Browsing by Subject "Biomarker"

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    ADAMTS4 is expressed in different cells and tissues in leprosy skin lesions: A potential biomarker and therapeutic target for leprosy and its reactional phenomena
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2026) Rafael Dantas Soares; Igor Bueno Garrido; Natália Silveira Virgili; Luciana Raquel Vincenzi Fachin; Patricia Sammarco Rosa; Ana Paula Fávaro Trombone; Andrea de Faria Fernandes Belone; Cleverson Teixeira Soares; Biología Celular e Histología
    Introduction. A disintegrin and metallo-proteinase with thrombospondin motifs-4 (ADAMTS4), a metalloproteinase involved in extracellular matrix (ECM) degradation, is implicated in several pathological conditions. This study evaluated ADAMTS4 in leprosy skin lesions. Methods. In total, 519 skin samples were selected, including 20 healthy controls (HC) and 499 samples with leprosy skin lesions. Leprosy lesions were divided into tuberculoid range “T” (n=95), lepromatous range “L” (n=115), type 1 reaction (n=120), type 2 reaction (n=128), and lesions in regression (n=41). Following standardization with an anti-ADAMTS4 marker, all samples were subjected to immunohistochemistry (IHC). Marker expression in cells or tissues with moderate or intense staining intensity (2+ or 3+) was considered positive, and the absence of or weak expression (0 or 1+) was considered negative. Results. ADAMTS4 was expressed in several cells involved in the inflammatory processes of leprosy, particularly macrophages and fibroblasts, and in different skin tissues affected by leprosy lesions. Marker expression was remarkable in different tissues affected by leprosy lesions compared with the control group. Conclusion. ADAMTS4 expression in different leprosy lesions and their reaction phenomena suggest its contribution to disease progression and reactive inflammatory amplification, indicating ADAMTS4 as a potential biomarker and therapeutic target in leprosy.
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    Annexin-V binds subpopulation of immune cells altering its interpretation as an in vivo biomarker for apoptosis in the retina
    (Ivyspring International Publisher., 2024-11-11) Miyagishima, Kiyoharu J.; Ma, Wenxin; Li, Wei ; Nadal-Nicolás, Francisco Manuel; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultades de la UMU::Facultad de Medicina
    In cells undergoing apoptosis phosphatidylserine, a major component of the plasma membrane, translocates to the outer leaflet where it provides eat-me signals for phagocytic recognition and is bound by annexin-V, an apoptotic marker. The need to track retinal ganglion cell death (RGC) in response to glaucomatous damage or optic neuropathy has led to the development of DARC (detection of apoptosing retinal cells) imaging, providing non-invasive, in vivo assessment of RGC death. Although the eye is an immune privileged site, resident and infiltrating immune cells are known to respond quickly to trauma or infection. Some immune cells have binding sites for annexin homologs; thus, their presence may confound estimates of apoptosis measured by annexin-V labeling. The purpose of this study was to re-examine the accuracy of annexin-V apoptotic labeling in the posterior eye and to temporally characterize contributions of non-apoptotic labeling in response to optic nerve (ON) injury. Here, we found annexin-V labeling consists of two phases. Initially, there is a rapid phase matching the time course of apoptotic cell death indicated by cleaved caspase-3 immunostaining observed ex vivo. This is followed by a sustained plateau phase that persists long after the peak of degeneration. We demonstrate that annexin-V binds to a specific subpopulation of myeloid cells in the retina, which were identified using simultaneous confocal scanning laser ophthalmoscopy. Optical coherence tomography and confocal imaging reveal these cells occupy the posterior hyaloid space above the retinal nerve fiber layer and at various retinal depths. Our results highlight the cellular morphological heterogeneity of non-apoptotic annexin-V labeling of retinal microglia. Accordingly, pharmacological depletion of microglia abolishes annexin-V labeling of elongated microglia in vivo revealing fainter labeling of round RGCs. Thus, consideration should be given to the time course of the immune response when interpreting fluorescently labeled annexin-V to visualize retinal cell apoptosis for clinical diagnosis.
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    Assessment of anogenital distance as a diagnostic tool in polycystic ovary syndrome
    (Elsevier, 2018) Hernández-Peñalver, Ana I.; Sánchez-Ferrer, María L.; Mendiola, Jaime; AdoamneI, Evdochia; Prieto-Sánchez, María T.; Corbalán-Biyang, Shiana; Carmona-Barnosi, Ana; Nieto, Aníbal; Torres-Cantero, Alberto M.; Cirugía, Pediatría y Obstetricia y Ginecología
    Is anogenital distance (AGD) a useful clinical tool for predicting polycystic ovarian syndrome (PCOS) and its main National Institutes of Health (NIH) phenotypes? Case-control study conducted between September 2014 and May 2016 at the Department of Obstetrics and Gynecology of the University Clinical Hospital 'Virgen de la Arrixaca' in the Murcia region (south-eastern Spain). One hundred and twenty-six cases of PCOS and 159 controls without PCOS were included. AGD measurements were taken from the anterior clitoral surface to the upper verge of the anus (AGDAC), and from the posterior fourchette to the upper verge of the anus (AGDAF). Parametric and non-parametric tests and receiver operating characteristic (ROC) curves were used to assess associations between AGD and the presence of PCOS and its phenotypes. AGDAC, but not AGDAF, was associated with PCOS and all its phenotypes (P-values < 0.001 to 0.048). The highest area under the curve (0.62; 95% confidence interval 0.55 to 0.71) was obtained for all PCOS with AGDAC with a sensitivity and specificity of 50.0% and 73.0%, and positive and negative predictive value of 59.0% and 64.4%, respectively. AGDAC could moderately discriminate the presence of PCOS and may be a useful clinical tool.
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    CD63 is a diagnostic marker of prostate cancer and a prognostic marker of biochemical progression following radical prostatectomy
    (2026) Marit Bernhardt1; Isabella Federica Bollen; Tobias Kreft; Anna Katrin Scherping; Xiaolin Zhou; Manuel Ritter; Jörg Ellinger; Carsten Stephan; Glen Kristiansen; Elisabeth Dingendorf; Biología Celular e Histología
    Aims. We aimed to analyze CD63, a cell surface protein that has been associated with tumor aggressiveness in several cancers, including breast, colorectal, and lung cancer, as well as melanoma, in prostate cancer. Methods. CD63 expression was analyzed immuno histochemically in a cohort of primary prostate cancers from 281 patients. The results were correlated with clinico-pathologic parameters, including biochemical recurrence. In addition, CD63 expression in 251 of the 281 patients with prostate cancer was compared with CD63 expression in matched benign tissue samples (490 tissue samples). The analysis was performed automatically using the open-source software QuPath© and tested for statistical significance. For comparison with the diagnostic markers AMACR and GOLPH2, CD63 was analyzed in an additional cohort of 198 prostate cancers. Results. CD63 expression was found in 100% of prostate cancer cases and benign tissue spots. Increased CD63 expression was significantly associated with higher tumor stage (pT), tumor grade (ISUP), as well as shorter progression-free survival (PFS). Compared with the CD63 intensity of benign tissue, expression in tumor tissue was higher in >80% of cases. In addition, combining the expression of CD63 and AMACR, positivity reached 97.2%, making CD63 a promising diagnostic biomarker in challenging cases. Conclusions. CD63 is commonly overexpressed in prostate cancer, and higher levels are associated with earlier biochemical tumor progression; hence, CD63 is a promising diagnostic and prognostic biomarker in primary prostate cancer.
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    Circadian pattern of acute phase proteins in the saliva of growing pigs
    (Elsevier, 2013-05) Gutiérrez Montes, Ana María; Escribano Tortosa, Damián; Fuentes Rubio, María; Cerón Madrigal, José Joaquín; Producción Animal
    The circadian rhythm of the acute phase proteins (APPs) haptoglobin (Hp) and C-reactive protein (CRP) was assessed in saliva samples from 18- and 21-week old pigs. Saliva was collected at 07.00, 11.00, 15.00 and 19.00 h on two consecutive days and the Hp and CRP concentrations were quantified using two species-specific, time-resolved immunofluorometric assays. Salivary Hp levels were significantly higher (P < 0.001) in the morning compared to late afternoon (0.68 and 0.37 lg/mL, respectively) although the magnitude of the difference was much lower than is produced by inflammatory conditions. No significant differences were observed in CRP concentrations. Although the concentration of both APPs was higher in the 21- compared to the 18-week old pigs (P < 0.0001), no differences were observed in the circadian rhythm of these APPs when the two age groups were com- pared. Animal gender did not influence the circadian pattern of either APP, although the mean salivary CRP levels were higher in females (P < 0.05).
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    Dataset of the project: Una Posible Diana Terapeutica para Bloquear la Progresión del Glioblastoma: la Autofagia Mediada por Chaperonas en Pericitos (PID2020-114010RB-I00)
    (2026-02-09) Rodríguez, Pablo; Rubio Pedraza, Gonzalo; Valdor Alonso, Rut; Salinas Hidalgo, María Dolores; Bioquímica y Biología Molecular B e Inmunología
    Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the PC secretome
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    Differential expression of WNT5A long and short isoforms in non-muscle-invasive bladder urothelial carcinoma
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Strope, Amy M.; Phillips, Cody; Khadgi, Sabin; Jenkinson, Scott A; Coschigano, Karen T.; Malgor, Ramiro
    Wnt ligands belong to a family of secreted glycoproteins in which binding to a range of receptors/co-receptors activates several intracellular pathways. WNT5A, a member of the Wnt family, is classified as a non-canonical Wnt whose activation triggers planar cell polarity (PCP) and Ca+2 downstream pathways. Aberrant expression of WNT5A has been shown to play both protective and harmful roles in an array of conditions, such as inflammatory disease and cancer. In the present study, using histological, immuno-histochemical, and molecular methods, we investigated the expression of two isoforms of WNT5A, WNT5A-Short (WNT5A-S) and WNT5A-Long (WNT5A-L) in bladder urothelial carcinoma (UC). Three UC cell lines (RT4, J82, and T24), as well as a normal urothelial cell line, and formalin-fixed, paraffin-embedded (FFPE) transurethral resection (TUR) tissue samples from 17 patients diagnosed with UC were included in the study. WNT5A-L was the predominantly expressed isoform in urothelial cells, although WNT5A-S was also detectable. Further, although no statistically significant difference was found between the percentage of WNT5A-S transcripts in low-grade versus high-grade tumors, we did find a difference between the percentage of WNT5A-S transcripts found in non-invasion versus invasion of the lamina propria, subgroups of non-muscle-invasive tumors. In conclusion, both WNT5A-S and WNT5A-L isoforms are expressed in UC, and the percentage of their expression levels suggests that a higher proportion of WNT5A-S transcription may be associated with lamina propria invasion, a process preceding muscle invasion.
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    Donor-derived cell-free DNA in acute and chronic rejection of solid allograft transplantation
    (Springer, 2026-01-02) Muro-Pérez, Javier; Muro-Pérez, Manuel; Galián, José Antonio; Pérez- López, Noelia; Legaz Pérez, Isabel; Muro, Manuel; Ciencias Sociosanitarias; Facultad de Química
    Today, there have been spectacular advances in surgical techniques, organ preservation for transplantation, optimal and efficient donor and recipient selection, more efficient diagnosis of transplant complications, and major progress in pharmacological immunosuppression procedures. In this regard, survival rates after transplantation of various organs have been gaining ground, particularly in the case of lung transplants, whose average survival rate is lower than other types of transplants. In this regard, it is important to detect acute and subclinical clinical rejection, as well as chronic allograft rejection. This is especially important in heart and lung transplants. In the latter type of transplant, and due to the chronic dysfunction of the lung allograft, it is key to detect rejection early and promptly, as it can affect up to half of the transplant patient population. Therefore, effective diagnostic tools are needed to visualize the level of allograft damage using genomic methods such as those that measure donor-derived cell-free DNA (dd-cfDNA). The plasma concentration of dd-cfDNA increases after graft injury or infection. Our team has experience quantifying this parameter in allograft injury progression, and our experience and comparison with the published literature will be presented in the following sections, discussing validated and non-validated results.
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    Donor-derived cell-free DNA in allograft transplantation: exaggerated hope or cautious reality?
    (MDPI, 2025-09-23) Fernández-González, Marina; Llorente, Santiago; Botella, Carmen; Galián, José Antonio; González-López, Rosana; Alegría-Marcos, María José; Hita, Alicia; Moya-Quiles, Rosa; Martínez-Banaclocha, Helios; Muro-Pérez, Manuel; Muro, Javier; Minguela, Alfredo; Legaz Pérez, Isabel; Muro, Manuel; Ciencias Sociosanitarias; Facultad de Química
    Nowadays, there have truly been spectacular advances in surgical techniques, the preservation of organs for transplants, the optimal and efficient selection of both donors and recipients, a more efficient diagnosis and prediction of possible complications of transplants, and important progress in the advances of pharmacological immunosuppression protocols and procedures. In this sense, survival rates after transplantation of various organs have been progressively increasing, especially in the case of lung transplants, whose average survival rate is usually lower than that of other types of solid organ transplants. Thus, detecting acute and subclinical rejection and chronic allograft rejection of any implant is important. This is important in all transplants, such as heart and lung transplants. In this last type of transplant, particularly, and due to the chronic dysfunction of the lung allograft, it is key to detect rejection early and on time, since it can reach close to half of the transplant patient population. Therefore, practical diagnostic tools are needed to visualize the level of allograft damage using genomic methods such as those that measure donor-derived cell-free DNA, where its amount increases in the plasma component of the transplant after tissue injury or due to allograft infection. This biomarker has become a key element with light and hope, but with some shadows of caution due to its use as a panacea. Our research team has experience in solid organ transplantation in quantifying this parameter in the progression of the lesion of the implanted allograft, and our experience and comparison with the published literature will be presented in the following review, discussing validated and non-validated results.
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    Editorial: molecular biomarkers in animal reproduction
    (Frontiers Media, 2021-12-01) Martínez, Cristina Alicia; Roca, Jordi; Barranco, Isabel; Medicina y Cirugía Animal
    Improving the reproductive efficiency of livestock species remains challenging the scientific community. Emerging 'omics technologies, such as genomics, transcriptomics, proteomics, and metabolomics, are helping to overcome this challenge (1, 2). These high-throughput technologies make it possible to identify the set of molecules and regulatory networks which are directly or indirectly involved in reproductive processes, and to recognize molecules that play a key role in major reproductive events (3). In this context, one of the purposes of this special issue was to highlight the increasing applicability of 'omics to identify key molecules involved in modulating main reproductive events of animal species of economic interest. Seven out of nine research papers included in this special issue used 'omics-tools, five of them using transcriptomics and the other two using metabolomics and proteomics.
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    Enzymatic activity changes in striped catfish Pseudoplatystoma magdaleniatum, induced by exposure to different concentrations of ibuprofen and triclosan.
    (Elsevier, 2021-05) Gallego Rios, Sara E.; Peñuela, Gustavo A.; Martínez-López, Emma; Ciencias Sociosanitarias
    The present study aimed to evaluate the effects of exposure for four months, with ibuprofen and triclosan at 25 and 50 μg/L in Striped catfish Pseudoplatystoma magdaleniatum, evaluated between sexes and exposure times. Biochemical biomarkers such as lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, acetylcholinesterase, creatine kinase, lipid peroxidation, albumin, globulins, creatinine, and urea were evaluated. The results of this study suggest that both ibuprofen and triclosan at concentrations of 25 and 50 μg/L can cause alterations to P. magdaleniatum, interfering with the activity of certain enzymes associated with energy production, immune response, architecture, and cellular physiology. Also, we determined the current state of contamination in fish, the concentration of ibuprofen and triclosan in P. magdaleniatum muscle samples from the different places markets located on the banks of the main rivers of Colombia was quantified by UHPLC-QqQ-MS/MS, in three climatic periods; finding triclosan levels in the dry season in some of the sampling points compatible with enzyme-level alterations in this species.
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    Evaluation of S100A12 protein as a porcine health status biomarker when quantified in saliva samples.
    Gutiérrez, A M; Matás-Quintanilla, M; Piñeiro, M; Sánchez, J; Fuentes, P; Medicina y Cirugía Animal
    Datos de investigación relativos a un artículo de investigación: validación de un biomarcador, la proteína S100A12, de salud porcina, validación analítica y clínica de un ensayo para cuantificar las concentraciones del biomarcador en muestras de saliva porcina.
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    Expression of lumican and osteopontin in perivascular areas of the glioblastoma peritumoral niche and its value for prognosis
    (MDPI, 2024-12-29) Rodríguez, Pablo; Rubio Pedraza, Gonzalo; Salinas Hidalgo, María Dolores; Valdor Alonso, Rut; Bioquímica y Biología Molecular B e Inmunología
    Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the PC secretome. The secretion of extracellular matrix (ECM) proteins with anti-tumor (Lumican) and pro-tumoral (Osteopontin, OPN) properties was shown to be dependent on the regulation of GB-induced CMA in PCs. As biomarkers are rarely studied in TME, in this work, we aimed to validate Lumican and OPN as prognostic markers in the perivascular areas of the peritumoral niche of a cohort of GB patients. Previously, we had validated their expression in GB xenografted mice presenting GB infiltration (OPN) or GB elimination (Lumican) dependent on competent or deficient CMA PCs, respectively. Then, patient sample classification by GB infiltration into the peritumoral brain parenchyma was related to GB-induced CMA in microvasculature PCs, analyzing the expression of the lysosomal receptor, LAMP-2A. Our results revealed a correlation between GB-induced CMA activity in peritumoral PCs and GB patients’ outcomes, identifying three degrees of severity. The perivascular expression of both immune activation markers, Iba1 and CD68, was related to CMA-dependent PC immune function and determined as useful for efficient GB prognosis. Lumican expression was identified in perivascular areas of patients with less severe outcome and partially co-localizing with PCs presenting low CMA activity, while OPN was primarily found in perivascular areas of patients with poor outcome and partially co-localizing with PCs presenting high CMA activity. Importantly, we found sex differences in the incidence of middle-aged patients, being significantly higher in men but with worse prognosis in women. Our results confirmed that Lumican and OPN in perivascular areas of the GB peritumoral niche are effective predictive biomarkers for evaluating prognosis and monitoring possible therapeutic immune responses dependent on PCs in tumor progression.
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    High Annexin A10 expression is correlated with poor prognosis in pancreatic ductal adenocarcinoma
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2022) Ishikawa, Akira; Kuraoka, Kazuya; Zaitsu, Junichi; Saito, Akihisa; Yamaguch, Atsushi; Kuwai, Toshio; Sudo, Takeshi; Hadano, Naoto; Tashiro, Hirotaka; Taniyama, Kiyomi; Yasui, Wataru
    Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death. Owing to its poor prognosis, new molecular biomarkers for PDAC are needed. Annexin A10 (ANXA10) is a calcium- /phospholipid-binding protein belonging to the annexin family of proteins. ANXA10 is not only associated with gastric phenotypes, but also acts an independent prognostic factor in several cancers. However, the role of ANXA10 in PDAC remains unknown. Therefore, we examined the relationship between ANXA10 and the prognosis of PDAC. We analyzed the expression of ANXA10 using data from public databases, and performed immunohistochemistry analysis for 81 PDAC cases. We then investigated the relationship between ANXA10 expression and clinicopathological features. ANXA10 was detected in 47 of 81 PDAC cases (58%). High expression of ANXA10 was significantly related to poor overall survival (OS; p=0.011). Univariate analysis of OS revealed three prognostic parameters: tumor grade (p=0.046), perineural invasion (p=0.017), and ANXA10 expression (p=0.012). Multivariate analysis indicated that ANXA10 expression (p<0.01) alone was a prognostic factor in PDAC cases. Our findings suggest that ANXA10 expression is an independent prognostic factor in PDAC cases and shows promise as a new biomarker in PDAC.
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    Higher expression of activated CD8+ T lymphocytes (CD8+CD25+, CD8+CD69+ and CD8+CD95+) mediate early post-transplant acute tubular injury in kidney recipients
    (IMR Press, 2023-06-27) Boix, Francisco; Jiménez Coll, Víctor; Alfaro, Rafael; Moya Quiles, María Rosa; Peña Moral, Jesús de la; Minguela, Alfredo; Llorente, Santiago; Muro, Manuel; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    Background: Acute kidney injury (AKI) is a leading cause of early post-transplant kidney damage. Furthermore, acute tubular necrosis (ATN) is appointed as the most prevalent form of AKI, a frequent multifactorial process associated with high morbidity and mortality, yet giving rise to delayed graft function (DGF) and, ultimately, allograft dysfunction. Common factors such as prolonged cold ischemia time, advanced donor age, cadaveric versus living donor, donor history of hypertension, as well as donation after cardiac death have all been deemed risk factors for ATN. With the increasing number of older cadaveric and cardiac donors in the donation process, ATN could have a detrimental impact on patient welfare. Therefore understanding the underlying process would benefit the transplant outcome. We aimed to prospectively monitor several T cell subsets in a cohort of kidney transplant recipients (KTrs) to investigate whether there is an adaptive immune-mediated involvement in the ATN process. Methods: Peripheral blood was collected from 31 KTrs at different time points within the first-year post-transplantation for in vitro stimulation with Concanavalin-A (Con-A) in a humidified 5% CO2 incubator at 37 °C for 72 hours. Upon cell stimulation, flow cytometry was applied to quantify the surface expression through the median fluorescence intensity (MFI) of CD4+CD25+, CD8+CD25+, CD4+CD38+, CD8+CD38+, CD4+CD154+, CD8+CD154+, CD4+CD69+, CD8+CD69+, CD4+CD95+, and CD8+CD95+ T cells. Statistical analysis was carried out with SPSS Statistics IBM v.25 (IBM Corp, Armonk, NY, USA). MFIs values were compared using a univariate analysis by a nonparametric U-Mann Whitney test. ROC analysis was applied to define cut-off values most capable of stratifying patients at high risk of ATN. Spearman’s rank-order coefficient test was applied to correlate biomarkers with allograft function. Multivariate regression independently validated CD8+ T lymphocytes as surrogate biomarkers of ATN. A p-value < 0.05 was considered statistically significant. Results: KTrs who developed ATN upon transplantation had significantly higher expression of CD25, CD69, and CD95 on CD8+ and lower expression of CD95 on CD4+ T lymphocytes than patients with stable graft function. ROC curve analysis showed that MFIs ≥1015.20 for CD8+CD25+, ≥2489.05 for CD8+CD69+, ≥4257.28 for CD8+CD95+, and ≤1581.98 for CD4+CD95+ were capable of stratifying KTrs at high risk of ATN. Furthermore, patients with an MFI below any cut-off were significantly less likely to develop ATN than those with other values. The allograft function was correlated with the CD4+CD95+/CD8+CD95+ ratio in KTrs who developed ATN. The multivariate analysis confirmed that, within the first-month post-transplant, MFI values of CD8+CD25+, CD4+CD95+, and CD8+CD95+ T lymphocytes, along with donor age, serum creatinine, and GFR were independent risk factors to ATN. Moreover, we were also able to corroborate previous immune factors of importance in immune-mediated response to the allograft, such as the patient’s maximum panel reactive antibody (PRA) or the maintenance immunosuppression therapy. Conclusions: Our results demonstrate evidence for the implication of CD8+ T lymphocytes in the development of ATN early in the post-transplant phase. Post-transplant monitoring of activated CD8+ T lymphocytes may help identify which patients require further clinical intervention to prevent graft damage.
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    Identification and validation of plasma AGRN as a novel diagnostic biomarker of hepatitis B Virus-related chronic hepatitis and liver fibrosis/cirrhosisy
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Ai, Rong; Li, Lu; Yuan, Xiwei; Zhao, Dandan; Miao, Tongguo; Guan, Weiwei; Dong, Shiming; Dong, Chen; Dou, Yao; Hou, Mengmeng; Nan, Yuemin
    Objective. The aim of this study was to find novel biomarkers and develop a non-invasive, effective diagnostic model for hepatitis B Virus-related chronic hepatitis and liver fibrosis/cirrhosis. Method. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to assess the expression of differentially expressed genes (AGRN, JAG1, CCL5, ID3, CCND1, and CAPN2) in peripheral blood mononuclear cells (PBMCs) from healthy subjects, chronic hepatitis B (CHB), and liver fibrosis/cirrhosis (LF/LC) patients. The molecular mechanisms underlying AGRN-regulated CHB were further explored and verified in LX2 cells, in which small interfering RNA (siRNA) was used to block AGRN gene expression. Finally, enzyme-linked Immunosorbent Assay (ELISA) was used to measure AGRN protein expression in 100 healthy volunteers, 100 CHB patients, and 100 LF/LC patients, and the efficacy of the diagnostic model was assessed by the Area Under the Curve (AUC). Results. AGRN mRNA displayed a steady rise in the PBMCs of normal, CHB, and LF/LC patients. Besides, AGRN expression was markedly elevated in activated LX2 cells, whereas the expression of COL1 and α-SMA decreased when AGRN was inhibited using siRNA. In addition, downregulation of AGRN can reduce the gene expression of β-catenin and c-MYC while upregulating the expression of GSK-3β. Furthermore, PLT and AGRN were used to develop a non-invasive diagnostic model (PA). To identify CHB patients from healthy subjects, the AUC of the PA model was 0.951, with a sensitivity of 87.0% and a specificity of 91.0%. The AUC of the PA model was 0.922 with a sensitivity of 82.0% and a specificity of 90.0% when differentiating between LF/LC and CHB patients. Conclusion. The current study indicated that AGRN could be a potential plasma biomarker and the established PA model could improve the diagnostic accuracy for HBV-related liver diseases.
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    Immunohistochemical localization of D-β-aspartic acid and periostin in benign parotid gland tumors
    (2026) Takahiro Suzuki; Teruyuki Sato; Kenji Izuhara; Kazue Ise; Hiroki Shimada; Keigo Murakami; Kazuhiro Murakami; Yasuhiro Nakamura; Nobuo Ohta; Yutaka Tateda; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
    Periostin is involved in airway remodeling, salivary tumors, and various otolaryngological diseases. D-β-aspartic acid is the major isomer of D-aspartic acid found in the tissues of elderly individuals. In this study, we investigated the expression and role of D-β-aspartic acid and periostin in the formation of benign parotid tumors. The data of 36 patients (16 male and 20 female) who underwent parotid tumor resection between April 2017 and March 2022 and were clinically and pathologically diagnosed as having benign parotid tumors were included in this study. The mean age of the patients was 59.2 (range 26-82) years. Tumors were histologically classified as pleomorphic adenomas, Warthin’s tumors, basal cell adenomas, oncocytomas, and myoepitheliomas. Increased D-β-aspartic acid expression was observed in the epithelium and stroma of benign parotid tumors. In the epithelium, D-β-aspartic acid was found in 35 of 38 samples (92.1%). In the stroma, it was found in 19 of 38 samples (50.0%). In the stroma of benign parotid tumors, increased expression of periostin was found in 32 of 38 samples (84.2%). Four periostin expression patterns were observed in benign parotid tumors: negative, superficial, infiltrative, and diffuse. Statistically significant differences were found between the expression pattern of D-β-aspartic acid in the stroma and the histological classification of benign parotid gland tumors. In addition, a statistically significant difference was found between the expression patterns of D-β-aspartic acid and periostin in the stroma. Our results suggest that D-β-aspartic acid and periostin may be involved in the pathogenesis of benign parotid gland tumors.
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    Influence of the circadian cycle, sex and production stage on the reference values of parameters related to stress and pathology in porcine saliva
    (Springer Nature, 2023) Saco, Y.; Peña, R.; Matas-Quintanilla, M.; Ibáñez-López, F. J.; Piñeiro, M.; Sotillo, J.; Bassols, A.; Gutiérrez, A. M.; Medicina y Cirugía Animal
    Background The concentration of biomarkers in saliva could be influenced by several factors not related to the specific condition under analyses, which should be considered for proper clinical interpretation. In the present study, the circadian rhythm of C-reactive protein (CRP), haptoglobin (Hp), Pig-MAP, S100A12, Cu, Zn, Adenosine deaminase (ADA), total protein (TP), total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), cortisol and α-amylase in saliva of 20 female and 20 male pigs was investigated. Moreover, the influence of sex and production phase (post-weaning, fattening and finishing) on the concentrations of biomarkers in a total of 414 healthy pigs was studied and the reference intervals for all salivary biomarkers were calculated accordingly. Results All parameters except Pig-MAP, OSI and α-amylase varied significantly along the daytime, and most of them peak around early afternoon (13–15 h). The cosinor analysis described the temporal dynamics of circadian rhythms for all parameters. The range values showed differences between male and female pigs in 8 out of the 13 biomarkers, with higher concentrations in females in comparison to male pigs. The influence of the production phase on the salivary concentrations was observed for all the biomarkers. The highest concentrations were observed for Pig-MAP, S100A12 and α-amylase in post-weaning animals, for TP in growing pigs and for OSI in finishing animals. Most of the sex-influenced biomarkers showed the highest concentrations at growing stages with some exceptions such as ADA or Hp that showed the peak at finishing and post-weaning stages respectively. Conclusions It is necessary to establish the optimal daytime for routine saliva sampling to avoid circadian variations and for that end, the time interval between 10:00 a.m. to 12:00 a.m. is highly recommended. The factors sex and production phase influence the concentration of biomarkers and should be considered for proper biomarker interpretation. The reference intervals presented here for each salivary biomarker will help to correctly interpret the results of these analytes and contribute to the use of saliva as a non-invasive sample for the diagnosis and monitoring of the health status of swine farms.
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    Loss of PDE10A is associated with metastasis of colon adenocarcinoma
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2026) Nicholas Nuechterlein; Vinny Ha; Allison Shelbourn; Ashis Chowdhury; Yeshavanth K Banasavadi-Siddegowda; Jerzy Lasota; Markku Miettinen; Patrick J. Cimino; Sumaita Arowa; Biología Celular e Histología
    Phosphodiesterase 10A (PDE10A), located on cytoband 6q27, acts as a haploinsufficient tumor suppressor in glioblastoma, where its loss drives aggressive tumor behavior and is associated with a proneural-to-mesenchymal (PN-MES) shift. Lever-aging bioinformatic analyses of The Cancer Genome Atlas (TCGA) pan-cancer dataset, we identified gastrointestinal carcinomas, specifically stomach adenocarcinoma and colon adenocarcinoma, as cancers where 6q27/PDE10A loss is prognostic. In both stomach adenocarcinoma and colon adenocarcinoma, PDE10A loss was associated with reduced overall survival (OS) and progression-free survival (PFS). Additionally, PDE10A loss correlated with increased lymphatic invasion and higher AJCC pathologic nodal stage in colon adenocarcinoma. In an independent institutional cohort, immunohistochemical analysis showed lower PDE10A expression in metastatic colon adenocarcinomas compared to primary tumors. Furthermore, PDE10A loss and decreased protein expression corresponded with an epithelial-to-mesenchymal transition (EMT) phenotype in both cohorts, consistent with the known PN-MES shift observed in glioblastoma. In summary, PDE10A loss in colon adenocarcinoma is associated with decreased OS and PFS, more frequent lymphatic invasion, higher pathologic nodal stage, metastatic disease, and an EMT phenotype.
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    MGRN1 as a phenotypic determinant of human melanoma cells and a potential biomarker.
    (MDPI, 2022-07-26) Abrisqueta, Marta; Sánchez-Beltrán, José; Martínez-Vicente, Idoya; Sevilla, Arrate; Alonso, Santos; Boyano, María Dolores; Cerdido Ochoa, Sonia; García-Borrón Martínez, José Carlos; Herraiz Serrano, Cecilia María; Jiménez-Cervantes Frigols, Celia; Lambertos Escudero, Ana; Olivares Sánchez, María Concepción; Bioquímica y Biología Molecular B e Inmunología
    Mahogunin Ring Finger 1 (MGRN1), a ubiquitin ligase expressed in melanocytes, interacts with the α melanocyte-stimulating hormone receptor, a well-known melanoma susceptibility gene. Previous studies showed that MGRN1 modulates the phenotype of mouse melanocytes and melanoma cells, with effects on pigmentation, shape, and motility. Moreover, MGRN1 knockdown augmented the burden of DNA breaks in mouse cells, indicating that loss of MGRN1 promoted genomic instability. However, data concerning the roles of MGRN1 in human melanoma cells remain scarce. We analyzed MGRN1 knockdown in human melanoma cells. Transient MGRN1 depletion with siRNA or permanent knockdown in human melanoma cells by CRISPR/Cas9 caused an apparently MITF-independent switch to a more dendritic phenotype. Lack of MGRN1 also increased the fraction of human cells in the S phase of the cell cycle and the burden of DNA breaks but did not significantly impair proliferation. Moreover, in silico analysis of publicly available melanoma datasets and estimation of MGRN1 in a cohort of clinical specimens provided preliminary evidence that MGRN1 expression is higher in human melanomas than in normal skin or nevi and pointed to an inverse correlation of MGRN1 expression in human melanoma with patient survival, thus suggesting potential use of MGRN1 as a melanoma biomarker.