[Proteomics in infectious diseases]. / Proteómica en enfermedades infecciosas.

Infectious diseases have a high incidence in the population, causing a major impact on global health. In vitro culture of microorganisms is the first technique applied for infection diagnosis which is laborious and time consuming. In recent decades, efforts have been focused on the applicability of "Omics" sciences, highlighting the progress provided by proteomic techniques in the field of infectious diseases. This review describes the management, processing and analysis of biological samples for proteomic research.

Biomarkers: a new approach to behavioural variant frontotemporal dementia.

INTRODUCTION: Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. DEVELOPMENT: We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. CONCLUSIONS: BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities.

Value of the biomarker soluble tyrosine kinase 1 type fms (sFLT-1) in the diagnosis and prognosis of sepsis: a systematic review. / Valor del biomarcador tirosina quinasa 1 soluble tipo fms (sFLT-1) en el diagnóstico y pronóstico de la sepsis: una revisión sistemática.

INTRODUCTION: The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022. MATERIALS AND METHODS: A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry). RESULTS: The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction. CONCLUSIONS: It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker.

Association between adipophilin expression and risk of dyslipidaemia in patients with granuloma annulare.

BACKGROUND: An association between granuloma annulare (GA) and dyslipidaemia has been reported. Adipophilin expression may play a plausible role as a cutaneous biomarker for dyslipidaemia in patients with GA; however, this potential link remains to be explored. METHODS: Patients with GA were identified at our hospital between January 1, 1990, and December 31, 2021, with a thorough review of their clinical and histological characteristics. Adipophilin staining was assessed in biopsies of GA lesions. RESULTS: A total of 107 patients with GA were included. The prevalence of dyslipidaemia in patients with positive adipophilin staining was clearly higher than in those with negative labelling (62.3% vs 13.3%). Relative to the dyslipidaemia risk for patients with negative adipophilin expression, the odds for patients with positive adipophilin expression were increased 10-fold (OR: 10.8; p-value<.01). We identified 23 incident cases of dyslipidaemia over a median follow-up period of 91 months among 54 patients with no history of dyslipidaemia. The patients with positive adipophilin expression showed a higher risk of developing dyslipidaemia (HR: 8.9; p-value<.01). CONCLUSIONS: Patients with positive adipophilin staining in their GA biopsies were found to be associated with a higher risk for both baseline and incident dyslipidaemia.

Biomarkers: how to consolidate them in clinical practice.

An inadequate biomarker validation can affect many patients' diagnosis, treatment, and follow-up. Therefore, special interest should be placed on performing these analyses correctly so that biomarkers can be applicable to patients and evidence of their clinical usefulness can be generated. A methodological work on the concept of biomarkers is presented, as well as the difficulties associated with the methodological approach to their development, validation, and implementation in clinical practice.

Extracellular vesicles in atherosclerosis: Current and forthcoming impact?

Atherosclerosis is the main pathogenic substrate for cardiovascular diseases (CVDs). Initially categorized as a passive cholesterol storage disease, nowadays, it is considered an active process, identifying inflammation among the key players for its initiation and progression. Despite these advances, patients with CVDs are still at high risk of thrombotic events and death, urging to deepen into the molecular mechanisms underlying atherogenesis, and to identify novel diagnosis and prognosis biomarkers for their stratification. In this context, extracellular vesicles (EVs) have been postulated as an alternative in search of novel biomarkers in atherosclerotic diseases, as well as to investigate the crosstalk between the cells participating in the processes leading to arterial remodelling. EVs are nanosized lipidic particles released by most cell types in physiological and pathological conditions, that enclose lipids, proteins, and nucleic acids from parental cells reflecting their activation status. First considered cellular waste disposal systems, at present, EVs have been recognized as active effectors in a myriad of cellular processes, and as potential diagnosis and prognosis biomarkers also in CVDs. This review summarizes the role of EVs as potential biomarkers of CVDs, and their involvement into the processes leading to atherosclerosis.

Value of long non-coding RNA HAS2-AS1 as a diagnostic and prognostic marker of glioma.

BACKGROUND: Glioma presents high incidence and poor prognosis, and therefore more effective treatments are needed. Studies have confirmed that long non-coding RNAs (lncRNAs) basically regulate various human diseases including glioma. It has been theorized that HAS2-AS1 serves as an lncRNA to exert an oncogenic role in varying cancers. This study aimed to assess the value of lncRNA HAS2-AS1 as a diagnostic and prognostic marker for glioma. METHODS: The miRNA expression data and clinical data of glioma were downloaded from the TCGA database for differential analysis and survival analysis. In addition, pathological specimens and specimens of adjacent normal tissue from 80 patients with glioma were used to observe the expression of HAS2-AS1. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic ability and prognostic value of HAS2-AS1 in glioma. Meanwhile, a Kaplan-Meier survival curve was plotted to evaluate the survival of glioma patients with different HAS2-AS1 expression levels. RESULTS: HAS2-AS1 was significantly upregulated in glioma tissues compared with normal tissue. The survival curves showed that overexpression of HAS2-AS1 was associated with poor overall survival (OS) and progression-free survival (PFS). Several clinicopathological factors of glioma patients, including tumor size and WHO grade, were significantly correlated with HAS2-AS1 expression in tissues. The ROC curve showed an area under the curve (AUC) value of 0.863, indicating that HAS2-AS1 had good diagnostic value. The ROC curve for the predicted OS showed an AUC of 0.906, while the ROC curve for predicted PFS showed an AUC of 0.88. Both suggested that overexpression of HAS2-AS1 was associated with poor prognosis. CONCLUSIONS: Normal tissues could be clearly distinguished from glioma tissues based on HAS2-AS1 expression. Moreover, overexpression of HAS2-AS1 indicated poor prognosis in glioma patients. Therefore, HAS2-AS1 could be used as a diagnostic and prognostic marker for glioma.

Use of Bladder Epicheck® in the follow-up of high-risk non-muscle-invasive Bladder cancer: A systematic literature review.

INTRODUCTION: In recent years, different urinary markers such as the Bladder Epicheck® have been developed in an attempt to reduce the number of cystoscopies in the follow-up of non-muscle invasive bladder cancer (NMIBC). AIM: To provide a systematic review of Bladder Epicheck® and its current clinical utility in the follow-up and detection of recurrence of NMIBC. MATERIAL AND METHODS: Systematic review based on a literature search of PubMed, Web of Science and Scopus databases until October 2023, according to PRISMA and Quadas-2 criteria. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the marker were calculated. Diagnostic performance was evaluated by the area under the curve (AUC). RESULTS: Fifteen studies were analyzed (n = 3761) including 86.7% prospective studies. Of the patient series, 53.2% had received previous intravesical instillations. The mean Se of the biomarker in the detection of recurrence varied according to tumor grade (87.9%-high grade/HG vs. 44.9%-low grade/LG, respectively). Their weighted mean Se and Sp were 71.6% and 84.5%, respectively. The mean recurrence rate was 29.1%. The weighted mean PPV and NPV were 56.4% and 92.8% (97.7% non-LG), respectively. The mean AUC was 85.63%. CONCLUSION: Bladder Epicheck® is a useful urinary marker in the follow-up of NMIBC, with significantly high Se and NPV in the detection of recurrences, especially in cases of HG disease. Its use can reduce the number of cystoscopies required in the follow-up of NMIBC, improving the quality of life of patients and potentially increasing health economic savings.

Presence of subfoveal hyperreflective dots as an anatomic and functional prognostic biomarker in macular holes.

OBJECTIVE: To evaluate the presence of subfoveal hyperreflective dots (SfHD) using optical coherence tomography (OCT) in macular holes (MH) and establish whether there is a relationship with postoperative anatomical and functional outcomes. METHODS: An observational cross-sectional study was conducted at the Dr. Elías Santana Hospital. Sixty-eight eyes of 67 patients with a tomographic diagnosis of full-thickness MH who underwent pars plana vitrectomy (PPV) and internal limiting membrane (ILM) peeling were included. Preoperative and postoperative measurements were obtained using radial macular scans and HD raster scans with Optovue and Cirrus 5000 (Zeiss) OCT machines. The main outcome measures were anatomical closure by OCT and functional outcome through best-corrected visual acuity (BCVA). RESULTS: The anatomical closure rate in our study was 63%. MHs that failed to achieve anatomical closure exhibited a higher number of hyperreflective dots and worse postoperative BCVA. A statistically significant association was found between exposed retinal pigment epithelium (RPE) in microns and the number of SfHD (P = .001). CONCLUSION: SfHD is a common tomographic finding in MH, and the presence of a higher number of these points is associated with poorer anatomical and functional outcomes. This imaging finding is a potential prognostic biomarker in this pathology.

Prognostic capacity of PIV (pan-immune-inflammation value) in patients with head and neck squamous cell carcinoma.

INTRODUCTION: The pan-immune-inflammation value (PIV), an index that results from the following ratio: (neutrophils × monocytes × platelets)/lymphocytes, has been proposed as a prognostic biomarker in different tumour models. The aim of this study is to analyse the prognostic capacity of PIV in patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Retrospective study of 1187 patients with HNSCC treated at our centre between 2000-2017. PIV value was obtained from an analysis performed within 3 weeks prior to the start of treatment. RESULTS: PIV value was significantly associated with toxic consumption (0.001), tumour location (0.0001), tumour extension (0.0001), and histological grade (0.016). Four categories were defined based on PIV value using a recursive partitioning analysis: category I: PIV < 136.3 (n = 118, 9.9%), category II: PIV 136.3-451.1 (n = 594, 50.0%), category III: PIV 451.1-1,141.2 (n = 357, 30.1%), and category IV: PIV > 1141.2 (n = 118, 9.9%). A significant and ordered decrease in disease-specific survival was observed as the PIV category increased. This decrease in survival was independent of the type of treatment, tumour extension, or location of the primary tumour. The PIV category was and independent prognostic factor of disease-specific survival in a multivariable study. CONCLUSIONS: PIV is a prognostic biomarker in patients with HNSCC.

Myosin 1g as a high-risk biomarker in a pediatric patient with lineage switch from acute lymphoblastic leukemia to myeloid phenotype.

BACKGROUND: Myosin 1g (Myo1g) has recently been identified as a potential diagnostic biomarker in childhood acute lymphocytic leukemia (ALL). CASE REPORT: We describe the case of a 1-year-old Mexican female patient. Although initially studied for hepatomegaly, an infectious or genetic etiology was excluded. Liver biopsy showed infiltration by neoplastic B-cell precursors (BCPs), and bone marrow (BM) aspirate showed 14.5% of BCPs. In a joint session of the oncology, hematology, and pathology departments, low-risk (LR) BCP-ALL of hepatic origin with aberrant myeloid markers was diagnosed. Although treatment was initiated, the patient presented early with BM relapse. Modest overexpression of Myo1g was observed from the onset. However, at the end of the steroid window, expression increased significantly and remained elevated during this first relapse to BM. The parents refused hematopoietic stem cell transplantation, but she continued chemotherapy. After a second BM relapse at 5 years of age, the phenotype switched to myeloid. Her parents then opted for palliative care, and the patient died two months later at home. CONCLUSIONS: This case shows the potential use of Myo1g in clinical practice as a high-risk indicator. Myo1g monitoring may reveal a high risk and relapse trend, even when typical parameter values are not altered: Myo1g could be used to classify patients from low to high risk from diagnosis, allowing patients to promptly receive the best treatment and potentially modifying prognosis and survival.

INTRODUCCIÓN: Recientemente se ha identificado a miosina 1g (Myo1g) como un potencial biomarcador de diagnóstico en la leucemia linfoblástica aguda (LLA) infantil. CASO CLÍNICO: Se describe el caso de una paciente mexicana de 1 año de edad. Aunque inicialmente se estudió por hepatomegalia, se descartó una etiología infecciosa o genética. La biopsia hepática mostró infiltración por precursores de células B neoplásicas (PCB) y un aspirado de médula ósea (MO) mostró 14.5% de PCB. En una sesión conjunta de los departamentos de oncología, hematología y patología, se diagnosticó PCB-LLA de bajo riesgo de origen hepático con marcadores mieloides aberrantes. Aunque se inició tratamiento, la paciente presentó tempranamente recaída de MO. Se observó una modesta sobreexpresión de Myo1g. Sin embargo, al final de la ventana de esteroides, la expresión aumentó considerablemente y permaneció elevada durante esta primera recaída a MO. El trasplante de células madre hematopoyéticas fue rechazado por los padres, pero se continuó con la quimioterapia. Tras una segunda recaída de MO a los 5 años, el fenotipo cambió a mieloide. Sus padres optaron entonces por cuidados paliativos y la paciente falleció dos meses después en su domicilio. CONCLUSIONES: Este caso muestra el potencial uso de Myo1g como indicador de alto riesgo en la práctica clínica. El seguimiento de Myo1g puede revelar una tendencia de alto riesgo y recaídas, incluso cuando los valores de los parámetros rutinarios son aparentemente normales; Myo1g podría utilizarse para clasificar a los pacientes de bajo a alto riesgo desde el diagnóstico, lo que permitiría que los pacientes reciban el mejor tratamiento de manera oportuna, modificando potencialmente el pronóstico y la supervivencia.

Predictive capacity of FAT1 transcriptional expression in patients with head and neck squamous cell carcinomas treated with radiotherapy.

OBJECTIVE: To analyze the predictive capacity at the primary location of the tumor of the FAT1 transcriptional expression in patients with head and neck squamous cell carcinoma treated with radiotherapy. MATERIAL AND METHODS: We conducted a retrospective study from biopsies of the primary location of the tumor in 82 patients with head and neck squamous cell carcinoma treated with radiotherapy. The transcriptional expression of FAT1 was determined by RT-PCR. The level of FAT1 transcriptional expression was categorized according to the local control after radiotherapy using a recursive partitioning analysis. RESULTS: Elevated FAT1 transcriptional expression was associated with an increased risk of local recurrence after radiotherapy. Patients with a high expression level of FAT1 (n=18; 22.0%) had a 5-year local recurrence-free survival of 42.1% (95% CI: 18.6%-65.6%), whereas for patients with a low expression (n=64; 78.0%) it was 72.4% (95% CI: 61.5%-83.3%) (p=0.002). According to the result of a multivariate analysis, patients with a high FAT1 expression category had a 2.3-fold increased risk of local recurrence (95% CI: 1.0-5.2; p=0.043). CONCLUSIONS: Elevated FAT1 transcriptional expression was associated with a significantly increased risk of local recurrence in patients with head and neck squamous cell carcinoma treated with radiotherapy.

Meteorin-like protein is associated with a higher risk profile and predicts a worse outcome in patients with STEMI.

INTRODUCTION AND OBJECTIVES: Meteorin-like protein (Metrnl) is a cytokine involved in the attenuation of inflammation. In patients with heart failure, high levels of this biomarker are associated with a worse outcome. In this study, we evaluated the circulating levels and prognostic value of Metrnl in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We enrolled STEMI patients undergoing primary percutaneous coronary intervention. Circulating Metrnl levels were measured in peripheral blood 12hours after symptom onset. The primary endpoint was a composite of all-cause mortality or nonfatal myocardial infarction (MI) at 3 years. RESULTS: We studied 381 patients (mean age 61 years, 21% female, 8% Killip class III/IV). Metrnl levels were associated with age, cardiovascular risk factors and the extent of coronary artery disease, as well as with STEMI complications, particularly heart failure and cardiogenic shock. Multivariable Cox regression analysis revealed that Metrnl independently predicted all-cause death or nonfatal MI at 3 years (HR, 1.86; 95%CI, 1.23-2.81; P=.003). Moreover, patients in the highest tertile (> 491.6 pg/mL) were at higher risk for the composite endpoint than those in the lowest tertiles (HR, 3.24; 95%CI, 1.92-5.44; P <.001), even after adjustment by age, diabetes mellitus, cardiac arrest, Killip-Kimball III/IV class, left ventricular ejection fraction, and creatinine clearance (HR, 1.90; 95%CI, 1.10-3.29; P=.021). CONCLUSIONS: Circulating Metrnl levels are associated with complications during the acute phase of STEMI and independently predict a worse outcome in these patients.

Static first-minute-frame (FMF) PET imaging after 18F-labeled amyloid tracer injection is correlated to [18F]FDG PET in patients with primary progressive aphasia.

OBJECTIVE: To study the correlation between a static PET image of the first-minute-frame (FMF) acquired with 18F-labeled amyloid-binding radiotracers and brain [18F]FDG PET in patients with primary progressive aphasia (PPA). MATERIAL AND METHODS: The study cohort includes 17 patients diagnosed with PPA with the following distribution: 9 nonfluent variant PPA, 4 logopenic variant PPA, 1 semantic variant PPA, 3 unclassifiable PPA. Regional SUVRs are extracted from FMFs and their corresponding [18F]FDG PET images and Pearson's correlation coefficients are calculated. RESULTS: SUVRs of both images show similar patterns of regional cerebral alterations. Intrapatient correlation analyses result in a mean coefficient of r=0.94±0.06. Regional interpatient correlation coefficients of the study cohort are greater than 0.81. Radiotracer-specific and variant-specific subcohorts show no difference in the similarity between the images. CONCLUSIONS: The static FMF could be a valid alternative to dynamic early-phase amyloid PET proposed in the literature, and a neurodegeneration biomarker for the diagnosis and classification of PPA in amyloid PET studies.

Cortisol response to traumatic stress to predict PTSD symptom development - a systematic review and meta-analysis of experimental studies.

Background: Pre-and post-traumatic hypothalamic-pituitary-adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events.Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms.Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (dSMC) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms.Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (kobservations = 25, dSMC = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = -.18 [-.35; -.01]), higher state happiness (k = 8, r = -.34 [-.59; -.03], variable inverted) and lower state anger (k = 9, r = -.14 [-.26; -.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = -.20 [-.33; -.06]) and lower state sadness (k = 17, r = -.16 [-.25; -.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]).Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms.

Experimental trauma paradigms successfully induced a cortisol response.Cortisol was predictive for single state, emotion-related symptoms, but not overall PTSD symptoms.Trauma paradigms shed light into the immediate post-trauma period that is hard to capture in real life, but the gap between experimental and naturalistic settings is difficult to overcome.

[Optimization biomarkers in the surveillance of non muscle invasive bladder cancer.] / Optimización del seguimiento de tumores vesicales no músculo invasivo con biomarcadores.

INTRODUCTION: Bladder cancer is thefifth most common tumor in the world. Moreover, it isone of the most expensive due to its high recurrencerate. Urinary biomarkers for surveillance of non muscleinvasive bladder cancer is a promising and growingfield due to the invasiveness of the actual methods, basedon cystoscopy and cytology. Although current EuropeanGuidelines only consider the use of biomarkersin the low risk scenario as an alternative to cystoscopywhen the patient declines invasive methods for the follow-up after surgery, there is increasing evidence oftheir safety in high risk tumors. MATERIAL AND METHODS: We have performeda review of the main urinary biomarkers, includingFDA-approved ones, protein-based and genetic biomarkers.We have also described the different options to incorporatethe biomarkers in the clinical practice. RESULTS: There are not randomized control trialscomparing any biomarker with the gold standard follow-up. Most of the papers published so far are cohortstudies, limitating the evidence of the results. Biomarkerscan be used as an alternative of cystoscopy, in a noninvasive follow-up, or alternating both tests. There arefew economical studies comparing both options, but theevidence supports the efficiency of the main biomarkers. CONCLUSIONS: Cystoscopy and cytology are the goldstandard for non muscle invasive bladder cancer surveillance.2021 European Guidelines suggest, for the firsttime, an alternative use of biomarkers in a concrete lowgrade scenario to avoid invasive explorations to patientswith low risk of progression. Paradoxically, biomarkers(mainly genetic ones) have a very good profile of sensitivityand negative predictive value in the high risk scenario.Although there is increasing evidence to supporttheir implementation, the lack of fase IV trials hinderstheir daily use.

INTRODUCCIÓN: El carcinoma vesicales el quinto tumor más frecuente en el mundo. Dehecho, es uno de los que más recursos económicosconsume debido a su alta tasa de recurrencia. Los biomarcadoresurinarios para el seguimiento del tumorvesical no músculo invasivo es un campo prometedory en pleno crecimiento debido a la invasividad de losactuales métodos de seguimiento, basados en la cistoscopiay la citología de orina. A pesar de que las actualesGuías Europeas sólo consideran el uso de biomarcadoresen el escenario del tumor vesical de bajoriesgo como alternativa a la cistoscopia cuando el pacienteno desee procedimientos invasivos para el seguimientotras la cirugía, existe creciente evidencia desu seguridad en los tumores de alto riesgo.MATERIAL Y MÉTODOS: Se ha realizado una revisiónnarrativa de los principales biomarcadores urinarios,incluyendo los aprobados por la FDA, los basados enproteínas y los marcadores genéticos. Se han descritoigualmente las diferentes opciones para la incorporaciónde los biomarcadores en la práctica clínica diaria.RESULTADOS: No existen ensayos clínicos randomizadosque comparen los biomarcadores urinariosfrente al gold estándar en el seguimiento. La mayoría delos artículos hasta la fecha son estudios de cohortes, limitandola evidencia de los resultados. Los biomarcadores pueden ser utilizados como alternativa a la cistoscopia,en un seguimiento no invasivo, o alternandoambas pruebas. Existen pocos estudios económicosque comparen ambas opciones, pero la evidencia parecesoportar la eficiencia de los principales biomarcadores.CONCLUSIONES: La cistoscopia y la citología son elgold estándar para el seguimiento del tumor vesicalno músculo infiltrante. Las Guías Europeas de 2021sugieren, por primera vez, el uso alternativo de losbiomarcadores urinarios en el escenario concreto delbajo grado con el fin de evitar exploraciones invasivasa pacientes con muy bajo riesgo de progresión. Paradójicamente,los biomarcadores (principalmente losgenéticos) presentan un mejor perfil de sensibilidad yvalor predictivo negativo en el escenario del alto riesgo.A pesar de que existe creciente evidencia para recomendarsu implementación, la ausencia de ensayosclínicos fase IV dificulta su aplicación en la práctica diaria.

Statistical characterization of a good biomarker in oncology. / Características bioestadísticas de un buen biomarcador en Oncología.

OBJECTIVE: The  aim of this article is to review and illustrate the attributes that analyze the performance of a predictive model, suchas discrimination, calibration and clinical utility. MATERIAL AND METHODS: To illustrate a biomarkervalidation process, we analyzed 216 patientsrecruited in the Miguel Servet University Hospital Zaragoza, Spain. The outcome of the study was clinicallysignificant prostate cancer (Gleason ≥ 7). A newbiomarker was built using logistic regression modelfrom age, prostate-specific antigen, prostate volumeand digital rectal exam variables. To analyze the discriminationability, the receiver operating characteristiccurve, its area under the curve (AUC), and Youdenindex were estimated. In addition, the calibration wasanalyzed through calibration curve, intercept and slope;and the clinical utility was studied by means of decisionand clinical utility curves. RESULTS: The discrimination ability was good:AUC 0.790 (0.127-0.853 95% C.I.), Youden index cutoffpoint 0.431 (specificity 0.811, sensitivity 0.697).The Intercept was 0 and Slope 1 showing a perfect calibration.Decision curve showed good net benefit in athreshold probability range 25%-80%. Clinical utilitycurve showed that for a 18% cutoff point, a minimum4.5% of CsPCa patients are wrongly classified belowthe cutoff point, saving 18.5% biopsies. CONCLUSIONS: A complete validation process isnecessary to analyze the performance of a biomarkerin oncology, based on their discrimination ability, theconcordance between predicted and actual occurrenceof the outcome, and its applicability in clinical practice.

OBJETIVO: El objetivo principal de esteartículo es revisar e ilustrar las propiedades para analizarel desempeño de un modelo predictivo, que sonla discriminación, calibración y utilidad clínica.MATERIAL Y MÉTODOS: Para ilustrar un procesode validación de biomarcadores, analizamos 216 pacientesreclutados en el Hospital Universitario MiguelServet, Zaragoza, España. El objetivo a predecir en elestudio fue un cáncer de próstata clínicamente significativo(Gleason ≥ 7). Se construyó un nuevo biomarcadorutilizando un modelo de regresión logísticausando la edad, el antígeno prostático específico, elvolumen de la próstata y el tacto rectal como variablespredictoras. Para analizar la capacidad de discriminaciónse estimó la curva característica de funcionamientodel receptor, su área bajo la curva (AUC) y elíndice de Youden. Además, la calibración se analizómediante curva de calibración, intersección y pendiente;y la utilidad clínica se estudió mediante curvasde decisión y utilidad clínica. RESULTADOS: La capacidad de discriminación fuebuena: AUC 0,790 (0,127-0,853 IC del 95%), punto decorte del índice de Youden 0,431 (especificidad 0,811,sensibilidad 0,697). La intersección fue 0 y la pendiente1, mostrando una calibración perfecta. La curva dedecisión muestra un buen beneficio neto en un rangode probabilidad del 25% al 80%. La curva de utilidadclínica mostró que para un punto de corte del 18%, seproduce un mínimo del 4,5% de los pacientes con CsPCaclasificados incorrectamente por debajo del puntode corte, ahorrando un 18,5% de biopsias. CONCLUSIONES: Es necesario un proceso de validacióncompleto para analizar el desempeño de un biomarcadoren oncología, en función de su capacidad dediscriminación, la concordancia entre las prediccionesque proporciona el marcador y la ocurrencia real delevento, y su aplicabilidad en la práctica clínica.

Plasma levels of miRNA-1-3p are associated with subclinical atrial fibrillation in patients with cryptogenic stroke.

INTRODUCTION AND OBJECTIVES: Identifying biomarkers of subclinical atrial fibrillation (AF) is of most interest in patients with cryptogenic stroke (CrS). We sought to evaluate the circulating microRNA (miRNA) profile of patients with CrS and AF compared with those in persistent sinus rhythm. METHODS: Among 64 consecutive patients with CrS under continuous monitoring by a predischarge insertable monitor, 18 patients (9 with AF and 9 in persistent sinus rhythm) were selected for high-throughput determination of 754 miRNAs. Nine patients with concomitant stroke and AF were also screened to improve the yield of miRNA selection. Differentially expressed miRNAs were replicated in an independent cohort (n=46). Biological markers were stratified by the median and included in logistic regression analyses to evaluate their association with AF at 6 and 12 months. RESULTS: Eight miRNAs were differentially expressed between patients with and without AF. In the replication cohort, miR-1-3p, a gene regulator involved in cardiac arrhythmogenesis, was the only miRNA to remain significantly higher in patients with CrS and AF vs those in sinus rhythm and showed a modest association with AF burden. High (= above the median) miR-1-3p plasma values, together with a low left atrial ejection fraction, were independently associated with the presence of AF at 6 and 12 months. CONCLUSIONS: In this cohort, plasma levels of miR-1-3p were elevated in CrS patients with subsequent AF. Our results preliminarily suggest that miR-1-3p could be a novel biomarker that, together with clinical parameters, could help identify patients with CrS and a high risk of occult AF.

[Urinary biomarkers in the diagnosis of prostate cancer.] / Biomarcadores urinarios en el diagnóstico de cancer de próstata.

INTRODUCTION: The use of prostatespecific antigen (PSA) is useful for the diagnosis ofprostate cancer. Its main limitation is its low specificity,which has led to the search for new biomarkersin order to identify clinically significant prostatecancer and to reduce overdiagnosis and overtreatment.The aim of this article is to summarize the currentliterature on urinary biomarkers used in thediagnosis of prostate cancer.A PubMed-based literature search was conductedup to December 2020. We selected the most recentand relevant original articles, clinical trials and reviewsthat have provided relevant information onthe use of biomarkers.In this review, we have discussed four importanturinary biomarkers useful for prostate cancer diagnosis:PCA3, Select MDX, ExoDX, TMPRSS2:ERG. CONCLUSION: The use of urinary biomarkers hasimproved of clinically significant prostate cancerdiagnosis. Their use reduces the number of unnecessarybiopsies and avoids overtreatment of indolentprostate cancer.

INTRODUCCIÓN: El uso del antígenoprostático específico (PSA) es útil para el diagnósticodel cáncer de próstata. Su principal limitación es labaja especificidad, esto ha llevado a la búsqueda denuevos biomarcadores con el fin de identificar el cáncerde próstata clínicamente significativo y poder disminuirel sobrediagnóstico y sobretratamiento.El objetivo de este artículo es resumir la literaturaactual sobre los biomarcadores urinarios utilizados enel diagnóstico de cáncer de próstata.Se llevó a cabo una búsqueda bibliográfica en Pub-Med hasta diciembre del 2020. Hemos seleccionadolos artículos originales, ensayos clínicos y revisionesmás recientes que proporcionan información sobre eluso de biomarcadores.En esta revisión, hemos discutido cuatro importantesbiomarcadores urinarios útiles para el diagnósticodel cáncer de próstata: PCA3, Select MDX, ExoDX, TMPRSS2:ERG.CONCLUSIÓN: El uso de biomarcadores urinariosha mejorado del diagnóstico de cáncer de próstata clínicamentesignificativo. Su uso reduce el número debiopsias innecesarias y evita el sobretratamiento delcáncer de próstata indolente.

A new survival model based on ferroptosis-related genes (FRGS) for prognostic prediction in bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is a malignant urothelial carcinoma with a high mortality rate. Ferroptosis is a new type of programmed cell death and functions in suppressing tumor growth and progression. However, few studies focus on ferroptosis and BLCA. MATERIALS AND METHODS: We explored the potential oncogenic roles of ferroptosis-related genes in BLCA based on multiple public datasets. We then used univariate and multivariate cox regression to build a new survival model based on ferroptosis-related genes to predict the survival of BLCA. RESULTS: We found that 23 ferroptosis-related genes had a strong correlation with each other in BLCA. Eight ferroptosis-related genes, CDKN1A, HSPA5, NFE2L2, MT1G, FANCD2, CISD1, TFRC, NCOA4, had a significantly different expression and heat-map. HSPA5 and CISD1 have a statistically significant difference in OS and DFS. Besides, CISD1 had an ideal nomogram to predict the 1-3-5-year OS (C-index: 0.701, P < .001). Furthermore, HSPA5 and CISD1 had a lower DNA methylation rate than normal tissue and HSPA5 had a positive connection with TMB (P = .02). In addition, HSPA5 participated in the DNA replication and P53 signaling pathway, and CISD1 mediated the oxidative phosphorylation and positive regulation of the intrinsic apoptotic signaling pathway. CONCLUSION: Ferroptosis-related genes had a strong correlation with BLCA, notably, HSPA5 and CISD1 may play a role in inducing ferroptosis to suppress bladder tumorigenesis and CISD1 can be a novel prognostic biomarker as well as an effective target for diagnosis and treatment in BLCA.