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Novel biomarkers and therapeutic strategies for glioblastoma, the most common malignant brain tumor with an extremely unfavorable prognosis, are urgently needed. Recent studies revealed a significant upregulation of the protein zonulin in glioblastoma, which correlates with patient survival. Originally identified as pre-haptoglobin-2, zonulin modulates both the intestinal barrier and the blood–brain barrier by disassembling tight junctions. An association of zonulin with various neuroinflammatory diseases has been observed. It can be suggested that zonulin links a putative impairment of the gut–brain barrier with glioblastoma carcinogenesis, leading to an interaction of the gut microbiome, the immune system, and glioblastoma. We therefore propose three interconnected hypotheses: (I) elevated levels of zonulin in glioblastoma contribute to its aggressiveness; (II) upregulated (serum-) zonulin increases the permeability of the microbiota–gut–brain barrier; and (III) this creates a carcinogenic and immunosuppressive microenvironment preventing the host from an effective antitumor response. The role of zonulin in glioblastoma highlights a promising field of research that could yield diagnostic and therapeutic options for glioblastoma patients and other diseases with a disturbed microbiota–gut–brain barrier. Full article

Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial–mesenchymal transition (EMT). This study examines HMGA2’s role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2. Full article

Primary focal segmental glomerulosclerosis (FSGS) is a disease of the podocytes and glomerulus, leading to nephrotic syndrome and progressive loss of renal function. One of the most serious aspects is its recurrence of disease in over 30% of patients following allogeneic kidney transplantation, leading to early graft loss. This research investigates the individual genetic predispositions and differences in the immune responses leading to recurrence of FSGS after transplantation. We performed exome sequencing on six patients with recurrent FSGS to identify variants in fifty-one genes and found significant variations in the alpha-2-macroglobulin (A2M). Immunoblotting was used to investigate effects of specific gene variants at the protein level. Further expression analysis identified A2M, exophilin 5 (EXPH5) and plectin (PLEC) as specific proteins linked to podocytes, endothelial cells, and the glomerulus. Subsequent protein array screening revealed the presence of non-HLA-specific antibodies, including TRIM21, after transplantation. Using Metascape for pathway and process enrichment analysis, we focused on the IL-17 signaling and chemotaxis pathways. ELISA measurements showed significantly elevated IL-17 levels in patients with recurrent FSGS (32.30 ± 9.12 pg/mL) compared to individuals with other glomerular diseases (23.16 ± 2.49 pg/mL; p < 0.01) and healthy subjects (22.28 ± 0.94 pg/mL; p < 0.01), with no significant difference in plasma CCL2/MCP-1 levels between groups. This study explores the molecular dynamics underlying recurrence of FSGS after transplantation, offering insights into potential biomarkers and therapeutic targets for the future development of individualized treatments for transplant patients. Full article

Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10⁻³ pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan–Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804–6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC. Full article

The purpose of this study was to assess the efficacy, specificity, and predictive value of a newly discovered biomarker, Zinc finger-like1 protein (referred to as neuroendocrine marker, NEM) for the detection of prostate cancer (PCa). We retrospectively analyzed banked plasma samples from 508 men, with a median age of 67 years (range 48–97), to compare the performance of NEM and PSA in predicting subsequent histologic PCa. The cohort consisted of four groups of patients visiting a urology clinic: (1) patients not diagnosed with either benign prostatic disease or prostate cancer (PCa) were defined as normal; (2) patients diagnosed with benign hyperplasia (BPH) but not PCa; (3) patients with confirmed PCa; and (4) patients with cancer other than PCa. The normal men displayed a mean NEM plasma level of 0.948 ± 0.051 ng/mL, which increased to 1.813 ± 0.315 ng/mL in men with BPH, 86.49 ± 15.51 ng/mL in men with PCa, and 10.47 ± 1.029 ng/mL in men with other Ca. The corresponding concentrations of prostate-specific antigen (PSA) in these subjects were 1.787 ± 0.135, 5.405 ± 0.699, 35.77 ± 11.48 ng/mL, and 8.036 ± 0.518, respectively. Receiver operating characteristic (ROC) curve analysis was performed to compare NEM and PSA performance, and the Jouden Index for each biomarker was calculated to determine cut-off points for each biomarker. The area under the ROC curve to predict PCa was 0.99 for NEM and 0.81 for PSA (p < 0.0001). The cut-off for NEM was at 1.9 ng/mL, with sensitivity of 98% and specificity of 97%. The corresponding PSA values were 4.4 ng/mL, with sensitivity of 76% and specificity of 95%. The predictive value of each biomarker in a patient was matched with his pathologic data to determine the accuracy of each biomarker. NEM was more accurate than PSA in differentiating cancer from benign conditions, such as BPH or prostatitis. In conclusion, NEM was a better predictor of PCa than PSA in patients visiting urology clinics. NEM tests, either alone or in conjunction with other biomarkers, provide a reliable, non-invasive, and inexpensive test to remarkably reduce false positives and thereby reduce the number of diagnostic biopsies and associated painful procedures and the loss of quality of life. Full article

Background and Objectives: Systemic-inflammation-based prognostic scores and hematological indices have shown value in predicting outcomes in various clinical settings. However, their effectiveness in predicting outcomes specifically for IgA nephropathy (IgAN) and membranous nephropathy (MN), the most common primary glomerular diseases diagnosed by kidney biopsy, has not been thoroughly investigated. Materials and Methods: We conducted a retrospective, observational study involving 334 adult patients with biopsy-proven IgAN (196 patients) and MN (138 patients) from January 2008 to December 2017 at a tertiary center. We assessed six prognostic scores [Glasgow prognostic score (GPS), modified GPS (mGPS), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-C-reactive protein ratio (LCRP)] and two hematological indices [red blood cell distribution width (RDW), platelet distribution width (PDW)] at diagnosis and examined their relationship with kidney and patient survival. Results: End-stage kidney disease (ESKD) occurred more frequently in the IgAN group compared to the MN group (37% vs. 12%, p = 0.001). The mean kidney survival time was 10.7 years in the IgAN cohort and 13.8 years in the MN cohort. After adjusting for eGFR and proteinuria, lower NLR and higher LCRP were significant risk factors for ESKD in IgAN. In the MN cohort, no systemic-inflammation-based scores or hematological indices were associated with kidney survival. There were 38 deaths (19%) in the IgAN group and 29 deaths (21%) in the MN group, showing no significant difference in mortality rates. The mean survival time was 13.4 years for the IgAN group and 12.7 years for the MN group. In the IgAN group, a lower PLR was associated with a higher mortality after adjusting for age, the Charlson comorbidity score, eGFR, and proteinuria. In patients with MN, higher NLR, PLR, and RDW were associated with increased mortality. Conclusions: NLR and LCRP are significant predictors of ESKD in IgAN, while PLR is linked to increased mortality. In MN, NLR, PLR, and RDW are predictors of mortality but not kidney survival. These findings underscore the need for disease-specific biomarkers and indicate that systemic inflammatory responses play varying roles in the progression and outcomes of these glomerular diseases. Future studies on larger cohorts are necessary to validate these markers. Full article

Subgroup J avian leukosis virus (ALV-J) is a major pathogen in poultry, causing substantial economic losses to the poultry industry worldwide. Exosomal small RNAs derived from virus-infected cells or biological fluids can serve as viral transmission vectors. However, the role and mechanism of exosomal miRNA in ALV-J infection are unclear. In this study, we demonstrated that exosomal microRNA-7-25207 (miR-7-25207) could increase the titers of ALV-J. Exosomes isolated from ALV-J-infected DF-1 cells (Exo-ALV-J) contained partial viral proteins from ALV-J and could transmit the infection to uninfected DF-1 cells, leading to productive infection. Additionally, the RNA expression profile of exosomes was altered following ALV-J infection. miRNA analysis revealed that the expression of exosomal miR-7-25207 increased. Overexpression of miR-7-25207 significantly increased the titers of ALV-J in transfected cells. Furthermore, miR-7-25207 directly suppressed the expression of Akt and PRC1. Akt, in turn, directly inhibited CyclinQ1 expression, while PRC1 directly interfered with YAF2 expression. In conclusion, ALV-J infection activates the expression of miR-7-25207, which is subsequently delivered via exosomes to uninfected cells, increasing ALV-J titers by targeting Akt-CyclinQ1 and PRC1-YAF2 dual pathways. These findings suggest that exosomal miR-7-25207 may serve as a potential biomarker for clinical parameters in ALV-J infection. Full article

This study investigated serum extracellular vesicles (EVs) in bitches with mammary neoplasms, in order to understand their size, shape, and concentration, as well as their association with tumor malignancy. Thirty bitches were categorized into control (n = 10), mammary tumor grades I and II (GI, n = 13), and grade III (GII, n = 7). Serum was separated from blood collected during mastectomy, and EVs were isolated using size exclusion chromatography. The analysis revealed no significant differences in EV concentrations among groups, with similar concentrations for control, GI, and GII. Ninety-one proteins were identified in EV-enriched samples, with six showing varied abundance across groups. Notably, keratin 18 was highly abundant in GI, while sushi domain-containing protein, EvC ciliary subunit 2, and the joining chain of multimeric IgM and IgA were increased in GII. Additionally, protocadherin 17 and albumin were upregulated in both GI and GII. ROC curves identified potential biomarkers for differentiating tumor grades. Enrichment pathway analysis revealed AFP gene upregulation in the GI. Mass spectrometry proteomics data were deposited in Mendeley Data. The study provides valuable insights into serum EV characterization in bitches, suggesting keratin 18 and protocadherin 17 as potential biomarkers for canine mammary neoplasia, with implications for future diagnostic and therapeutic strategies. Full article

Gliomas, particularly glioblastoma (GBM), represent the most prevalent and aggressive tumors of the central nervous system (CNS). Despite recent treatment advancements, patient survival rates remain low. The diagnosis of GBM traditionally relies on neuroimaging methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scans and postoperative confirmation via histopathological and molecular analysis. Imaging techniques struggle to differentiate between tumor progression and treatment-related changes, leading to potential misinterpretation and treatment delays. Similarly, tissue biopsies, while informative, are invasive and not suitable for monitoring ongoing treatments. These challenges have led to the emergence of liquid biopsy, particularly through blood samples, as a promising alternative for GBM diagnosis and monitoring. Presently, blood and cerebrospinal fluid (CSF) sampling offers a minimally invasive means of obtaining tumor-related information to guide therapy. The idea that blood or any biofluid tests can be used to screen many cancer types has huge potential. Tumors release various components into the bloodstream or other biofluids, including cell-free nucleic acids such as microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs) or exosomes, metabolites, and other factors. These factors have been shown to cross the blood-brain barrier (BBB), presenting an opportunity for the minimally invasive monitoring of GBM as well as for the real-time assessment of distinct genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes associated with brain tumors. Despite their potential, the clinical utility of liquid biopsy-based circulating biomarkers is somewhat constrained by limitations such as the absence of standardized methodologies for blood or CSF collection, analyte extraction, analysis methods, and small cohort sizes. Additionally, tissue biopsies offer more precise insights into tumor morphology and the microenvironment. Therefore, the objective of a liquid biopsy should be to complement and enhance the diagnostic accuracy and monitoring of GBM patients by providing additional information alongside traditional tissue biopsies. Moreover, utilizing a combination of diverse biomarker types may enhance clinical effectiveness compared to solely relying on one biomarker category, potentially improving diagnostic sensitivity and specificity and addressing some of the existing limitations associated with liquid biomarkers for GBM. This review presents an overview of the latest research on circulating biomarkers found in GBM blood or CSF samples, discusses their potential as diagnostic, predictive, and prognostic indicators, and discusses associated challenges and future perspectives. Full article

Background and Objectives: To investigate whether circulating malondialdehyde (cMDA) at diagnosis could contribute to reflecting cross-sectional comprehensive inflammation or vasculitis activity and further predicting all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: This study included 78 patients with AAV. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were collected as indices reflecting cross-sectional comprehensive inflammation, whereas the Birmingham vasculitis activity score (bVAS), and the five-factor score (FFS) were reviewed as AAV-specific indices. All-cause mortality was considered to be a poor outcome during follow-up. cMDA was measured from stored sera. Results: The median age of the 78 patients (32 men and 46 women) was 63.0 years. The median BVAS, FFS, ESR, and CRP were 5.0, 0, 24.5 mm/h, and 3.4 mg/L, respectively. Six patients died during the median follow-up duration based on all-cause mortality at 26.7 months. At diagnosis, cMDA was significantly correlated with cross-sectional ESR but not with BVAS or FFS. Compared to patients with cMDA < 221.7 ng/mL, those with cMDA ≥ 221.7 ng/mL at diagnosis exhibited an increased relative risk (RR 12.4) for all-cause mortality and further showed a decreased cumulative patient survival rate. Cox analyses revealed that cMDA ≥ 221.7 ng/mL (hazard ratio 24.076, p = 0.007) exhibited an independent association with all-cause mortality during follow-up in patients with AAV. Conclusions: cMDA at diagnosis may be a potential biomarker for predicting all-cause mortality during follow-up by reflecting comprehensive inflammation at diagnosis in patients with AAV. Full article

CD19-targeted CAR-T cell therapy has revolutionized the treatment of relapsed/refractory (r/r) pre-B acute lymphoblastic leukemia (ALL). However, it can be associated with acute toxicities related to immune activation, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokines released from activated immune cells play a key role in their pathophysiology. This study was a prospective analysis of proinflammatory proteins and cytokines in children treated with tisagenlecleucel. Serial measurements of C-reactive protein, fibrinogen, ferritin, IL-6, IL-8, IL-10, IFNγ, and TNFα were taken before treatment and on consecutive days after infusion. The incidence of CRS was 77.8%, and the incidence of ICANS was 11.1%. No CRS of grade ≥ 3 was observed. All complications occurred within 14 days following infusion. Higher biomarker concentrations were found in children with CRS grade ≥ 2. Their levels were correlated with disease burden and CAR-T cell dose. While cytokine release syndrome was common, most cases were mild, primarily due to low disease burden before lymphodepleting chemotherapy (LDC). ICANS occurred less frequently but exhibited various clinical courses. None of the toxicities were fatal. All of the analyzed biomarkers rose within 14 days after CAR-T infusion, with most reaching their maximum around the third day following the procedure. Full article

Temporal lobe epilepsy has various origins, involving or not involving structural changes in brain tissue. The mechanisms of epileptogenesis are associated with cell regulation and signaling disruptions expressed in varied levels of proteins. The blood plasma proteomic profiling of temporal lobe epilepsy patients (including magnetic resonance imaging (MRI)-positive and MRI-negative ones) and healthy volunteers using mass spectrometry and label-free quantification revealed a list of differently expressed proteins. Several apolipoproteins (APOA1, APOD, and APOA4), serpin protease inhibitors (SERPINA3, SERPINF1, etc.), complement components (C9, C8, and C1R), and a total of 42 proteins were found to be significantly upregulated in the temporal lobe epilepsy group. A classification analysis of these proteins according to their biological functions, as well as a review of the published sources, disclosed the predominant involvement of the processes mostly affected during epilepsy such as neuroinflammation, intracellular signaling, lipid metabolism, and oxidative stress. The presence of several proteins related to the corresponding compensatory mechanisms has been noted. After further validation, the newly identified temporal lobe epilepsy biomarker candidates may be used as epilepsy diagnostic tools, in addition to other less specific methods such as electroencephalography or MRI. Full article

Aquaculture production has been growing consistently over the last few decades to meet the increasing animal protein demand of the human population. However, increased production and rearing intensities raise the challenges of guaranteeing fish health and welfare, which is essential to avoid losses and ensure product quality. Biomarkers can provide insights into the fish’s nutritional, physiological, and health status, and aid in the evaluation of early nutritional and physiological imbalances, distress conditions, and pathological diagnosis. The discovery and validation of biomarkers rely mostly on the use of information provided by different parameters, including biochemical, metabolic, or immunologic, as well as several omics, from genomics and transcriptomics to proteomics and metabolomics. In this review, a summary of the main biomarkers used in aquaculture is provided along with an overview of the main omics technologies available for further biomarker research. This review also highlights the need to develop non-lethal biomarkers that can easily and quickly be measured to provide a prompt response to producers. Full article

Background: Despite great scientific efforts, understanding the role of COVID-19 clinical biomarkers remains a challenge. Methods: A cross-sectional descriptive study in two Peruvian cities at different altitudes for comparison: Lima and Huaraz. In each place, three groups were formed, made up of 25 patients with COVID-19 in the ICU, 25 hospitalized patients with COVID-19 who did not require the ICU, and 25 healthy subjects as a control group. Five biomarkers were measured: IL-6, hepcidin, ferritin, C-reactive protein, and zinc using ELISA assays. Results: Ferritin, C-reactive protein, and IL-6 levels were significantly higher in the ICU and non-ICU groups at both study sites. In the case of hepcidin, the levels were significantly higher in the ICU group at both study sites compared to the non-ICU group. Among the groups within each study site, the highest altitude area presented statistically significant differences between its groups in all the markers evaluated. In the lower altitude area, differences were only observed between the groups for the zinc biomarker. Conclusion: COVID-19 patients residing at high altitudes tend to have higher levels of zinc and IL-6 in all groups studied compared to their lower altitude counterparts. Full article

Alzheimer’s disease (AD) represents the most common form of dementia and affects million people worldwide, with a high social burden and considerable economic costs. AD diagnosis benefits from a well-established panel of laboratory tests that allow ruling-in patients, along with FDG and amyloid PET imaging tools. The main laboratory tests used to identify AD patients are Aβ40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated Tau 181 (pTau181) and total Tau (tTau). Although they are measured preferentially in the cerebrospinal fluid (CSF), some evidence about the possibility for blood-based determination to enter clinical practice is growing up. Unfortunately, CSF biomarkers for AD and, even more, the blood-based ones, present a few flaws, and twenty years of research in this field did not overcome these pitfalls. The tale even worsens when the issue of treating AD is addressed due to the lack of effective strategies despite the many decades of attempts by pharmaceutic industries and scientists. Amyloid-based drugs failed to stop the disease, and no neuroinflammation-based drugs have been demonstrated to work so far. Hence, only symptomatic therapy is available, with no disease-modifying treatment on hand. Such a desolate situation fully justifies the active search for novel biomarkers to be used as reliable tests for AD diagnosis and molecular targets for treating patients. Recently, a novel group of molecules has been identified to be used for AD diagnosis and follow-up, the nuclei acid-based biomarkers. Nucleic acid-based biomarkers are a composite group of extracellular molecules consisting of DNA and RNA alone or in combination with other molecules, including proteins. This review article reports the main findings from the studies carried out on these biomarkers during AD, and highlights their advantages and limitations. Full article