Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.

BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18. AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes. METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects. RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal. DISCUSSION: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.

Does valerian work for insomnia? An umbrella review of the evidence.

Valerian is one of the most used herbal agents (phytotherapeutics) to manage sleep disturbances, in particular, sleep-onset difficulties in young adults. However, the evidence based on primary studies and systematic reviews that supports its use in this domain is weak or inconclusive. In the current study, an umbrella review was performed on the efficacy of valerian for sleep disturbances with a focus on insomnia. As such, only systematic reviews (with or without meta-analysis) were considered for this study. Systematic searches in PubMed, Web of Science, Scopus, Cochrane Database of Systematic Reviews, PROSPERO and CNKI databases retrieved 70 records. Only 8 articles were considered eligible for qualitative analysis. Overall, data suggested that valerian has a good safety profile, however, the results showed no evidence of efficacy for the treatment of insomnia. Moreover, valerian appears to be effective concerning subjective improvement of sleep quality, although its effectiveness has not been demonstrated with quantitative or objective measurements. Despite its widespread use and prescription by general practitioners, psychiatrists and other professionals, valerian does not have empirical support for insomnia. Further studies, in particular high quality randomized controlled trials, are highly recommended since there are scarce studies and the existing ones are quite heterogeneous and with low methodological quality. The implications of our findings for clinical practice are critically discussed.

HJURP is recruited to double-strand break sites and facilitates DNA repair by promoting chromatin reorganization.

HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.

Vascular Function and Intima-Media Thickness in Children and Adolescents with Growth Hormone Deficiency: Results from a Prospective Case-Control Study.

INTRODUCTION: Growth hormone deficiency (GHD) may be associated with subtle cardiovascular abnormalities, reversible upon starting GH treatment. Data on vascular morphology and function in GHD children are scanty and inconclusive. The aim of our study was to evaluate the effects of GHD and GH treatment on endothelial function and intima-media thickness (IMT) in children and adolescents. METHODS: We enrolled 24 children with GHD (10.85 ± 2.71 years) and 24 age-, sex-, and BMI-matched controls. We evaluated anthropometry, lipid profile, asymmetric dimethylarginine (ADMA), brachial flow-mediated dilatation (FMD), and IMT of common (cIMT) and internal (iIMT) carotid artery at study entry in all subjects and after 12 months of treatment in GHD children. RESULTS: At baseline GHD, children had higher total cholesterol (163.17 ± 18.66 vs. 149.83 ± 20.68 mg/dL, p = 0.03), LDL cholesterol (91.18 ± 20.41 vs. 77.08 ± 19.73 mg/dL, p = 0.019), atherogenic index (AI) (2.94 ± 0.71 vs. 2.56 ± 0.4, p = 0.028), and ADMA (215.87 ± 109.15 vs. 164.10 ± 49.15 ng/mL, p < 0.001), compared to controls. GHD patients also exhibited increased higher waist-to-height ratio (WHtR) compared to controls (0.48 ± 0.05 vs. 0.45 ± 0.02 cm, p = 0.03). GH therapy resulted in a decrease in WHtR (0.44 ± 0.03 cm, p = 0.001), total (151.60 ± 15.23 mg/dL, p = 0.001) and LDL cholesterol (69.94 ± 14.40 mg/dL, p < 0.0001), AI (2.28 ± 0.35, p = 0.001), and ADMA (148.47 ± 102.43 ng/mL, p < 0.0001). GHD showed lower baseline FMD than controls (8.75 ± 2.44 vs. 11.85 ± 5.98%, p = 0.001), which improved after 1-year GH treatment (10.60 ± 1.69%, p = 0.001). Baseline cIMT and iIMT were comparable between the two groups, but slightly reduced in GHD patients after treatment. CONCLUSION: GHD children may exhibit endothelial dysfunction in addition to other early atherosclerotic markers like visceral adiposity, and altered lipids, which can be restored by GH treatment.

Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and often fatal neurodegenerative disease characterized by the loss of Motor Neurons (MNs) in spinal cord, motor cortex and brainstem. Despite significant efforts in the field, the exact pathogenetic mechanisms underlying both familial and sporadic forms of ALS have not been fully elucidated, and the therapeutic possibilities are still very limited. Here we investigate the molecular mechanisms of neurodegeneration induced by chronic exposure to the environmental cyanotoxin L-BMAA, which causes a form of ALS/Parkinson's disease (PD) in several populations consuming food and/or water containing high amounts of this compound. METHODS: In this effort, mice were chronically exposed to L-BMAA and analyzed at different time points to evaluate cellular and molecular alterations and behavioral deficits, performing MTT assay, immunoblot, immunofluorescence and immunohistochemistry analysis, and behavioral tests. RESULTS: We found that cyanotoxin L-BMAA determines apoptotic cell death and a marked astrogliosis in spinal cord and motor cortex, and induces neurotoxicity by favoring TDP-43 cytoplasmic accumulation. CONCLUSIONS: Overall, our results characterize a new versatile neurotoxic animal model of ALS that may be useful for the identification of new druggable targets to develop innovative therapeutic strategies for this disease.

