Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations

Recently, a new form of autosomal recessive early-onset parkinsonism (PARK20), due to mutations in the gene encoding the phosphoinositide phosphatase, Synaptojanin 1 (Synj1), has been reported. Several genes responsible for hereditary forms of Parkinson's disease are implicated in distinct steps of the endolysosomal pathway. However, the nature and the degree of endocytic membrane trafficking impairment in early-onset parkinsonism remains elusive. Here, we show that depletion of Synj1 causes drastic alterations of early endosomes, which become enlarged and more numerous, while it does not affect the morphology of late endosomes both in non-neuronal and neuronal cells. Moreover, Synj1 loss impairs the recycling of transferrin, while it does not alter the trafficking of the epidermal growth factor receptor. The ectopic expression of Synj1 restores the functions of early endosomes, and rescues these trafficking defects in depleted cells. Importantly, the same alterations of early endosomal compartments and trafficking defects occur in fibroblasts of PARK20 patients. Our data indicate that Synj1 plays a crucial role in regulating the homeostasis and functions of early endosomal compartments in different cell types, and highlight defective cellular pathways in PARK20. In addition, they strengthen the link between endosomal trafficking and Parkinson's disease

Contrast-induced nephropathy after percutaneous coronary intervention in simple lesions: risk factors and incidence are affected by the definition utilized.

Aim To compare the incidence, and risk factors, in-hospital and at the 18-month prognosis of contrastinduced nephropathy (CIN) according to the definition utilized: as an increase in serum creatinine (Scr) 0.5 mg/dL (CIN 1) or as an increase in Scr 25% above baseline values (CIN 2). Methods and Results We prospectively evaluated CIN according to two different definitions in 150 patients who underwent percutaneous coronary intervention (PCI) in simple lesions employing a low-medium dose of contrast media. Incidence of CIN was higher using the CIN 2 definition than CIN 1 (9.3% vs. 4%; p=0.0133). Patients with CIN 1 had a higher incidence of chronic kidney disease (CKD) (66.7% vs. 13.9%; p=0.006), higher mean serum creatinine levels (1.35±0.42 vs. 0.98±0.35; p=0.001) and lower mean eGFR levels (58.3±19.6 vs. 84±25.9; p=0.002). Patients with CIN 2 had a higher incidence of anemia (57.1% vs. 30.9%; p=0.049) and a higher mean contrast media volume was used (142.6±62.2 mL vs. 110.6±57.2 mL; p=0.05). In the multivariate analysis the only significant variable associated with CIN (CIN 2) was a higher volume of contrast media (OR=1.01; p=0.04). There were no differences in the major in-hospital events, but patients with CIN (both definitions) had a longer in-hospital stay. A persistent rise in serum creatinine at discharge occurred in only one patient. There were no differences between patients with and without CIN in events at the follow-up, with the exception of an increased risk of new hospitalization in patients with CIN 2. Conclusion After PCI employing low-medium dose of contrast media the incidence of CIN varied according to the definition used. Neither of the two definitions offers additional information compared with the other. Chronic kidney disease and baseline parameters of renal function are the risk factors associated with CIN 1; anemia and higher volume of contrast media are associated with CIN 2

Verso la felicità. Prospettive ermeneutiche e antropologiche

Il volume raccoglie 12 saggi incentrati sulla riflessione intorno al concetto di felicità, condotta da diverse prospettive: letteraria, filosofica e linguistica. L’idea nasce da alcuni interrogativi sulla particolare congiuntura storica che stiamo vivendo, sebbene ogni epoca della storia umana è segnata dal tentativo di definire la felicità, individuata ora nella buona sorte, nella prosperità, nell’accumulo di beni, ora nella libertà, nella pienezza dell’anima e nell’armonia tra lo spirito e il corpo, così come tra l’io e il mondo

N6-isopentenyladenosine dual targeting of AMPK and Rab7 prenylation inhibits melanoma growth through the impairment of autophagic flux

Targeting the autophagic process is considered a promising therapeutic strategy in cancer since a great number of tumors, including melanoma, show high basal levels of protective autophagy that contributes to tumor progression and chemoresistance. Here, exploiting both in vitro and in vivo approaches, we identified N6-isopentenyladenosine (iPA), an end product of the mevalonate pathway, as a novel autophagy inhibitor with an interesting anti-melanoma activity. iPA, after being phosphorylated by adenosine kinase into 5'-iPA-monophosphate, induces autophagosome accumulation through AMPK activation, measured by increased fluorescent GFP-LC3 puncta and enhanced conversion into the lipidated autophagosome-associated LC3-II. However, at a later stage iPA blocks the autophagic flux monitored by p62 accumulation, Luciferase reporter-based assay for LC3 turnover in living cells and fluorescence of a tandem RFP-GFP-LC3 construct. Impaired autophagic flux is due to the block of autophagosome-lysosome fusion through the defective localization and function of Rab7, whose prenylation is inhibited by iPA, resulting in a net inhibition of autophagy completion that finally leads to melanoma apoptotic cell death. AMPK silencing prevents apoptosis upon iPA treatment, whereas basal autophagosome turnover is still inhibited due to unprenylated Rab7. These results strongly support the advantage of targeting autophagy for therapeutic gain in melanoma and provide the preclinical rational to further investigate the antitumor action of iPA, able to coordinately induce autophagosome accumulation and inhibit the autophagic flux, independently targeting AMPK and Rab7 prenylation. This property may be particularly useful for the selective killing of tumors, like melanoma, that frequently develop chemotherapy resistance due to protective autophagy activation.Cell Death and Differentiation advance online publication, 13 October 2017; doi:10.1038/cdd.2017.165

The urokinase receptor takes control of cell migration by recruiting integrins and FPR1 on the cell surface.

The receptor (uPAR) of the urokinase-type plasminogen activator (uPA) is crucial in cell migration since it concentrates uPA proteolytic activity at the cell surface, binds vitronectin and associates to integrins. uPAR cross-talk with receptors for the formylated peptide fMLF (fMLF-Rs) has been reported; however, cell-surface uPAR association to fMLF-Rs on the cell membrane has never been explored in detail. We now show that uPAR co-localizes at the cell-surface and co-immunoprecipitates with the high-affinity fMLF-R, FPR1, in uPAR-transfected HEK-293 (uPAR-293) cells. uPAR/β1 integrin and FPR1/β1 integrin co-localization was also observed. Serum or the WKYMVm peptide (W Pep), a FPR1 ligand, strongly increased all observed co-localizations in uPAR-293 cells, including FPR1/β1 integrin co-localization. By contrast, a low FPR1/β1 integrin co-localization was observed in uPAR-negative vector-transfected HEK-293 (V-293) cells, that was not increased by serum or W Pep stimulations. The role of uPAR interactions in cell migration was then explored. Both uPAR-293 and V-293 control cells efficiently migrated toward serum or purified EGF. However, cell treatments impairing uPAR interactions with fMLF-Rs or integrins, or inhibiting specific cell-signaling mediators abrogated uPAR-293 cell migration, without exerting any effect on V-293 control cells. Accordingly, uPAR depletion by a uPAR-targeting siRNA or uPAR blocking with an anti-uPAR polyclonal antibody in cells constitutively expressing high uPAR levels totally impaired their migration toward serum. Altogether, these results suggest that both uPAR-positive and uPAR-negative cells are able to migrate toward serum; however, uPAR expression renders cell migration totally and irreversibly uPAR-dependent, since it is completely inhibited by uPAR blocking. We propose that uPAR takes control of cell migration by recruiting fMLF-Rs and β1 integrins, thus promoting their co-localization at the cell-surface and driving pro-migratory signaling pathways

A Prospective Cohort Analysis of the Prevalence and Predictive Factors of Delayed Discharge After Laparoscopic Cholecystectomy in Italy: The DeDiLaCo Study

Background: The concept of early discharge ≤24 hours after Laparoscopic Cholecystectomy (LC) is still doubted in Italy. This prospective multicentre study aims to analyze the prevalence of patients undergoing elective LC who experienced a delayed discharge >24 hours in an extensive Italian national database and identify potential limiting factors of early discharge after LC. Methods: This is a prospective observational multicentre study performed from January 1, 2021 to December 31, 2021 by 90 Italian surgical units. Results: A total of 4664 patients were included in the study. Clinical reasons were found only for 850 patients (37.7%) discharged >24 hours after LC. After excluding patients with nonclinical reasons for delayed discharge >24 hours, 2 groups based on the length of hospitalization were created: the Early group (≤24 h; 2414 patients, 73.9%) and the Delayed group (>24 h; 850 patients, 26.1%). At the multivariate analysis, ASA III class (P<0.0001), Charlson's Comorbidity Index (P=0.001), history of choledocholithiasis (P=0.03), presence of peritoneal adhesions (P<0.0001), operative time >60 min (P<0.0001), drain placement (P<0.0001), pain (P=0.001), postoperative vomiting (P=0.001) and complications (P<0.0001) were independent predictors of delayed discharge >24 hours. Conclusions: The majority of delayed discharges >24 hours after LC in our study were unrelated to the surgery itself. ASA class >II, advanced comorbidity, the presence of peritoneal adhesions, prolonged operative time, and placement of abdominal drainage were intraoperative variables independently associated with failure of early discharge

I tumori in Italia. Rapporto 2011: La sopravvivenza dei pazienti oncologici in Italia

INTRODUCTION: population-based survival analyses are fundamental to assess the impact of public health interventions and new therapies in cancer control. This monograph updates previous reports on cancer patient survival in Italy up to the year 2007. MATERIAL AND METHODS: we extracted from the Network of Italian Cancer Registries (AIRTUM) database over 1,490,000 records of tumours diagnosed during 1990-2007 and followed up to the end of 2008, including all multiple tumours. We used the Ederer II method to estimate relative survival (RS) for 29 different types of neoplasm. Five-year relative survival rates were analysed by gender and macroarea. Trends in 5-, 10- and 15-year RS were studied by gender over six 3-year diagnostic periods, from 1990 to 2007. Conditional 5-year RS was also computed by gender and macroarea. Hybrid approaches were applied to exploit the recent survival experiences of cases diagnosed up to 2007. Adjustment for age was performed using EUROCARE weights. Additional sections describe cancer patient survival in childhood and in elderly patients and provide a comparison of cancer patient survival rates in Italy with those of other countries. RESULTS: Standardized 5-year RS for all tumours but skin in 52% for men and 61% for women. Patient survival has improved for almost all types of cancer: from 1990 to 2007 5-year RS has increased by 15% for all cancers but skin; the exceptions are some cancers with poor prognosis, where patient survival has remained basically unchanged. In males, RS was usually lower than in females, but trend analysis shows that the gap is narrowing. We also report persisting lower RS in southern Italy: 5-year RS in the South is usually from 4% to 10% lower than in the North and Centre. CONCLUSION: this study provides valuable information for all stakeholders in cancer control, both in Italy and elsewhere. Increasing survival reflects improvements in various areas of cancer control. On the other hand, delayed diagnosis and suboptimal management are consistent with the reported differences in survival within the country