👤 Mirella Russo

Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um ​+ ​DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action. Show less

BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODSWe investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTSIn the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33-2.49 and 3.53, 95% CI: 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONSRare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDINGEuropean Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH. Show less

We evaluated the accuracy of standard machine learning (ML) algorithms in predicting 1-year cognitive decline in Alzheimer's disease patients with mild cognitive impairment (ADMCI) using resting-state electroencephalographic (rsEEG) biomarkers enriched with APOE genotype, sex, age, and educational attainment data. The study analyzed datasets from 63 ADMCI patients obtained from an international archive. The ML algorithms included Simple Logistic Regression, Model Trees, Logistic Regression, K-nearest neighbor, and Support Vector Machine. Input features comprised lobar rsEEG source activities across delta (<4 Hz) to alpha (≈10-12 Hz) bands, cerebrospinal fluid (CSF Aβ1-42/p-tau), and structural magnetic resonance imaging (sMRI) biomarkers. Cognitive decline was assessed over a 1-year follow-up ("stable" vs. "decliner") based on Mini-Mental State Examination (MMSE) scores. The four independent ML algorithms accurately predicted changes in the MMSE score over a 1-year follow-up, with accuracies of 77-78% in ADMCI participants aged ≥ 70 years and 74-77% in those aged < 70 years. These findings suggest that rsEEG biomarkers in ADMCI patients may not only reveal underlying pathophysiological mechanisms affecting cortical arousal and vigilance but also hold predictive value for cognitive outcomes. Show less

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder in which numerous interconnected pathological processes, such as cholinergic deficits, Aβ and tau aggregation, oxidative stress, metal dyshomeostasis, mitochondrial dysfunction, and neuroinflammation, synergistically drive neuronal damage and cognitive decline. This heterogeneity has limited the effectiveness of the clinically available single-target therapies which only provide symptomatic relief and underscores the need for molecular frameworks capable of addressing multiple pathogenic pathways simultaneously to stop the progression of the disease. Hydrazones have emerged as highly versatile scaffolds in medicinal chemistry thanks to their straightforward synthesis, structural adaptability, and rich repertoire of interaction modes with different biological targets. In recent literature, an increasing number of hydrazone-based molecules have been designed as multitarget-directed ligands (MTDLs) to modulate key enzymes and pathological mechanisms relevant to AD. This review provides a comprehensive and critical overview of hydrazone-containing compounds reported over the last years (2020-2025) with potential application in AD therapy, highlighting their activity on classical targets, especially cholinesterases (ChEs), as well as emerging targets including carbonic anhydrase, BACE1, and α-glycosidase. Particular emphasis is placed on structure-activity relationships (SARs), multitarget profiles, and rational design strategies aimed at exploiting the hydrazone moiety to address the multifactorial nature of AD. Show less

Elevated lipoprotein(a) [Lp(a)] levels have been strongly related to cardiovascular (CV) risk. However, its association with Hypertension Mediated Organ Damage (HMOD) and CV events in the primary prevention setting remains unclear. To evaluate in these patients, the correlation between Lp(a) levels and: (i) heart, vessels and kidney HMOD and; (ii) CV events and all-cause mortality in a primary prevention setting. 747 low CV risk subjects were recruited between 2009 and 2014. HMOD was assessed through Pulse Wave Velocity, carotid Intima-Media Thickness (IMT), presence of carotid plaques, Left Ventricular Hypertrophy (LVH) and Ejection Fraction and glomerular filtration rate. All-cause mortality and CV events up to 2021 were retrieved by electronic health records, for a median follow-up time of 10 years (I-III quartiles 9.6-11.1). Mean age was 50.8 ± 13.0 years and 63.5% of the subjects were men. The prevalence of hypertension was 37.9%, dyslipidemia 67.2%, smoking 17.8%, and diabetes mellitus 8.7%. Median Lp(a) value was 17 mg/dL (5.9-56.0), and 26.5% of patients had values above 50 mg/dL. Regarding HMOD, 10.3% subjects had arterial stiffness, 7.2% increased IMT, 19.8% carotid plaques while only 0.7% had LVH. No significant correlation was found between Lp(a) levels and indices of subclinical HMOD. Furthermore, no relationship was found between CV events and all-cause mortality and Lp(a) levels. In this primary prevention cohort, elevated Lp(a) levels were not associated with significant structural damage to the heart, carotid arteries, or increased aortic stiffness and were not associated with CV events and all-cause mortality. Show less

Although recommended for cardiovascular (CV) risk stratification in adults, the role of lipoprotein(a) [Lp(a)] in hypertension is not fully established. To evaluate Lp(a) levels in adult outpatients with essential arterial hypertension. A retrospective, observational study was conducted in outpatients of both sexes, aged ≥ 18 years, with treated or untreated essential hypertension, who were consecutively evaluated at the Hypertension Unit, Excellence Hypertension Center, Sant'Andrea Hospital, Rome, Italy. Participants underwent office and out-of-office blood pressure (BP) measurements, as well as assessment of hypertension-mediated organ damage (HMOD). BP measurements were performed, and hypertension phenotypes were classified according to 2023 European hypertension guidelines. Lp(a) levels were measured, and the study population was stratified according to a Lp(a) cut-off value of ≥50 mg/dl. Due to the non-uniform distribution, absolute Lp(a) values were logarithmically transformed. A total of 230 patients with available Lp(a) values were included (42.6% women, mean age 66.3 ± 11.5 years, BMI 27.1 ± 4.5 kg/m2, office BP 137.1 ± 18.1/83.7 ± 11.0 mmHg, 24-hour BP 129.8 ± 14.5/79.6 ± 9.8 mmHg, Lp(a) 51.4 ± 65.3 mg/dL), among whom 32.2% had Lp(a) ≥50 mg/dl. There were significantly higher proportions of men (74.3% vs. 49.4%; P < 0.001), dyslipidaemia (97.3% vs. 75.0%; P < 0.001) and comorbidities (55.4% vs. 30.8%; P < 0.001) in patients with high Lp(a) than in those with normal Lp(a), who also received more frequently lipid lowering therapies (P < 0.001) and aspirin (P = 0.003). However, lower office systolic BP values (133.5±18.8 vs. 138.8±17.6 mmHg: P = 0.036) were observed in patients with Lp(a) ≥50 mg/dL than in those with < 50 mg/dl. Also, no significant differences for Lp(a) levels were observed among various hypertension phenotypes, as defined by office (P = 0.156) or out-of-office BP values (P = 0.065). No significant correlations were found between Lp(a) and office or out-of-office BP levels, both in treated and untreated hypertensive outpatients. In our population, Lp(a) levels were not associated with either office or out-of-office BP values, irrespective of antihypertensive treatment status. The role of Lp(a) in hypertension warrants further investigation. Show less

Mammalian genomes harbor hundreds of thousands of RNA polymerase II (RNA Pol II) landing pads, enhancers, and promoters from which transcription initiates bidirectionally. Nevertheless, processive transcription is largely restricted to the small gene-containing fraction of the genome. An essential metazoan complex, Restrictor, composed of WDR82 and ZC3H4, restrains processive RNA Pol II activity at extragenic transcription units, thus representing a critical enforcer of genome utilization. However, because of the widespread recruitment of Restrictor to both genic and non-genic transcription sites, the mechanistic basis for its selectivity for extragenic transcription is unclear. Here, we show that while WDR82 tethers Restrictor to transcription initiation sites, the C3H1-type zinc fingers of ZC3H4 make sequence-specific interactions with motifs enriched at the 5' end of extragenic transcripts, with such interactions being required for transcription termination. Hence, although Restrictor recruitment requires WDR82-dependent tethering to the initiating RNA Pol II, its selectivity mainly arises from sequence-specific RNA recognition. Show less

Chronic kidney disease (CKD) is a growing global health burden, strongly associated with cardiovascular disease, the leading cause of mortality in this population. Dyslipidemia is a key metabolic abnormality in CKD, but traditional lipid measures such as total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides often fail to capture the complexity of lipid disturbances in CKD and after kidney transplantation. Apolipoproteins have emerged as more reliable markers of cardiovascular and renal risk. Elevated apolipoprotein B (ApoB), reduced apolipoprotein A1 (ApoA1), and a higher ApoB/ApoA1 ratio are linked to CKD progression, cardiovascular events, and post-transplant complications, including post-transplant diabetes mellitus. Lipoprotein(a), a genetically determined atherogenic lipoprotein, accumulates in CKD due to impaired clearance and further increases cardiovascular risk. Other apolipoproteins, such as APOL1 and APOE, modulate CKD susceptibility through lipid-dependent and independent mechanisms. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of lipid metabolism, and PCSK9 inhibitors may represent a promising therapeutic option, though evidence in advanced CKD and transplant recipients is still limited, especially regarding their effects on apolipoproteins. This review summarizes current evidence on apolipoproteins and PCSK9 in CKD and transplantation, with attention to their potential as biomarkers and therapeutic targets. Show less

Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs themselves are elevated in the myocardium of patients with HF, potentially due to a defect in BCAA catabolic breakdown. The rate limiting step of BCAA catabolism is the decarboxylation by the enzyme branched chain ketoacid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically. Here, using two pre-clinical CKM models, the hyperphagic ZSF1 obese rat and the uninephrectomized SDT fatty rat with high salt drinking water, we applied unbiased proteomic, transcriptomic and metabolomic profiling to assess overall kidney gene expression and mitochondrial function. We show that BCAA catabolic impairment is associated with and may be causal to CKM and demonstrated impairment in BCAA catabolism within ZSF1 obese rat kidneys. In both CKM animal models, treatment with the BDK inhibitor BT2 improved urine protein content, kidney hypertrophy, and kidney pathology. Furthermore, coadministration of BT2 and the sodium-glucose cotransporter-2 inhibitor empagliflozin demonstrated additive effects to improve kidney parameters, kidney gene expression signatures, and kidney mitochondrial density and function. Our study suggests that in addition to its previously reported beneficial effects on metabolism and cardiac function, BDK inhibition may also improve kidney health and therefore could represent a new therapeutic avenue for CKM. Show less

Molecular analysis of Each participating institution was requested to apply its own diagnostic testing strategy on 8 sections obtained from artificial reference specimens built to harbor Overall, cell resuspension yielded higher amounts of DNA and RNA (SNU16 61.5 ng/µl, 38100.0 pg/µl; RT112 118.0/µl, 2140.0 pg/µl, respectively) in comparison with SNU16+ RT112 mixing cell block (0.7 ng/µl DNA and 412.0 pg/µl RNA). Moreover, FFPE samples showed a higher fragmentation index (DIN 1.2 and RIN not calculated) compared with cell line resuspension (DIN 2.2 and 9.5 for SNU16 and RT112; RIN 3.9 and 6.8 for SNU16 and RT112). All participating institutions identified NGS represents the most suitable approach in molecular profiling of Show less

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field. Show less

Aortic valve stenosis (AVS) is the most common valvular disease in developed countries, and no pharmacological therapy is currently available. Increasing evidence identifies lipoprotein(a) [Lp(a)] as a causal factor linking lipid metabolism, inflammation, and valve calcification. Lp(a) levels are largely genetically determined and remain stable throughout life, making them a potential therapeutic target. This review summarizes the current evidence on Lp(a) and AVS pathophysiology, the diagnostic and prognostic role of Lp(a), and the therapeutic potential of Lp(a)-lowering agents. Emerging Lp(a)-targeted therapies, including antisense oligonucleotides and siRNA-based agents, could reshape AVS management by providing the first pharmacological option to slow disease progression in selected high-risk patients. Show less

Obesity is a multifactorial condition with a relevant genetic correlation. Recent advances in genomic research have identified several single nucleotide polymorphisms (SNPs) in genes such as FTO, MCM6, HLA, and MC4R, associated with obesity. This study aimed to evaluate the association of 102 SNPs with BMI and weight loss treatment response in a multi-ethnic population. The study analyzed 9,372 patients for the correlation between SNPs and BMI (dataset A). The correlation between SNP and weight loss was accessed in 474 patients undergoing different treatments (dataset B). Patients in dataset B were further divided into 3 categories based on the type of intervention: dietary therapy, intragastric balloon procedures, or surgeries. SNP association analysis and multiple models of inheritance were performed. In dataset A, ten SNPs, including rs9939609 (FTO), rs4988235 (MCM6), and rs2395182 (HLA), were significantly associated with increased BMI. Additionally, other four SNPs, rs7903146 (TCF7L2), (rs6511720), rs5400 (SLC2A2), and rs7498665 (SH2B1), showed sex-specific correlation. For dataset B, SNPs rs2016520 (PPAR-Delta) and rs2419621 (ACSL5) demonstrated significant correlation with weight loss for all treatment types. In patients who adhered to dietary therapy, SNPs rs6544713 (ABCG8) and rs762551 (CYP1A2) were strongly correlated with weight loss. Patients undergoing surgical or endoscopic procedures exhibited differential correlations with several SNPs, including rs1801725 (CASR) and rs12970134 (MC4R), and weight loss. This study provides valuable insights into the genetic factors influencing BMI and weight loss response to different treatments. The findings highlight the potential for personalized weight management approaches based on individual genetic profiles. Show less

A 43-year-old came to our observation for progressive cognitive impairment, confirmed by the neuropsychological evaluation. A diagnosis of multidomain amnestic mild cognitive impairment, due to unknown reasons, was posited at the first assessment. The patient's neurological exam was otherwise completely normal. The patient's mother was clinically diagnosed with frontotemporal dementia in her forties. The patient underwent neuroimaging investigations and cerebrospinal fluid analysis. Our diagnostic work-up pointed toward a neurodegenerative etiology, but the presence of concurrent cardiomyopathy emerged in the meantime. Due to the patient's family history, a thorough genetic screening was performed. The results revealed a unique genetic asset, with heterozygotic variants of three amyloid-related genes (PSEN1, APP, and MYBPC3). PSEN1 and MYBPC3 mutations showed distinct pathogenic features and accounted for the patient's brain and cardiac amyloidosis, whereas the APP variant was of uncertain pathological implications. Show less

Aqueous humor (AH) can be easily and safely used to evaluate disease-specific biomarkers in ocular disease. The aim of this study was to identify specific proteins biomarkers in the AH of retinoblastoma (RB) patients at various stages of the disease. We analyzed the proteome of 53 AH samples using high-resolution mass spectrometry. We grouped the samples according to active vitreous seeding (Group 1), active aqueous seeding (Group 2), naive RB (group 3), inactive RB (group 4), and congenital cataracts as the control (Group 5). We found a total of 889 proteins in all samples. Comparative parametric analyses among the different groups revealed three additional proteins expressed in the RB groups that were not expressed in the control group. These were histone H2B type 2-E (HISTH2B2E), InaD-like protein (PATJ), and ubiquitin conjugating enzyme E2 V1 (UBE2V1). Upon processing the data of our study with the OpenTarget Tool software, we found that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and CD44 were more highly expressed in the RB groups. Our results provide a proteome database regarding AH related to RB disease that may be used as a source of biomarkers. Further prospective studies should validate our finding in a large cohort of RB patients. Show less

The pathogenesis of Crohn's disease [CD] is still unclear. Disorders in the mucosal immunoregulation and its crosstalk with the microbiota may represent an important component in tissue injury. We aimed to characterize the molecular immune response distribution within the ileal layers and to evaluate the correlated microbiota in pathological/healthy settings comparing first surgery/relapse clinical conditions. We enrolled 12 CD patients. A comprehensive analysis of an ileal mucosa, submucosa and serosa broad-spectrum cytokine panel was performed through a multiplex approach. In addition, ileal microbiota composition was assessed through next generation sequencing. We observed a distinct profile [of IL1-α, IL-1β, IL-4, IL-8, ICAM-1, E-Selectin, P-Selectin, IP-10, IL 6 and IL 18] across the CD vs healthy ileal layers; and a different distribution of IFN- γ, P-Selectin, IL-27 and IL-21 in first surgery vs relapse patients. In addition, the phylum Tenericutes, the family Ruminococcaceae, and the genera Mesoplasma and Mycoplasma were significantly enriched in the pathological setting. Significant microbiota differences were observed between relapse and first surgery patients regarding the class Bacteroidia, and the genera Prevotella, Flavobacterium, Tepidimonas and Escherichia/Shigella. Finally, the abundance of the genus Mycoplasma was positively correlated with IL-18. We describe a dissimilarity of cytokine distribution and microbiota composition within CD and adjacent healthy ileal tissue layers and between first operation and surgical relapse. Our results give potential insight into the dynamics of the gut microbiota-immune axis in CD patients, leading to detection of new biomarkers. Show less

Interactions between the splicing machinery and RNA polymerase II increase protein-coding gene transcription. Similarly, exons and splicing signals of enhancer-generated long noncoding RNAs (elncRNAs) augment enhancer activity. However, elncRNAs are inefficiently spliced, suggesting that, compared with protein-coding genes, they contain qualitatively different exons with a limited ability to drive splicing. We show here that the inefficiently spliced first exons of elncRNAs as well as promoter-antisense long noncoding RNAs (pa-lncRNAs) in human and mouse cells trigger a transcription termination checkpoint that requires WDR82, an RNA polymerase II-binding protein, and its RNA-binding partner of previously unknown function, ZC3H4. We propose that the first exons of elncRNAs and pa-lncRNAs are an intrinsic component of a regulatory mechanism that, on the one hand, maximizes the activity of these cis-regulatory elements by recruiting the splicing machinery and, on the other, contains elements that suppress pervasive extragenic transcription. Show less

As the prevalence of metabolic syndrome (MetS) in children and young adults is increasing, a better understanding of genetics that underlie MetS will provide critical insights into the origin of the disease. We examined associations of common genetic variants and repeated MetS score from early childhood to adolescence in a pan-European, prospective IDEFICS/I.Family cohort study with baseline survey and follow-up examinations after two and six years. We tested associations in 3067 children using a linear mixed model and confirmed the results with meta-analysis of identified SNPs. With a stringent Bonferroni adjustment for multiple comparisons we obtained significant associations(p < 1.4 × 10 Show less

Biliary atresia is a neonatal liver disease with extrahepatic bile duct obstruction and progressive liver fibrosis. The etiology and pathogenesis of the disease are unknown. We previously identified a plant toxin, biliatresone, responsible for biliary atresia in naturally-occurring animal models, that causes cholangiocyte destruction in in-vitro models. Decreases in reduced glutathione (GSH) mimic the effects of biliatresone, and agents that replenish cellular GSH ameliorate the effects of the toxin. The goals of this study were to define signaling pathways downstream of biliatresone that lead to cholangiocyte destruction and to determine their relationship to GSH. Using cholangiocyte culture and 3D cholangiocyte spheroid cultures, we found that biliatresone and decreases in GSH upregulated RhoU/Wrch1, a Wnt signaling family member, which then mediated an increase in Hey2 in the NOTCH signaling pathway, causing downregulation of the transcription factor Sox17. When these genes were up- or down-regulated, the biliatresone effect on spheroids was phenocopied, resulting in lumen obstruction. Biopsies of patients with biliary atresia demonstrated increased RhoU/Wrch1 and Hey2 expression in cholangiocytes. We present a novel pathway of cholangiocyte injury in a model of biliary atresia, which is relevant to human BA and may suggest potential future therapeutics. Show less

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM. Show less

Cardiomyopathies caused by double gene mutations are rare but conferred a remarkably increased risk of end-stage progression, arrhythmias, and poor outcome. Compound genetic mutations leading to complex phenotype in the setting of cardiomyopathies represent an important challenge in clinical practice, and genetic tests allow risk stratification and personalized clinical management of patients. We report a case of a 50-year-old woman with congestive heart failure characterized by dilated cardiomyopathy, diffuse coronary disease, complete atrioventricular block, and missense mutations in cardiac myosin-binding protein C (MYBPC3) and myopalladin (MYPN). We discuss the plausible role of genetic profile in phenotype determination. Show less

Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms. A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. In vitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T > C (W113R), c.644G > A (G215E) and c.1211T > G (M404R); patient 2 was heterozygous for the known variant c.658A > C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G > T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein. We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic. Show less

T-lineage ALL is an aggressive disease that needs to be treated with intensive treatment schedules. A late relapse rarely occurs and a clear choice for second-line treatment is on debate. We report on a young adult with a very late isolated extramedullary relapse of PICALM-MLLT10 positive T-ALL, successfully treated with a chemotherapy-based and radiotherapy-based pediatric protocol. We demonstrate that relapse can occur in T-ALL although a SR-MRD behavior treated with a high-risk protocol; specific molecular diagnostic aberrations, as PICALM-MLLT10, are still conserved at very late relapse; a second-line treatment based on pediatric protocol can be effective. Show less

Recent evidence indicates that immune cells contribute to the formation of tumor metastases by regulating the pre-metastatic niche. Whether tumor-derived factors involved in primary tumor formation play a role in metastasis formation is poorly characterized. Oxysterols act as endogenous regulators of lipid metabolism through the interaction with the nuclear Liver X Receptors-(LXR)α and LXRβ. In the context of tumor development, they establish a pro-tumor environment by dampening antitumor immune responses, and by recruiting pro-angiogenic and immunosuppressive neutrophils. However, the ability of LXR/oxysterol axis to promote tumor invasion and metastasis by exploiting immune cells, is still up to debate. In this study we provide evidence that oxysterols participate in the primary growth of orthotopically implanted 4T1 breast tumors by establishing a tumor-promoting microenvironment. Furthermore, we show that oxysterols are involved in the metastatic spread of 4T1 breast tumors, since their enzymatic inactivation mediated by the sulfotransferase 2B1b, reduces the number of metastatic cells in the lungs of tumor-bearing mice. Finally, we provide evidence that oxysterols support the metastatic cascade by modifying the lung metastatic niche, particularly allowing the recruitment of tumor-promoting neutrophils. These results identify a possible new metastatic pathway to target in order to prevent metastasis formation in breast cancer patients. Show less

The development of effective strategies to prevent childhood obesity and its comorbidities requires new, reliable early biomarkers. Here, we aimed to identify in peripheral blood cells potential transcript-based biomarkers of unhealthy metabolic profile associated to overweight/obesity in children. We performed a whole-genome microarray analysis in blood cells to identify genes differentially expressed between overweight and normal weight children to obtain novel transcript-based biomarkers predictive of metabolic complications. The most significant enriched pathway of differentially expressed genes was related to oxidative phosphorylation, for which most of genes were downregulated in overweight versus normal weight children. Other genes were involved in carbohydrate metabolism/glucose homoeostasis or in lipid metabolism (for example, TCF7L2, ADRB3, LIPE, GIPR), revealing plausible mechanisms according to existing biological knowledge. A set of differentially expressed genes was identified to discriminate in overweight children those with high or low triglyceride levels. Functional microarray analysis has revealed a set of potential blood-cell transcript-based biomarkers that may be a useful approach for early identification of children with higher predisposition to obesity-related metabolic alterations. Show less

Diabetic kidney disease (DKD) and retinopathy (DR) develop in a considerable number of subjects with Type 2 Diabetes (T2D) despite the achievement of the recommended targets for glycaemia and blood pressure. Atherogenic dyslipidemia may play a relevant role, especially in T2DM women. We report our findings on the effect of diabetic dyslipidaemia, the HDL subclasses distribution and the common cholesteryl ester transfer protein (CETP)TaqIB variant on the incidence or the progression of DKD and DR in 97 T2D women, after a ∼9years of follow-up. At baseline, T2D women presented with low HDL-C levels and higher levels of large lipid rich α-1 (16.34mg/dl), α-2 (33.39mg/dl) and pre- α1 (4.81mg/dl) HDL subparticles. The CETP TaqIB polymorphism and baseline HbA1c, triglycerides, and HDL-C levels as well as specific HDL subpopulations were associated to the occurrence of RD after ∼9years of follow-up. At stepwise regression analysis, HbA1c, triglycerides and the less atheroprotective α-3 HDL particles were the only factors independently associated to the incidence of RD. These same variables were also associated with the progression from background to proliferative RD. BMI, LDL/HDL ratio and low levels of α-1 HDL particles were associated to the occurrence of DKD at univariate analysis, although BMI was the only significant predictor at stepwise multivariate regression analysis. In T2D women, atherogenic dyslipidemia as well as subtle modifications in lipoprotein particles profile are associated with incidence and progression of microvascular disease. Show less

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder. Show less

The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP. A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to <10 years from six European countries was included. The association between rs174546 (TShow less