Macrophage Cell Membrane Coating on Piperine-Loaded MIL-100(Fe) Nanoparticles for Breast Cancer Treatment.

Piperine (PIP), a compound found in Piper longum, has shown promise as a potential chemotherapeutic agent for breast cancer. However, its inherent toxicity has limited its application. To overcome this challenge, researchers have developed PIP@MIL-100(Fe), an organic metal-organic framework (MOF) that encapsulates PIP for breast cancer treatment. Nanotechnology offers further treatment options, including the modification of nanostructures with macrophage membranes (MM) to enhance the evasion of the immune system. In this study, the researchers aimed to evaluate the potential of MM-coated MOFs encapsulated with PIP for breast cancer treatment. They successfully synthesized MM@PIP@MIL-100(Fe) through impregnation synthesis. The presence of MM coating on the MOF surface was confirmed through SDS-PAGE analysis, which revealed distinct protein bands. Transmission electron microscopy (TEM) images demonstrated the existence of a PIP@MIL-100(Fe) core with a diameter of around 50 nm, surrounded by an outer lipid bilayer layer measuring approximately 10 nm in thickness. Furthermore, the researchers evaluated the cytotoxicity indices of the nanoparticles against various breast cancer cell lines, including MCF-7, BT-549, SKBR-3, and MDA. The results demonstrated that the MOFs exhibited between 4 and 17 times higher cytotoxicity (IC50) in all four cell lines compared to free PIP (IC50 = 193.67 ± 0.30 µM). These findings suggest that MM@PIP@MIL-100(Fe) holds potential as an effective treatment for breast cancer. The study's outcomes highlight the potential of utilizing MM-coated MOFs encapsulated with PIP as an innovative approach for breast cancer therapy, offering improved cytotoxicity compared to free PIP alone. Further research and development are warranted to explore the clinical translation and optimize the efficacy and safety of this treatment strategy.

Cardiovascular Side Effects of Anthracyclines and HER2 Inhibitors among Patients with Breast Cancer: A Multidisciplinary Stepwise Approach for Prevention, Early Detection, and Treatment.

Cardiovascular (CV) diseases (CVD) are a major cause of long-term morbidity and mortality affecting life expectancy amongst cancer survivors. In recent years, because of the possibility of early diagnosis and the increased efficacy of neo-adjuvant and adjuvant systemic treatments (targeting specific molecular pathways), the high percentage of survival from breast cancer led CVD to become the first cause of death among survivors. Therefore, it is mandatory to adopt cardioprotective strategies to minimize CV side effects and CVD in general in breast cancer patients. Cancer therapeutics-related cardiac dysfunction (CTRCD) is a common group of side effects of chemotherapeutics widely employed in breast cancer (e.g., anthracycline and human epidermal growth factor receptor 2 inhibitors). The aim of the present manuscript is to propose a pragmatic multidisciplinary stepwise approach for prevention, early detection, and treatment of cardiotoxicity in patients with breast cancer.

Phloroglucinol-Derived Medications are Effective in Reducing Pain and Spasms of Urinary and Biliary Tracts: Results of Phase 3 Multicentre, Open-Label, Randomized, Comparative Studies of Clinical Effectiveness and Safety.

INTRODUCTION: Pain and spasms of urinary and biliary tracts are conditions causing poor quality of life. Treatment with analgesic drugs such as non-steroidal anti-inflammatory drugs and modulators of the parasympathetic system are not always tolerated, and often additional therapeutic options are necessary. The present analysis aimed to evaluate the pharmacokinetics and effectiveness of oral and parenteral preparations based on phloroglucinol in reducing pain and spasms associated with renal or biliary colic in phase 3, multicentre, open-label, randomized, comparative studies on clinical effectiveness and safety. METHODS: Pharmacokinetic and pharmacodynamic studies were carried out. Four phase 3 multicentre, open-label, randomized, comparative studies were conducted to evaluate the clinical effectiveness and safety in patients with pain and spasms of urinary or biliary tracts. Eligible patients randomly received either phloroglucinol orally or via intramuscular (IM)/intravenous (IV) administration and reference drug, dexketoprofen for urinary spasms and pain, the non-steroidal anti-inflammatory drug metamizole or scopolamine-based reference drug for biliary colic. The primary outcomes were symptoms and observed frequency of spasms, while the secondary outcome was the duration of improvement or the time between the drug administration and the recurrence of symptoms. Comparison of groups by quantitative characteristics was performed using the T-test for independent samples or the Mann-Whitney test. Intragroup comparisons were performed using the Wilcoxon test, or the T-test for linked samples. Qualitative signs were analysed using the Pearson's χ2 test and Fisher's exact test. RESULTS: The pharmacokinetic studies showed that (i) most of the phloroglucinol (> 80% for IV and per os formulations) was eliminated in the first 6 h after dosing, (ii) the drug was eliminated in urine as unchanged phloroglucinol (1,3,5-trihydroxybenzene) in a small proportion (< 3% of the dose) and (iii) a considerable amount of the drug was detected after enzymatic deconjugation with ß-glucoronidase/arylsulfatase from Helix pomatia. As for the pharmacokinetic study, a total of 364 patients were enrolled, divided in four studies: two designed to test the effectiveness of oral and IM/IV preparations in biliary colic and two in urinary colic. Baseline characteristics between groups were similar. Phloroglucinol oral or IV/IM showed an effectiveness comparable to the reference drug in reducing pain and spasms associated with both urinary and biliary colic. There was no difference between all groups by survival analysis. CONCLUSION: Oral and parenteral preparations based on phloroglucinol are as effective in reducing pain and spasms associated with renal or biliary colic as current therapeutic options. Therefore, phloroglucinol may be considered as useful to treat pain and spasms associated with urinary and biliary colic.

How to Treat Right Heart Failure. Tips for Clinicians in Everyday Practice.

In recent years, several observations reported that intolerance of physical exertion and other cardinal symptoms in heart failure (HF) are closely related to the functionality of the right ventricular (RV), regardless of left heart. It has been demonstrated that the RV dysfunction complicates the course, aggravates the quality of life, and increases the mortality of HF patients. The present review is aimed to report tips physicians about the current therapeutic management of right HF during acute stage and chronic phase, shedding light on the RV and its failure and providing physicians with essential information for everyday clinical practice.

HIPK2 in cancer biology and therapy: Recent findings and future perspectives.

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates and regulates a plethora of transcriptional regulators and chromatin modifiers. The heterogeneity of its interactome allows HIPK2 to modulate several cellular processes and signaling pathways, ultimately regulating cell fate and proliferation. Because of its p53-dependent pro-apoptotic activity and its downregulation in many tumor types, HIPK2 is traditionally considered a bone fide tumor suppressor gene. However, recent findings revealed that the role of HIPK2 in the pathogenesis of cancer is much more complex, ranging from tumor suppressive to oncogenic, strongly depending on the cellular context. Here, we review the very recent data emerged in the last years about the involvement of HIPK2 in cancer biology and therapy, highlighting the various alterations of this kinase (downregulation, upregulation, mutations and/or delocalization) in dependence on the cancer types. In addition, we discuss the recent advancement in the understanding the tumor suppressive and oncogenic functions of HIPK2, its role in establishing the response to cancer therapies, and its regulation by cancer-associated microRNAs. All these data strengthen the idea that HIPK2 is a key player in many types of cancer; therefore, it could represent an important prognostic marker, a factor to predict therapy response, and even a therapeutic target itself.

Testosterone deficiency independently predicts mortality in women with HFrEF: insights from the T.O.S.CA. registry.

AIMS: Testosterone deficiency (TD) is associated with increased morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). However, data in women are scanty. The aim of this study was to investigate the prognostic impact of TD on women with HFrEF. METHODS: Among 480 patients prospectively enrolled in the T.O.S.CA. (Terapia Ormonale Scompenso CArdiaco) registry, a prospective, multicentre, nationwide, observational study, 94 women were included in the current analysis. The TD was defined as serum testosterone levels lower than 25 ng/dl. Data regarding clinical status, echocardiography, exercise performance, cardiovascular hospitalization, and survival after an average follow-up of 36 months were analysed. RESULTS: Thirty patients (31.9%) displayed TD. TD was associated with lower tricuspid annular plane excursion (TAPSE) to pulmonary arterial systolic pressure PASP ratio (TAPSE/PASP) (P = 0.008), peak oxygen consumption (VO2 peak) (P = 0.03) and estimated glomerular filtration rate (P < 0.001). TD was an independent predictor of the combined endpoint of all-cause mortality/cardiovascular hospitalization (HR: 10.45; 95% CI: 3.54-17.01; P = 0.001), all-cause mortality (HR: 8.33; 95%: 5.36-15.11; P = 0.039), and cardiovascular hospitalization (HR: 2.41; 95% CI: 1.13-4.50; P = 0.02). CONCLUSIONS: One-third of women with HFrEF displays TD that impacts remarkably on their morbidity and mortality. TD is associated with a worse clinical profile including exercise capacity, right ventricular-pulmonary arterial coupling, and renal function. These findings lend support to an accurate profiling of women with HF, a problem often overlooked in clinical trials.

