A Systematization of Cybersecurity Regulations, Standards and Guidelines for the Healthcare Sector

The growing adoption of IT solutions in the healthcare sector is leading to a steady increase in the number of cybersecurity incidents. As a result, organizations worldwide have introduced regulations, standards, and best practices to address cybersecurity and data protection issues in this sector. However, the application of this large corpus of documents presents operational difficulties, and operators continue to lag behind in resilience to cyber attacks. This paper contributes a systematization of the significant cybersecurity documents relevant to the healthcare sector. We collected the 49 most significant documents and used the NIST cybersecurity framework to categorize key information and support the implementation of cybersecurity measures.Comment: 14 page

Ramie fibers in a comparison between chemical and microbiological retting proposed for application in biocomposites

Due to light weight, renewability, sustainability and generally moderate costs, natural fibers are addressed for the production of composites for application in packaging, automotive and other indus- tries. Several approaches are under investigation to improve compatibility with polymer matrices and improve mechanical performances of composites with natural fibers. The retting process is the major limitation to efficient and high-quality natural fiber production. The conventional retting is normally done chemically by treatment of decorticated fibers with hot alkaline solutions. Such a process requires high energy input and produces hazardous wastes. Microbiological and enzymatic methods represent a reliable replacement, however their application on ramie (Boehmeria nivea (L.) Gaud.) has not yet been optimized and tuned for use on a large scale. Consequently, the aim of this work was to evaluate the role of microbiological retting on the morphological, chemical and physical–mechanical properties of the derived ramie fibers for application in biocomposites. The decorticated ramie fibers, obtained by mature crop stands grown at the experimental station of the Department of Agriculture, Food and Environment (DAFE) of the University of Pisa, were subjected to a water based microbiological degumming performed with the use of two selected strains of Clostridium felsineum L. at 30◦C for 7 days. The results obtained with this method were compared with those recorded adopting the conventional chemical process with NaOH water solution at 100 ◦ C for 2 h. The morphological, chemical (hemicellulose, cellulose, lignin and ash) and physico-mechanical (tensile strength, elastic modulus and elongation at break) properties of retted ramie fibers were investigated. The fibers produced were evaluated for the production of compos- ites by using polyhydroxyalkanoates (PHAs) as polymeric matrix, as targeted in the EC running project OLI-PHA. Significant differences were observed between the two types of degumming in terms of yield and quality of the fibers. Even if the highest fiber yields were recorded with chemical retting, the perfor- mances of fibers modified by microbiological treatments were comparable with those of the composite prepared with fibers modified by chemical treatment. Scanning electron microscopy analysis revealed a good removal of non-cellulosic gummy material from the surface of ramie fibers. According to the mechanical properties, the ramie fibers obtained by both degumming processes, were suitable for use in PHAs composites

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

The multifaceted landscape behind imatinib resistance in gastrointestinal stromal tumors (GISTs): A lesson from ripretinib

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal sarcomas and the gold-standard treatment is rep-resented by tyrosine kinase inhibitors (TKIs). Unfortunately, first-line treatment with the TKI imatinib usually promotes partial response or stable disease rather than a complete response, and resistance appears in most pa-tients. Adaptive mechanisms are immediately relevant at the beginning of imatinib therapy, and they may rep-resent the reason behind the low complete response rates observed in GISTs. Concurrently, resistant subclones can silently continue to grow or emerge de novo, becoming the most representative populations. Therefore, a slow evolution of the primary tumor gradually occurs during imatinib treatment, enriching heterogeneous ima-tinib resistant clonal subpopulations. The identification of secondary KIT/PDGFRA mutations in resistant GISTs prompted the development of novel multi-targeted TKIs, leading to the approval of sunitinib, regorafenib, and ripretinib. Although ripretinib has broad anti-KIT and-PDGFRA activity, it failed to overcome sunitinib as second-line treatment, suggesting that imatinib resistance is more multifaceted than initially thought. The present review summarizes several biological aspects suggesting that heterogeneous adaptive and resistance mechanisms can also be driven by KIT or PDGFRA downstream mediators, alternative kinases, as well as non -coding RNAs, which are not targeted by any TKI, including ripretinib. This may explain the modest effect observed with ripretinib and all anti-GIST agents in patients.& COPY; 2023 Elsevier Inc. All rights reserved

Polimorfizmi u genima za popravak DNA: poveznica s biomarkerima mikronukleus-testa u medicinskih radnika kronično izloženih niskim dozama ionizirajućeg zračenja

Individual sensitivity to ionising radiation (IR) is the result of interaction between exposure, DNA damage, and its repair, which is why polymorphisms in DNA repair genes could play an important role. We examined the association between DNA damage, expressed as micronuclei (MNi), nuclear buds (NBs), and nucleoplasmic bridges (NPBs) and single nucleotide polymorphisms in selected DNA repair genes (APE1, hOGG1, XRCC1, XRCC3, XPD, PARP1, MGMT genes; representative of the different DNA repair pathways operating in mammals) in 77 hospital workers chronically exposed to low doses of IR, and 70 matched controls. A significantly higher MNi frequency was found in the exposed group (16.2±10.4 vs. 11.5±9.4; P=0.003) and the effect appeared to be independent from the principal confounding factor. Exposed individuals with hOGG1, XRCC1, PARP1, and MGMT wild-type alleles or APEX1, as well as XPD (rs13181) heterozygous showed a significantly higher MNi frequency than controls with the same genotypes. Genetic polymorphism analysis and cytogenetic dosimetry have proven to be a powerful tool complementary to physical dosimetry in regular health surveillance programmes.Individualna osjetljivost na ionizirajuće zračenje rezultat je međudjelovanja samog izlaganja zračenju, oštećenja DNA nastalog prilikom tog izlaganja te samog popravka nastalog oštećenja. Veliki doprinos razlikama čine i polimorfizmi u genima za popravak DNA. U ovom radu istražili smo povezanost nastalih oštećenja DNA u obliku mikronukleusa (MN), jezgrinih pupova (NB) i nukleoplazmatskih mostova (NPB) s polimorfizmima jednog nukleotida (SNP) u genima za popravak DNK (APE1, hOGG1, XRCC1, XRCC3, XPD, PARP1, MGMT) koji sudjeluju u različitim mehanizmima popravka. Rezultati skupine od 77 medicinskih radnika kronično izloženih niskim dozama ionizirajućeg zračenja uspoređeni su s rezultatima skupine od 70 odgovarajućih kontrola. Izložena skupina imala je značajno veću učestalost MN-a (16,2±10,4 vs. 11.5±9.4; P=0,003), a sama pojavnost oštećenja bila je neovisna o medijatornoj varijabli (kovarijati). Značajno više učestalosti MN nađene su u izloženoj skupini u homozigotnih nositelja divljeg tipa gena hOGG1, XRCC1, PARP1 i MGMT i u heterozigotnih nositelja gena APEX1 i XPD (rs13181) u odnosu na kontrolnu skupinu istoga genotipa. Analiza genskih polimorfizama i citogenetička dozimetrija važna su dopuna osobnom dozimetrijskom nadzoru izloženih radnika

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

Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM

Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids. Here, we report the derivation of NLSDM-induced pluripotent stem cells (NLSDM-iPSCs) from fibroblasts of two patients carrying different PNPLA2 mutations. The first patient was homozygous for the c.541delAC, while the second was homozygous for the c.662G>C mutation in the PNPLA2 gene. We verified that the two types of NLSDM-iPSCs possessed properties of embryonic-like stem cells and could differentiate into the three germ layers in vitro. Immunofluorescence analysis revealed that iPSCs had an abnormal accumulation of triglycerides in LDs, the hallmark of NLSDM. Furthermore, NLSDM-iPSCs were deficient in long chain fatty acid lipolysis, when subjected to a pulse chase experiment with oleic acid. Collectively, these results demonstrate that NLSDM-iPSCs are a promising in vitro model to investigate disease mechanisms and screen drug compounds for NLSDM, a rare disease with few therapeutic options

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