Treatment of Chronic Heart Failure in Advanced Chronic Kidney Disease: The HAKA Multicenter Retrospective Real-World Study.

INTRODUCTION: Chronic heart failure (HF) has high rates of mortality and hospitalization in patients with advanced chronic kidney disease (aCKD). However, randomized clinical trials have systematically excluded aCKD population. We have investigated current HF therapy in patients receiving clinical care in specialized aCKD units. METHODS: The Heart And Kidney Audit (HAKA) was a cross-sectional and retrospective real-world study including outpatients with aCKD and HF from 29 Spanish centers. The objective was to evaluate how the treatment of HF in patients with aCKD complied with the recommendations of the European Society of Cardiology Guidelines for the diagnosis and treatment of HF, especially regarding the foundational drugs: renin-angiotensin system inhibitors (RASi), angiotensin receptor blocker/neprilysin inhibitors (ARNI), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). RESULTS: Among 5,012 aCKD patients, 532 (13%) had a diagnosis of HF. Of them, 20% had reduced ejection fraction (HFrEF), 13% mildly reduced EF (HFmrEF), and 67% preserved EF (HFpEF). Only 9.3% of patients with HFrEF were receiving quadruple therapy with RASi/ARNI, BB, MRA, and SGLT2i, but the majority were not on the maximum recommended doses. None of the patients with HFrEF and CKD G5 received quadruple therapy. Among HFmrEF patients, approximately half and two-thirds were receiving RASi and/or BB, respectively, while less than 15% received ARNI, MRA, or SGLT2i. Less than 10% of patients with HFpEF were receiving SGLT2i. CONCLUSIONS: Under real-world conditions, HF in aCKD patients is sub-optimally treated. Increased awareness of current guidelines and pragmatic trials specifically enrolling these patients represent unmet medical needs.

SUMOylation modulates eIF5A activities in both yeast and pancreatic ductal adenocarcinoma cells.

BACKGROUND: The eukaryotic translation initiation protein eIF5A is a highly conserved and essential factor that plays a critical role in different physiological and pathological processes including stress response and cancer. Different proteomic studies suggest that eIF5A may be a small ubiquitin-like modifier (SUMO) substrate, but whether eIF5A is indeed SUMOylated and how relevant is this modification for eIF5A activities are still unknown. METHODS: SUMOylation was evaluated using in vitro SUMOylation assays, Histidine-tagged proteins purification from His6-SUMO2 transfected cells, and isolation of endogenously SUMOylated proteins using SUMO-binding entities (SUBES). Mutants were engineered by site-directed mutagenesis. Protein stability was measured by a cycloheximide chase assay. Protein localization was determined using immunofluorescence and cellular fractionation assays. The ability of eIF5A1 constructs to complement the growth of Saccharomyces cerevisiae strains harboring thermosensitive mutants of a yeast EIF5A homolog gene (HYP2) was analyzed. The polysome profile and the formation of stress granules in cells expressing Pab1-GFP (a stress granule marker) by immunofluorescence were determined in yeast cells subjected to heat shock. Cell growth and migration of pancreatic ductal adenocarcinoma PANC-1 cells overexpressing different eIF5A1 constructs were evaluated using crystal violet staining and transwell inserts, respectively. Statistical analysis was performed with GraphPad Software, using unpaired Student's t-test, or one-way or two-way analysis of variance (ANOVA). RESULTS: We found that eIF5A is modified by SUMO2 in vitro, in transfected cells and under endogenous conditions, revealing its physiological relevance. We identified several SUMO sites in eIF5A and found that SUMOylation modulates both the stability and the localization of eIF5A in mammalian cells. Interestingly, the SUMOylation of eIF5A responds to specific stresses, indicating that it is a regulated process. SUMOylation of eIF5A is conserved in yeast, the eIF5A SUMOylation mutants are unable to completely suppress the defects of HYP2 mutants, and SUMOylation of eIF5A is important for both stress granules formation and disassembly of polysomes induced by heat-shock. Moreover, mutation of the SUMOylation sites in eIF5A abolishes its promigratory and proproliferative activities in PANC-1 cells. CONCLUSIONS: SUMO2 conjugation to eIF5A is a stress-induced response implicated in the adaptation of yeast cells to heat-shock stress and required to promote the growth and migration of pancreatic ductal adenocarcinoma cells.

Viral protein-based nanoparticles (part 2): Pharmaceutical applications.

Viral protein nanoparticles (ViP NPs) such as virus-like particles and virosomes are structures halfway between viruses and synthetic nanoparticles. The biological nature of ViP NPs endows them with the biocompatibility, biodegradability, and functional properties that many synthetic nanoparticles lack. At the same time, the absence of a viral genome avoids the safety concerns of viruses. Such characteristics of ViP NPs offer a myriad of opportunities for theirapplication at several points across disease development: from prophylaxis to diagnosis and treatment. ViP NPs present remarkable immunostimulant properties, and thus the vaccination field has benefited the most from these platforms capable of overcoming the limitations of both traditional and subunit vaccines. This was reflected in the marketing authorization of several VLP- and virosome-based vaccines. Besides, ViP NPs inherit the ability of viruses to deliver their cargo to target cells. Because of that, ViP NPs are promising candidates as vectors for drug and gene delivery, and for diagnostic applications. In this review, we analyze the pharmaceutical applications of ViP NPs, describing the products that are commercially available or under clinical evaluation, but also the advances that scientists are making toward the implementation of ViP NPs in other areas of major pharmaceutical interest.

Viral protein nanoparticles (Part 1): Pharmaceutical characteristics.

Viral protein nanoparticles fill the gap between viruses and synthetic nanoparticles. Combining advantageous properties of both systems, they have revolutionized pharmaceutical research. Virus-like particles are characterized by a structure identical to viruses but lacking genetic material. Another type of viral protein nanoparticles, virosomes, are similar to liposomes but include viral spike proteins. Both systems are effective and safe vaccine candidates capable of overcoming the disadvantages of both traditional and subunit vaccines. Besides, their particulate structure, biocompatibility, and biodegradability make them good candidates as vectors for drug and gene delivery, and for diagnostic applications. In this review, we analyze viral protein nanoparticles from a pharmaceutical perspective and examine current research focused on their development process, from production to administration. Advances in synthesis, modification and formulation of viral protein nanoparticles are critical so that large-scale production of viral protein nanoparticle products becomes viable and affordable, which ultimately will increase their market penetration in the future. We will discuss their expression systems, modification strategies, formulation, biopharmaceutical properties, and biocompatibility.

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation.

The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.

eIF5A is activated by virus infection or dsRNA and facilitates virus replication through modulation of interferon production.

Active hypusine-modified initiation elongation factor 5A is critical for cell proliferation and differentiation, embryonic development, and innate immune response of macrophages to bacterial infection. Here, we demonstrate that both virus infection and double-stranded RNA viral mimic stimulation induce the hypusination of eIF5A. Furthermore, we show that activation of eIF5A is essential for the replication of several RNA viruses including influenza A virus, vesicular stomatitis virus, chikungunya virus, mayaro virus, una virus, zika virus, and punta toro virus. Finally, our data reveal that inhibition of eIF5A hypusination using the spermidine analog GC7 or siRNA-mediated downmodulation of eIF5A1 induce upregulation of endoplasmic reticulum stress marker proteins and trigger the transcriptional induction of interferon and interferon-stimulated genes, mechanisms that may explain the broad-spectrum antiviral activity of eIF5A inhibition.

Quality of life in patients with heart failure and improved ejection fraction: one-year changes and prognosis.

AIMS: The criteria for patients with heart failure (HF) and improved ejection fraction (HFimpEF) are a baseline left ventricular ejection fraction (LVEF) ≤40%, a ≥10-point increase from baseline LVEF, and a second LVEF measurement >40%. We aimed to (i) assess patients with HF and reduced LVEF (HFrEF) at baseline and compare quality of life (QoL) changes between those that fulfilled and those that did not fulfil the HFimpEF criteria 1 year later and (ii) assess the prognostic role of QoL in patients with HFimpEF. METHODS: We reviewed data from a prospective registry of real-world outpatients with HF that were assessed for LVEF and QoL at a first visit to the HF clinic and 1 year later. QoL was evaluated with the Minnesota Living with Heart Failure Questionnaire (MLWHFQ). The primary prognostic endpoint was the composite of all-cause death or HF hospitalization. RESULTS: Baseline and 1-year LVEF and MLWFQ scores were available for 1040 patients with an initial LVEF ≤40% (mean age, 65.2 ± 11.7 years; 75.9% men). The main aetiology was ischaemic heart disease (52.9%), and patients were mostly in New York heart Association Classes II (71.1%) and III (21.6%). At baseline, the mean LVEF was 28.5% ± 7.3, and the mean MLWHFQ score was 30.2 ± 19.5. After 1 year, the mean LVEF increased to 38.0% ± 12.2, and the MLWHFQ scores improved to 17.4 ± 16.0. In 361 patients that fulfilled the HFimpEF criteria (34.7%), significant improvements were observed in both LVEF (from 28.7% ± 6.6 to 50.9% ± 7.6, P < 0.001) and QoL (from 32.9 ± 20.6 to 16.9 ± 16.0, P < 0.001). Patients that did not fulfil the HFimpEF criteria also showed significant improvements in LVEF (from 28.4% ± 7.6 to 31.1% ± 7.9, P < 0.001) and QoL (from 28.7 ± 18.8 to 17.6 ± 15.9, P < 0.001). However, the QoL improvement was significantly higher in the HFimpEF group (-16.0 ± 23.8 vs. -11.1 ± 20.3, P = 0.001), despite the worse mean baseline MLWHFQ score, compared with the non-HFimpEF group (P = 0.001). The 1-year QoL was similar between groups (P = 0.50). The 1-year MLWHFQ score was independently associated with outcomes; the hazard ratio for the composite endpoint was 1.02 (95% CI: 1.01-1.03, P = 0.006). In contrast, the QoL improvement (with a cut-off ≥5 points) was not independently associated with the composite outcome. CONCLUSIONS: Patients with HFrEF showed improved QoL after 1 year, regardless of whether they met the HFimpEF criteria. The similar 1-year QoL perception between groups suggested that factors other than LVEF influenced QoL perception. The 1-year QoL was superior to the QoL change from baseline for predicting prognosis in patients with HFimpEF.

Overview of the regulation of the class IA PI3K/AKT pathway by SUMO.

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is a major regulator of metabolism, migration, survival, proliferation, and antiviral immunity. Both an overactivation and an inhibition of the PI3K/AKT pathway are related to different pathologies. Activation of this signaling pathway is tightly controlled through a multistep process and its deregulation can be associated with aberrant post-translational modifications including SUMOylation. Here, we review the complex modulation of the PI3K/AKT pathway by SUMOylation and we discuss its putative incvolvement in human disease.

Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture.

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration.

Lung ultrasound in outpatients with heart failure: the wet-to-dry HF study.

AIMS: In ambulatory patients with chronic heart failure (HF), congestion and decongestion assessment may be challenging. The aim of this study is to assess the value of lung ultrasound (LUS) in outpatients with HF in characterizing decompensation and recompensation, and in outcomes prediction. METHODS AND RESULTS: Heart failure outpatients attended to establish HF decompensation were included. LUS was blindly performed at baseline (LUS1) and at clinical recompensation (LUS2). B-lines were counted in eight scanned areas. Diagnosis of no HF decompensation vs. right-sided, left-sided, or global HF decompensation, and patients' management were performed by physicians blinded to LUS1. Outcome was the composite of all-cause death or HF-related hospitalization. Two hundred and thirty-three suspicions of HF decompensation were included in 187 patients (71.4 ± 11.3 years, 66.8% men). Mean B-line (LUS1) was 17.6 ± 11.2 vs. 3.7 ± 4.5 for episodes with and without HF decompensation, respectively (P < 0.001). Global HF decompensation showed the highest number of B-lines (20.6 ± 11), followed by left-sided (19.7 ± 11.6) and right-sided (13.5 ± 9.8). B-lines declined to 6.9 ± 6.7 (LUS2) (P < 0.001 vs. LUS1) after treatment, within a mean time of 24.2 ± 23.7 days [median 13.5 days (interquartile range 6-40)]. B-lines were significantly associated with the composite endpoint at 30 days (hazard ratio [HR] 1.04 [95% confidence interval 1.01-1.07], P = 0.02), but not at 60 (P = 0.22) or 180 days (P = 0.54). In multivariable analysis, B-line number remained as an independent predictor of the composite endpoint at 30 days, [HR 1.04 (1.01-1.07), P = 0.014], with a 4% increase risk per B-line added. B-lines correlated significantly with CA125 (R = 0.30, P = 0.001). CONCLUSIONS: Lung ultrasound supports the diagnostic work-up of congestion and decongestion in chronic HF outpatients and identifies patients at high risk of short-term events.

Head-to-head comparison of contemporary heart failure risk scores.

AIMS: Several heart failure (HF) web-based risk scores are currently used in clinical practice. Currently, we lack head-to-head comparison of the accuracy of risk scores. This study aimed to assess correlation and mortality prediction performance of Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC-HF) risk score, which includes clinical variables + medications; Seattle Heart Failure Model (SHFM), which includes clinical variables + treatments + analytes; PARADIGM Risk of Events and Death in the Contemporary Treatment of Heart Failure (PREDICT-HF) and Barcelona Bio-Heart Failure (BCN-Bio-HF) risk calculator, which also include biomarkers, like N-terminal pro B-type natriuretic peptide (NT-proBNP). METHODS AND RESULTS: A total of 1166 consecutive patients with HF from different aetiologies that had NT-proBNP measurement at first visit were included. Discrimination for all-cause mortality was compared by Harrell's C-statistic from 1 to 5 years, when possible. Calibration was assessed by calibration plots and Hosmer-Lemeshow test and global performance by Nagelkerke's R2 . Correlation between scores was assessed by Spearman rank test. Correlation between the scores was relatively poor (rho value from 0.66 to 0.79). Discrimination analyses showed better results for 1-year mortality than for longer follow-up (SHFM 0.817, MAGGIC-HF 0.801, PREDICT-HF 0.799, BCN-Bio-HF 0.830). MAGGIC-HF showed the best calibration, BCN-Bio-HF overestimated risk while SHFM and PREDICT-HF underestimated it. BCN-Bio-HF provided the best discrimination and overall performance at every time-point. CONCLUSIONS: None of the contemporary risk scores examined showed a clear superiority over the rest. BCN-Bio-HF calculator provided the best discrimination and overall performance with overestimation of risk. MAGGIC-HF showed the best calibration, and SHFM and PREDICT-HF tended to underestimate risk. Regular updating and recalibration of online web calculators seems necessary to improve their accuracy as HF management evolves at unprecedented pace.

Expression of the Ebola Virus VP24 Protein Compromises the Integrity of the Nuclear Envelope and Induces a Laminopathy-Like Cellular Phenotype.

Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response, preventing nuclear import of signal transducer and activator of transcription 1 (STAT1). Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell biology. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane, such as lamin A/C and lamin B. We also show that VP24 diminishes the interaction between emerin and lamin A/C and compromises the integrity of the nuclear membrane. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, expression of VP24 also promoted the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), a common interactor of lamin A/C and emerin, leading to repression of the BAF-regulated CSF1 gene. Importantly, we found that EBOV infection results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. In summary, here we demonstrate that VP24 acts at the nuclear membrane, causing morphological and functional changes in cells that recapitulate several of the hallmarks of laminopathy diseases. IMPORTANCE The Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein with multiple functions. Proteomic studies have identified the cellular nuclear membrane component emerin as a potential VP24 interactor. Here, we demonstrate that VP24 not only interacts with emerin but also with lamin A/C and lamin B, prompting nuclear membrane disruption. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, VP24 also promotes the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), leading to repression of the BAF-regulated CSF1 gene. Finally, we show that EBOV infection also results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. These results reveal novel activities of EBOV VP24 protein, resulting in a cell phenotype similar to that of most laminopathies, with potential impact on EBOV replication.

Thirst distress in outpatients with heart failure in a Mediterranean zone of Spain.

AIMS: This study aimed to evaluate psychometric properties of the Spanish version of the Thirst Distress Scale for patients with Heart Failure (TDS-HF) and to describe thirst distress-associated factors in outpatients at a heart failure (HF) clinic in Spain. Thirst is common in patients with HF, but thirst distress has rarely been addressed and may significantly decrease quality of life. METHODS AND RESULTS: A cross-sectional study was performed assessing perceived thirst distress by patients with HF during the preceding 3 days, with the TDS-HF (scores 8 to 40). Univariable and multivariable linear regression analyses were performed to identify variables independently associated with thirst distress. Three-hundred two HF outpatients were included (age 67 ± 12 years, 74% male, HF duration 82 ± 75 months, left ventricular ejection fraction 42 ± 14%). Most patients were on treatment with fluid restriction (99%), sodium restriction (99%), and diuretics (70%). The psychometric evaluation of the Spanish version of the TDS-HF showed satisfactory item-total and inter-item correlations (range from 0.77 to 0.85 and 0.60 to 0.84, respectively), and internal consistency was 0.95 (Cronbach's alpha). The majority perceived mild to moderate thirst distress, and 18% perceived it as high or severe. The mean score obtained was 16.2 ± 9.3 (median 13, Q1-Q3 8-20). Higher serum urea {beta coefficient 1.6 [95% confidence interval (CI) 0.267 to 2.92], P = 0.019} and lower potassium [beta coefficient -3.63 (85% CI -6.32 to -0.93), P = 0.009] remained significantly associated with thirst distress in the multivariable analysis, together with the dose of diuretics [beta coefficient 2.98 (95% CI 1.37 to 4.59), P < 0.001]. Treatment with angiotensin receptor blocker showed an independent protective effect [beta coefficient -3.62 (95% CI -6.89 to -0.345), P = 0.03]. CONCLUSIONS: The psychometric evaluation of the Spanish version of the TDS-HF showed good psychometric properties. One in five patients experienced severe distress by thirst, but the majority had mild to moderate thirst distress. The dose of diuretics and angiotensin receptor blocker treatment influence thirst distress and could be clinically important targets to relieve thirst distress in patients with HF.

SUMOylation modulates the stability and function of PI3K-p110ß.

Class I PI3K are heterodimers composed of a p85 regulatory subunit and a p110 catalytic subunit involved in multiple cellular functions. Recently, the catalytic subunit p110ß has emerged as a class I PI3K isoform playing a major role in tumorigenesis. Understanding its regulation is crucial for the control of the PI3K pathway in p110ß-driven cancers. Here we sought to evaluate the putative regulation of p110ß by SUMO. Our data show that p110ß can be modified by SUMO1 and SUMO2 in vitro, in transfected cells and under completely endogenous conditions, supporting the physiological relevance of p110ß SUMOylation. We identify lysine residue 952, located at the activation loop of p110ß, as essential for SUMOylation. SUMOylation of p110ß stabilizes the protein increasing its activation of AKT which promotes cell growth and oncogenic transformation. Finally, we show that the regulatory subunit p85ß counteracts the conjugation of SUMO to p110ß. In summary, our data reveal that SUMO is a novel p110ß interacting partner with a positive effect on the activation of the PI3K pathway.

Tightening Bonds in Latin America Through Phage Discovery.

Between 2015 and 2019, we hosted an International Phage Course at Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina. The 2-week full-time course was hands-on and included lectures from renowned phage biologists. Participating students were able to meet and discuss with recognized experts from around the world in a familiar setting, facilitating the establishment of scientific collaborations and the expansion of their networks. Eighty-four students from 14 Latin American countries have participated in the course, which included isolation, characterization, genome sequencing, and annotation of novel phages. We have successfully created a coursework that enabled the acquisition of new knowledge and expertise in bacteriophage biology and strengthened ties among Latin American colleagues.

Prognostic value of lung ultrasound in chronic stable ambulatory heart failure patients.

INTRODUCTION AND OBJECTIVES: The role of lung ultrasound (LUS) in acute heart failure (HF) has been widely studied, but little is known about its usefulness in chronic HF. This study assessed the prognostic value of LUS in a cohort of chronic HF stable ambulatory patients. METHODS: We included consecutive outpatients who attended a scheduled follow-up visit in a HF clinic. LUS was performed in situ. The operators were blinded to clinical data and examined 8 thoracic areas. The sum of B-lines across all lung zones and the quartiles of this addition were used for the analyses. Linear regression and Cox regression analyses were performed. The main clinical outcomes were a composite of all-cause death or hospitalization for HF and mortality from any cause. RESULTS: A total of 577 individuals were included (72% men; 69± 12 years). The mean number of B-lines was 5±6. During a mean follow-up of 31±7 months, 157 patients experienced the main clinical outcome and 111 died. Having ≥ 8 B-lines (Q4) doubled the risk of experiencing the composite primary event (P <.001) and increased the risk of death from any cause by 2.6-fold (P <.001). On multivariate analysis, the total sum of B-lines remained independent predictive factor of the composite endpoint (HR, 1.04; 95%CI, 1.02-1.06; P=.002) and of all-cause death (HR, 1.04; 95%CI, 1.02-1.07; P=.001), independently of whether or not N-terminal pro-B-type natriuretic peptide (NT-proBNP) was included in the model (P=.01 and P=.008, respectively), with a 3% to 4% increased risk for each 1-line addition. CONCLUSIONS: LUS identified patients with stable chronic HF at high risk of death or HF hospitalization.

The Interaction of Viruses with the Cellular Senescence Response.

