Back to The Fusion: Mitofusin-2 in Alzheimer's Disease

Mitochondria are dynamic organelles that undergo constant fission and fusion. Mitochondria dysfunction underlies several human disorders, including Alzheimer's disease (AD). Preservation of mitochondrial dynamics is fundamental for regulating the organelle's functions. Several proteins participate in the regulation of mitochondrial morphology and networks, and among these, Mitofusin 2 (Mfn2) has been extensively studied. This review focuses on the role of Mfn2 in mitochondrial dynamics and in the crosstalk between mitochondria and the endoplasmic reticulum, in particular in AD. Understanding how this protein may be related to AD pathogenesis will provide essential information for the development of therapies for diseases linked to disturbed mitochondrial dynamics, as in AD

Isothiocyanates Are Promising Compounds against Oxidative Stress, Neuroinflammation and Cell Death that May Benefit Neurodegeneration in Parkinson's Disease

Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder and is characterized by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Despite intensive research, the mechanisms involved in neuronal loss are not completely understood yet; however, misfolded proteins, oxidative stress, excitotoxicity and inflammation play a pivotal role in the progression of the pathology. Neuroinflammation may have a greater function in PD pathogenesis than initially believed, taking part in the cascade of events that leads to neuronal death. To date, no efficient therapy, able to arrest or slow down PD, is available. In this context, the need to find novel strategies to counteract neurodegenerative progression by influencing diseases' pathogenesis is becoming increasingly clear. Isothiocyanates (ITCs) have already shown interesting properties in detoxification, inflammation, apoptosis and cell cycle regulation through the induction of phase I and phase II enzyme systems. Moreover, ITCs may be able to modulate several key points in oxidative and inflammatory evolution. In view of these considerations, the aim of the present review is to describe ITCs as pleiotropic compounds capable of preventing and modulating the evolution of PD

Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18-36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic) and the patient DNA (germline)

DNA Repair Gene Polymorphisms and Sensitivity to Ionising Radiation

Cilj ovog istraživanja bio je procijeniti razinu oštećenja DNA u leukocitima periferne krvi prije, neposredno nakon i 120 min nakon ozračivanja dozom zračenja od 2 Gy te usporediti razine nastalih oštećenja između kontrolne skupine i skupine medicinskih radnika izloženih niskim dozama ionizirajućeg zračenja na svojim radnim mjestima. Istražen je utjecaj polimorfi zma u genima koji sudjeluju u popravku DNA; *hOGG1, XRCC1 i MGMT na razinu izmjerenih oštećenja. Istraživanjem je obuhvaćeno 40 zdravih ispitanika obaju spolova (20 kontrola i 20 izloženih). Razina oštećenja DNA mjerena je komet-testom u alkalnim uvjetima, pri čemu su za svakog ispitanika i svaku vremensku točku analizirane vrijednosti dužine repa, % DNA u repu i repnog momenta kometa. Rezultati pokazuju da su vrijednosti % DNA u repu i repni moment kometa bili statistički značajno viši u izloženoj populaciji prije, neposredno nakon i 120 min nakon ozračivanja. Pokazano je da nosioci polimorfnih alela ovih gena u izloženoj skupini imaju statistički značajno više razine oštećenja DNA, kako naspram homozigota pripadne skupine, tako i naspram cijele kontrolne skupine te da početno oštećenje DNA značajno negativno korelira s ukupnom dozom zračenja koju su primili tijekom radnog vijeka. Dobiveni rezultati upućuju na vrijednost kombiniranja alkalnoga komet-testa i genotipizacije izloženih pojedinaca u genima za popravak DNA, što bi moglo pridonijeti prepoznavanju subpopulacija sklonijih nakupljanju oštećenja DNA, a time i sklonijih riziku od razvoja tumorskih bolesti.Increasing exposure to ionising radiation raises a great concern about potential DNA damage in occupationally exposed individuals. Polymorphisms of DNA repair genes can determine individual sensitivity and DNA damage response to low doses of ionising radiation. The objective of this study was to assess DNA damage in leukocytes at baseline, immediately after and 120 min after exposure to gamma-radiation of 2 Gy, to compare DNA damage between the control group of subjects and subjects occupationally exposed to low-dose gamma-radiation, and to determine the relationship between hOGG1 (8-oxoG specifi c DNA glycosylase/AP-Lyase, Ser326Cys), XRCC1 (X-ray repair cross-complementing protein-group 1, Arg194Trp), and MGMT(O6-methylguanine-DNA methyltransferase, Leu84Phe) gene and DNA damage. The study enrolled 40 healthy subjects (20 controls and 20 occupationally exposed subjects), whose leukocytes were exposed to ionising radiation and tested for DNA damage (tail length, percentage od DNA in comet tail, and tail moment) using the alkaline version of the comet assay. Our results show that tail DNA percentage and tail moment were signifi cantly higher in the exposed group at baseline, immediately after, and 120 min after exposure to 2 Gy. The exposed subjects carrying polymorphic alleles had signifi cantly higher DNA damage than homozygous carriers of the same gene and controls. Combined use of the alkaline comet assay and genotyping of DNA repair genes could help discover sensitive occupationally exposed individuals who can accumulate higher DNA damage and are at higher risk of developing tumours

Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an omic approach to identify novel druggable targets

Background: Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance. Methods: For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells. Results: We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism. Conclusion: Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets

Emerging Role of MicroRNAs in the Therapeutic Response in Cervical Cancer: A Systematic Review

Cervical cancer is a common female cancer, with nearly 600,000 cases and more than 300,000 deaths worldwide every year. From a clinical point of view, surgery plays a key role in early cancer management, whereas advanced stages are treated with chemotherapy and/or radiation as adjuvant therapies. Nevertheless, predicting the degree of cancer response to chemotherapy or radiation therapy at diagnosis in order to personalize the clinical approach represents the biggest challenge in locally advanced cancers. The feasibility of such predictive models has been repeatedly assessed using histopathological factors, imaging and nuclear methods, tissue and fluid scans, however with poor results. In this context, the identification of novel potential biomarkers remains an unmet clinical need, and microRNAs (miRNAs) represent an interesting opportunity. With this in mind, the aim of this systematic review was to map the current literature on tumor and circulating miRNAs identified as significantly associated with the therapeutic response in cervical cancer; finally, a perspective point of view sheds light on the challenges ahead in this tumor

miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs

Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5-7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset