Does Financial Institution Proximity Affect the Development of Entrepreneurship?

The present contribution joins the stream of research investigating the relationship between local financial development, economic growth, and entrepreneurship. Relevant contributions highlighted that the probability of an individual to start a new business is higher when he/she moves from the least financially developed region to the most financially developed one. Indeed, higher levels of local financial development allow for easier access to external funds, which are crucial for the growth of new businesses. In this entrepreneurial context, the need of financial resources is especially relevant for research spin-offs (ROSs), which require significant resources to transfer to the market their innovative technologies. This chapter deepens the role of local financial development on entrepreneurship and, in particular, on research spin-offs. Empirical evidence highlight that at the time of ROSs’ incubation, local financial development does not affect the performance of spin-offs, as they mainly rely on Universities and public contributions. Vice versa, when the RSOs enter the market, they are more in need of funds from the financial system, for which local financial development interestingly becomes strongly relevant to them, affecting corporate performance. Consequently, despite the internationalization of financial markets, policymakers should carefully encourage entrepreneurship through the development of local financial systems

Acid ceramidase controls apoptosis and increases autophagy in human melanoma cells treated with doxorubicin

Acid ceramidase (AC) is a lysosomal hydrolase encoded by the ASAH1 gene, which cleaves ceramides into sphingosine and fatty acid. AC is expressed at high levels in most human melanoma cell lines and may confer resistance against chemotherapeutic agents. One such agent, doxorubicin, was shown to increase ceramide levels in melanoma cells. Ceramides contribute to the regulation of autophagy and apoptosis. Here we investigated the impact of AC ablation via CRISPR-Cas9 gene editing on the response of A375 melanoma cells to doxorubicin. We found that doxorubicin activates the autophagic response in wild-type A375 cells, which effectively resist apoptotic cell death. In striking contrast, doxorubicin fails to stimulate autophagy in A375 AC-null cells, which rapidly undergo apoptosis when exposed to the drug. The present work highlights changes that affect melanoma cells during incubation with doxorubicin, in A375 melanoma cells lacking AC. We found that the remarkable reduction in recovery rate after doxorubicin treatment is strictly associated with the impairment of autophagy, that forces the AC-inhibited cells into apoptotic path

Italian Children Exposure to Bisphenol A: Biomonitoring Data from the LIFE PERSUADED Project

A human biomonitoring (HBM) study on bisphenol A (BPA) in Italian children and adolescents was performed within the LIFE PERSUADED project, considering the residing areas, sex and age. The median urinary BPA level was 7.02 mu g/L, with children living in the South of Italy or in urban areas having higher levels than those residing in the North or in rural areas. Children aged 4-6 years had higher BPA levels than those aged 7-10 and 11-14 years, but no differences were detected between sexes. The exposure in Italian children was higher compared to children from other countries, but lower than the HBM guidance value (135 mu g/L). The estimated daily intake was 0.17 mu g/kg body weight (bw) per day, about 24-fold below the temporary Tolerable Daily Intake of 4 mu g/kg bw per day established by the European Food Safety Authority. However, this threshold was exceeded in 1.44% of the enrolled children, raising concern about the overall exposure of Italian young population

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

ackground: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. Methods: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. Results: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. Conclusions: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction. Keywords: aging; endothelial cells; microcirculation; mitochondria; obesity; sirtuin

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Valutazione del ruolo delle ceramidi nella sensibilizzazione al trattamento chemioterapico nel melanoma

Il melanoma rappresenta il 5% di tutti i tumori cutanei, ma è responsabile del 75% dei decessi per cancro alla pelle, perché ha elevato potenziale metastatico e in molti casi è refrattario alle terapie. In linee di melanoma è stata osservata una sovra-espressione di un enzima chiave nel metabolismo degli sfingolipidi: la ceramidasi acida (AC). AC è un enzima lisosomiale che catalizza l’idrolisi di ceramidi in sfingosina e acidi grassi liberi. La sfingosina è poi fosforilata in sfingosina-1-fosfato (S1P). Le ceramidi e S1P attivano diversi, ma opposti processi cellulari: le ceramidi regolano positivamente l’apoptosi, la senescenza e l’autofagia; S1P regola la progressione del ciclo cellulare, la motilità cellulare e l’angiogenesi. Il ruolo di AC nel bilanciare i livelli di ceramidi e sfingosina è correlato alla progressione tumorale e alla resistenza chemio/radio-terapica di diversi tumori. AC è infatti considerato un importante target terapeutico e sono stati sviluppati molteplici inibitori farmacologici che hanno mostrato avere un effetto adiuvante ai trattamenti chemio/radio-terapici. In uno studio su linee di cancro alla prostata che sovra-esprimono AC è stato osservato un incremento dell’attività autofagica messo in atto come meccanismo protettivo, che contribuisce alla resistenza agli stress in queste linee tumorali. Lo scopo della mia tesi è stato quello di indagare con approcci farmacologici e molecolari sulla chemio-resistenza indotta dalla sovra-espressione di AC in linee di melanoma proliferativo e sulla possibile implicazione dell’autofagia. Nelle linee di melanoma proliferativo utilizzate abbiamo osservato l’espressione di proteine autofagiche sia in condizioni basali sia in seguito a deprivazione di nutrienti, come LC3-II, proteina marker dell’autofagia, a differenza della linea di melanoma A375 KO per AC. Questa differenza ci ha portato ad effettuare un silenziamento genico di AC utilizzando un siRNA nelle linee di melanoma proliferativo e, sorprendentemente, nella linea SK-Mel-28 è stata osservata un decremento dell’espressione di LC3-II. Abbiamo osservato nella stessa linea di melanoma, che in risposta alla condizione di deprivazione di nutrienti c’è un incremento dell’espressione genica di AC, suggerendo che questa proteina svolga un ruolo importante nella risposta allo stress in questa linea tumorale. Infatti, le linee di melanoma che sovra-esprimono AC si sono mostrate resistenti alla condizione di deprivazione di nutrienti, mentre la linea di melanoma KO per AC ha mostrato elevata mortalità, destino che è stato eluso in seguito a trasfezione transiente con plasmide-AC. Abbiamo valutato il ruolo degli inibitori di AC nella regolazione del flusso autofagico e abbiamo osservato che le cellule in presenza degli inibitori presentano una forma cellulare alterata, con alterata forma delle vescicole autofagiche. Questo dato preliminare potrebbe suggerire un possibile rallentamento del flusso autofagico in presenza degli inibitori di AC e ciò eluciderebbe sul ruolo adiuvante degli inibitori al trattamento chemioterapico. Abbiamo deciso di testare un nuovo composto terapeutico basato su ceramidi a catena lunga (C14:0) non degradabili da enzimi ceramidasi, per ovviare alla sovra-espressione di AC e valutare gli effetti dell’accumulo di ceramidi come possibile terapia adiuvante nel melanoma proliferativo. Le ceramidi a catena lunga C14:0 non degradabili si sono rilevate tollerabili anche ad alte concentrazioni nelle linee di melanoma utilizzate mentre, in associazione ad un chemioterapico verso il quale le linee utilizzate sono resistenti, la Doxorubicina, hanno dimostrato avere un forte effetto adiuvante nella linea di melanoma SK-Mel-28, ma non nella linea MeWo. In seguito al trattamento con ceramidi C14:0 è stato osservato l’attivazione del pathway apoptotico e l’incremento dell’espressione genica di BNIP3, gene pro-apoptotico. Questo lavoro pone le basi per valutare i meccanismi molecolari alla base dell’azione degli inibitori di AC, ancora poco noti e poco utilizzati. Successivi esperimenti porteranno a chiarire se sia l’autofagia il meccanismo che contribuisce alla resistenza in queste linee di melanoma e, ciò potrebbe portare alla migliore caratterizzazione per un approccio più specifico alle terapie e allo sviluppo di nuove strategie terapeutiche verso i melanomi maligni

Sphingolipid/Ceramide Pathways and Autophagy in the Onset and Progression of Melanoma: Novel Therapeutic Targets and Opportunities

Melanoma is a malignant tumor deriving from neoplastic transformation of melanocytes. The incidence of melanoma has increased dramatically over the last 50 years. It accounts for most cases of skin cancer deaths. Early diagnosis leads to remission in 90% of cases of melanoma; conversely, for melanoma at more advanced stages, prognosis becomes more unfavorable also because dvanced melanoma is often resistant to pharmacological and radiological therapies due to genetic plasticity, presence of cancer stem cells that regenerate the tumor, and efficient elimination of drugs. This review illustrates the role of autophagy in tumor progression and resistance to therapy, focusing on molecular targets for future drugs

Leptin as immune mediator: Interaction between neuroendocrine and immune system

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates