Pancreatic ductal adenocarcinoma can be detected by analysis of volatile organic compounds (VOCs) in alveolar air

Background: In the last decade many studies showed that the exhaled breath of subjects suffering from several pathological conditions has a peculiar volatile organic compound (VOC) profile. The objective of the present work was to analyse the VOCs in alveolar air to build a diagnostic tool able to identify the presence of pancreatic ductal adenocarcinoma in patients with histologically confirmed disease. Methods: The concentration of 92 compounds was measured in the end-tidal breath of 65 cases and 102 controls. VOCs were measured with an ion-molecule reaction mass spectrometry. To distinguish between subjects with pancreatic adenocarcinomas and controls, an iterated Least Absolute Shrinkage and Selection Operator multivariate Logistic Regression model was elaborated. Results: The final predictive model, based on 10 VOCs, significantly and independently associated with the outcome had a sensitivity and specificity of 100 and 84% respectively, and an area under the ROC curve of 0.99. For further validation, the model was run on 50 other subjects: 24 cases and 26 controls; 23 patients with histological diagnosis of pancreatic adenocarcinomas and 25 controls were correctly identified by the model. Conclusions: Pancreatic cancer is able to alter the concentration of some molecules in the blood and hence of VOCs in the alveolar air in equilibrium. The detection and statistical rendering of alveolar VOC composition can be useful for the clinical diagnostic approach of pancreatic neoplasms with excellent sensitivity and specificity

Mining genes involved in indoxacarb resistance of Lobesia botrana (Denis and Schifferm\ufcller) by de novo transcriptome assembly and differential expression analysis.

Lobesia botrana (Denis and Schifferm\ufcller) (Lepidoptera: Tortricidae) is one of the most important grapevine pests in Europe but, being a non-model organism, only limited genomic and transcriptomic resources are available for functional studies at the molecular level, such as those relevant to insecticide resistance and pest control. Hence, to gain insight into the mechanism of indoxacarb resistance, a blocker of insect voltage-gated sodium channels (NaV), we analysed the transcriptome and expression profile in 2nd instars of L. botrana from susceptible and field selected populations (LC50 resistance ratio 72). De novo transcriptome assembly using Trinity resulted in 141,581 isoforms clustered in 94,290 putative genes. The transcriptome completeness was supported by BUSCO: 92% of conserved orthologs (n= 1,658) were retrieved as a complete sequence, 6.3% displayed fragmented ORFs, and only 1.7% were missing. 36,250 genes were preliminary annotated relaying on the longest isoform per gene, by running Annocript pipeline against non-redundant protein databases (Nr), gene ontology (GO), cluster of orthologous groups of proteins (COG), KEGG orthology (KO) and long non-coding RNAs (lncRNAs). Conditional Reciprocal Best BLAST analysis of protein isoforms performed on Lepidoptera proteomes identified putative orthologs of multigene family members potentially involved in metabolic resistance (61 cytochrome P450 monooxygenases, 25 glutathione S-transferases, 13 carboxylesterases, 25 UDP-glucuronosyltransferases) as well as alternatively spliced isoforms of the NaV gene. Among 263 upregulated and annotated genes in the resistant population, functional GO enrichment analysis revealed overrepresentation of terms for cytochrome P450, due to up-regulation of CYP6B and CYP9A subfamily members as well as increased transcript level for UGT genes. Hydrolases were, on the contrary, overrepresented in 293 annotated genes, downregulated in the resistant population. These data tentatively suggest the reduced susceptibility to indoxacarb might be related to an increase of Phase I and II detoxification along with reduced bioactivation of the insecticide

Prospective randomised pilot study of management of the pancreatic stump following distal resection

Background Numerous surgical techniques have been described in the literature for pancreatic stump management following left resection, but there is only one prospective, randomised study. A prospective randomised pilot study was designed to assess five different pancreatic stump management techniques after distal resection in an attempt to identify which was the most effective in terms of complications and ease of execution. Methods Sixty-nine consecutive patients were randomly assigned to five different treatment groups: manual suturing, suturing plus fibrin glue, suturing plus polypropylene mesh, pancreaticojejunostomy and suturing with a stapler. All presented a soft residual pancreas. Results The overall incidence of pancreatic fistula was 19%, ranging from 7% to 33% in the different treatment groups. None of the techniques Significantly reduced the incidence of postoperative complications. Discussion On weighing the complications observed against ease and speed of execution, the construction of a pancreaticojejunostomy and closure of the stump with a mechanical stapler may be regarded as the procedures to be tested in future

Slow evolution toward "Super-Aggregation" of the oligomers formed through the swapping of RNase A N-Termini: a wish for amyloidosis?

Natively monomeric RNase A can oligomerize upon lyophilization from 40% acetic acid solutions or when it is heated at high concentrations in various solvents. In this way, it produces many dimeric or oligomeric conformers through the three-dimensional domain swapping (3D-DS) mechanism involving both RNase A N- or/and C-termini. Here, we found many of these oligomers evolving toward not negligible amounts of large derivatives after being stored for up to 15 months at 4 degrees C in phosphate buffer. We call these species super-aggregates (SAs). Notably, SAs do not originate from native RNase A monomer or from oligomers characterized by the exclusive presence of the C-terminus swapping of the enzyme subunits as well. Instead, the swapping of at least two subunits' N-termini is mandatory to produce them. Through immunoblotting, SAs are confirmed to derive from RNase A even if they retain only low ribonucleolytic activity. Then, their interaction registered with Thioflavin-T (ThT), in addition to TEM analyses, indicate SAs are large and circular but not "amyloid-like" derivatives. This confirms that RNase A acts as an "auto-chaperone", although it displays many amyloid-prone short segments, including the 16-22 loop included in its N-terminus. Therefore, we hypothesize the opening of RNase A N-terminus, and hence its oligomerization through 3D-DS, may represent a preliminary step favoring massive RNase A aggregation. Interestingly, this process is slow and requires low temperatures to limit the concomitant oligomers' dissociation to the native monomer. These data and the hypothesis proposed are discussed in the light of protein aggregation in general, and of possible future applications to contrast amyloidosis

Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition

Mutations in TP53 gene play a pivotal role in tumorigenesis and cancer development. Here, we report that gain-of-function mutant p53 proteins inhibit the autophagic pathway favoring antiapoptotic effects as well as proliferation of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes as BECN1 (and P-BECN1), DRAM1, ATG12, SESN1/2 and P-AMPK with the concomitant stimulation of mTOR signaling. As a paradigm of this mechanism, we show that atg12 gene repression was mediated by the recruitment of the p50 NF-\u3baB/mutant p53 protein complex onto the atg12 promoter. Either mutant p53 or p50 NF-\u3baB depletion downregulates atg12 gene expression. We further correlated the low expression levels of autophagic genes (atg12, becn1, sesn1, and dram1) with a reduced relapse free survival (RFS) and distant metastasis free survival (DMFS) of breast cancer patients carrying TP53 gene mutations conferring a prognostic value to this mutant p53-and autophagy-related signature. Interestingly, the mutant p53-driven mTOR stimulation sensitized cancer cells to the treatment with the mTOR inhibitor everolimus. All these results reveal a novel mechanism through which mutant p53 proteins promote cancer cell proliferation with the concomitant inhibition of autophagy

Компетентностный подход в профессиональной подготовке будущих дизайнеров: возможности проектной деятельности

Анализ феномена "проектная деятельность" и ее возможности в развитии профессиональных компетенций будущих специалистов-дизайнеро

Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas - A multicentric European study on radically resected patients

Background: Acinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. Methods: This is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. Results: 59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. Discussion: Radical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting

Minimally invasive spleen-preserving distal pancreatectomy: real-world data from the italian national registry of minimally invasive pancreatic surgery

Aim: Minimally invasive distal pancreatectomy has become the standard of care for benign and low malignant lesions. Spleen preservation in this setting has been proposed to reduce surgical trauma and long-term sequelae. The aim of the current study is to present real-world data on indications, techniques, and outcomes of spleen-preserving distal pancreatectomy (SPDP). Methods: Patients who underwent SPDP and distal pancreatectomy with splenectomy (DPWS) were extracted from the 2019-2022 Italian National Registry for Minimally Invasive Pancreatic Surgery (IGoMIPS). Perioperative and pathological data were collected. Results: One hundred and ten patients underwent SPDP and five hundred and seventy-eight underwent DPWS. Patients undergoing SPDP were significantly younger (56 vs. 63.5 years; P < 0.001). Seventy-six percent of SPDP cases were performed in six out of thirty-four IGoMIPS centers. SPDP was performed predominantly for Neuroendocrine Tumors (43.6% vs.23.5%; P < 0.001) and for smaller lesions (T1 57.6% vs. 29.8%; P < 0.001). The conversion rate was higher in the case of DPWS (7.6% vs. 0.9%; P = 0.006), even when pancreatic cancer was ruled out (5.0% vs. 0.9%; P = 0.045). The robotic approach was most commonly used for SPDP (50.9% vs. 29.7%; P < 0.001). No difference in postoperative outcomes and length of stay was observed between the two groups, as well as between robotic and laparoscopic approaches in the SPDP group. A trend toward a lower rate of postoperative sepsis was observed after SPDP (0.9% vs. 5.2%; P = 0.056). In 84.7% of SPDP, splenic vessels were preserved (Kimura procedure) without an impact on short-term postoperative outcomes. Conclusion: In this registry analysis, SPDP was feasible and safe. The Kimura procedure was prevalent over the Warshaw procedure. The typical patient undergoing SPDP was young with a neuroendocrine tumor at an early stage. Robotic assistance was used more frequently for SPDP than for DPWS

Biopsychosocial model of resilience in young adults with multiple sclerosis (BPS-ARMS): an observational study protocol exploring psychological reactions early after diagnosis

INTRODUCTION: Multiple sclerosis (MS), the most common neurological disease causing disability in young adults, is widely recognised as a major stress factor. Studies have shown that the first years after the diagnosis are distressing in terms of adjustment to the disease and that MS negatively affects patients' psychological well-being, quality of life (QoL) and social functioning. However, the links between disease-specific variables at diagnosis, resilience and psychological adjustment of patients with MS remain largely unexplored, especially in adolescents and young adults. This observational study aims to fill the gap of knowledge on biopsychosocial characteristics and resilience of young adults with MS to evaluate the relationship among these variables and to develop a biopsychosocial model of resilience. METHODS AND ANALYSIS: Biological and clinical characteristics of young adults newly diagnosed with MS will be investigated by collecting clinical information, performing neurological examinations, MRI and analysing cerebrospinal fluid and blood biomarkers (eg, measures of inflammation), body composition, gut microbiota and movement/perceptual markers. Psychosocial characteristics (eg, psychological distress, coping strategies), QoL, psychological well-being and resilience will be assessed by self-report questionnaires. Comparative statistics (ie, analysis of variance or unpaired samples t-test, correlation and regression analyses) will be applied to evaluate the relationship among biological, psychological and social factors. The results are expected to allow a comprehensive understanding of the determinants of resilience in young patients with MS and to inform resilience interventions, tailored to young patients' specific needs, aiming to reduce the risk of maladaptive reactions to the disease and to improve psychological well-being and QoL. ETHICS AND DISSEMINATION: The study has been approved by the Verona University Hospital Ethics Committee (approval number: 2029CESC). The findings will be disseminated through scientific publications in peer-reviewed journals, conference presentations, social media and specific websites. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03825055)