A Novel DNA Variant in SMARCA4 Gene Found in a Patient Affected by Early Onset Colon Cancer.

Colorectal cancer is the third leading cause of death from neoplasia worldwide. Thanks to new screening programs, we are now seeing an increase in Early Onset of ColoRectal Cancer (EOCRC) in patients below the age of 50. Herein, we report a clinical case of a woman affected by EOCRC. This case illustrates the importance of genetic predisposition testing also in tumor patients. Indeed, for our patient, we used a combined approach of multiple molecular and cellular biology technologies that revealed the presence of an interesting novel variant in the SMARCA4 gene. The latter gene is implicated in damage repair processes and related, if mutated, to the onset of various tumor types. In addition, we stabilized Patient-Derived Organoids from the tumor tissue of the same patient and the result confirmed the presence of this novel pathogenic variant that has never been found before even in early onset cancer. In conclusion, with this clinical case, we want to underscore the importance of including patients even those below the age of 50 years in appropriate screening programs which should also include genetic tests for predisposition to early onset cancers.

RP1 Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod-Cone Dystrophy: Potential Founder Effect in Western Sicily.

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.

A Familial Novel Putative-Pathogenic Mutation Identified in Plaque-Psoriasis by a Multigene Panel Analysis.

Psoriasis is a chronic multifactorial skin disorder with an immune basis. It is characterized by patches of skin that are usually red, flaky and crusty, and that often release silvery scales. The patches appear predominantly on the elbows, knees, scalp and lower back, although they may also appear on other body areas and severity may be variable. The majority of patients (about 90%) present small patches known as "plaque psoriasis". The roles of environmental triggers such as stress, mechanical trauma and streptococcal infections are well described in psoriasis onset, but much effort is still needed to unravel the genetic component. The principal aim of this study was to use a next-generation sequencing technologies-based approach together with a 96 customized multigene panel in the attempt to determine if there are germline alterations that can explain the onset of the disease, and thus to find associations between genotypes and phenotypes. To this aim, we analyzed a family in which the mother showed mild psoriasis, and her 31-year-old daughter had suffered from psoriasis for several years, whereas an unaffected sister served as a negative control. We found variants already associated directly to psoriasis in the TRAF3IP2 gene, and interestingly we found a missense variant in the NAT9 gene. The use of multigene panels in such a complex pathology such as psoriasis can be of great help in identifying new susceptibility genes, and in being able to make early diagnoses especially in families with affected subjects.

Microbiome composition indicate dysbiosis and lower richness in tumor breast tissues compared to healthy adjacent paired tissue, within the same women.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women, in whom it reaches 20% of the total neoplasia incidence. Most BCs are considered sporadic and a number of factors, including familiarity, age, hormonal cycles and diet, have been reported to be BC risk factors. Also the gut microbiota plays a role in breast cancer development. In fact, its imbalance has been associated to various human diseases including cancer although a consequential cause-effect phenomenon has never been proven. METHODS: The aim of this work was to characterize the breast tissue microbiome in 34 women affected by BC using an NGS-based method, and analyzing the tumoral and the adjacent non-tumoral tissue of each patient. RESULTS: The healthy and tumor tissues differed in bacterial composition and richness: the number of Amplicon Sequence Variants (ASVs) was higher in healthy tissues than in tumor tissues (p = 0.001). Moreover, our analyses, able to investigate from phylum down to species taxa for each sample, revealed major differences in the two richest phyla, namely, Proteobacteria and Actinobacteria. Notably, the levels of Actinobacteria and Proteobacteria were, respectively, higher and lower in healthy with respect to tumor tissues. CONCLUSIONS: Our study provides information about the breast tissue microbial composition, as compared with very closely adjacent healthy tissue (paired samples within the same woman); the differences found are such to have possible diagnostic and therapeutic implications; further studies are necessary to clarify if the differences found in the breast tissue microbiome are simply an association or a concausative pathogenetic effect in BC. A comparison of different results on similar studies seems not to assess a universal microbiome signature, but single ones depending on the environmental cohorts' locations.

A novel smaller ß-defensin-derived peptide is active against multidrug-resistant bacterial strains.

Antibiotic resistance is becoming a severe obstacle in the fight against acute and chronic infectious diseases that accompany most degenerative illnesses from neoplasia to osteo-arthritis and obesity. Currently, the race is on to identify pharmaceutical molecules or combinations of molecules able to prevent or reduce the insurgence and/or progression of infectivity. Attempts to substitute antibiotics with antimicrobial peptides have, thus far, met with little success against multidrug-resistant (MDR) bacterial strains. During the last decade, we designed and studied the activity and features of human ß-defensin analogs, which are salt-resistant, and hence active also under high salt concentrations as, for instance, in cystic fibrosis. Herein, we describe the design, synthesis, and major features of a new 21 aa long molecule, peptide γ2. The latter derives from the γ-core of the ß-defensin natural molecules, a small fragment of these molecules still bearing high antibacterial activity. We found that peptide γ2, which contains only one disulphide bond, recapitulates most of the biological properties of natural human ß-defensins and can also counteract both Gram-positive and Gram-negative MDR bacterial strains and biofilm formation. Moreover, it has great stability in human serum thereby enhancing its antibacterial presence and activity without cytotoxicity in human cells. In conclusion, peptide γ2 is a promising new weapon also in the battle against intractable infectious diseases.

Interaction of the Fungal Metabolite Harzianic Acid with Rare-Earth Cations (La3+, Nd3+, Sm3+, Gd3+).

Rare-earth elements are emerging contaminants of soil and water bodies which destiny in the environment and effects on organisms is modulated by their interactions with natural ligands produced by bacteria, fungi and plants. Within this framework, coordination by harzianic acid (H2L), a Trichoderma secondary metabolite, of a selection of tripositive rare-earth cations Ln3+ (Ln3+ = La3+, Nd3+, Sm3+, and Gd3+) was investigated at 25 °C, and in a CH3OH/0.1 M NaClO4 (50/50 w/w) solvent, using mass spectrometry, circular dichroism, UV-Vis spectrophotometry, and pH measurements. Experimental data can be satisfactorily explained by assuming, for all investigated cations, the formation of a mono-complex (LnL+) and a bis-complex (LnL2-). Differences were found between the formation constants of complexes of different Ln3+ cations, which can be correlated with ionic radius. Since gadolinium is the element that raises the most concern among lanthanide elements, its effects on organisms at different levels of biological organization were explored, in the presence and absence of harzianic acid. Results of ecotoxicological tests suggest that harzianic acid can decrease gadolinium biotoxicity, presumably because of complex formation with Gd3+.

Secondary Metabolites, including a New 5,6-Dihydropyran-2-One, Produced by the Fungus Diplodia corticola. Aphicidal Activity of the Main Metabolite, Sphaeropsidin A.

An undescribed 5,6-dihydropyran-2-one, namely diplopyrone C, was isolated and characterized from the cultures of an isolate of the fungus Diplodia corticola recovered from Quercus suber in Algeria. The structure and relative stereostructure of (5S,6S,7Z,9S,10S)-5-hydroxy-6-(2-(3-methyloxiran-2-yl)vinyl)-5,6-dihydro-2H-pyran-2-one were assigned essentially based on NMR and MS data. Furthermore, ten known compounds were isolated and identified in the same cultures. The most abundant product, the tetracyclic pimarane diterpene sphaeropsidin A, was tested for insecticidal effects against the model sucking aphid, Acyrthosiphon pisum. Results showed a toxic dose-dependent oral activity of sphaeropsidin A, with an LC50 of 9.64 mM.

Interaction of the Fungal Metabolite Harzianic Acid with Rare-Earth Cations (Pr3+, Eu3+, Ho3+, Tm3+).

