Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation

Sporadic cases account for 90-95% of all patients with Parkinson's Disease (PD). Atypical Parkinsonism comprises approximately 20% of all patients with parkinsonism. Progressive Supranuclear Palsy (PSP) belongs to the atypical parkinsonian diseases and is histopathologically classified as a tauopathy. Here, we report that mesenchymal stem cells (MSCs) derived from the bone marrow of patients with PSP exhibit mitochondrial dysfunction in the form of decreased membrane potential and inhibited NADH-dependent respiration. Furthermore, mitochondrial dysfunction in PSP-MSCs led to a significant increase in mitochondrial ROS generation and oxidative stress, which resulted in decrease of major cellular antioxidant GSH. Additionally, higher basal rate of mitochondrial degradation and lower levels of biogenesis were found in PSP-MSCs, together leading to a reduction in mitochondrial mass. This phenotype was biologically relevant to MSC stemness properties, as it heavily impaired their differentiation into adipocytes, which mostly rely on mitochondrial metabolism for their bioenergetic demand. The defect in adipogenic differentiation was detected as a significant impairment of intracellular lipid droplet formation in PSP-MSCs. This result was corroborated at the transcriptional level by a significant reduction of PPARγ and FABP4 expression, two key genes involved in the adipogenic molecular network. Our findings in PSP-MSCs provide new insights into the etiology of 'idiopathic' parkinsonism, and confirm that mitochondrial dysfunction is important to the development of parkinsonism, independent of the type of the cell

Fighting viral infections and virus-driven tumors with cytotoxic CD4+ T cells

CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors

Effect of primary lesions in cytoskeleton proteins on red cell membrane stability in patients with hereditary spherocytosis

We investigated by targeted next generation sequencing the genetic bases of hereditary spherocytosis in 25 patients and compared the molecular results with the biochemical lesion of RBC membrane obtained by SDS-PAGE analysis. The HS diagnosis was based on available guidelines for diagnosis of congenital hemolytic anemia, and patients were selected because of atypical clinical presentation or intra-family variability, or because presented discrepancies between laboratory investigation and biochemical findings. In all patients but 5 we identified pathogenic variants in SPTA1, SPTB, ANK1, SLC4A1, EPB42 genes able to justify the clinical phenotype. Interestingly, a correspondence between the biochemical lesion and the molecular defect was identified in only 11/25 cases, mostly with band 3 deficiency due to SLC4A1 mutations. Most of the mutations in SPTB and ANK1 gene didn’t hesitate in abnormalities of RBC membrane protein; conversely, in two cases the molecular lesion didn’t correspond to the biochemical defect, suggesting that a mutation in a specific cytoskeleton protein may result in a more complex RBC membrane damage or suffering. Finally, in two cases the HS diagnosis was maintained despite absence of both protein defect and molecular lesion, basing on clinical and family history, and on presence of clear laboratory markers of HS. The study revealed complex relationships between the primary molecular lesion and the final effect in the RBC membrane cytoskeleton, and further underlines the concept that there is not a unique approach to the diagnosis of HS

Electrocardiographic changes in hiatal hernia: a case report

We describe the case of a 78-year-old woman admitted to our department for suspected silent myocardial ischaemia with the evidence of T wave inversion in anterior lead. All the instrumental exams excluded inducible myocardial ischaemia. A gastroscopy showed a moderate hiatal hernia. We postulate that electrocardiogram modification could be attributed to hiatal hernia

Liquid biopsy in non-small cell lung cancer: a meta-analysis of state-of-the-art and future perspectives

Introduction: To date, tissue biopsy represents the gold standard for characterizing non-small-cell lung cancer (NSCLC), however, the complex architecture of the disease has introduced the need for new investigative approaches, such as liquid biopsy. Indeed, DNA analyzed in liquid biopsy is much more representative of tumour heterogeneity. Materials and methods: We performed a meta-analysis of 17 selected papers, to attest to the diagnostic performance of liquid biopsy in identifying EGFR mutations in NSCLC. Results: In the overall studies, we found a sensitivity of 0.59, specificity of 0.96 and diagnostic odds ratio of 24,69. Since we noticed a high heterogeneity among different papers, we also performed the meta-analysis in separate subsets of papers, divided by 1) stage of disease, 2) experimental design and 3) method of mutation detection. Liquid biopsy has the highest sensitivity/specificity in high-stage tumours, and prospective studies are more reliable than retrospective ones in terms of sensitivity and specificity, both NGS and PCR-based techniques can be used to detect tumour DNA in liquid biopsy. Discussion: Overall, liquid biopsy has the potential to help the management of NSCLC, but at present the non-homogeneous literature data, lack of optimal detection methods, together with relatively high costs make its applicability in routine diagnostics still challenging

A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type with Different Phenotypes in the Same Family

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain (COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance

Atherosclerotic spontaneous coronary artery dissection (A-SCAD) in a patient with COVID-19: case report and possible mechanisms

AbstractBackgroundSpontaneous coronary artery dissection (SCAD) may be atherosclerotic (A-SCAD) or non-atherosclerotic (NA-SCAD) in origin. Contemporary usage of the term ‘SCAD’ is typically synonymous with NA-SCAD. COVID-19 could induce a vascular inflammation localized in the coronary adventitia and periadventitial fat and contribute to the development of an A-SCAD of a vulnerable plaque in a susceptible patient.Case summaryIn this report we describe a case of a COVID-19 patient with past cardiac history of CAD who was admitted for acute coronary syndrome (ACS). Coronary angiography demonstrated the culprit lesion in the proximal LAD that presented with a very complex and unusual morphology, indicative of an A-SCAD. The diagnosis of A-SCAD was supported by the presence of a mild stenosis in the same coronary segment in the last angiogram performed 3 years previously. He was successfully treated by PCI, had a favourable course of the COVID-19 with no symptoms of pneumonia, and was discharged from the hospital after two negative tests for SARS-CoV-2.DiscussionA higher index of suspicion of A-SCAD is needed in patients with suspected or confirmed COVID-19 presenting with ACS. The proposed approach with ‘thrombolysis first’ for treating STEMI patients with suspected or confirmed COVID-19 infection could be unsafe in the case of underlying A-SCAD.</jats:sec