PICMI: mapping point mutations on genomes

Motivation: Several international collaborations and local projects are producing extensive catalogues of genomic variations that are supplementing existing collections such as the OMIM catalogue. The flood of this type of data will keep increasing and, especially, it will be relevant to a wider user base, including not only molecular biologists, geneticists and bioinformaticians, but also clinical researchers. Mapping the observed variations, sometimes only described at the amino acid level, on a genome, identifying whether they affect a gene and—if so—whether they also affect different isoforms of the same gene, is a time consuming and often frustrating task

RNA-based strategies for cancer therapy: in silico design and evaluation of ASOs for targeted exon skipping

Precision medicine in oncology has made significant progress in recent years by approving drugs that target specific genetic mutations. However, many cancer driver genes remain challenging to pharmacologically target ("undruggable"). To tackle this issue, RNA-based methods like antisense oligonucleotides (ASOs) that induce targeted exon skipping (ES) could provide a promising alternative. In this work, a comprehensive computational procedure is presented, focused on the development of ES-based cancer treatments. The procedure aims to produce specific protein variants, including inactive oncogenes and partially restored tumor suppressors. This novel computational procedure encompasses target-exon selection, in silico prediction of ES products, and identification of the best candidate ASOs for further experimental validation. The method was effectively employed on extensively mutated cancer genes, prioritized according to their suitability for ES-based interventions. Notable genes, such as NRAS and VHL, exhibited potential for this therapeutic approach, as specific target exons were identified and optimal ASO sequences were devised to induce their skipping. To the best of our knowledge, this is the first computational procedure that encompasses all necessary steps for designing ASO sequences tailored for targeted ES, contributing with a versatile and innovative approach to addressing the challenges posed by undruggable cancer driver genes and beyond

Coherent QED, Giant Resonances and (e+e−)(e^{+}e^{-}) Pairs in High Energy Nucleus-Nucleus Collisions

We show that the coherent oscillations of the e.m. field induced by the collective quantum fluctuations of the nuclear matter field associated with the giant resonances, with frequencies $\omega_{A}\simeq 78A^{-{1/3}}$ MeV, give rise to a significant $(e^+e^-)$ pair production in high energy Heavy Ion collisions. The approximate parameterless calculation of such yield is in good agreement with recent experimental observations.Comment: 27 pages, 13 figure

Genome-wide identification of direct HBx genomic targets

Background: The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. Results: ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Conclusions: Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication

Salvage neck dissection for isolated neck recurrences in head and neck tumors: Intra and postoperative complications

Background and Objectives: The current evidence regarding complications after salvage neck dissection (ND) for isolated regional recurrences (IRRs) in head and neck cancers is poor. The aim of this study is to evaluate the incidence and differences in complication rates of salvage ND after primary surgery, radiotherapy, chemoradiotherapy, or combined treatments. Methods: This was a multicentric retrospective study on 64 patients who underwent salvage ND for IRR in three Italian institutes between 2008 and May 2020. Results: Complications were detected in 7 of the 34 patients (20.8%) and surgeons described difficult dissection in 20 patients (58.82%). Accidental vascular ligations or nervous injury during surgery were never detected. None of the variables analyzed were statistically significant in predicting the risk of complications, disease-free survival, or overall survival. Conclusions: IRR represents a rare entity among total relapses. The incidence of complications after salvage ND for IRR is higher than after primary surgery but at an acceptable rate in experienced hands. However, an adequate balance between functional and oncological outcomes is mandatory

Effects of Preoperative Quadruple Therapy for Helicobacter pylori on Bariatric Surgery Metabolic Outcomes

Altres ajuts: Universitat Pompeu FabraTo assess the effects of Helicobacter pylori (HP) eradication with an omeprazole, clarithromycin, amoxicillin, and metronidazole (OCAM) regimen on the metabolic profile and weight loss 12 months after bariatric surgery (BS). Retrospective analysis of a prospective cohort of patients with morbid obesity undergoing BS. HP presence was tested preoperatively by gastric biopsy and treated with OCAM when positive. Short-term metabolic outcomes and weight loss were evaluated. HP infection was detected in 75 (45.7%) of the 164 patients included. OCAM effectiveness was 90.1%. HP-negative patients had a greater reduction in glucose levels at 3 (−14.6 ± 27.5 mg/dL HP-treated vs −22.0 ± 37.1 mg/dL HP-negative, p =0.045) and 6 months (−13.7 ± 29.4 mg/dL HP-treated vs −26.4 ± 42.6 mg/dL HP-negative, p = 0.021) and greater total weight loss (%TWL) at 6 (28.7 ± 6.7% HP-treated vs 30.45 ± 6.48% HP-negative, p = 0.04) and 12 months (32.21 ± 8.11% HP-treated vs 35.14 ± 8.63% HP-negative, p = 0.023). Preoperative treatment with OCAM has been associated to poorer glycemic and weight loss outcomes after BS. More research is needed on the influence of OCAM on gut microbiota, and in turn, the effect of the latter on metabolic and weight loss outcomes after BS

The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug targe

Standing balance in persistent whiplash: A comparison between subjects with and without dizziness

Objective: Dizziness and unsteadiness, associated with altered balance, are frequent complaints in subjects suffering persistent whiplash associated disorders. Research has been inconclusive with respect to possible aetiology. This study assessed balance responses in subjects with whiplash associated disorders, taking into account several possible causes

Coding potential of the products of alternative splicing in human

Background: Analysis of the human genome has revealed that as much as an order of magnitude more of the genomic sequence is transcribed than accounted for by the predicted and characterized genes. A number of these transcripts are alternatively spliced forms of known protein coding genes; however, it is becoming clear that many of them do not necessarily correspond to a functional protein. Results: In this study we analyze alternative splicing isoforms of human gene products that are unambiguously identified by mass spectrometry and compare their properties with those of isoforms of the same genes for which no peptide was found in publicly available mass spectrometry datasets. We analyze them in detail for the presence of uninterrupted functional domains, active sites as well as the plausibility of their predicted structure. We report how well each of these strategies and their combination can correctly identify translated isoforms and derive a lower limit for their specificity, that is, their ability to correctly identify non-translated products. Conclusions: The most effective strategy for correctly identifying translated products relies on the conservation of active sites, but it can only be applied to a small fraction of isoforms, while a reasonably high coverage, sensitivity and specificity can be achieved by analyzing the presence of non-truncated functional domains. Combining the latter with an assessment of the plausibility of the modeled structure of the isoform increases both coverage and specificity with a moderate cost in terms of sensitivity