The new world of RNA diagnostics and therapeutics.

The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27-28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled "The New World of RNA diagnostics and therapeutics" highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials. Non-coding RNAs in particular have been the focus of this workshop due to their unique properties that make them attractive tools for the diagnosis and therapy of cancer.This report collected the presentations of many scientists from different institutions that discussed recent oncology research providing an excellent overview and representative examples for each possible application of RNA as biomarker, for therapy or to increase the number of patients that can benefit from precision oncology treatment.In particular, the meeting specifically emphasized two key features of RNA applications: RNA diagnostic (Blandino, Palcau, Sestito, Díaz Méndez, Cappelletto, Pulito, Monteonofrio, Calin, Sozzi, Cheong) and RNA therapeutics (Dinami, Marcia, Anastasiadou, Ryan, Fattore, Regazzo, Loria, Aharonov).

A diagnostic circulating miRNA signature as orchestrator of cell invasion via TKS4/TKS5/EFHD2 modulation in human gliomas.

BACKGROUND: Altered microRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a stable form thus representing interesting biomarker candidates. This study aimed to identify a microRNA signature as a non-invasive biomarker and to investigate its impact on glioma biology. METHODS: MicroRNAs were selected using a global expression profile in preoperative serum samples from 37 glioma patients. Comparison between serum samples from age and gender-matched controls was performed by using the droplet digital PCR. The ROC curve and Kaplan-Meier survival analyses were used to evaluate the diagnostic/prognostic values. The functional role of the identified signature was assessed by gain/loss of function strategies in glioma cells. RESULTS: A three-microRNA signature (miR-1-3p/-26a-1-3p/-487b-3p) was differentially expressed in the serum of patients according to the isocitrate dehydrogenase (IDH) genes mutation status and correlated with both patient Overall and Progression Free Survival. The identified signature was also downregulated in the serum of patients compared to controls. Consistent with these results, the signature expression and release in the conditioned medium of glioma cells was lower in IDH-wild type cells compared to the mutated counterpart. Furthermore, in silico analysis of glioma datasets showed a consistent deregulation of the signature according to the IDH mutation status in glioma tumour tissues. Ectopic expression of the signature negatively affects several glioma functions. Notably, it impacts the glioma invasive phenotype by directly targeting the invadopodia-related proteins TKS4, TKS5 and EFHD2. CONCLUSIONS: We identified a three microRNA signature as a promising complementary or even an independent non-invasive diagnostic/prognostic biomarker. The signature displays oncosuppressive functions in glioma cells and impacts on proteins crucial for migration and invasion, providing potential targets for therapeutic intervention.

New aspects in cardiorenal syndrome and HFpEF.

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidneys are simultaneously affected, and subsequently, the malfunction of one organ promotes the deterioration of the other. Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF. The pathophysiology of CRS is not well known and several mechanisms have been proposed. An elevation of central venous pressure seems to be one of the key points to consider, among others such as an increase in intraabdominal pressure. Several diagnostic tools have been identified to establish the diagnosis of CRS in patients with HFpEF. Currently, the availability of biomarkers of renal and cardiac injury, the use of pulmonary ultrasound, the monitoring of the size of the inferior vena cava and the study of the renal venous pattern offer a new dimension in accurately diagnosing and quantifying organ damage in CRS. Beyond the symptomatic treatment of congestion, until recently specific therapeutic tools for patients with CRS and HFpEF were not available. Interestingly, the development of new drugs such as the angiotensin/neprilysin inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer new therapeutic strategies with potential benefits in reduction of cardiorenal adverse outcomes in this population. Randomized clinical trials that focus on patients with HFpEF are currently ongoing to delineate optimal new treatments that may be able to modify their prognosis. In addition, multidisciplinary teamwork (nephrologist, cardiologist and nurse) is expected to decrease the number of visits and the rate of hospitalizations, with a subsequent patient benefit.

Association of renin-angiotensin system blockers with COVID-19 diagnosis and prognosis in patients with hypertension: a population-based study.

BACKGROUND: The effect of renin-angiotensin system (RAS) blockade either by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) susceptibility, mortality and severity is inadequately described. We examined the association between RAS blockade and COVID-19 diagnosis and prognosis in a large population-based cohort of patients with hypertension (HTN). METHODS: This is a cohort study using regional health records. We identified all individuals aged 18-95 years from 87 healthcare reference areas of the main health provider in Catalonia (Spain), with a history of HTN from primary care records. Data were linked to COVID-19 test results, hospital, pharmacy and mortality records from 1 March 2020 to 14 August 2020. We defined exposure to RAS blockers as the dispensation of ACEi/ARBs during the 3 months before COVID-19 diagnosis or 1 March 2020. Primary outcomes were: COVID-19 infection and severe progression in hospitalized patients with COVID-19 (the composite of need for invasive respiratory support or death). For both outcomes and for each exposure of interest (RAS blockade, ACEi or ARB) we estimated associations in age-, sex-, healthcare area- and propensity score-matched samples. RESULTS: From a cohort of 1 365 215 inhabitants we identified 305 972 patients with HTN history. Recent use of ACEi/ARBs in patients with HTN was associated with a lower 6-month cumulative incidence of COVID-19 diagnosis {3.78% [95% confidence interval (CI) 3.69-3.86%] versus 4.53% (95% CI 4.40-4.65%); P < 0.001}. In the 12 344 patients with COVID-19 infection, the use of ACEi/ARBs was not associated with a higher risk of hospitalization with need for invasive respiratory support or death [OR = 0.91 (0.71-1.15); P = 0.426]. CONCLUSIONS: RAS blockade in patients with HTN is not associated with higher risk of COVID-19 infection or with a worse progression of the disease.

Time to focus on circulating nucleic acids for diagnosis and monitoring of gliomas: A systematic review of their role as biomarkers.

Gliomas are diffusely growing tumours arising from progenitors within the central nervous system. They encompass a range of different molecular types and subtypes, many of which have a well-defined profile of driver mutations, copy number changes and DNA methylation patterns. A majority of gliomas will require surgical intervention to relieve raised intracranial pressure and reduce tumour burden. A proportion of tumours, however, are located in neurologically sensitive areas and a biopsy poses a significant risk of a deficit. A majority of gliomas recur after surgery, and monitoring tumour burden of the recurrence is currently achieved by imaging. However, most imaging modalities have limitations in assessing tumour burden and infiltration into adjacent brain, and sometimes imaging is unable to discriminate between tumour recurrence and pseudo-progression. Liquid biopsies, obtained from body fluids such as cerebrospinal fluid or blood, contain circulating nucleic acids or extracellular vesicles containing tumour-derived components. The studies for this systematic review were selected according to PRISMA criteria, and suggest that the detection of circulating tumour-derived nucleic acids holds great promises as biomarker to aid diagnosis and prognostication by monitoring tumour progression, and thus can be considered a pathway towards personalized medicine.

Diffuse large B-cell lymphoma: Time to focus on circulating blood nucleic acids?

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous neoplasm with diverse genetic abnormalities and outcomes. To date, DLBCL is invasively diagnosed by tissue biopsy and few biomarkers are available to predict patient outcome, treatment response and progression. The identification of patient-specific biomarkers would allow a "personalized medicine" approach for DLBCL patients. In this regard, "liquid biopsies" hold great promise, capturing the entire genetic landscape of the tumour and allowing a rapid and dynamic management of cancer. Liquid biopsy studies particularly focus on cell-free nucleic acids, such as cell-free DNA (cfDNA) and microRNAs, which are easy to collect and analyse. In accordance with the PRISMA criteria, we performed a systematic review on circulating nucleic acids as potential biomarkers for DLBCL management. The results suggest that combining information from the genetic (cfDNA) and epigenetic (microRNAs) landscape of the disease could lead to developing an integrated network of non-invasive biomarkers for the better management of DLBCL.

Urinary expression of let-7c cluster as non-invasive tool to assess the risk of disease progression in patients with high grade non-muscle invasive bladder Cancer: a pilot study.

BACKGROUND: High grade non-muscle-invasive bladder cancer (HG-NMIBC) is a heterogeneous disease with variable risk of progression. Urinary microRNAs are promising biomarkers for BC detection and surveillance. Let-7c-5p miRNA, clustered with miR-99a-5p and -125b-5p, is deregulated in cancer, including BC. The aim of this study is to evaluate urinary let-7c cluster expression in Ta/T1 HG-NMIBC patients and its impact on progression-free survival (PFS). METHODS: Quantitative Real-Time-Polymerase-Chain-Reaction (qRT-PCR) was used to analyze the let-7c cluster expression in 57 urine and 49 neoplastic paired tissue samples prospectively collected from transurethral resection (TUR) HG-NMIBC patients. Twenty urine and 10 bladder tissue samples were collected and analyzed as normal controls. QRT-PCR was also used to detect intra-/extra-cellular let-7c cluster in BC cells. Receiver Operating Characteristic (ROC) curves were used to identify urinary miRNAs cut-off values predicting T-stage and PFS. Uni/multivariable Cox regression was performed to identify predictors of PFS. A nomogram predicting progression risk and a decision curve analysis (DCA) were performed. RESULTS: Urinary let-7c was significantly up-regulated in patients compared with controls, while the whole cluster was down-regulated in tumor tissues. Supporting these findings, in vitro comparison of extra-/intra-cellular ratios of cluster levels between BC cells, showed a higher ratio for let-7c in HG-NMIBC versus low-grade cells. Urinary let-7c cluster expression was increased in higher T-stage and was an independent predictor of progression. Lower EORTC-score and downregulation of urinary cluster were predictors of higher PFS on univariable Cox regression, while on multivariable analysis only cluster expression was an independent progression predictor. On DCA, a benefit was evident for patients with a PFS probability > 20%. CONCLUSIONS: Urinary let-7c cluster evaluation may improve prognosis, identifying patients at risk of progression and addressing early radical treatment.

Unusual case of new-onset heart failure due to cor triatriatum sinister.

We report the case of a 30-year old man who came to the emergency department of our hospital with acute left heart failure, and was diagnosed with a rare congenital anomaly (cor triatriatrum sinister), which can mimic a severe mitral stenosis. Cor triatriatum sinister is a rare anomaly (0.1% of all cases of congenital heart disease) that is seldom diagnosed in adult patients. The hallmark of this congenital defect is the presence of a fibromuscular membrane that divides the left atrium (LA) into two chambers: a postero-superior chamber into which the pulmonary veins drain and an infero-anterior chamber (true LA) containing the mitral valve and atrial appendage. Both chambers communicate through a membrane in which one or more drain holes can be found. When the hole is significantly obstructive, it results in increased venous and arterial pressures. Even though the definitive treatment of cor triatriatum is the surgical excision of the membrane, we present a balloon dilatation case with a good response to percutaneous therapy, both initially and in the ensuing months.

Prevalencia de los factores de riesgo cardiovascular en trabajadores de una planta metalúrgica / Prevalence of cardiovascular risk factors among workers in a metallurgical factory

Objetivo: El estudio pretende conocer la prevalencia y la distribución de los factores de riesgo cardiovascular en una población concreta para poder implementar las medidas preventivas necesarias con criterios de eficiencia. Métodos: Estudio descriptivo transversal de la distribución de los factores de riesgo cardiovascular mayores (dislipemia, tabaquismo, hipertensión arterial y diabetes mellitus) y subyacentes (sobrepeso/obesidad, sedentarismo, hipertrigliceridemia, consumo de alcohol y antecedentes familiares) en función de la edad y el sexo obtenidos mediante la aplicación de un protocolo estandarizado efectuado durante los reconocimientos médicos laborales periódicos de un grupo de 358 trabajadores, 330 varones y 28 mujeres, de una industria metalúrgica de Cantabria con una edad media de 42 ± 8 años. Resultado: La dislipemia constituye el factor de riesgo más relevante por su elevada prevalencia (52%) en una población relativamente joven, seguido del tabaquismo (35%) y de la obesidad (22%). Estos tres factores de riesgo son también los que presentan un riesgo atribuible mayor en la incidencia de cardiopatía isquémica en la población general española, por lo que deben ser objeto de intervención. Conclusiones. Los servicios de salud laboral de las empresas tienen una posición privilegiada por su accesibilidad para evaluar y tratar los factores de riesgo cardiovascular presentes en la población trabajadora a la que sirven (AU)

Objective: The study aims to determine the prevalence and distribution of cardiovascular risk factors in a specific population in order to implement the necessary preventative measures with efficiency criterias. Methods: Cross-sectional study of the distribution of major cardiovascular risk factors (dyslipidemia, smoking, hypertension and diabetes mellitus) and the underlying factors (overweight / obesity, physical inactivity, hypertriglyceridemia, alcohol consumption and family history) as a function of age and sex obtained by applying a standardized protocol performed during periodic medical examinations at work to a group of 358 workers, 330 men and 28 women, in a metallurgical industry in Cantabria with a mean age of 42 ± 8 years. Result: Dyslipidemia is the most important risk factor for its high prevalence (52%) in a relatively young population, followed by smoking (35%) and obesity (22%). These three risk factors are also those with a higher attributable risk in the incidence of ischemic heart disease in the general Spanish population, so they should be subject to intervention. Conclusions: Occupational Health Service companies have a privileged position due to their accessibility to evaluate and treat cardiovascular risk factors present in the working population they serve (AU)