Cellular senescence is viewed as a mechanism to prevent malignant transformation, but when it is chronic, as occurs in age-related diseases, it may have adverse effects on cancer. Therefore, targeting senescent cells is a novel therapeutic strategy against senescence-associated diseases. In addition to its role in cancer protection, cellular senescence is also considered a mechanism to control virus replication. Both interferon treatment and some viral infections can trigger cellular senescence as a way to restrict virus replication. However, activation of the cellular senescence program is linked to the alteration of different pathways, which can be exploited by some viruses to improve their replication. It is, therefore, important to understand the potential impact of senolytic agents on viral propagation. Here we focus on the relationship between virus and cellular senescence and the reported effects of senolytic compounds on virus replication.

SUMO and Cytoplasmic RNA Viruses: From Enemies to Best Friends.

SUMO is a ubiquitin-like protein that covalently binds to lysine residues of target proteins and regulates many biological processes such as protein subcellular localization or stability, transcription, DNA repair, innate immunity, or antiviral defense. SUMO has a critical role in the signaling pathway governing type I interferon (IFN) production, and among the SUMOylation substrates are many IFN-induced proteins. The overall effect of IFN is increasing global SUMOylation, pointing to SUMO as part of the antiviral stress response. Viral agents have developed different mechanisms to counteract the antiviral activities exerted by SUMO, and some viruses have evolved to exploit the host SUMOylation machinery to modify their own proteins. The exploitation of SUMO has been mainly linked to nuclear replicating viruses due to the predominant nuclear localization of SUMO proteins and enzymes involved in SUMOylation. However, SUMOylation of numerous viral proteins encoded by RNA viruses replicating at the cytoplasm has been lately described. Whether nuclear localization of these viral proteins is required for their SUMOylation is unclear. Here, we summarize the studies on exploitation of SUMOylation by cytoplasmic RNA viruses and discuss about the requirement for nuclear localization of their proteins.

Mini Nutritional Assessment Short Form is a morbi-mortality predictor in outpatients with heart failure and mid-range left ventricular ejection fraction.

BACKGROUND & AIMS: Nutritional status is an important prognostic factor in patients with heart failure (HF). In a pilot study we previously observed that the Mini Nutritional Assessment Short Form tool (MNA-SF) was the best approach for the screening of nutritional status in HF outpatients over other screening tools. The current study aimed to determine whether the MNA-SF has prognostic value in outpatients with HF and whether the impact of malnutrition differs depending on left ventricular ejection fraction (LVEF). METHODS: Prospective study performed in outpatients attending a HF clinic at a university hospital. All subjects completed the MNA-SF at study entry. The primary endpoint was all-cause mortality. Secondary end-points were the number of recurrent HF-related hospitalizations and the composite end-point of all-cause death or HF-related hospitalizations. Patients with malnutrition and at risk of malnutrition were merged and considered as having abnormal nutritional status for statistical analysis. RESULTS: From October 2016 to November 2017, 555 patients were included (age 69 ± 11.5 years, 71% male, LVEF 44.6 ± 13.2). Abnormal nutritional status was identified in 103 (18.6%) subjects. HF patients with preserved LVEF had a higher proportion of abnormal nutritional status (23%) than patients with HF and mid-range LVEF (HFmrEF) (16.4%) or those with HF with reduced LVEF (HFrEF) (15.9%.). During a mean follow-up of 23.8 ± 6.6 months, 99 patients died (17.8%), 74 were hospitalized due to HF (13.3%) and the composite end-point was observed in 181 (32.6%). In the univariate analysis, abnormal nutritional status was significantly associated with all-cause mortality (p = 0.02) and the composite end-point (p = 0.02) in the total cohort. However, in the multivariate analysis including age, sex, NYHA functional class, BMI, ischemic aetiology, diabetes, hypertension and HF duration, abnormal nutritional status remained significantly associated with all-cause mortality (HR 3.32 [95%CI 1.47-7.52], p = 0.004), and the composite end-point (HR 2.53 [95%CI 1.30-4.94], p = 0.006) only in HFmrEF patients. Patients with abnormal nutritional status suffered double the crude number of recurrent HF-related hospitalizations (16.4 vs. 8.4 per 100 patients-years, p < 0.001). CONCLUSIONS: The implementation of MNA-SF as a routine screening tool allowed the detection of abnormal nutritional status in almost one out of five ambulatory HF patients. Nutritional status assessed by the MNA-SF was an independent predictor of all-cause death and the composite end-point of all-cause death or HF-related hospitalization in outpatients with HFmrEF. Furthermore, abnormal nutritional status was significantly related to recurrent hospitalizations across the HF spectrum.