Rare-earth elements (REEs) are in all respect a class of new contaminants that may have toxic effects on organisms and microorganisms and information on their interactions with natural ligands should be of value to predict and control their diffusion in natural environments. In the current study, we investigate interactions of tripositive cations of praseodymium, europium, holmium, and thulium with harzianic acid (H2L), a secondary metabolite produced by selected strains of fungi belonging to the Trichoderma genus. We applied the same techniques and workflow previously employed in an analogous study concerning lanthanum, neodymium, samarium, and gadolinium tripositive cations. Therefore, in the current study, HPLC-ESI-HRMS experiments, circular dichroism (CD), and UV-Vis spectrophotometric absorption data, as well as accurate pH measurements, were applied to characterize bonding interactions between harzianic acid and Pr3+, Eu3+, Ho3+, and Tm3+ cations. Problems connected to the low solubility of harzianic acid in water were overcome by employing a 0.1 M NaClO4/(CH3OH + H2O 50/50 w/w) mixed solvent. For Pr3+, Ho3+, and Tm3+, only the mono complexes PrL+, HoL+, and TmL+ were detected and their formation constant determined. Eu3+ forms almost exclusively the bis complex EuL2- for which the corresponding formation constant is reported; under our experimental conditions, the mono complex EuL+ is irrelevant. Combining the results of the present and previous studies, a picture of interactions of harzianic acid with rare-earth cations extending over 8 of the 17 REEs can be composed. In order to complement chemical information with toxicological information, a battery of bioassays was applied to evaluate the effects of praseodymium, europium, holmium, and thulium tripositive cations on a suite of bioindicators including Aliivibrio fischeri (Gram-negative bacterium), Raphidocelis subcapitata (green alga), and Daphnia magna (microcrustacean), and median effective concentration (EC50) values of Pr3+, Eu3+, Ho3+, and Tm3+ for the tested species were assessed.

Is extensive cardiopulmonary screening useful in athletes with previous asymptomatic or mild SARS-CoV-2 infection?

OBJECTIVE: During the COVID-19 pandemic, it is essential to understand if and how to screen SARS-CoV-2-positive athletes to safely resume training and competitions. The aim of this study is to understand which investigations are useful in a screening protocol aimed at protecting health but also avoiding inappropriate examinations. METHODS: We conducted a cohort study of a professional soccer team that is based on an extensive screening protocol for resuming training during the COVID-19 pandemic. It included personal history, antigen swabs, blood tests, spirometry, resting/stress-test ECG with oxygen saturation monitoring, echocardiogram, Holter and chest CT. We also compared the findings with prior data from the same subjects before infection and with data from SARS-CoV-2-negative players. RESULTS: None of the players had positive swab and/or anti-SARS-CoV-2 IgM class antibodies. Out of 30 players, 18 (60%) had IgG class antibodies. None had suffered severe SARS-CoV-2-related disease, 12 (66.7%) had complained of mild COVID-19-related symptoms and 6 (33.3%) were asymptomatic. None of the players we examined revealed significant cardiovascular abnormalities after clinical recovery. A mild reduction in spirometry parameters versus pre-COVID-19 values was observed in all athletes, but it was statistically significant (p<0.05) only in SARS-CoV-2-positive athletes. One SARS-CoV-2-positive player showed increased troponin I level, but extensive investigation did not show signs of myocardial damage. CONCLUSION: In this small cohort of athletes with previous asymptomatic/mild SARS-CoV-2 infection, a comprehensive screening protocol including blood tests, spirometry, resting ECG, stress-test ECG with oxygen saturation monitoring and echocardiogram did not identify relevant anomalies. While larger studies are needed, extensive cardiorespiratory and haematological screening in athletes with asymptomatic/mild SARS-CoV-2 infection appears unnecessary.

GC-MS-Based Metabolomics Study of Single- and Dual-Species Biofilms of Candida albicans and Klebsiella pneumoniae.

Candida albicans and Klebsiella pneumoniae frequently co-exist within the human host as a complex biofilm community. These pathogens are of interest because their association is also related to significantly increased morbidity and mortality in hospitalized patients. With the aim of highlighting metabolic shifts occurring in the dual-species biofilm, an untargeted GC-MS-based metabolomics approach was applied to single and mixed biofilms of C. albicans and K. pneumoniae. Metabolomic results showed that among the extracellular metabolites identified, approximately 40 compounds had significantly changed relative abundance, mainly involving central carbon, amino acid, vitamin, and secondary metabolisms, such as serine, leucine, arabitol, phosphate, vitamin B6, cyclo-(Phe-Pro), trehalose, and nicotinic acid. The results were related to the strict interactions between the two species and the different microbial composition in the early and mature biofilms.

An Integrated Analysis of Intracellular Metabolites and Virulence Gene Expression during Biofilm Development of a Clinical Isolate of Candida tropicalis on Distinct Surfaces.

Emergence of Candida tropicalis, which causes potential life-threatening invasive candidiasis, is often associated with colonization of medical devices as biofilm. Biofilm plays an important role in the virulence of the pathogen because of its complex structure, which provides resistance to conventional antimicrobials. In this study, the metabolic response of a clinical strain of C. tropicalis colonizing three distinct surfaces (polytetrafluoroethylene (PTFE), polystyrene, and polycarbonate) as well as the expression of virulence and stress related genes (ALS3, Hsp21, SAP1, SAP2, SAP3, and CYR1), were explored. Our results showed that lesser biofilm was developed on PTFE compared to polystyrene and polycarbonate. GS-MS metabolic analysis identified a total of 36 metabolites in the intracellular extract of cells grown on polystyrene, polycarbonate, and PTFE, essentially belonging to central carbon metabolism, amino acids, and lipids metabolism. The metabolic analysis showed that saturated and unsaturated fatty acids are preferentially produced during biofilm development on polycarbonate, whereas trehalose and vitamin B6, known as cellular protectors against a variety of stressors, were characteristic of biofilm on PTFE. The results of the transcriptomic analysis consider the different degrees of colonization of the three substrates, being CYR1, which encodes the component of signaling pathway of hyphal formation-cAMP-PKA, downregulated in PTFE biofilm compared to polycarbonate or polystyrene biofilms, while Hsp21 was upregulated in concomitance with the potential unfavorable conditions for biofilm formation on PTFE. Overall, this work provides new insights into the knowledge of C. tropicalis biofilm development on surfaces of medical relevance in the perspective of improving the management of Candida infections.

16S rRNA of Mucosal Colon Microbiome and CCL2 Circulating Levels Are Potential Biomarkers in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignancies in the Western world and intestinal dysbiosis might contribute to its pathogenesis. The mucosal colon microbiome and C-C motif chemokine 2 (CCL2) were investigated in 20 healthy controls (HC) and 20 CRC patients using 16S rRNA sequencing and immunoluminescent assay, respectively. A total of 10 HC subjects were classified as overweight/obese (OW/OB_HC) and 10 subjects were normal weight (NW_HC); 15 CRC patients were classified as OW/OB_CRC and 5 patients were NW_CRC. Results: Fusobacterium nucleatum and Escherichia coli were more abundant in OW/OB_HC than in NW_HC microbiomes. Globally, Streptococcus intermedius, Gemella haemolysans, Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were significantly increased in CRC patient tumor/lesioned tissue (CRC_LT) and CRC patient unlesioned tissue (CRC_ULT) microbiomes compared to HC microbiomes. CCL2 circulating levels were associated with tumor presence and with the abundance of Fusobacterium nucleatum, Bacteroides fragilis and Gemella haemolysans. Our data suggest that mucosal colon dysbiosis might contribute to CRC pathogenesis by inducing inflammation. Notably, Fusobacterium nucleatum, which was more abundant in the OW/OB_HC than in the NW_HC microbiomes, might represent a putative link between obesity and increased CRC risk.

Sudden Cardiac Death in Athletes in Italy during 2019: Internet-Based Epidemiological Research.

Background and objectives: An Italian nationwide pre-participation screening approach for prevention of sudden cardiac death in athletes (SCD-A) in competitive sportspeople showed promising results but did not achieve international consensus, due to cost-effectiveness and the shortfall of a monitoring plan. From this perspective, we tried to provide an epidemiological update of SCD-A in Italy through a year-long internet-based search. Materials and Methods: One year-long Google search was performed using mandatory and non-mandatory keywords. Data were collected according to prevalent SCD-A definition and matched with sport-related figures from Italian National Institute of Statistics (ISTAT) and Italian National Olympic Committee (CONI). Results: Ninety-eight cases of SCD-A in 2019 were identified (48.0% competitive, 52.0% non-competitive athletes). Male/female ratio was 13:1. The most common sports were soccer (33.7%), athletics (15.3%) and fitness (13.3%). A conclusive diagnosis was achieved only in 37 cases (33 of cardiac origin), with the leading diagnosis being coronary artery disease in 27 and a notably higher occurrence among master athletes. Combining these findings with ISTAT and CONI data, the SCD-A incidence rate in the whole Italian sport population was found to be 0.47/100,000 persons per year (1.00/100,000 in the competitive and 0.32/100,000 in the non-competitive population). The relative risk of SCD-A is 3.1 (CI 2.1-4.7; p < 0.0001) for competitive compared to non-competitive athletes; 9.9 for male (CI 4.6-21.4; p < 0.0001) with respect to female. Conclusions: We provided an updated incidence rate of SCD-A in both competitive and non-competitive sport in Italy. A higher risk of SCD-A among competitive and male athletes was confirmed, thus corroborating the value of Italian pre-participation screening in this population.

The abundance of the long intergenic non-coding RNA 01087 differentiates between luminal and triple-negative breast cancers and predicts patient outcome.

The molecular complexity of human breast cancer (BC) renders the clinical management of the disease challenging. Long non-coding RNAs (lncRNAs) are promising biomarkers for BC patient stratification, early detection, and disease monitoring. Here, we identified the involvement of the long intergenic non-coding RNA 01087 (LINC01087) in breast oncogenesis. LINC01087 appeared significantly downregulated in triple-negative BCs (TNBCs) and upregulated in the luminal BC subtypes in comparison to mammary samples from cancer-free women and matched normal cancer pairs. Interestingly, deregulation of LINC01087 allowed to accurately distinguish between luminal and TNBC specimens, independently of the clinicopathological parameters, and of the histological and TP53 or BRCA1/2 mutational status. Moreover, increased expression of LINC01087 predicted a better prognosis in luminal BCs, while TNBC tumors that harbored lower levels of LINC01087 were associated with reduced relapse-free survival. Furthermore, bioinformatics analyses were performed on TNBC and luminal BC samples and suggested that the putative tumor suppressor activity of LINC01087 may rely on interferences with pathways involved in cell survival, proliferation, adhesion, invasion, inflammation and drug sensitivity. Altogether, these data suggest that the assessment of LINC01087 deregulation could represent a novel, specific and promising biomarker not only for the diagnosis and prognosis of luminal BC subtypes and TNBCs, but also as a predictive biomarker of pharmacological interventions.

The shift of the paradigm between ageing and diseases.

In the area of the Medical Sciences, the chronological age has always been, and still is, an indicator by which we try to understand the health status of an individual. However, besides considering people born with an already expressed disease, each human genome has sequence alterations called predisposing mutations; carriers of such genetic alterations have an increased risk of contracting diseases during their life. In addition, the exposome, i.e. the totality of environmental noxae ("hits") to which our body is exposed throughout life (through ingestion, breathing, body surface hits, and psychosociological stress agents, etc.) contributes to increase gradually but inexorably the frailty of an organism, and this process is usually referred to as "physiological ageing". This position paper proposes that we invert our visual angle and view the passage-of-time not as the cause of diseases, but consider the genome alterations present at birth and the noxae received during our life as the real major causes of ageing. The Biomedical Sciences are now increasingly unraveling the etiopathogenesis of most chronic degenerative diseases; thus, it will be possible to monitor and treat those that most contribute to the increased frailty of each person, which is now referred to with the misnomer "physiological ageing". These concepts are not banal; indeed, they imply that we must try to avoid the causes of alterations that result later in chronic degenerative diseases. Thus, we should shift our attention from the cure to the prevention of alterations/diseases also to improve both the length and quality of our life. Moreover, this approach involves real personalized or individualized medicine, thus conferring a more direct benefit to each of us by finalizing either the cure or the monitoring of diseases.

Effect of γ-Aminobutyric Acid (GABA) on the Metabolome of Two Strains of Lasiodiplodia theobromae Isolated from Grapevine.

The effect of γ-aminobutyric acid (GABA) on the metabolome of two strains of Lasiodiplodia theobromae isolated from grapevine that hold a different degree of virulence to the host plant (LA-SOL3 (more virulent), LA-SV1 (less virulent)) was investigated. The culture filtrates and crude extracts from the two strains grown in the presence and absence of 10 mM of GABA were tested for phytotoxicity on tomato plant cuttings and leaves, respectively. Considering the opportunistic nature of this fungus for humans, crude extracts were also tested for cytotoxicity on mammalian cell lines. We found that culture filtrates and crude extracts have a decreased toxicity in the presence of GABA. Metabolomic analysis, conducted on both strains at both growth conditions, revealed the production of several compounds, such as indole-3-carboxylic acid (ICA, which is the main compound produced by L. theobromae), 3-indolecarboxyaldehyde, (3R,4S)-botryodiplodin, (R)-mellein. Finally, data demonstrate that GABA both induces a decrease in the amount of ICA, and a diversification of the metabolites produced by L. theobromae.

Bivalent Metal-Chelating Properties of Harzianic Acid Produced by Trichoderma pleuroticola Associated to the Gastropod Melarhaphe neritoides.

Harzianic acid is a secondary metabolite of Trichoderma, structurally belonging to the dienyltetramic acid subgroup of the tetramic acids. Biological activities of harzianic acid are of great interest for its antimicrobial and plant growth-promoting activities, which might be related to its chelating properties. In the present work harzianic acid, isolated from cultures of a strain of Trichoderma pleuroticola associated to the gastropod Melarhaphe neritoides, was studied as a complexant agent of a number of biologically relevant transition metals (i.e., Zn2+, Fe2+, Cu2+, and Mn2+), using UV-VIS, potentiometry, MS and NMR techniques. Our findings show the coordination capacity of harzianic acid toward the above cations through the formation of neutral or charged complexes in a variable ratio depending on the metal and pH conditions.

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-ß-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-ß signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-ß activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-ß/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.10.1093/brain/awy039_video1awy039media15742053534001.

Fully covered self-expandable metal stents to dilate persistent pancreatic strictures in chronic pancreatitis: long-term follow-up from a prospective study.

BACKGROUND AND AIMS: Symptomatic main pancreatic duct (MPD) strictures secondary to chronic pancreatitis (CP) may benefit from endoscopic insertion of single or multiple plastic stents. MPD stricture resolution after single plastic stent removal is uncommon. The use of removable fully covered, self-expandable metal stents (FC-SEMSs) to dilate MPD strictures secondary to CP was evaluated. METHODS: Patients with CP and symptomatic MPD stricture located in the head of the pancreas persisting for 3 months or more after placement of a single plastic stent were enrolled in a prospective single-arm trial. A nitinol FC-SEMS was inserted and removed after 6 months. The FC-SEMS diameter and length were chosen according to the stricture anatomy and MPD diameter above the stricture. Our primary objective was FC-SEMS removability. Secondary outcomes were MPD stricture resolution rate and adverse events. RESULTS: Between December 2012 and October 2014, 15 patients (10 male, mean age 60 years) were enrolled. Pancreatic calcifications were present in 6 (40%) patients. Four patients (27%) had a history of alcohol abuse. In 10 patients, the FC-SEMS was inserted through the major papilla, whereas 5 patients (3 pancreas divisum, 2 dominant dorsal duct) received the stent through the minor papilla. One patient developed cholangitis after 24 hours due to occlusion of the biliary sphincterotomy from the FC-SEMS; cholangitis resolved after insertion of a plastic biliary stent. Complete distal migration of the FC-SEMS was reported in 7 patients (47%) (5 asymptomatic, 2 symptomatic with recurrence of pancreatitis). All migrations occurred with the 3-cm-long FC-SEMS. Four patients (27%) developed de novo stricture induced by the FC-SEMS at the level of the flared end and were excluded from the follow-up; 1 patient with FC-SEMS migration had failed stricture resolution. One patient was lost to follow-up. Finally, 9 patients with MPD stricture resolution had a mean follow-up of 38.9 months (range, 5.3-55.3 months), and 89% were asymptomatic. CONCLUSIONS: FC-SEMS removability from the MPD in CP was feasible in all cases, and 90% of the patients were asymptomatic after 3 years. Migration seems more frequent with the 3-cm-long FC-SEMS. Occurrence of FC-SEMS-induced pancreatic strictures is a major issue and deserves further assessment. According to our experience, pancreatic FC-SEMSs have promising results, but a careful evaluation in the setting of clinical trials is needed.