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The severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) poses a threat to human life worldwide. Since early March, 2020, coronavirus disease 2019 (COVID-19), characterized by an acute and often severe form of pneumonia, has been declared a pandemic. This has led to a boom in biomedical research studies at all stages of the pipeline, from the in vitro to the clinical phase. In line with this global effort, known drugs, currently used for the treatment of other pathologies, including antivirals, immunomodulating compounds and antibodies, are currently used off-label for the treatment of COVID-19, in association with the supportive standard care. Yet, no effective treatments have been identified. A new hope stems from medical oncology and relies on the use of immune-checkpoint inhibitors (ICIs). In particular, amongst the ICIs, antibodies able to block the programmed death-1 (PD-1)/PD ligand-1 (PD-L1) pathway have revealed a hidden potential. In fact, patients with severe and critical COVID-19, even prior to the appearance of acute respiratory distress syndrome, exhibit lymphocytopenia and suffer from T-cell exhaustion, which may lead to viral sepsis and an increased mortality rate. It has been observed that cancer patients, who usually are immunocompromised, may restore their anti-tumoral immune response when treated with ICIs. Moreover, viral-infected mice and humans, exhibit a T-cell exhaustion, which is also observed following SARS-CoV-2 infection. Importantly, when treated with anti-PD-1 and anti-PD-L1 antibodies, they restore their T-cell competence and efficiently counteract the viral infection. Based on these observations, four clinical trials are currently open, to examine the efficacy of anti-PD-1 antibody administration to both cancer and non-cancer individuals affected by COVID-19. The results may prove the hypothesis that restoring exhausted T-cells may be a winning strategy to beat SARS-CoV-2 infection.

When diabetes mellitus is not properly controlled with drugs and a healthy lifestyle, it exposes patients with advanced peripheral arterial disease or critical limb ischaemia (CLI) to the most serious complications, in particular lower limb ulcers. Surgical or endovascular treatments represent the first line of intervention; in addition, the adequate management of ulcers can guarantee not only a faster wound healing but also the improvement of the patient's prognosis. To speed up this process, negative pressure wound therapy (NPWT), platelet‐rich plasma (PRP), and other advanced moist wound dressing have been proposed. During Coronavirus disease 2019 (COVID‐19) pandemic, many patients with CLI and diabetes mellitus had difficult access to advanced treatments with a significant reduction in life expectancy. We report the cases of patients with non‐healing ulcers and CLI treated with an empiric multistage approach after successful endovascular revascularisation; the postoperative course was eventful in all patients, and foot ulcers are currently in an advanced state of healing. The association between adequate revascularisation, systemic anti‐inflammatory, and antibiotic therapy with the multistage advanced medications ensures healing of ulcers, limb salvage, and improvement of patient prognosis.

Cardiovascular disease and cancer are responsible for the majority of deaths in the Western world. These two entities share common risk factors and their intersection will be more and more frequent in future due to general population aging and long-term cancer control. Clinical presentation, management and outcome of acute coronary syndromes (ACS) in cancer patients could differ from noncancer ones. Cancer patients were frequently excluded from clinical trials and so the paucity of data further complicates the scenario. The management of ACS in cancer patients represents a unique setting in which the risk/benefit ratio of invasive treatment should be carefully evaluated. This review focused on the available evidence of all aspects of ACS in cancer patients providing a guide to a multidisciplinary approach.

Adult patients with simple congenital heart disease (sACHD) represent an expanding population vulnerable to atrial arrhythmias (AA). CHA2DS2-VASc score estimates thromboembolic risk in non-valvular atrial fibrillation patients. We investigated the prognostic role of CHA2DS2-VASc score in a non-selected sACHD population regardless of cardiac rhythm. Between November 2009 and June 2018, 427 sACHD patients (377 in sinus rhythm, 50 in AA) were consecutively referred to our ACHD service. Cardiovascular hospitalization and/or all-cause death were considered as composite primary end-point. Patients were divided into group A with CHA2DS2-VASc score = 0 or 1 point, and group B with a score greater than 1 point. Group B included 197 patients (46%) who were older with larger prevalence of cardiovascular risk factors than group A. During a mean follow-up of 70 months (IQR 40–93), primary end-point occurred in 94 patients (22%): 72 (37%) in group B and 22 (10%, p < 0.001) in group A. Rate of death for all causes was also significantly higher in the group B than A (22% vs 2%, respectively, p < 0.001). Multivariable Cox regression analysis revealed that CHA2DS2-VASc score was independently related to the primary end-point (HR 1.84 [1.22–2.77], p = 0.004) together with retrospective AA, stroke/TIA/peripheral thromboembolism and diabetes. Furthermore, CHA2DS2-VASc score independently predicted primary end-point in the large subgroup of 377 patients with sinus rhythm (HR 2.79 [1.54–5.07], p = 0.01). In conclusion, CHA2DS2-VASc score accurately stratifies sACHD patients with different risk for adverse clinical events in the long term regardless of cardiac rhythm.

Background Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world’s population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multi-drug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project “In Silico Trial for Tuberculosis Vaccine Development” (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare. Results We present the application of the Universal Immune System Simulator (UISS) computational modeling infrastructure as a disease model for TB. The model is capable to simulate the main features and dynamics of the immune system activities i.e., the artificial immunity induced by RUTI® vaccine, a polyantigenic liposomal therapeutic vaccine made of fragments of Mycobacterium tuberculosis cells (FCMtb). Based on the available data coming from phase II Clinical Trial in subjects with latent tuberculosis infection treated with RUTI® and isoniazid, we generated simulation scenarios through validated data in order to tune UISS accordingly to STriTuVaD objectives. The first case simulates the establishment of MTB latent chronic infection with some typical granuloma formation; the second scenario deals with a reactivation phase during latent chronic infection; the third represents the latent chronic disease infection scenario during RUTI® vaccine administration. Conclusions The application of this computational modeling strategy helpfully contributes to simulate those mechanisms involved in the early stages and in the progression of tuberculosis infection and to predict how specific therapeutical strategies will act in this scenario. In view of these results, UISS owns the capacity to open the door for a prompt integration of in silico methods within the pipeline of clinical trials, supporting and guiding the testing of treatments in patients affected by tuberculosis.

Purpose: In order to study novel therapeutic approaches taking advantage of natural compounds showing anticancer and anti-proliferative effects, we focused our interest on S-adenosyl-l-methionine, a naturally occurring sulfur-containing nucleoside synthesized from adenosine triphosphate and methionine by methionine adenosyltransferase, and its potential in overcoming drug resistance in colon cancer cells devoid of p53. Results: In the present study, we demonstrated that S-adenosyl-l-methionine overcomes uL3-mediated drug resistance in p53 deleted colon cancer cells. In particular, we demonstrated that S-adenosyl-l-methionine causes cell cycle arrest at the S phase, inhibits autophagy, augments reactive oxygen species, and induces apoptosis in these cancer cells. Conclusions: Results reported in this paper led us to propose S-adenosyl-l-methionine as a potential promising agent for cancer therapy by examining p53 and uL3 profiles in tumors to yield a better clinical outcomes.

Background To date, only a few comparisons between subcutaneous implantable cardioverter-defibrillator (S-ICD) patients undergoing and those not undergoing defibrillation testing (DT) at implantation (DT+ vs DT–) have been reported. Objective The purpose of this study was to compare long-term clinical outcomes of 2 propensity-matched cohorts of DT+ and DT– patients. Methods Among consecutive S-ICD patients implanted across 17 centers from January 2015 to October 2020, DT– patients were 1:1 propensity-matched for baseline characteristics with DT+ patients. The primary outcome was a composite of ineffective shocks and cardiovascular mortality. Appropriate and inappropriate shock rates were deemed secondary outcomes. Results Among 1290 patients, a total of 566 propensity-matched patients (283 DT+; 283 DT–) served as study population. Over median follow-up of 25.3 months, no significant differences in primary outcome event rates were found (10 DT+ vs 14 DT–; P = .404) as well as for ineffective shocks (5 DT– vs 3 DT+; P = .725). At multivariable Cox regression analysis, DT performance was associated with a reduction of neither the primary combined outcome nor ineffective shocks at follow-up. A high PRAETORIAN score was positively associated with both the primary outcome (hazard ratio 3.976; confidence interval 1.339–11.802; P = .013) and ineffective shocks alone at follow-up (hazard ratio 19.030; confidence interval 4.752–76.203; P = .003). Conclusion In 2 cohorts of strictly propensity-matched patients, DT performance was not associated with significant differences in cardiovascular mortality and ineffective shocks. The PRAETORIAN score is capable of correctly identifying a large percentage of patients at risk for ineffective shock conversion in both cohorts.

The open abdomen (OA) procedure as part of damage control surgery represents a significant surgical advance in severe intra-abdominal infections. Major techniques used for OA are negative pressure wound therapy (NPWT) and non-NPWT. The aim of this retrospective study is to evaluate the effects of different abdominal closure methods and their outcomes in patients presenting with abdominal sepsis treated with OA. We retrospectively analyzed clinical outcomes of patients affected by severe intra-abdominal sepsis treated with OA. Demographic features, mortality prediction score, abdominal closure methods, length of hospital stay, complications and mortality rates of patients were determined and compared. This study included 106 patients, of whom 77 underwent OA with NPWT and 29 with non-NPWT. OA duration was longer in NPWT patients (p = 0.007). In-hospital mortality rates in NPWT and in non-NPWT patients were 40.3% and 51.7%, respectively (p = 0.126), with an overall 30-day mortality rate of 18.2% and 51.7%, respectively (p = 0.0002). After emergency colorectal surgery, patients who underwent OA with NPWT had a lower rate of colostomy (p = 0.025). NPWT is the best temporary abdominal closure technique to decrease mortality and colostomy rates in patients managed with OA for severe intra-abdominal infections.

Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.

An ever-increasing number of tools and databases offers pieces of evidence and knowledge about gene function annotations, protein interactions, and experimentally validated biological pathways. These resources represent an excellent and essential instrument to facilitate pathway analysis. Among them, particular attention should be given to the one capable of finding alternative pathways or cross-talks events and potential drug target candidates. Here, we evaluated PETAL predictive capability, a Python tool that automatically explores and scans the relevant nodes within a KEGG pathway. Starting from three specific cancer scenarios (chronic myelogenous leukemia, non-small cell lung cancer, and head and neck squamous cell carcinoma) and related literature results about potential driver genes of drug resistance to EGFR tyrosine kinases inhibitors (SNCA, BCL-6 and YAP-1), we used PETAL to test its capability to identify in parallel these potential target genes involved in tumor progression and EGFR inhibitors resistance. By searching in-depth for ancestor and descendent nodes of SNCA, BCL-6 and YAP-1, across the EGFR pathway, we found that PETAL was able to detect the same targets investigated in the recent literature. Finally, this retrospective work emphasizes that PETAL could represent a powerful tool that can be used to improve the understanding of complex biological pathways and speed-up the identification of potential biomarkers and therapeutical candidates in cancer potentially in any other disease.

Background The STriTuVaD project, funded by Horizon 2020, aims to test through a Phase IIb clinical trial one of the most advanced therapeutic vaccines against tuberculosis. As part of this initiative, we have developed a strategy for generating in silico patients consistent with target population characteristics, which can then be used in combination with in vivo data on an augmented clinical trial. Results One of the most challenging tasks for using virtual patients is developing a methodology to reproduce biological diversity of the target population, ie, providing an appropriate strategy for generating libraries of digital patients. This has been achieved through the creation of the initial immune system repertoire in a stochastic way, and through the identification of a vector of features that combines both biological and pathophysiological parameters that personalise the digital patient to reproduce the physiology and the pathophysiology of the subject. Conclusions We propose a sequential approach to sampling from the joint features population distribution in order to create a cohort of virtual patients with some specific characteristics, resembling the recruitment process for the target clinical trial, which then can be used for augmenting the information from the physical the trial to help reduce its size and duration.

Background High diagnostic accuracy for pneumonia, absence of radiation exposure and repeatability are intrinsic features of lung ultrasonography making it an attractive tool in the assessment of patients with COVID-19 pneumonia. The aim of our prospective, observational study was to detect COVID-19-associated sonographic features and assess the potential value of LUS in predicting adverse events. Methods From March 12th to April 20th 2020 patients admitted to two medium-intensive wards with a discharge diagnosis of COVID-19 pneumonia were enrolled and underwent lung ultrasonography. The prognostic value of several ultrasonographic scores at admission and after 72 hours from the first examination (the total score, the anterolateral score, the number of positive region and the presence of consolidation) were analysed with logistic regression along with other potential prognostic factors. The primary outcome was a composite of death and transfer to Intensive Care Unit (ICU), while the secondary was continuous positive airways pressure (CPAP) support. Results 190 patients were enrolled in the study. The primary outcome was seen in 25 patients (13%), the secondary outcome in 36 (22%). At multivariate regression no sonographic score at admission was independently correlated with the primary outcome while the total score, the anterolateral score, the number of positive regions were associated with CPAP support. When considering the subgroup of patients undergoing lung ultrasonography after 72 hours (128 patients) the total score was independently associated with both the primary and secondary outcome. Conclusion Lung ultrasonography can be a promising prognostic tool in patients admitted to non-ICU units for COVID-19 pneumonia.

Eukaryotic cells are exposed to many internal and external stimuli that affect their fate. In particular, the exposure to some of these stimuli induces stress triggering a variety of stress responses aimed to re-establish cellular homeostasis. It is now established that the deregulation of stress response pathways plays a central role in cancer initiation and progression, allowing the adaptation of cells to an altered state in the new environment. Autophagy is a tightly regulated pathway which exerts “housekeeping” role in physiological processes. Recently, a growing amount of evidence highlighted the crucial role of autophagy in the regulation of integrated stress responses, including nucleolar and endoplasmic reticulum. In this review, we attempt to afford an overview of the complex role of nucleolar and endoplasmic reticulum stress-response mechanisms in the regulation of autophagy in cancer and cancer treatment.

The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is still unexplored. We have recently described the antiproliferative activity of a heterochiral thrombin binding aptamer (TBA) derivative, namely, LQ1. Here, we investigate the molecular mechanisms of LQ1 activity and the structural and antiproliferative properties of two further TBA derivatives, differing from LQ1 only by the small loop base-compositions. We demonstrate that in p53 deleted colon cancer cells, LQ1 causes nucleolar stress, impairs ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrests cells in the G2/M phase and induces early apoptosis. Importantly, the depletion of uL3 abrogates all these effects, indicating that uL3 is a crucial player in the mechanism of action of LQ1. Taken together, our findings identify p53-independent and uL3-dependent nucleolar stress as a novel stress response pathway activated by a specific G-quadruplex TBA derivative. To the best of our knowledge, this investigation reveals, for the first time, the involvement of the nucleolar stress pathway in the mechanism of action of antiproliferative G-quadruplex aptamers.

We present an improved version of an agent-based model developed to reproduce the typical oscillating behavior of relapsing remitting multiple sclerosis, a demyelinating autoimmune disease of the central nervous system. The model now includes the effects of vitamin D, a possible immune-modulator that can potentially influence the disease course, as well as the mechanisms of action of daclizumab, a monoclonal antibody that was previously reported as the unique third line treatment for MS, i.e., to be used only in patients who had an inadequate response to the other therapies, but then retired from market due to the arising of severe side effects. The use of this computational approach, capable of qualitatively reproducing the main effects of daclizumab, is used to grasp some useful insights to delineate the possible causes that led to the withdrawal of the drug. Furthermore, we explore the possibility to combine vitamin D administration with a reduced dosage of daclizumab, in order to qualitatively delineate if a combined treatment can lead to similar efficacy, thus entitling a reduced risk of adverse effects.

Motivation Val600Glu (V600E) mutation is the most common BRAF mutation detected in thyroid cancer. Hence, recent research efforts have been performed trying to explore several inhibitors of the V600E mutation-containing BRAF kinase as potential therapeutic options in thyroid cancer refractory to standard interventions. Among them, vemurafenib is a selective BRAF inhibitor approved by Food and Drug Administration for clinical practice. Unfortunately, vemurafenib often displays limited efficacy in poorly differentiated and anaplastic thyroid carcinomas probably because of intrinsic and/or acquired resistance mechanisms. In this view, cancer stem cells (CSCs) may represent a possible mechanism of resistance to vemurafenib, due to their self-renewal and chemo resistance properties. Results We present a computational framework to suggest new potential targets to overcome drug resistance. It has been validated with an in vitro model based upon a spheroid-forming method able to isolate thyroid CSCs that may mimic resistance to vemurafenib. Indeed, vemurafenib did not inhibit cell proliferation of BRAF V600E thyroid CSCs, but rather stimulated cell proliferation along with a paradoxical over-activation of ERK and AKT pathways. The computational model identified a fundamental role of mitogen-activated protein kinase 8 (MAP3K8), a serine/threonine kinase expressed in thyroid CSCs, in mediating this drug resistance. To confirm model prediction, we set a suitable in vitro experiment revealing that the treatment with MAP3K8 inhibitor restored the effect of vemurafenib in terms of both DNA fragmentation and poly (ADP-ribose) polymerase cleavage (apoptosis) in thyroid CSCs. Moreover, MAP3K8 expression levels may be a useful marker to predict the response to vemurafenib. Availability and implementation The model is available in GitHub repository visiting the following URL: https://github.com/francescopappalardo/MAP3K8-Thyroid-Spheres-V-3.0. Supplementary information Supplementary data are available at Bioinformatics online.

Personalized target therapies represent one of the possible treatment strategies to fight the ongoing battle against cancer. New treatment interventions are still needed for an effective and successful cancer therapy. In this scenario, we simulated and analyzed the dynamics of BRAF V600E melanoma patients treated with BRAF inhibitors in order to find potentially interesting targets that may make standard treatments more effective in particularly aggressive tumors that may not respond to selective inhibitor drugs. To this aim, we developed a continuous Petri Net model that simulates fundamental signalling cascades involved in melanoma development, such as MAPK and PI3K/AKT, in order to deeply analyze these complex kinase cascades and predict new crucial nodes involved in melanomagenesis. The model pointed out that some microRNAs, like hsa-mir-132, downregulates expression levels of p120RasGAP: under high concentrations of p120RasGAP, MAPK pathway activation is significantly decreased and consequently also PI3K/PDK1/AKT activation. Furthermore, our analysis carried out through the Genomic Data Commons (GDC) Data Portal shows the evidence that hsa-mir-132 is significantly associated with clinical outcome in melanoma cancer genomic data sets of BRAF-mutated patients. In conclusion, targeting miRNAs through antisense oligonucleotides technology may suggest the way to enhance the action of BRAF-inhibitors.

Background Human papillomavirus infection is a global social burden that, every year, leads to thousands new diagnosis of cancer. The introduction of a protocol of immunization, with Gardasil and Cervarix vaccines, has radically changed the way this infection easily spreads among people. Even though vaccination is only preventive and not therapeutic, it is a strong tool capable to avoid the consequences that this pathogen could cause. Gardasil vaccine is not free from side effects and the duration of immunity is not always well determined. This work aim to enhance the effects of the vaccination by using a new class of adjuvants and a different administration protocol. Due to their minimum side effects, their easy extraction, their low production costs and their proven immune stimulating activity, citrus-derived molecules are valid candidates to be administered as adjuvants in a vaccine formulation against Hpv. Results With the aim to get a stronger immune response against Hpv infection we built an in silico model that delivers a way to predict the best adjuvants and the optimal means of administration to obtain such a goal. Simulations envisaged that the use of Neohesperidin elicited a strong immune response that was then validated in vivo. Conclusions We built up a computational infrastructure made by a virtual screening approach able to preselect promising citrus derived compounds, and by an agent based model that reproduces HPV dynamics subject to vaccine stimulation. This integrated methodology was able to predict the best protocol that confers a very good immune response against HPV infection. We finally tested the in silico results through in vivo experiments on mice, finding good agreement.

Cardiovascular disease and cancer are leading causes of death. Both diseases share the same risk factors and, having the highest incidence and prevalence in the elderly, they often coexist in the same individual. Furthermore, the enhanced survival of cancer patients registered in the last decades and linked to early diagnosis and improvement of care, not infrequently exposes them to the appearance of ominous cardiovascular complications due to the deleterious effects of cancer treatment on the heart and circulatory system. The above considerations have led to the development of a new branch of clinical cardiology based on the principles of multidisciplinary collaboration between cardiologists and oncologists: Cardio-oncology, which aims to find solutions to the prevention, monitoring, diagnosis and treatment of heart damage induced by cancer care in order to pursue, in the individual patient, the best possible care for cancer while minimizing the risk of cardiac toxicity. In this consensus document we provide practical recommendations on how to assess, monitor, treat and supervise the candidate or patient treated with potentially cardiotoxic cancer therapy in order to treat cancer and protect the heart at all stages of the oncological disease. Cardiovascular diseases and cancer often share the same risk factors and can coexist in the same individual. Such possibility is amplified by the deleterious effects of cancer treatment on the heart. The above considerations have led to the development of a new branch of clinical cardiology, based on multidisciplinary collaboration between cardiologist and oncologist: the cardio-oncology. It aims to prevent, monitor, and treat heart damages induced by cancer therapies in order to achieve the most effective cancer treatment, while minimizing the risk of cardiac toxicity. In this paper, we provide practical recommendations on how to assess, monitor, treat and supervise patients treated with potential cardiotoxic cancer therapies.

It is well known that the response of individuals to disease varies, either because of unpredictable exogenous events, such as possibly unknown environmental effects, or just because of endogenous factors, i.e. different genetic background. In particular, when a treatment effectiveness has to be validated, the individual variability should be taken into account by exploiting stochastic models. Relapsing Remitting Multiple Sclerosis (RRMS) is an unpredictable and complex disease, whose random behaviour perfectly fits the study with stochastic models. RRMS is the most common form of Multiple Sclerosis (MS), an immune-mediated inflammatory disease of the central nervous system, characterized by alternate episodes of symptom exacerbation (relapses) with periods of disease stability (remission). Several treatments were proposed to contrast the disease progression. Among these, Daclizumab initially exhibited promising results. However, due to the risk of serious side effects the treatment has been retired. We propose a stochastic and an hybrid extension, based on a generalization of the high level Petri Net formalism, of an existing model of Daclizumab effects on RRMS. The model is developed to investigate the complex mechanisms and unpredictable behaviour characterizing the RRMS disease and its relapsing, especially under the Daclizumab administration.

Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cells, Comment: 5 pages

The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging “hallmark” of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed.

Spinal muscular atrophy is a destructive motor neuron disease that mostly affects children and represents the most common cause of hereditary infant mortality. It is mainly caused by harmful variants in survival of motor neuron (SMN1), which drive to depletion of the survival motor neuron protein (SMN), along with specific immune organ defects that compromise immune function and consequently the survival and quality of life of SMA patients. In this work, we present an application of a computational modeling approach in order to analyze and suggest possible therapeutic interventions through the inhibitory strategies directed against spinal muscular atrophy.

Background DNA methylation is an epigenetic mechanism of genomic regulation involved in the maintenance of homeostatic balance. Dysregulation of DNA methylation status is one of the driver alterations occurring in neoplastic transformation and cancer progression. The identification of methylation hotspots associated to gene dysregulation may contribute to discover new prognostic and diagnostic biomarkers, as well as, new therapeutic targets. Results We present EpiMethEx (Epigenetic Methylation and Expression), a R package to perform a large-scale integrated analysis by cyclic correlation analyses between methylation and gene expression data. For each gene, samples are segmented according to the expression levels to select genes that are differentially expressed. This stratification allows to identify CG methylation probesets modulated among gene-stratified samples. Subsequently, the methylation probesets are grouped by their relative position in gene sequence to identify wide genomic methylation events statically related to genetic modulation. Conclusions The beta-test study showed that the global methylation analysis was in agreement with scientific literature. In particular, this analysis revealed a negative association between promoter hypomethylation and overexpression in a wide number of genes. Less frequently, this overexpression was sustained by intragenic hypermethylation events. Electronic supplementary material The online version of this article (10.1186/s12859-018-2397-6) contains supplementary material, which is available to authorized users.

MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.

Patient: Male, 72-year-old Final Diagnosis: Metastatic squamous cell carcinoma Symptoms: None Medication:— Clinical Procedure: — Specialty: Cardiology Objective: Rare disease Background: Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. Case Report: A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. Conclusions: This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.

With the aim to develop alternative therapeutic tools for the treatment of resistant cancers, here we propose targeted Pluronic(®) P123/F127 mixed micelles (PMM) delivering niclosamide (NCL) as a repositioning strategy to treat multidrug resistant non-small lung cancer cell lines. To build multifunctional PMM for targeting and imaging, Pluronic(®) F127 was conjugated with biotin, while Pluronic(®) P123 was fluorescently tagged with rhodamine B, in both cases at one of the two hydroxyl end groups. This design intended to avoid any interference of rhodamine B on biotin exposition on PMM surface, which is a key fundamental for cell trafficking studies. Biotin-decorated PMM were internalized more efficiently than non-targeted PMM in A549 lung cancer cells, while very low internalization was found in NHI3T3 normal fibroblasts. Biotin-decorated PMM entrapped NCL with good efficiency, displayed sustained drug release in protein-rich media and improved cytotoxicity in A549 cells as compared to free NCL (P

Objectives The aim of this study was to assess the relationship between gait speed and the risk for death and/or hospital admission in older patients with heart failure (HF). Background Gait speed is a reliable single marker of frailty in older people and can predict falls, disability, hospital admissions, and mortality. Methods In total, 331 community-living patients ≥70 years of age (mean age 78 ± 6 years, 43% women, mean ejection fraction 35 ± 11%, mean New York Heart Association functional class 2.7 ± 0.6) in stable condition and receiving optimized therapy for chronic HF were prospectively enrolled and followed for 1 year. Gait speed was measured at the usual pace over 4 m, and cutoffs were defined by tertiles: ≤0.65, 0.66 to 0.99, and ≥1.0 m/s. Results There was a significant association between gait speed tertiles and 1-year mortality: 38.3%, 21.9%, and 9.1% (p Conclusions Gait speed is independently associated with death, hospitalization for HF, and all-cause hospitalization and improves risk stratification in older patients with HF evaluated using the Cardiac and Comorbid Conditions Heart Failure score. Assessment of frailty using gait speed is simple and should be part of the clinical evaluation process.

L-cysteine is currently recognized as a conditionally essential sulphur amino acid. Besides contributing to many biological pathways, cysteine is a key component of the keratin protein by its ability to form disulfide bridges that confer strength and rigidity to the protein. In addition to cysteine, iron represents another critical factor in regulating keratins expression in epidermal tissues, as well as in hair follicle growth and maturation. By focusing on human keratinocytes, the aim of this study was to evaluate the effect of cysteine supplementation as nutraceutical on keratin biosynthesis, as well as to get an insight on the interplay of cysteine availability and cellular iron status in regulating keratins expression in vitro. Herein we demonstrate that cysteine promotes a significant up-regulation of keratins expression as a result of de novo protein synthesis, while the lack of iron impairs keratin expression. Interestingly, cysteine supplementation counteracts the adverse effect of iron deficiency on cellular keratin expression. This effect was likely mediated by the up-regulation of transferrin receptor and ferritin, the main cellular proteins involved in iron homeostasis, at last affecting the labile iron pool. In this manner, cysteine may also enhance the metabolic iron availability for DNA synthesis without creating a detrimental condition of iron overload. To the best of our knowledge, this is one of the first study in an in vitro keratinocyte model providing evidence that cysteine and iron cooperate for keratins expression, indicative of their central role in maintaining healthy epithelia.

Cancer patients have an increased risk of severe COVID-19 infection due to the suppression of the immune system and the development of cytokine release syndrome (CRS) that favor respiratory syndromes and interstitial pneumonia. However, substantial differences exist between patients treated with chemotherapy and patients treated with immune checkpoint inhibitors (ICIs), for which the risk of COVID-19 infection and the immunologic and cytokine profile in case of infection have not yet been well characterized. The administration of ICIs for the treatment of severe COVID-19 infection has been recently suggested. However, no conclusive data have been generated on this matter. To recognize the therapeutic potential of ICIs administration in COVID-19 patients with or without cancer, the Universal Immune System Simulator (UISS) prediction model was used to simulate the immunologic response of COVID-19 patients after ICIs administration. Briefly, UISS represents an appropriate computational modeling infrastructure able to simulate the dynamics of every single entity of the immune system after a stimulus or a therapeutic intervention by using an agent-based methodology. Therefore, the UISS platform, already used for the prediction of the efficacy of specific SARS-CoV-2 candidate vaccines, was here adopted to characterize the immunologic behavior in both COVID-19 and cancer patients and to predict the effects of ICIs in these patients. The computational results allowed us to identify key inflammatory and immune-related factors responsible for severe respiratory syndromes in COVID-19 infected patients with and without cancer. UISS results suggest that the administration of ICIs modulates the immune system and the inflammatory status in both groups of patients with COVID-19 infection, reducing the risk of severe symptoms. Although the results of the present study are still under validation in peripheral blood samples obtained from COVID-19 patients and from cancer patients after two cycles of treatment with ICIs, we can speculate that ICIs may be a good therapeutic approach for the treatment of COVID-19 severe respiratory syndrome even with a concomitant cancer diagnosis. If this is the case, the lower expression levels of inflammatory biomarkers can result in the drop-down of the viral load, assessed by droplet digital PCR in COVID-19 patients. Citation Format: Giulia Russo, Luca Falzone, Bruno Cacopardo, Giuseppe Nunnari, Francesco Torino, Giuseppa Scandurra, Stefania Stefani, Francesco Pappalardo, Massimo Libra. Computational modeling of immunologic response to immune checkpoint inhibitors in COVID-19 patients with and without cancer [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-050.

Tuberculosis is one of the world’s deadliest diseases that infects one third of the world’s population, mostly in developing countries. However, tuberculosis is becoming again very dangerous also for developed countries, due to the increased mobility of the world population, and the appearance of several new bacterial strains that are multi-drug resistant. With the aim to help in finding new therapeutic interventions against tuberculosis, we present the application of a computational modeling infrastructure named UISS (Universal Immune System Simulator) able to simulate the main features and dynamics of the immune system activities. We show a further development of UISS to consider the underlying tuberculosis pathogenesis and its interaction with the host immune system. Even though the model can be further personalized employing immunological parameters and genetic information, based on the available data, we obtained simulation scenarios able to reproduce persistent latent infection or the development of active disease. In particular, UISS is able to simulate those mechanisms in which M. tuberculosis is involved in the early influx of alveolar macrophages and recruited neutrophils until the formation of the tuberculous granuloma, at both cellular and molecular levels.

Dysregulation of DNA methyltransferase activity, through global hypomethylation and localized hypermethylation phenomena, has been associated with cancer development. Even though the role of promoter methylation in gene regulation has been widely described, the regulatory function of methylation status of intergenic and intragenic regions has been not yet clarified. High-throughput technology and bioinformatics analysis represent useful tools to investigate the functional role of global methylation patterns in gene regulation. Therefore, a specific bionformatic tool was generated to identify methylation hotspots as well as extended genomic methylation regions in order to analyze specific genetic methylation patterns associated with cancer gene deregulation. In the present study, melanoma was selected as tumor model for its aggressive phenotype. Melanoma samples were obtained from the Cancer Genome Atlas (TCGA) to analyze DNA methylation and gene expression profiling data. We developed an algorithm, using R language, that performs cyclic correlation analysis between gene expression and methylation levels of all genes. Our results show that in melanoma there are different methylation patterns that positively and negatively correlate with gene expression. In particular, the hypomethylation of the promoter (TSS1500, TSS200, 5'UTR) leads to the over-expression of selected gene (p Citation Format: Saverio Candido, Giuseppe A. Parasiliti Palumbo, Giulia Russo, Luca Falzone, Giulia C. Leonardi, Francesco Pappalardo, Massimo Libra. DNA methylation and gene expression in melanoma: A large-scale integrated analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5305.

The lowering of costs of whole exome sequencing (WES) services registered in the last two years has greatly increased the demand for managing different metabolic diseases, including autism spectrum disorders (ASD). WES allows the detection of a large part of exome single nucleotide polymorphisms (SNPs), whose expression can be in some cases modulated by epigenetics, life style and microbioma changes. However, such raw data usually needs to be manipulated in order to allow useful interpretation and analysis. We present BIOESOnet, a tool for the filtering and visualization of exome 23andMe raw data into a customized methylation pathway. The tool, available at: http://www.bionumeri.org/joomla/restricted-area/onecarbon-tool, enables a fast and extensive overview of possible mutations inside an extended metabolic pathway.

Background Patients who underwent a successful repair of the aortic coarctation (CoA) show high risk for cardiovascular (CV) events. Mechanical and structural abnormalities in the ascending aorta (Ao) might have a role in the prognosis of CoA patients. We analyzed the elastic properties of Ao measured as aortic stiffness index (AoSI) in CoA patients in the long-term period and we compared AoSI with a cohort of 38 patients with rheumatoid arthritis (RA) and 38 non-RA matched controls. Methods Data from 19 CoA patients were analyzed 28 ± 13 years after surgery. Abnormally high AoSI was diagnosed if AoSI > 6.07% (95th percentile of the AoSI detected in our reference healthy population). AoSI was assessed at the level of the aortic root by two-dimensional guided M-mode evaluation. Results CoA patients showed more than two-fold higher AoSI compared to RA and controls (9.8 ± 12.6 vs 4.8 ± 2.5% and 3.1 ± 2.0%, respectively; all p

OBJECTIVES: Due to the chronic inflammatory status, specific neuro-hormones and progression of arterial stiffness, patients with rheumatoid arthritis (RA) are exposed to the development of excessive left ventricular mass disproportionate to the need to compensate left ventricular load. This condition, named inappropriately high left ventricular mass (iLVM), is associated with unfavorable prognosis in patients with hypertension, aortic stenosis or diabetes. In this study, we assessed prevalence and factors associated with iLVM in a large cohort of patients with RA and tested the hypothesis that RA per se is a condition related to iLVM. METHODS: We prospectively analyzed 235 RA patients without overt cardiac disease recruited between January and December 2014, who were compared with 235 controls matched for age, sex, BMI, prevalence of hypertension and diabetes. iLVM was defined as measured/predicted LVM ratio above 123%. LVM was predicted in each individual by using a simple equation considering height, sex and left ventricular work. RESULTS: iLVM was detected in 150 RA patients (64%) and in 30 controls (15%; P

The CKD-EPI equation is more accurate than the MDRD equation in the general population. We performed this study to establish whether chronic kidney disease (CKD) is commonly recognized by clinicians and whether the CKD-EPI equation improves prognosis estimation in patients with chronic cardiovascular disease (CVD). We analyzed data on 12394 CVD patients consecutively examined at the Cardiovascular Center of Trieste (Italy) between November 2009 and October 2013. The outcomes were all-cause death and a composite outcome of death/hospitalization for CV events (D+cvH). CKD-EPI formula reclassified 1786 (14.4 %) patients between KDIGO categories compared to the MDRD: 2.3 % (n = 280) placed in a lower risk and 12.1 % (n = 1506) into a higher risk group. CKD, defined as eGFR-CKD-EPI formula 60 but eGFR-CKD-EPI formula

Aims Unplanned readmissions early after a discharge from acute heart failure hospitalization are common and have become a reimbursement benchmark and marker of hospital quality. However, the competing risk of short-term post-discharge mortality is substantial. Methods and results Using data from the prospective, nationwide Registry IN-HF Outcome, we analysed the incidence and predictors of 30-day mortality or readmissions and associated days-alive-out-of-hospital (DAOH) in 1520 patients discharged alive after admission for acute heart failure. Within 30 days after discharge, 94 patients (6.2%) were readmitted (91% for cardiovascular causes; 60% recurrent heart failure) and 42 (2.8%) died, 10 of which occurred during readmission. Overall, 126 patients (8.3%) met the combined endpoint. By multivariable logistic regression, worsening chronic heart failure as clinical presentation [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.21–2.77, P = 0.005), inotropes during admission (OR 2.19, 95% CI 1.40–3.43, P = 0.0006), length of stay (OR 1.02, 95% CI 1.01–1.04, P = 0.002) and renin–angiotensin system inhibitors at discharge (OR 0.52, 95%CI 0.35–0.77, P = 0.001) independently predicted 30-day all-cause mortality and/or readmission (c-statistic = 0.695). Per cent 30-day DAOH was lower in patients with in-hospital inotrope use, no renin–angiotensin system inhibitors prescription at discharge, New York Heart Association III–IV class at discharge, and correlated inversely with length of stay and age. Conclusion A clinical and biohumoral profile consistent with chronic advanced heart failure and end-organ damage identifies acute heart failure patients discharged home from cardiology units, who are at highest risk of early death and/or readmission. These findings have practical implications for tailoring specific follow-up.

Background The CHA2DS2-VASc score well stratifies the risk for thromboembolic events in non-valvular atrial fibrillation (NVAF) patients. This score may also predict thromboembolic events in sinus rhythm populations. Purpose The purpose of this study was to assess the prognostic role of CHA2DS2-VASc in a Caucasian community population of patients with arterial hypertension and sinus rhythm. Methods A total of 12,599 arterial hypertension residents not receiving anticoagulation were selected from a community population in Trieste between November 2009 and October 2014: 11,159 sinus rhythm and 1440 NVAF patients. We considered thromboembolic events, cardiovascular hospitalisation and all-cause death in all patients divided according to CHA2DS2-VASc. Results Sinus rhythm patients were 74 (interquartile range 65-81) years old, 50% were women, 32% with CAD, mean CHA2DS2-VASc 3.68 ± 1.47 points, significantly lower than NVAF patients (4.26 ± 1.50, P

Malignant melanoma is an invasive skin cancer commonly resistant to conventional therapeutic approaches. Genetic and molecular alterations as mutations of BRAF gene, able to constitutively activate MAPK and PI3K/PDK1/Akt signalling pathways, seem to be responsible of malignant melanocytic transformation and lead to aberrant cellular physiological processes. Specific regulators and modulators of both signaling pathways may represent promising therapeutic targets to investigate drug resistance typical of BRAF-inhibitors such as Dabrafenib. We developed a continuous Petri Net model that simulates both MAPK and PI3K/PDK1/Akt pathways and their interactions in order to analyze the complex kinase cascades in melanoma and to predict new crucial nodes involved in drug resistance like in the Ras arm.

5-FU is a chemotherapy drug commonly used for the treatment of human cancers; however drug resistance represents a major challenge for its clinical application. In the present study, we reporte that rpL3 induced by 5-FU treatment in Calu-6 cells represses CBS transcription and reduces CBS protein stability leading to a decrease of CBS protein levels. rpL3 also regulates negatively the activation of NFκB by preventing NFκB nuclear translocation through IκB-α up-regulation. Furthermore, we demonstrate that rpL3 significantly enhances the apoptosis of 5-FU treated Calu-6 cells promoting the overexpression of the pro-apoptotic proteins Bax and the inhibition of the anti-apoptotic protein Bcl-2. We finally demonstrate that rpL3 potentiates 5-FU efficacy inhibiting cell migration and invasion. Our results suggest that combination of rpL3 and 5-FU is a promising strategy for chemotherapy of lung cancers lacking functional p53 that are resistant to 5-FU.

Identifying latently infected individuals is crucial for the elimination of tuberculosis (TB). We evaluated for the first time the performance of a new type of interferon-γ release assay, QuantiFERON-TB Plus (QFT-Plus), which includes an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T-cells in contacts of TB patients.Contacts were screened for latent TB infection by tuberculin skin test, QFT-Plus and QuantiFERON-TB Gold in Tube (QFT-GIT).In 119 TB contacts, the overall agreement between QFT-Plus and QFT-GIT was high, with a Cohen's κ of 0.8. Discordant results were found in 12 subjects with negative QFT-GIT and positive QFT-Plus results. In analyses of markers of TB exposure and test results, the average time spent with the index case was the strongest risk factor for positivity in each of these tests. The difference in interferon-γ production between the two antigen tubes (TB2−TB1) was used as an estimate of CD8+ stimulation provided by the TB2. TB2−TB1 values >0.6 IU·mL−1 were significantly associated with proximity to the index case and European origin.QFT-Plus has a stronger association with surrogate measures of TB exposure than QFT-GIT in adults screened for latent TB infection. Interferon-γ response in the new antigen tube used an indirect estimate of specific CD8+ response correlates with increased Mycobacterium tuberculosis exposure, suggesting a possible role in identifying individuals with recent infection.

Background Malignant melanoma is an aggressive tumor of the skin and seems to be resistant to current therapeutic approaches. Melanocytic transformation is thought to occur by sequential accumulation of genetic and molecular alterations able to activate the Ras/Raf/MEK/ERK (MAPK) and/or the PI3K/AKT (AKT) signalling pathways. Specifically, mutations of B-RAF activate MAPK pathway resulting in cell cycle progression and apoptosis prevention. According to these findings, MAPK and AKT pathways may represent promising therapeutic targets for an otherwise devastating disease. Result Here we show a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. Overall, this computational approach may accelerate the drug discovery process and encourages the identification of novel pathway activators with consequent development of novel antioncogenic compounds to overcome tumor cell resistance to conventional therapeutic agents. The source code of the various versions of the model are available as S1 Archive.; Extracted text

Background A proper prognostic stratification is crucial for organizing an effective clinical management and treatment decision-making in patients with chronic heart failure (CHF). In this study, we selected and characterized a sub-group of CHF patients at very low risk for death aiming to assess predictors of death in subjects with an expected probability of 1-year mortality near to 5%. Methods We used the Cardiac and Comorbid Conditions HF (3C-HF) Score to identify CHF patients with the best mid-term prognosis. We selected patients belonging to the lowest quartile of 3C-HF score (≤9 points). Results We recruited 1777 consecutive CHF patients at 3 Italian Cardiology Units (age 76±10years, 43% female, 32% with preserved ejection fraction). Subjects belonging to the lowest quartile of 3C-HF score were 609. During a median follow-up of 21 [12–40] months, 48 of these patients (8%) died, and 561 (92%) survived. The variables that contributed to death prediction by Cox regression multivariate analysis were older age (HR 1.03[CI 1.00–1.07]; p =0.04), male gender (HR 2.93[CI 1.50–5.51]; p =0.002) and a higher degree of renal dysfunction (HR 0.96[CI 0.94–0.98]; p Conclusions The prognostic stratification of CHF patients by 3C-HF score allows one to select patients at different outcome and to identify the factors associated with death in outliers with a very low mortality risk at mid-term follow-up. The reasons why these patients do not outlive the matching part of subjects who expectedly survive are related to a declined renal function and unmodifiable conditions including older age and male gender.

There is a growing body of evidence highlighting the applications of computational modeling in the field of biomedicine. It has recently been applied to the in silico analysis of cancer dynamics. In the era of precision medicine, this analysis may allow the discovery of new molecular targets useful for the design of novel therapies and for overcoming resistance to anticancer drugs. According to its molecular behavior, melanoma represents an interesting tumor model in which computational modeling can be applied. Melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease as it is resistant to current therapeutic approaches.This review discusses the basics of computational modeling in melanoma drug discovery and development. Discussion includes the in silico discovery of novel molecular drug targets, the optimization of immunotherapies and personalized medicine trials.Mathematical and computational models are gradually being used to help understand biomedical data produced by high-throughput analysis. The use of advanced computer models allowing the simulation of complex biological processes provides hypotheses and supports experimental design. The research in fighting aggressive cancers, such as melanoma, is making great strides. Computational models represent the key component to complement these efforts. Due to the combinatorial complexity of new drug discovery, a systematic approach based only on experimentation is not possible. Computational and mathematical models are necessary for bringing cancer drug discovery into the era of omics, big data and personalized medicine.

BACKGROUND: Tissue Doppler Imaging (TDI) is a sensible and feasible method to detect longitudinal left ventricular (LV) systolic dysfunction (LVSD) in patients with diabetes mellitus, hypertension or ischemic heart disease. In this study, we hypothesized that longitudinal LVSD assessed by TDI predicted inducible myocardial ischemia independently of other echocardiographic variables (assessed as coexisting potential markers) in patients at increased cardiovascular (CV) risk. METHODS: Two hundred one patients at high CV risk defined according to the ESC Guidelines 2012 underwent exercise stress echocardiography (ExSEcho) for primary prevention. Echocardiographic parameters were measured at rest and peak exercise. RESULTS: ExSEcho classified 168 (83.6 %) patients as non-ischemic and 33 (16,4 %) as ischemic. Baseline clinical characteristics were similar between the groups, but ischemic had higher blood pressure, received more frequently beta-blockers and antiplatelet agents than non-ischemic patients. The former had greater LV size, lower relative wall thickness and higher left atrial systolic force (LASF) than the latter. LV systolic longitudinal function (measure as peak S') was significantly lower in ischemic than non-ischemic patients (8.7 ± 2.1 vs 9.7 ± 2.7 cm/sec, p = 0.001). The factors independently related to myocardial ischemia at multivariate logistic analysis were: lower peak S', higher LV circumferential end-systolic stress and LASF. CONCLUSIONS: In asymptomatic patients at increased risk for adverse CV events baseline longitudinal LVSD together with higher LV circumferential end-systolic stress and LASF were the factors associated with myocardial ischemia induced by ExSEcho. The assessment of these factors at standard echocardiography might help the physicians for improving the risk stratification among these patients for ExSEcho.

// Annapina Russo 1 , Sara Maiolino 2 , Valentina Pagliara 1 , Francesca Ungaro 2 , Fabiana Tatangelo 3 , Alessandra Leone 3 , Giulia Scalia 4 , Alfredo Budillon 3 , Fabiana Quaglia 2, * , Giulia Russo 1, * 1 Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy 2 Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy 3 Istituto Nazionale Tumori “Fondazione Pascale”-IRCCS, 80131 Napoli, Italy 4 CEINGE-Biotecnologie Avanzate, 80145 Napoli, Italy * These authors contributed equally to this work Correspondence to: Annapina Russo, email: annapina.russo@unina.it Keywords: 5-FU, p53, ribosomal protein rpL3, colon cancer, apoptosis Received: July 29, 2016 Accepted: October 14, 2016 Published: November 08, 2016 ABSTRACT Colon cancer is one of the leading causes of cancer-related death worldwide and the therapy with 5-fluorouracil (5-FU) is mainly limited due to resistance. Recently, we have demonstrated that nucleolar stress upon 5-FU treatment leads to the activation of ribosome-free rpL3 (L3) as proapoptotic factor. In this study, we analyzed L3 expression profile in colon cancer tissues and demonstrated that L3 mRNA amount decreased with malignant progression and the intensity of its expression was inversely related to tumor grade and Bcl-2/Bax ratio. With the aim to develop a combined therapy of 5-FU plus plasmid encoding L3 (pL3), we firstly assessed the potentiation of the cytotoxic effect of 5-FU on colon cancer cells by L3. Next, 10 μM 5-FU and 2 μg of pL3 were encapsulated in biocompatible nanoparticles (NPs) chemically conjugated with HA to achieve active tumor-targeting ability in CD44 overexpressing cancer cells. We showed the specific intracellular accumulation of NPs in cells and a sustained release for 5-FU and L3. Analysis of cytotoxicity and apoptotic induction potential of combined NPs clearly showed that the 5-FU plus L3 were more effective in inducing apoptosis than 5-FU or L3 alone. Furthermore, we show that the cancer-specific chemosensitizer effect of combined NPs may be dependent on L3 ability to affect 5-FU efflux by controlling P-gp (P-glycoprotein) expression. These results led us to propose a novel combined therapy with the use of 5-FU plus L3 in order to establish individualized therapy by examining L3 profiles in tumors to yield a better clinical outcomes.

Anthracyclines, taxanes and trastuzumab are used for therapy in early breast cancer (EBC) overexpressing Human Epidermal Growth Factor 2 (HER2+). These drugs, considered alone, do not present potential nephrotoxicity. However, renal dysfunction (RD) may increase the myocardial sensibility to the insult of these chemotherapies used in combination. The aim of the study is to assess the role of RD on the development of cardiotoxicity associated with trastuzumab-based adjuvant therapy (aTrastC) for EBC. Clinical and echocardiographic data of 499 women with ERB2+ EBC were analyzed. At 12-month evaluation, any symptoms of heart failure or decrease in left ventricular ejection fraction (LVEF) were recorded. Patients who had cardiotoxicity (n = 130, 26 %) were older (57 ± 11 vs. 55 ± 11 years; p = 0.03), had lower glomerular filtration rate (GFR) (76 ± 15 vs. 83 ± 19 ml/min/1.73 m(2); p = 0.003), higher LVEF (69 ± 6 vs. 63 ± 5 %; p < 0.001) and received more frequent doses of doxorubicin (18 vs. 9 %; p = 0.01) than those who did not. In patients with GFR 60-90 and

In the year 2006 the Italian Association of Hospital Cardiologists (ANMCO) promoted a Consensus Conference among professional Scientific Societies in order to redefine the role and core responsibilities of each health professionals involved in heart failure management in a novel integrated network. Five years later, a questionnaire has been proposed to each Italian Regional President of the Association, in order to assess the implementation of the proposed management strategies in the different clinical scenarios of the Italian Regions. Although the Document utilization is not homogeneous through Italy, it is still considered a valuable tool of work.

Multiple sclerosis is a disease of the central nervous system that involves the destruction of the insulating sheath of axons, causing severe disabilities. Since the etiology of the disease is not yet fully understood, the use of novel techniques that may help to understand the disease, to suggest potential therapies and to test the effects of candidate treatments is highly advisable. To this end we developed an agent based model that demonstrated its ability to reproduce the typical oscillatory behavior observed in the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis. The model has then been used to test the potential beneficial effects of vitamin D over the disease. Many scientific studies underlined the importance of the blood-brain barrier and of the mechanisms that influence its permeability on the development of the disease. In the present paper we further extend our previously developed model with a mechanism that mimics the blood-brain barrier behavior. The goal of our work is to suggest the best strategies to follow for developing new potential treatments that intervene in the blood-brain barrier. Results suggest that the best treatments should potentially prevent the opening of the blood-brain barrier, as treatments that help in recovering the blood-brain barrier functionality could be less effective.