Exploiting code mobility for dynamic binary obfuscation

Software protection aims at protecting the integrity of software applications deployed on un-trusted hosts and being subject to illegal analysis. Within an un-trusted environment a possibly malicious user has complete access to system resources and tools in order to analyze and tamper with the application code. To address this research problem, we propose a novel binary obfuscation approach based on the deployment of an incomplete application whose code arrives from a trusted network entity as a flow of mobile code blocks which are arranged in memory with a different customized memory layout. This paper presents our approach to contrast reverse engineering by defeating static and dynamic analysis, and discusses its effectivenes

Bicruciate-retaining total knee arthroplasty: What's new?

Primary total knee arthroplasty (TKA) is a widespread procedure to address end stage osteoarthritis with good results, clinical outcomes, and long-term survivorship. Although it is frequently performed in elderly, an increased demand in young and active people is expected in the next years. However, a considerable dissatisfaction rate has been reported by highly demanding patients due to the intrinsic limitations provided by the TKA. Bicruciate-retaining (BCR) TKA was developed to mimic knee biomechanics, through anterior cruciate ligament preservation. First-generation BCR TKA has not gained popularity due to its being a challenging technique and having poor survival outcomes. Thanks to implant design improvement and surgeon-friendly instrumentation, second-generation BCR TKA has seen renewed interest. This review will focus on surgical indications, kinematical basis, clinical results and latest developments of second-generation BCR TKA

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

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Exploiting Code Mobility for Dynamic Binary Obfuscation

Software protection aims at protecting the integrity of software applications deployed on un-trusted hosts and being subject to illegal analysis. Within an un-trusted environment a possibly malicious user has complete access to system resources and tools in order to analyze and tamper with the application code. To address this research problem, we propose a novel binary obfuscation approach based on the deployment of an incomplete application whose code arrives from a trusted network entity as a flow of mobile code blocks which are arranged in memory with a different customized memory layout. This paper presents our approach to contrast reverse engineering by defeating static and dynamic analysis, and discusses its effectiveness

Case Report: A Peculiar Case of Inflammatory Colitis After SARS-CoV-2 Infection

open14noWe report a case of inflammatory colitis after SARS-CoV-2 infection in a patient with no additional co-morbidity who died within three weeks of hospitalization. As it is becoming increasingly clear that SARS-CoV-2 infection can cause immunological alterations, we investigated the expression of the inhibitory checkpoint PD-1 and its ligand PD-L1 to explore the potential role of this axis in the break of self-tolerance. The presence of the SARS-CoV-2 virus in colon tissue was demonstrated by qRT-PCR and immunohistochemical localization of the nucleocapsid protein. Expression of lymphocyte markers, PD-1, and PD-L1 in colon tissue was investigated by IHC. SARSCoV- 2-immunoreactive cells were detected both in the ulcerated and non-ulcerated mucosal areas. Compared to healthy tissue, where PD-1 is weakly expressed and PD-L1 is absent, PD-1 and PD-L1 expression appears in the inflamed mucosal tissue, as expected, but was mainly confined to non-ulcerative areas. At the same time, these markers were virtually undetectable in areas of mucosal ulceration. Our data show an alteration of the PD-1/PD-L1 axis and suggest a link between SARS-CoV-2 infection and an aberrant autoinflammatory response due to concomitant breakdown of the PD-1/ PD-L1 interaction leading to early death of the patient.openRutigliani, Mariangela; Bozzo, Matteo; Barberis, Andrea; Greppi, Marco; Anelli, Emanuela; Castellaro, Luca; Bonsignore, Alessandro; Azzinnaro, Antonio; Pesce, Silvia; Filauro, Marco; Rollandi, Gian Andrea; Castagnola, Patrizio; Candiani, Simona; Marcenaro, EmanuelaRutigliani, Mariangela; Bozzo, Matteo; Barberis, Andrea; Greppi, Marco; Anelli, Emanuela; Castellaro, Luca; Bonsignore, Alessandro; Azzinnaro, Antonio; Pesce, Silvia; Filauro, Marco; Rollandi, Gian Andrea; Castagnola, Patrizio; Candiani, Simona; Marcenaro, Emanuel

Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells

Background Humans produce heat through non-shivering thermogenesis, a metabolic process that occurs in inducible beige adipocytes expressing uncoupling protein 1 (UCP1). UCP1 dissipates the proton gradient of the mitochondrial inner membrane and converts that energy into heat. It is unclear whether cancer cells can exhibit autonomous thermogenesis. Previously, we found that the knockdown of hypoxia-inducible fatty acid binding protein 7 (FABP7) increased reactive oxygen species (ROS) in breast cancer cells. ROS are known to induce beige adipocyte differentiation. Methods We investigated the association of tumor hypoxia, FABP7, and UCP1 across breast cancer patients using METABRIC and TCGA data sets. Furthermore, using a breast cancer cell line, HCC1806, we tested the effect of FABP7 knockdown on cellular physiology including thermogenesis. Results We found a strong mutual exclusivity of FABP7 and UCP1 expression both in METABRIC and in TCGA, indicating major metabolic phenotypic differences. FABP7 was preferentially distributed in poorly differentiated-, estrogen receptor (ER) negative tumors. In contrast, UCP1 was highly expressed in normal ducts and well-differentiated-, ER positive-, less hypoxic tumors. In the cell line-based experiments, UCP1 and its transcriptional regulators were upregulated upon FABP7 knockdown. UCP1 was induced in about 20% of cancer cells, and the effect was increased further in hypoxia. UCP1 depolarized mitochondrial membranes at the site of expression. UCP1 induction was associated with the increase in proton leak, glycolysis, and maximal respiration, mimicking the typical energy profile of beige adipocytes. Most importantly, UCP1 induction elevated cancer cell temperature associated with increased vulnerability to hypoxia and gamma-irradiation. Conclusions We demonstrated that breast cancer cells can undergo thermogenesis through UCP1 induction. Disrupting FABP7-mediated fatty acid metabolism can unlock UCP1-mediated thermogenesis, potentially making it possible to develop therapies to target thermogenesis. Further study would be warranted to investigate the effect of rise in temperature of cancer cells on patients' outcomes and the relationship to other metabolic pathways

Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1

open15siGenetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome-maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.openCapponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; Bandettini di Poggio, Monica; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia; Timmerman, VincentCapponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; BANDETTINI DI POGGIO, MONICA LAURA; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia; Timmerman, Vincen

Resources for assessing parents’ vaccine hesitancy: a systematic review of the literature

Vaccine hesitancy (VH) is a complex and country-specific issue, responsible for the decreasing vaccination rate and subsequent spread of vaccine-preventable diseases. In literature, several questionnaires were developed to assess VH. The aim of this systematic review was to evaluate the published questionnaires assessing parental VH. The search was conducted in PubMed/Medline, Web of Science and The Cochrane Library, in December 2017, following the PRISMA guidelines. The search strategy included 4 types of keywords: parents, vaccine hesitancy/acceptance, immunization and survey. Only English and Italian original papers were included. 17 reviewers independently screened titles and abstracts. Only the included articles were downloaded in full and, after a second screening, data were extracted and recorded in an ad hoc spreadsheet. A total of 5,139 articles were retrieved, after duplicates elimination 3,508 papers were screened. After a screening selection, 334 studies were included in the analysis. Most studies were cross-sectional (92.8%), followed by case-control (4.8%) and cohort studies (2.4%). The population interviewed was mainly parents, without any further details (73.1%); mothers were the only parent surveyed in approximately 20% of the studies, while only 1 study involved selectively the fathers. The sample size ranged from 7 to 59,897. Only 38% of the included studies reported both the number and type of items used. Regarding the type, more than half consisted of closed questions, followed by Likert scales, while open-ended questions were used in 14.8% of the surveys. Frequently, the survey was conducted using a self-reported questionnaire or interview. The questionnaires were mostly administered on paper, while online forms were used in 20.1% of the cases. However, 80.2% of the questionnaires were not attached to the paper. HPV vaccine was the most frequently investigated (39.2%), followed by influenza (13.5%) and measles (10.8%). While 22.4% of the articles referred to paediatrics vaccinations in general. Data about the immunization behaviours were reported in 294 studies: the subjects involved showed a behaviour defined as “acceptance” in 129 studies (38.6%), as “hesitancy/scepticism/doubt” in 145 studies (43.1%) and as “refusal” in 22 studies (6.6%). This information was not reported in 12% of the studies. VH is still a public health challenge, as confirmed by the high number of studies and questionnaires retrieved. This study offers a deeper perspec- tive on the available questionnaires, helping to identify the best one in terms of aim and study setting.     &nbsp

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma