Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Dynasore, a Dynamin Inhibitor, Inhibits Trypanosoma cruzi Entry into Peritoneal Macrophages

BACKGROUND: Trypanosoma cruzi is an intracellular parasite that, like some other intracellular pathogens, targets specific proteins of the host cell vesicular transport machinery, leading to a modulation of host cell processes that results in the generation of unique phagosomes. In mammalian cells, several molecules have been identified that selectively regulate the formation of endocytic transport vesicles and the fusion of such vesicles with appropriate acceptor membranes. Among these, the GTPase dynamin plays an important role in clathrin-mediated endocytosis, and it was recently found that dynamin can participate in a phagocytic process. METHODOLOGY/PRINCIPAL FINDINGS: We used a compound called dynasore that has the ability to block the GTPase activity of dynamin. Dynasore acts as a potent inhibitor of endocytic pathways by blocking coated vesicle formation within seconds of its addition. Here, we investigated whether dynamin is involved in the entry process of T. cruzi in phagocytic and non-phagocytic cells by using dynasore. In this aim, peritoneal macrophages and LLC-MK2 cells were treated with increasing concentrations of dynasore before interaction with trypomastigotes, amastigotes or epimastigotes. We observed that, in both cell lines, the parasite internalization was drastically diminished (by greater than 90% in LLC-MK2 cells and 70% in peritoneal macrophages) when we used 100 microM dynasore. The T. cruzi adhesion index, however, was unaffected in either cell line. Analyzing these interactions by scanning electron microscopy and comparing peritoneal macrophages to LLC-MK2 cells revealed differences in the stage at which cell entry was blocked. In LLC-MK2 cells, this blockade is observed earlier than it is in peritoneal macrophages. In LLC-MK2 cells, the parasites were only associated with cellular microvilli, whereas in peritoneal macrophages, trypomastigotes were not completely engulfed by a host cell plasma membrane. CONCLUSIONS/SIGNIFICANCE: Taken together our results demonstrate that dynamin is an essential molecule necessary for cell invasion and specifically parasitophorous vacuole formation by host cells during interaction with Trypanosoma cruzi

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18–49, 50–69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

MoBShield: a novel XML approach for securing mobile banking

Mobile banking security has witnessed significant R&D attention from both financial institutions and academia. This is due to the growing number of mobile baking applications and their reachability and usefulness to society. However, these applications are also attractive prey for cybercriminals, who use a variety of malware to steal personal banking information. Related literature in mobile banking security requires many permissions that are not necessary for the application's intended security functionality. In this context, this paper presents a novel efficient permission identification approach for securing mobile banking (MoBShield) to detect and prevent malware. A permission-based dataset is generated for mobile banking malware detection that consists large number of malicious adware apps and benign apps to use as training datasets. The dataset is generated from 1650 malicious banking apps of the Canadian Institute of Cybersecurity, University of New Brunswick and benign apps from Google Play. A machine learning algorithm is used to determine whether a mobile banking application is malicious based on its permission requests. Further, an eXplainable machine learning (XML) approach is developed to improve trust by explaining the reasoning behind the algorithm’s behaviour. Performance evaluation tests that the approach can effectively and practically identify mobile banking malware with high precision and reduced false positives. Specifically, the adapted artificial neural networks (ANN), convolutional neural networks (CNN) and XML approaches achieve a higher accuracy of 99.7% and the adapted deep neural networks (DNN) approach achieves 99.6% accuracy in comparison with the state-of-the-art approaches. These promising results position the proposed approach as a potential tool for real-world scenarios, offering a robust means of identifying and thwarting malware in mobile-based banking applications. Consequently, MoBShield has the potential to significantly enhance the security and trustworthiness of mobile banking platforms, mitigating the risks posed by cyber threats and ensuring a safer user experience

Network layer for cognitive radio sensor networks

Based on recent trends, Cognitive Radio paradigm has become an integral part of future communication networks of which Wireless Sensor Network is an integral part. However, Cognitive Radio (CR) introduces critical issues that have to be addressed for communication in networks to be achieved. Routing, being the core of communication, has to be critically examined within the context of Cognitive Radio Sensor Networks. In this chapter, the authors discuss relevant issues on the topic of routing in Cognitive Radio Sensor Networks (CRSN). As a basis, a general overview of routing in the Wireless Sensor Network (WSN) is made. The applicability of these protocols in CRSN is discussed and the need for integrating Opportunistic Spectrum Access components into existing Wireless Sensor Network protocols is exposed. Factors affecting routing in CRSN are outlined with an emphasis on a cross layering design approach based on a generalized framework. Recent works in this respect are categorized, and finally, open issues in need for research attention are pinpointed

Distinct clinical and biological implications of CUX1 in myeloid neoplasms

Somatic mutations of the CUT-like homeobox 1 (CUX1) gene (CUX1(MT)) can be found in myeloid neoplasms (MNs), in particular, in myelodysplastic syndromes (MDSs). The CUX1 locus is also deleted in 3 of 4 MN cases with -7/del(7q). A cohort of 1480 MN patients was used to characterize clinical features and clonal hierarchy associated with CUX1(MT) and CUX1 deletions (CUX1(DEL)) and to analyze their functional consequences in vitro. CUX1(MT) were present in 4% of chronic MNs. CUX1(DEL) were preferentially found in advanced cases (6%). Most MDS and acute myeloid leukemia (AML) patients with -7/del(7q) and up to 15% of MDS patients and 5% of AML patients diploid for the CUX1 locus exhibited downmodulated CUX1 expression. In 75% of mutant cases, CUX1(MT) were heterozygous, whereas microdeletions and homozygous and compound-heterozygous mutations were less common. CUXMT/DEL were associated with worse survival compared with CUX1(WT). Within the clonal hierarchy, 1 of 3 CUX1(MT) served as founder events often followed by secondary BCOR and ASXL1 subclonal hits, whereas TET2 was the most common ancestral lesion, followed by subclonal CUX1(MT). Comet assay of patients' bone marrow progenitor cells and leukemic cell lines performed in various experimental conditions revealed that frameshift mutations, hemizygous deletions, or experimental CUX1 knockdown decrease the repair of oxidized bases. These functional findings may explain why samples with either CUX1(MT) or low CUX1 expression coincided with significantly higher numbers of somatic hits by whole-exome sequencing. Our findings implicate the DNA repair dysfunction resulting from CUX1 lesions in the pathogenesis of MNs, in which they lead to a mutator phenotype