Evaluation of first- and third-trimester afamin levels in preeclampsia

SUMMARY OBJECTIVE: The aim of this study was to investigate serum afamin levels in the first and third trimesters in preeclampsia. METHODS: Serum samples from 118 patients in the first and third trimesters were analyzed. Serum samples were collected from pregnant women who had enrolled in the first trimester. Blood was then collected from pregnant women who had developed preeclampsia and from healthy controls in the third trimester. The collected blood samples were resolved for analysis, and serum afamin concentrations were measured in the first and third trimesters. Preeclampsia and healthy controls were compared. RESULTS: There was no significant difference between the control and preeclampsia groups in terms of age, body mass index, and smoking. Afamin levels in the first and third trimesters were higher in the preeclampsia group than in the control group (p<0.05). In the subgroup analysis of the preeclampsia group, afamin levels were higher in the early-onset preeclampsia group than in the late-onset preeclampsia group in the first and third trimesters (p<0.05). In the receiver operating characteristic analysis afamin levels were 96.23 ng/mL in the first trimester and 123.57 ng/mL in the third trimester as cut-off values for preeclampsia. CONCLUSION: Serum afamin levels are useful for predicting preeclampsia in the first trimester in pregnant women and can be used in clinical practice as a supportive biomarker for the diagnosis of preeclampsia in the third trimester. Meta-analyzes are needed to investigate the effect of afamin levels in the prediction and diagnosis of preeclampsia and to determine the cut-off value.

Research progress on emerging biomarkers in kidney transplantation / 器官移植

The hosts could show complex and diverse immune responses to the allografts. Whether biomarkers can be employed to explain the complexity of graft immune responses and the degree of disease damage are of significance. Conventional biomarkers, such as estimated glomerular filtration rate and blood concenrtation of immunosuppressant, lack of sensitivity and specificity in accurately identifying between immune and non-immune renal allograft injuries. Although renal biopsy is the "gold standard" for the diagnosis of postoperative complications, it still has disadvantages, such as invasiveness and high price, etc. Emerging biomarkers have potential advantages in the non-invasive diagnosis of subclinical injury of renal allograft, prediction of treatment response and individualized adjustment of immunosuppressive regimen. In this article, emerging biomarkers including blood, urine and tissue biomarkers that have been applied and are expected to be applied in clinical practice in the field of kidney transplantation were reviewed, and the range of application and effect of these biomarkers were evaluated, aiming to promote appropriate and rational application of these promising emerging biomarkers in clinical practice.

The promising role of Gelsolin expression to predict survival in patients with squamous cell carcinoma of the larynx

Abstract Introduction: Gelsolin protein has important cellular functions, including cell motility and apoptosis. Altered gelsolin expression has been reported in several types of neoplasms, but clinicopathological features of gelsolin are currently unclear in patients with laryngeal squamous cell carcinoma. Objectives: Our aim is to investigate the clinicopathological significance of gelsolin as a prognostic biomarker for laryngeal squamous cell carcinoma. Methods: Tissue specimens from 168 patients with laryngeal squamous cell carcinoma were immunohistochemically assessed for the Gelsolin expression. Prognostic significance of Gelsolin and its interaction with clinical parameters was analysed. Results: Gelsolin expression was confirmed in 70.2% of cases. Gelsolin expression is significantly associated with tumor stage, tumor grade, and locoregional recurrence. Kaplan-Meier survival curves revealed that Gelsolin expression inversely correlated with both disease-specific and overall survival. Conclusion: This research is the first to demonstrate that Gelsolin expression is associated with a poor prognosis in laryngeal squamous cell carcinoma. Gelsolin is a novel promising biomarker and attractive target for the treatment of laryngeal squamous cell carcinoma.

COVID-19 Outcome Prediction by Integrating Clinical and Metabolic Data using Machine Learning Algorithms

ABSTRACT Background: The coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and is responsible for nearly 6 million deaths worldwide in the past 2 years. Machine learning (ML) models could help physicians in identifying high-risk individuals. Objectives: To study the use of ML models for COVID-19 prediction outcomes using clinical data and a combination of clinical and metabolic data, measured in a metabolomics facility from a public university. Methods: A total of 154 patients were included in the study. "Basic profile" was considered with clinical and demographic variables (33 variables), whereas in the "extended profile," metabolomic and immunological variables were also considered (156 characteristics). A selection of features was carried out for each of the profiles with a genetic algorithm (GA) and random forest models were trained and tested to predict each of the stages of COVID-19. Results: The model based on extended profile was more useful in early stages of the disease. Models based on clinical data were preferred for predicting severe and critical illness and death. ML detected trimethylamine N-oxide, lipid mediators, and neutrophil/lymphocyte ratio as important variables. Conclusion: ML and GAs provided adequate models to predict COVID-19 outcomes in patients with different severity grades.

Omalizumab versus cyclosporin-A for the treatment of chronic spontaneous urticaria: can we define better-responding endotypes?

Abstract Background: Chronic Spontaneous Urticaria (CSU) is characterized by recurrent wheals and/or angioedema for longer than 6-weeks. Guidelines recommend Omalizumab (Oma) as first-line and Cyclosporine-A (Cs-A) as second-line treatment in antihistamine resistant CSU. This step-wise algorithm might be time-consuming and costly. Objective: To determine indicators of response to Oma or Cs-A in CSU patients. Methods: We retrospectively analyzed data from seven centers in Turkey; the inclusion criteria for patients were to receive both Oma and Cs-A treatment (not concurrently) at some point in time during their follow-up. Clinical and laboratory features were compared between groups. Results: Among 110 CSU patients; 47 (42.7%) were Oma-responders, 15 (13.6%) were Cs-A-responders, and 24 (21.8%) were both Oma and Cs-A responders and 24 (21.8%) were non-responders to either drug. High CRP levels were more frequent in Cs-A-responders (72.7% vs. 40.3%; p = 0.055). Oma-responders had higher baseline UCT (Urticaria Control Test) scores (6 vs. 4.5; p = 0.045). Responders to both drugs had less angioedema and higher baseline UCT scores compared to other groups (33.3% vs. 62.8%; p = 0.01 and 8 vs. 5; p = 0.017). Non-responders to both drugs had an increased frequency in the female gender and lower baseline UCT scores compared to other groups (87.5% vs. 61.6%; p = 0.017 and 5 vs. 7; p = 0.06). Study Limitations: Retrospective nature, limited number of patients, no control group, the lack of the basophil activation (BAT) or BHRA (basophil histamine release assay) tests. Conclusions: Baseline disease activity assessment, which considers the presence of angioedema and disease activity scores, gender, and CRP levels might be helpful to predict treatment outcomes in CSU patients and to choose the right treatment for each patient. Categorizing patients into particular endotypes could provide treatment optimization and increase treatment success. © 2022 Published by Elsevier España, S.L.U. on behalf of Sociedade Brasileira de Dermatologia. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Inflammatory cytokines and alcohol use disorder: systematic review and meta-analysis

Objective: To assess differences in blood inflammatory cytokines between people with alcohol use disorder (AUD) and healthy controls (HC). Methods: Searches were performed from inception through April 14, 2021. Meta-analyses with random-effects models were used to calculate the standardized mean difference ([SMD], 95%CI), and potential sources of heterogeneity were explored trough meta-regressions and subgroup analysis. Results: The meta-analysis included 23 studies on the following 14 cytokines: tumor necrosis factor (TNF)-α, IL-1, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IL15, interferon (IFN)-γ and sCD14. There were significantly higher concentrations of IL-6 (n=462 AUD and 408 HC; SMD = 0.523; 95%CI 0.136-0.909; p = 0.008) in AUD than HC. No significant differences were found in the other 13 cytokines. Conclusion: We found that IL-6 levels were significantly higher in individuals with AUD than HC and that other cytokines were not altered. This can be explained by the small number of studies, their methodological heterogeneity, and confounding factors (active use, abstinence, quantity, and physical or psychiatric illnesses, for example). Despite a great deal of evidence about alcohol and inflammatory diseases, studies assessing the role of neuroimmune signaling in the development and severity of AUD are still lacking.

Update on Novel Blood-Based Biomarkers for Lupus Nephritis Beyond Diagnostic Approaches

ABSTRACT Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with a wide range of clinical presentations. Lupus nephritis (LN) is a frequent complication of SLE, representing a significant cause of morbidity and mortality in these patients. In addition, LN diagnosis remains suboptimal in most clinical contexts. The current gold standard for LN clinical diagnosis is a renal biopsy. Still, the invasiveness of this technique is an obstacle to the early detection of renal involvement and further monitoring of treatment results. Consequently, there are different areas for improvement in the field of LN, such as the search for novel non-invasive clinical biomarkers with an adequate correlation between clinical manifestations and actual histological damage. Although urine component-related studies are promising, the more robust blood/serum biomarkers may still be helpful in developing point-of-care systems that can be adapted to most clinical scenarios. Therefore, this brief review aims to highlight and summarize some of the most recently reported non-classical serum/blood potential LN biomarkers.

Determinants of Clinical Behavior and Prognosis in Cushing's Disease: A Quest for Useful Biomarkers

ABSTRACT Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic.

Lipoproteína de Alta Densidade (HDL) como Biomarcador de Prognóstico de Mortalidade em Pacientes Sépticos em Hospital da Região Metropolitana de Porto Alegre/RS / High-Density Lipoprotein (HDL) as a Prognostic Biomarker of Mortality in Septic Patients in a Hospital in the Metropolitan Region of Porto Alegre/RS

Introdução: Pacientes com quadro de sepse ocupam 30% dos leitos das Unidades de Terapia Intensiva (UTI) no Brasil, com letalidade de 55%, impactando diretamente a saúde e economia brasileiras. A Lipoproteína de Alta Densidade (HDL) expressa funções imunomoduladoras, previne liberação de citocinas e neutraliza toxinas bacterianas. Dosagens de HDL abaixo de 20mg/ dL em pacientes sépticos estão associadas a maior mortalidade. Objetivos: Analisar a correlação dos níveis séricos de HDL com o prognóstico de mortalidade em pacientes sépticos admitidos na UTI do Hospital Universitário de Canoas (HU). Objetivos específicos incluem a correlação dos níveis de HDL com marcadores clássicos de gravidade lactato, proteína C reativa (PCR), albumina e escore SOFA. Métodos: Estudo observacional analítico de coorte prospectiva, que incluiu 292 pacientes admitidos na UTI do HU diagnosticados com Sepse, conforme diretriz SEPSIS3: ≥ 2 pontos no SOFA (Sequential Organ Failure Assesment Score) no período de 1º de agosto de 2019 a 30 de agosto de 2020. Resultados: Óbitos foram estatisticamente mais frequentes nos indivíduos que apresentaram HDL <20mg/dL (47,5%) do que naqueles com valores de HDL ≥20mg/dL (32,80%). Conclusão: Embora não haja na literatura relação de causalidade entre baixos níveis de HDL e sepse, é verificado na literatura e corroborado neste estudo que pacientes sépticos com níveis baixos de HDL tiveram pior desfecho quando comparados a pacientes com níveis normais. Também foi encontrada associação significativa de maiores níveis séricos de PCR e lactato com baixos níveis de HDL, sendo esses marcadores de pior prognóstico na sepse.

Introduction: Septic patients occupy 30% of the beds in the Brazilian intensive care units (ICU), with a mortality rate of 55%, strongly impacting Brazilian health and the economy. High-density lipoprotein (HDL) has immunomodulatory functions, prevents cytokine release, and neutralizes bacterial toxins. HDL levels below 20mg/dL in septic patients are associated with higher mortality. Objectives: To analyze the correlation of serum HDL levels with mortality prognosis in septic patients admitted to the Canoas University Hospital (Hospital Universitário de Canoas [HU]) ICU. The specific objectives include the correlation of HDL levels with classic markers of severity - lactate, C-reactive protein (CRP), albumin, and SOFA score. Methods: an observational analytical prospective cohort study, which included 292 patients admitted to the HU ICU diagnosed with sepsis - as per SEPSIS-3 guideline: ≥ 2 points in SOFA (Sequential Organ Failure Assessment Score) - in the period from August 1, 2019, to August 30, 2020. Results: deaths were statistically more frequent in individuals who had HDL <20mg/dL (47.5%) than in those with HDL values ≥ 20mg/dL (32.80%). Conclusion: Although there is no causal relationship, in the literature, between low HDL levels and sepsis, it is verified in the literature and corroborated in this study that septic patients with low HDL levels had worse outcomes compared to patients with normal levels. It was also found a significant association of higher serum levels of CRP and lactate with low HDL levels, these being markers of worse prognosis in sepsis.

Biomarker potential of hsa-miR-145-5p in peripheral whole blood of manic bipolar I patients

Objective: Bipolar I disorder (BD-I) is a type of bipolar spectrum disorder characterized by manic or mixed episodes. Detecting microRNA regulations as epigenetic actors in BD-I is important to elucidate the pathogenesis of the disease and reveal the potential of microRNAs (miRNAs) as biomarkers. Methods: We evaluated the expression profile of six candidate miRNAs (hsa-miR-145-5p, hsa-miR-376a-3p, hsa-miR-3680-5p, hsa-miR-4253-5p, hsa-miR-4482-3p, and hsa-miR-4725) in patients with BD-I and in healthy controls (aged 11-50 years). We also determined the potential target genes of these miRNAs through in silico analysis. The diagnostic values of the miRNAs were calculated through receiver operating characteristic curve analysis. Results: Four miRNAs were upregulated (hsa-miR-376a-3p, hsa-miR-3680-5p, hsa-miR-4253-5p, hsa-miR-4482-3p) and hsa-miR-145-5p was downregulated in patients (p < 0.001). The target gene analyses showed that hsa-miR-145-5p specifically targets the dopamine decarboxylase (DDC) gene. The area under the curve of hsa-miR-145-5p was 0.987. Conclusion: Differential expression of five miRNAs in peripheral blood may be associated with the pathogenesis of BD-I, and hsa-miR-145-5p has potential as a BD-I biomarker. This miRNA can be used in dopamine-serotonin regulation and dose adjustment in drug therapy via the DDC gene.

Diagnostic value of serum levels of galanin and obestatin in patients with gastric cancer

SUMMARY OBJECTIVE: Gastric cancer ranks the third among the cancer-related deaths. It is diagnosed at advanced stage in many patients due to malignant proliferation and has a poor prognosis. Currently, no instrument or biomarker has been proven to diagnose the disease before the advanced stages. This study aimed to measure the serum levels of galanin and obestatin, which were examined in various studies including cancer studies, and to discuss their diagnostic value in gastric cancers. METHODS: In this study, 30 adult patients with gastric cancer and 30 healthy adults in the control group were examined prospectively. The demographic characteristics and serum levels of galanin and obestatin in the patient and control groups were recorded. RESULTS: The mean serum level of galanin in the patient and control groups was 19.73±5.04 and 35.59±10.94 pg/mL, respectively. The mean serum level of obestatin in the patient and control groups was 40.21±5.82 and 15.15±3.32 ng/mL, respectively. A significant difference was found between the groups (p<0.001). CONCLUSION: Serum levels of galanin were lower and serum levels of obestatin were higher in patients with gastric cancer compared to the healthy individuals. Serum levels of obestatin and galanin can be used as potential biomarkers in the diagnosis of gastric cancer.

Proteína tau como biomarcador en Alzheimer preclínico / Tau protein as a biomarker in preclinical Alzheimer's disease

El desarrollo de biomarcadores de la proteína tau para el diagnóstico temprano de la enfermedad de Alzheimer (EA) emerge como un desafío fundamental, pudiendo mejorar la efectividad de un tratamiento preventivo o que enlentezca la progresión de la enfermedad. Esta revisión analiza las evidencias que justificarían el uso de la proteína tau como biomarcador en Alzheimer preclínico. Para esto se seleccionaron artículos científicos (2011-2021) que incluyeran a la proteína tau en plasma y plaquetas como biomarcador. La presencia de la proteína tau fosforilada en el líquido cefalorraquídeo presenta limitaciones por su carácter invasivo mientras que las técnicas de imagen son costosas. La medición de tau en plaquetas se correlaciona con la severidad de la demencia, y sería útil en el seguimiento de la EA. Sin embargo, la pertinencia de su uso en la detección temprana de EA se mantiene en discusión. La presencia de proteína tau fosforilada en plasma correspondería al biomarcador con mayor nivel de desarrollo, respecto de beta amiloide. La proteína tau plas-mática detecta la EA con gran precisión en casos de demencia y ha sido validada por estudios neuropatológicos. p-tau217 plasmática medida por primera vez junto a técnicas de imagen, fue importante en la etapa preclínica de EA pudiendo predecir la formación de ovillos neurofibrilares. La correlación entre especies fosforiladas de tau en plasma y EA preclínica ha sido bien establecida, por lo que su uso como biomarcador podría ser de utilidad para la comprensión del proceso fisiopatológico de la neurodegeneración y la detección temprana de EA

The development of tau protein biomarkers for the early diagnosis of Alzheimer's disease (AD) emerges as a fundamental challenge, which may improve the effectiveness of preventive treatment or slow the progression of the disease. This review analyzes the evidence that would justify the use of tau protein as a biomarker in preclinical Alzheimer's disease. For this purpose, we selected scientific arti-cles (2011-2021) that included tau protein in plasma and platelets as a biomarker. Phosphorylated tau protein in cerebrospinal fluid has limitations due to its invasiveness, while imaging techniques are expensive. The tau measurement in platelets correlates with the severity of dementia and would be helpful in the follow-up of AD. However, the relevance of its use in the early detection of AD remains under discussion. Plasma phosphorylated tau protein would correspond to the biomarker with the highest level of development for beta-amyloid. Plasma tau protein detects AD with high accuracy in cases of dementia, and neuropathological studies validate its use. Plasma p-tau217 measured for the first time with imaging techniques was important in preclinical AD and could predict the formation of neurofibrillary tangles. The correlation between plasma phosphorylated tau species and preclinical AD is well-established, so its use as a biomarker would help understand the pathophysiological process of neurodegeneration and early AD detection.

Potencial de disparidad o Mismatch negativity y P3a en pacientes con esquizofrenia / Mismatch negativity and P3a in patients with Schizophrenia

Resumen Antecedentes: la esquizofrenia es una enfermedad crónica que genera gran discapacidad, para la cual se han reportado biomarcadores potenciales, pero sin suficiente validez clínica. El mismatch negativity (MMN) y el P3a son potenciales relacionados con eventos que han demostrado ser indicadores neurofisiológicos del procesamiento auditivo pre-atencional y potenciales biomarcadores. Objetivo: evaluar el MMN y P3a en pacientes con diagnóstico de esquizofrenia y su relación con variables sociodemográficas y clínicas. Método: estudio cuantitativo transversal de 23 sujetos con esquizofrenia (ESQ) y 22 controles sanos (SN). Las amplitudes promedio y latencias del MMN/P3a para la condición infrecuente en duración y frecuencia fueron obtenidas mediante un paradigma oddball auditivo en un EEG de 32 canales. Resultados: se encontraron diferencias para la condición frecuencia en la amplitud del MMN (p=0.046; CI 95% 0.009; 0.87) y la amplitud del P3a (p=0.042; CI 95% 0.025; 1.24) entre los grupos; la amplitud del MMN fue menor en el grupo ESQ (-0.36 DE 0.51 µV) en comparación con los participantes del grupo de SN (-0.81 DE 0.89 µV), mientras que la amplitud del P3a fue menor en el grupo SN (0.18 DE 0.97 µV) versus el grupo ESQ (0.82 DE 1.05 µV). En relación con las variables sociodemográficas y clínicas, las asociaciones con el P3a fueron moderadas y con el MMN débiles. Conclusiones: la reducción de la amplitud del MMN a la condición frecuencia exhibe mayor utilidad que el P3a como medida de alta estabilidad en pacientes con esquizofrenia, lo que reitera su posible uso como biomarcador.

Abstract Background: schizophrenia is a chronic disease that generates great disability, which currently has potential biomarkers but without sufficient clinical validity. Mismatch negativity (MMN) and P3a are event-related potentials that have been shown to be neurophysiological indicators of pre-attentional auditory processing and potential biomarkers. Objective: to evaluate MMN and P3a in patients with a diagnosis of schizophrenia and their relationship with sociodemographic and clinical variables. Method: a quantitative cross-sectional study of 23 subjects with schizophrenia and 22 healthy controls was performed. The average amplitudes and latencies of the MMN/P3a for the condition infrequent in duration and infrequent in frequency were obtained using an auditory oddball paradigm on a 32-channel EEG. Results: differences were found for the frequency condition in the amplitude of the MMN (p=0.046; 95% CI 0.009; 0.87) and the amplitude of the P3a (p=0.042; 95% CI 0.025; 1.24) between the groups; MMN amplitude was lower in schizophrenia (-0.36 SD 0.51 µV) compared to healthy controls (-0.81 SD 0.89 µV), while P3a amplitude was lower in healthy controls (0.18 SD 0.97 µV) versus the group with schizophrenia (0.82 SD 1.05 µV). In regard to sociodemographic and clinical variables, the associations with P3a were moderate, and showed weak MMN. Conclusions: MMN amplitude reduction to the frequency condition exhibits greater utility than P3a as a measure of high stability in schizophrenia, restating its potential use as a biomarker.

Proadrenomedullin in Patients with Preserved Left Ventricular Systolic Function Undergoing Coronary Artery Bypass Grafting

Abstract Introduction: A potentially new marker of cardiovascular diseases — proadrenomedullin is the precursor of adrenomedullin, which is a multifunctional peptide hormone, produced in most of the tissues in response to cellular stress, ischemia, and hypoxia. Methods: Ninety-three people, aged 51-79 years, were included in the study. Exclusion criteria were severe or corrected valvular disease, acute coronary syndrome, age ≥ 80 years, glomerular filtration rate < 45 ml/min, active infectious diseases, and cancer. The subjects were observed for adverse events, including reduced left ventricular ejection fraction (LVEF) by ≥ 10%, first incidence of atrial fibrillation (AF), and the necessity of using dopamine during hospitalization. Results: Use of pressure amines, occurrence of the first AF episode, and left ventricular dysfunction defined by a decrease in LVEF by at least 10% compared to the value before surgery were reported in the perioperative period. No death, sudden cardiac arrest with effective resuscitation, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, or heart failure were observed. Significantly higher proadrenomedullin concentration was observed in the group with reduced postoperative LVEF (1.68 vs. 0.77 nmol/l, P=0.005). The relative risk of a decrease in ejection fraction in the group of patients with proadrenomedullin concentration ≥ 0.77 nmol/l was more than twelve-fold higher (95% confidence interval 1.69-888.33; P=0.013) than in the group of patients with a concentration of proadrenomedullin < 0.77 nmol/l. Conclusion: The higher baseline concentration of proadrenomedullin has a predominantly predictive value of postoperative left ventricular systolic dysfunction.

Wnt3a but not CDX-2 expression is associated with differentiated thyroid cancer

SUMMARY OBJECTIVE: Thyroid neoplasm incidence has increased worldwide, mostly due to the advancements in medical imaging and screening rates. The aberrant Wnt/β-catenin pathway has been identified as a key mechanism, and it has also been related to the metastatic activity of differentiated thyroid cancer. We aimed to verify the difference in the expression of Wnt3a, a canonical activator of the β-catenin signaling, and CDX-2, a transcription factor upregulated by Wnt/β-catenin pathway, in multinodular goiter and differentiated thyroid cancer and to determine their prognostic value. METHODS: We included 194 thyroid tissue surgical specimen and their clinicopathological data: study group (differentiated thyroid cancer, n=154) and control group (multinodular goiter, n=40). Immunohistochemistry (IHC) was performed on formalin-fixed, paraffin-embedded tissue by the primary antibodies Wnt3a and CDX-2. RESULTS: High Wnt3a expression was significantly associated with differentiated thyroid cancer (p=0.031). CDX-2 was negative in all differentiated thyroid cancer cases (100%) and also in multinodular goiter. Wnt3a expression was significantly associated with tumors ≤20 mm (p=0.044) and with the absence of capsule invasion (p=0.031). The multivariate analyses suggested that older age (≥55), independent of capsular invasion and tumor size, was an independent prognostic factor for Wnt3a expression (p=0.058). CONCLUSIONS: Wnt3a expression but not CDX-2 is correlated with differentiated thyroid cancer samples in comparison to multinodular goiter. Although its prognostic value was limited to tumor size and capsule invasion, a combined model in a panel of immune markers can add accuracy in the classification of challenging thyroid follicular-derived lesions.

Biomarcador FLT3-ITD: perspectivas y retos / FLT3-ITD biomarker: perspectives and challenges

Introducción: Las mutaciones del gen que codifica para el factor de la tirosina quinasa 3 (FLT3) son de especial importancia en la leucemia mieloide aguda debido a que sirven de guía para la confirmación del diagnóstico, la estimación del pronóstico y la toma de decisiones terapéuticas. Entre las alteraciones más importantes está la duplicación interna en tándem (FLT3-ITD). Objetivo: Exponer los aspectos más relevantes respecto al biomarcador FLT3-ITD en el contexto de la leucemia mieloide aguda. Métodos: Se realizó una búsqueda de artículos científicos actualizados en los idiomas inglés y español, en PubMed, EMBASE, Google Scholar y SciELO. Se seleccionaron artículos publicados en los últimos cinco años. Se revisaron los aspectos más relevantes sobre el biomarcador en el contexto de la leucemia mieloide aguda, su base biológica, el impacto del tamaño de los fragmentos y la carga alélica en la estimación del pronóstico de los pacientes, las nuevas estrategias terapéuticas y los retos en cuanto a los métodos de laboratorio para su diagnóstico. Análisis y síntesis de la información: Más allá de la positividad o no de dicho biomarcador, el tamaño de la duplicación interna en tándem, así como la carga alélica -determinada por la razón alelo mutado/alelo salvaje-, podrían tener un gran impacto en el pronóstico. Sin embargo, persisten diferencias en los criterios para establecer los algoritmos de predicción del riesgo, el punto de corte a utilizar como referencia y el protocolo de laboratorio específico para un estudio más detallado del biomarcador. Conclusiones: La comunidad científica necesita seguir trabajando en el esclarecimiento de la utilidad práctica de estos parámetros, validándolos en series amplias y diversas epidemiológicamente. Se debe determinar el punto de corte exacto para comparar la razón y estandarizar los métodos de laboratorio más adecuados y factibles para su estudio(AU)

ABSTRACT Introduction: Mutations in the tyrosine kinase 3 gene (FLT3) are of special importance in acute myeloid leukemia because they serve as a guide to confirm the diagnosis, estimate the prognosis, and make therapeutic decisions in the patient. Internal tandem duplication (FLT3-ITD) is the most important alteration of this gene. Objective: To present the most relevant aspects regarding the FLT3-ITD biomarker in the context of acute myeloid leukemia. Methods: a search was carried out for updated scientific articles, in English and Spanish, in PubMed, EMBASE, Google Scholar and SciELO. Articles published in the last five years were selected. The most relevant aspects of the biomarker in the context of acute myeloid leukemia, its biological basis, the impact of the size of the fragments and the allelic load in the estimation of the prognosis of the patients, the new therapeutic strategies and the challenges in regarding the laboratory methods for its diagnosis. Information analysis and synthesis: Beyond the biomarker positivity or not, the size of the ITD, as well as the allelic ratio determined by the mutated allele / wild-type allele, could have a great impact on the prognosis of patients. However, differences persist in the criteria for establishing risk prediction algorithms, the cut-off point to be used as a reference, and the specific laboratory protocol for a more detailed study of the biomarker. Conclusions: The scientific community needs to continue working to clarify the practical utility of these parameters, validating them in broad and epidemiologically diverse series. The exact cut-off point should be determined as a reference to compare the relationship and standardize the most suitable and feasible laboratory methods for its study(AU)

Diagnostic and prognostic significance of long noncoding RNA LINC00173 in patients with melanoma

