biomarker for cerebral infarction. We assessed a total of 132 patients with cerebral infarctions. The serum levels of total and adiponectin multimers were measured using enzyme-linked immunosorbent assay (ELISA). The total and HMW adiponectin levels were significantly lower in atherothrombotic infarction (AI) than in cerebral embolism (CE) (total, p < 0.05; HMW, p < 0.05). In male patients, the MMW adiponectin level was significantly lower in the lacunar infarction (LI) group than in the AI group (p < 0.05). The LMW adiponectin level was significantly lower in the AI group than in the LI and CE groups (LI, p < 0.001; CE, p = 0.001). However, there were no significant differences in adiponectin multimer levels among the stroke subtypes in female subjects. Additionally, in female patients with AI and LI, the LMW adiponectin levels were negatively associated with C-reactive protein (CRP; AI, p < 0.05; LI, p < 0.05). These findings suggest that a decrease in adiponectin is associated with AI and that serum LMW adiponectin level represents a potential biomarker for AI.