Circulating tissue inhibitor of metalloproteinases 1 (TIMP-1) at COVID-19 onset predicts severity status.

Background: Systemic biomarkers for severity of SARS-CoV-2 infection are of great interest. In this study, we evaluated a set of collagen metabolites and extracellular matrix remodeling biomarkers including procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1) and hyaluronic acid (HA) as prognostic indicators in COVID-19 patients. Methods: Ninety COVID-19 patients with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, and HA were measured and correlated with inflammatory indices and clinical variables. Patients were stratified for disease severity according to WHO criteria in two groups, based on the requirement of oxygen support. Results: Serum TIMP-1, but not PIIINP and HA was significantly higher in patients with WHO score ≥5 compared to patients with WHO score <5 [PIIINP: 7.2 (5.4-9.5) vs. 7.1 (4.5-9.9), p = 0.782; TIMP-1: 298.1 (20.5-460) vs. 222.2 (28.5-452.8), p = 0.01; HA: 117.1 (55.4-193.7) vs. 75.1 (36.9-141.8), p = 0.258]. TIMP-1 showed moderate correlation with CRP (r = 0.312, p = 0.003) and with LDH (r = 0.263, p = 0.009). CRP and serum LDH levels were significantly higher in COVID-19 patients with WHO score ≥5 compared to the group of patients with WHO score < 5 [15.8 (9-44.5) vs. 9.3 (3.4-33.8), p = 0.039 and 373 (282-465) vs. 289 (218-383), p = 0.013, respectively]. Conclusion: In patients with COVID-19, circulating TIMP-1 was associated with disease severity and with systemic inflammatory index, suggesting that TIMP-1 could represent a promising non-invasive prognostic biomarker in COVID-19 patients. Interestingly, our results prompted that serum TIMP-1 level may potentially be used to select the patients for therapeutic approaches targeting matrix metalloproteases pathway.

Effects of Exercise on Heart Failure with Preserved Ejection Fraction: An Updated Review of Literature.

Heart failure with preserved ejection fraction (HFpEF) represents the most common HF phenotype of patients aged > 65 years, with an incidence and a prevalence that are constantly growing. The HFpEF cardinal symptom is exercise intolerance (EI), defined as the impaired ability to perform physical activity and to reach the predicted age-related level of exercise duration in the absence of symptoms­such as fatigue or dyspnea­and is associated with a poor quality of life, a higher number of hospitalizations, and poor outcomes. The evidence of the protective effect between exercise and adverse cardiovascular outcomes is numerous and long-established. Regular exercise is known to reduce cardiovascular events and overall mortality both in apparently healthy individuals and in patients with established cardiovascular disease, representing a cornerstone in the prevention and treatment of many cardio-metabolic conditions. Several studies have investigated the role of exercise in HFpEF patients. The present review aims to dwell upon the effects of exercise on HFpEF. For this purpose, the relevant data from a literature search (PubMed, EMBASE, and Medline) were reviewed. The analysis of these studies underlines the fact that exercise training programs improve the cardiorespiratory performance of HFpEF patients in terms of the increase in peak oxygen uptake, the 6 min walk test distance, and the ventilatory threshold; on the other hand, diastolic or systolic functions are generally unchanged or only partially modified by exercise, suggesting that multiple mechanisms contribute to the improvement of exercise tolerance in HFpEF patients. In conclusion, considering that exercise training programs are able to improve the cardiorespiratory performance of HFpEF patients, the prescription of exercise training programs should be encouraged in stable HFpEF patients, and further research is needed to better elucidate the pathophysiological mechanisms underpinning the beneficial effects described.

What have we learned so far from the sex/gender issue in heart failure? An overview of current evidence.

There are important differences in epidemiology, pathophysiology, HF patterns, prognosis, and treatment. Women have a higher incidence of HFpEF due to sex-specific factors (such as anthropometry, role of estrogens, pregnancy-related cardiomyopathies), increased incidence of comorbidities, and gender-specific conditions. Men instead present a predisposition to the development of HFrEF due to a higher incidence of coronary artery disease and myocardial infarction. However, there are still gaps in the management of women with HF. The poor inclusion of women in clinical trials may have contributed to a lesser understanding of disease behavior than in men. In addition, a full understanding of gender-specific factors that are studied in small populations is lacking in the literature, and only in recent years, studies have increased their focus on this issue. Understanding how society, family, and environment affect the prognosis of HF patients may help clinicians provide more appropriate levels of care. In this overview, we aimed at summarizing all the key available evidence regarding sex/gender differences in heart failure.

Down Syndrome Fetal Fibroblasts Display Alterations of Endosomal Trafficking Possibly due to SYNJ1 Overexpression.

Endosomal trafficking is essential for cellular homeostasis. At the crossroads of distinct intracellular pathways, the endolysosomal system is crucial to maintain critical functions and adapt to the environment. Alterations of endosomal compartments were observed in cells from adult individuals with Down syndrome (DS), suggesting that the dysfunction of the endosomal pathway may contribute to the pathogenesis of DS. However, the nature and the degree of impairment, as well as the timing of onset, remain elusive. Here, by applying imaging and biochemical approaches, we demonstrate that the structure and dynamics of early endosomes are altered in DS cells. Furthermore, we found that recycling trafficking is markedly compromised in these cells. Remarkably, our results in 18-20 week-old human fetal fibroblasts indicate that alterations in the endolysosomal pathway are already present early in development. In addition, we show that overexpression of the polyphosphoinositide phosphatase synaptojanin 1 (Synj1) recapitulates the alterations observed in DS cells, suggesting a role for this lipid phosphatase in the pathogenesis of DS, likely already early in disease development. Overall, these data strengthen the link between the endolysosomal pathway and DS, highlighting a dangerous liaison among Synj1, endosomal trafficking and DS.

PIMREG expression level predicts glioblastoma patient survival and affects temozolomide resistance and DNA damage response.

PIMREG expression strongly correlates with cellular proliferation in both malignant and normal cells. Throughout embryo development, PIMREG expression is prominent in the central nervous system. Recent studies have described elevated PIMREG expression in different types of tumors, which correlates with patient survival and tumor aggressiveness. Given the emerging significance of PIMREG in carcinogenesis and its putative role in the context of the nervous system, we investigated the expression and function of PIMREG in gliomas, the most common primary brain tumors. We performed an extensive analysis of PIMREG expression in tumors samples from glioma patients. We then assessed the effects of PIMREG silencing and overexpression on the sensitivity of glioblastoma cell lines treated with genotoxic agents commonly used for treating patients and assessed for treatment response, proliferation and migration. Our analysis shows that glioblastoma exhibits the highest levels of PIMREG expression among all cancers analyzed and that elevated PIMREG expression is a biomarker for glioma progression and patient outcome. Moreover, PIMREG is induced by genotoxic agents, and its silencing renders glioblastoma cells sensitive to temozolomide treatment and affects ATR- and ATM-dependent signaling. Our data demonstrate that PIMREG is involved in DNA damage response and temozolomide resistance of glioblastoma cells and further supports a role for PIMREG in tumorigenesis.

Anabolic hormones and heart failure with preserved ejection fraction: looking for Ariadne's thread.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome that accounts for more than half of all heart failure patients. Identification, early diagnosis and management of patients are still complex, and no targeted treatment is available, since all tested drugs were not able to lower hard clinical outcomes. A multi-hormonal deficiency syndrome has been described in HFpEF patients suggesting that different hormones may represent new biomarkers of the disease, but their clinical utility is still debated. The natriuretic peptides are the cornerstone biomarker in heart failure, predicting cardiovascular death and heart failure hospitalization. Testosterone and DHEA-S deficiencies have been reported in HFpEF and associated with right ventricular impairment and diastolic dysfunction. IGFBP-1/IGF-1 axis correlates with echocardiographic parameters of HFpEF patients and with several prognostic biomarkers including NT-proBNP and C reactive protein. Low triiodothyronine syndrome is frequently found in HFpEF and thyroid hormones should represent a potential biomarker of risk stratification and prognosis.

Phenotypic Effects of Homeodomain-Interacting Protein Kinase 2 Deletion in Mice.

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.