SUMMARY OBJECTIVE: A growing volume of literature has suggested long noncoding RNAs (lncRNAs) as important players in tumor progression. In this study, we aimed to investigate the expression and prognostic value of lncRNA LINC00173 (LINC00173) in melanoma. METHODS: LINC00173 expression was measured in 163 paired cancerous and noncancerous specimen samples by real-time polymerase chain reaction. The correlations between LINC00173 expression with clinicopathological characteristics and prognosis were analyzed by chi-square test, log-rank test, and multivariate survival analysis. Receiver-operating characteristic curves were used for the assessment of the diagnostic value of LINC00173 for melanoma patients. RESULTS: The expression level of LINC00173 in melanoma specimens was distinctly higher than that in adjacent non-neoplasm specimens (p<0.01). Besides, LINC00173 was expressed more frequently in patients with advanced melanoma than in patients with early melanoma. Multivariate assays confirmed that LINC00173 expression level was an independent prognostic predictor of melanoma patients (p<0.05). CONCLUSION: Our data indicated that LINC00173 expression could serve as an unfavorable prognostic biomarker for melanoma patients.

Genótipos e Fenótipos de Resistência a Metais Pesados e Agrotóxicos em Patógenos de Alto Risco em Saúde Única / Genotypes and Phenotypes of Resistance to Heavy Metals and Pesticides in High-Risk Pathogens in Single Health

As atividades industriais e de agronegócio, embora necessárias para o desenvolvimento da sociedade, tem causado sérios problemas ambientais devido à eliminação inadequada de seus efluentes, sendo o tratamento destes um dos assuntos mais importantes em relação ao controle de poluição. Os microrganismos podem ser utilizados como biomarcadores de contaminação, portanto, o conhecimento de mecanismos associados à resistência e a capacidade de imobilização e biotransformação de poluentes é um fator importante para a identificação de linhagens adaptadas, que podem ser eficientes no tratamento e na recuperação de áreas contaminadas. O objetivo do presente projeto foi avaliar o perfil de tolerância de patógenos bacterianos de alto risco em saúde única, aos metais pesados (mercúrio, prata, telúrio e arsênio) e ao agrotóxico glifosato; identificando o resistoma associado. A correlação fenótipo-genótipo foi avaliada em isolados de Klebsiella pneumoniae (n= 35), Escherichia coli (n=46), e Salmonella spp. (n=19), determinando a CIM pelo método de microdiluição, e analisando as respectivas sequências genômicas. Entre os isolados de K. pneumoniae, 32 cepas apresentaram CIM elevadas (64- 512µg/mL) para o metal prata, dos quais 20 carregam o operon silPABCRSE responsável por conferir resistência. Uma cepa de K. pneumoniae carregando genes terABCE apresentou uma CIM de 64 µg/mL para telúrio. Seis cepas de E. coli apresentaram uma CIM >32 µg/mL para telúrio, sendo que 3 cepas carregam os genes tehA/B. Outras 6 cepas de E. coli apresentaram CIM para prata de 256-512 µg/mL, mas só duas carregaram genes silPFCE. Duas cepas de Salmonella apresentaram CIM 64-128 µg/mL para telúrio, e carregam genes tehA/B e terABCDEF. Em relação ao arsênio, 24 cepas de E. coli apresentaram uma CIM ≥ 512 µg/mL, e destas, 12 cepas carregam os genes arsRBC. Salmonella spp., que carregam o gene merR apresentaram CIMs de 8-16 µg/mL para mercúrio. Não foi possível correlacionar a presença do operon phnC-P (sugerido como responsável pela tolerância ao glifosato) com CIMs elevadas para este composto. Os resultados obtidos suportam a hipóteses que a exposição de bactérias de origem humana, animal e ambiental, aos metais pesados pode estar contribuindo para a seleção de linhagens tolerantes, sendo que a tolerância à prata mediada pelo operon silPABCRSE em K. pneumoniae foi predominante no grupo clonal CG258, característica com potencial de biomarcador que pode ser utilizado para monitorar o impacto do uso deste metal nas diferentes atividades humanas. Neste trabalho foi possível padronizar a técnica de PCR com os genes do operon sil de interesse

Industrial and agribusiness activities have caused serious environmental problems due to the inadequate disposal of their effluents, the treatment of which being one of the most important issues in relation to pollution control. Microorganisms can be used as biomarkers of contamination, therefore the knowledge of mechanisms associated with resistance and the immobilization and biotransformation capacity of pollutants can be an important factor for the identification of adapted strains, efficient in the treatment and recovery of contaminated areas. The aim of this study was to evaluate the tolerance profile of critical priority bacterial pathogens relevant in One Health, to heavy metals (mercury, silver, tellurium, and arsenic) and to the pesticide glyphosate, identifying the associated resistome. The phenotype-genotype correlation was evaluated in antibiotic-resistant isolates of Klebsiella pneumoniae (n= 35), Escherichia coli (n= 46), and Salmonella spp. (n= 19), by MIC determination using the microdilution method, and by analysis of their respective genomic sequences. Among the isolates of K. pneumoniae, 32 strains showed elevated MIC (64-512 µg/mL) for silver metal, of which 20 carried the silPABCRSE operon responsible for conferring resistance. A strain of K. pneumoniae carrying terrace genes showed a MIC of 64 µg/mL for tellurium. Six strains of E. coli showed an MIC> 32 µg/mL for tellurium, with 3 strains carrying the Thea/B genes. Other 6 strainsof E. coli showed MIC for silver of 256-512 µg/mL, but only two carried silPFCE genes. Two strains of Salmonella showed MIC 64-128 µg/mL for tellurium and carried the/B and terABCDEF genes. In relation to arsenic, 24 strains of E. coli had a MIC 512 µg/mL, and of these, 12 strains carried the arsRBC genes. Salmonella spp., which carriedthe mer gene, had MICs of 8-16 µg/mL for mercury. It was not possible to correlate thepresence of the phonic-P operon (suggested as responsible for glyphosate tolerance) with elevated MICs for this compound. The silver tolerance mediated by the operon sil was a predominant feature in K. pneumoniae strains belonging to the clonal group CG258, suggesting a intrinsic property that has contributed to the persistence and wide dissemination of CG258 within a One Health context, which could be as a biomarkerto monitor the impact of the use of silver compounds and silver-based biomaterial on different human activities. In this work it was possible to standardize the PCR technique with the genes of the sil operon of interest

Whole blood circular RNA hsa_circ_0002171 serves as a potential diagnostic biomarker for human adenovirus pneumonia in children

Severe pneumonia related to human adenoviruses (HAdVs) has a high lethality rate in children and its early diagnosis and treatment remain a major challenge. Circular RNAs (circRNAs) are novel long noncoding RNAs that play important roles in gene regulation and disease pathogenesis. To investigate the roles of circRNAs in HAdV pneumonia, we analyzed the circRNA profiles of healthy children and children with HAdV pneumonia, including both mild and severe cases, and identified 139 significantly upregulated circRNAs in children with HAdV pneumonia vs healthy controls and 18 significantly upregulated circRNAs in children with severe HAdV pneumonia vs mild HAdV pneumonia. In particular, hsa_circ_0002171 was differentially expressed in both groups and might thus be useful as a diagnostic biomarker of HAdV pneumonia and severe HAdV pneumonia. To identify the underlying mechanisms of circRNAs in HAdV pneumonia, we analyzed the transcriptome of children with HAdV pneumonia and established a circRNA-mRNA regulatory network. Enrichment analysis of differentially expressed target mRNAs demonstrated that the differentially expressed genes between healthy controls and HAdV pneumonia patients were mainly involved in RNA splicing while the differentially expressed genes between children with mild and severe HAdV pneumonia were mainly involved in regulating lymphocyte activation. Receiver operating characteristic (ROC) curve analysis suggested that hsa_circ_0002171 had a significant value in the diagnosis of HAdV pneumonia and of severe HAdV pneumonia. Taken together, the circRNA expression profile was altered in children with HAdV pneumonia. These results demonstrated that hsa_circ_0002171 is a potential diagnostic biomarker of HAdV pneumonia.

High expression of prolyl 4-hydroxylase subunit alpha-2 in lung adenocarcinoma indicates poor prognosis

Abstract Objective To analyze the Prolyl 4-Hydroxylase subunit Alpha-2 (P4HA2) expression in Lung Adenocarcinoma (LAUD). Methods The authors assessed P4HA2 expression in the LUAD tumor ecosystem using single-cell analysis. The authors analyzed the relationship between P4HA2 expression and clinical features in LUAD and Brain Metastasis (BM) cases. The authors assessed the biological functions of P4HA2 using The Cancer Genome Atlas-LUAD dataset. Results P4HA2 was more highly expressed in fibroblasts than in epithelial cells in normal lung and lung adenocarcinoma tissues (p < 0.001). P4HA2 was more highly expressed in malignant epithelial cells than in fibroblasts in the BM tissue (p = 0.002). P4HA2 expression was significantly higher in female cases than in male cases (p = 0.049) and was related to lymph node metastasis (p = 0.019) and a higher TNM stage (p = 0.020). High P4HA2 expression indicated a poor prognosis and served as an independent prognostic risk factor in lung cancer. P4HA2 was mainly enriched in the extracellular matrix organization, NADH regeneration, and canonical glycolysis. P4HA2 expression was negatively correlated with naive B cells, T-cells, CD8, and activated natural killer cells, but positively correlated with CD4 memory-activated T cells, regulatory T-cells, resting dendritic cells, and dendritic cell activation. P4HA2 messenger RNA expression was correlated with programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein 4. Conclusion P4HA2 is highly expressed in LUAD tumor cells, especially for the BM subtype, and is a valuable prognostic indicator of LUAD. It may be involved in a biological activity of distant metastasis of LUAD tumor cells and serve as a potential treatment target.