Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms. Results: Acquired resistance to FK866 was independent of NAMPT mutations but rather was based on a shift towards a glycolytic metabolism and on lactate dehydrogenase A (LDHA) activity. In addition, resistant CCRF-CEM cells, which exhibit high quinolinate phosphoribosyltransferase (QPRT) activity, also exploited amino acid catabolism as an alternative source for NAD+ production, becoming addicted to tryptophan and glutamine and sensitive to treatment with the amino acid transport inhibitor JPH203 and with L-asparaginase, which affects glutamine exploitation. Vice versa, in line with their low QPRT expression, FK866-resistant MDA MB231 did not rely on amino acids for their resistance phenotype. Conclusions: Our study identifies novel mechanisms of resistance to NAMPT inhibition, which may be useful to design more rational strategies for targeting cancer metabolism

Bovine Colostrum Supplementation Modulates the Intestinal Microbial Community in Rabbits

Simple Summary Recently, research has focused on the modulation of the gut microbiota because of its central role in several digestive physiological functions and its involvement in the onset of not only gastrointestinal but also systemic diseases. Supplementing rabbit diets with nutraceutical substances could be a strategy to prevent dysbiosis, strengthen the immune system, and reduce mortality during the critical weaning period. Bovine colostrum (BC) is a by-product of the dairy industry and is very rich in compounds with several biological activities. Its use as an intestinal microbiota modulator in rabbits has never been investigated. This study evaluates the effects of diet supplementation with two different percentages of BC (2.5 and 5%) on luminal and mucosa-associated microbiota and its metabolism-associated pathways in the jejunum, caecum, and colon of rabbits. Although our results showed no effect of BC on microbiota biodiversity, there were significant differences between experimental groups in the microbial composition, mainly at the level of sub-dominant components depending on the dose of supplementation. The metabolism-associated pathways have also been affected, and particularly interesting are the results on the amino acids and lactose metabolism. Overall, findings suggest that BC could be used as a supplement in rabbit feed, although its effects on productive and reproductive performances, intestinal disease resistance, and economic aspects need to be further evaluated. BC is a nutraceutical that can modulate intestinal microbiota. This study investigates the effects of BC diet supplementation on luminal and mucosa-associated microbiota in the jejunum, caecum, and colon of rabbits. Twenty-one New Zealand White female rabbits were divided into three experimental groups (n = 7) receiving a commercial feed (CTRL group) and the same diet supplemented with 2.5% and 5% BC (2.5% BC and 5% BC groups, respectively), from 35 (weaning) to 90 days of age (slaughtering). At slaughter, the digestive tract was removed from each animal, then both content and mucosa-associated microbiota of jejunum, caecum, and colon were collected and analysed by Next Generation 16SrRNA Gene Sequencing. Significant differences were found in the microbial composition of the three groups (i.e., beta-diversity: p < 0.01), especially in the caecum and colon of the 2.5% BC group. The relative abundance analysis showed that the families most affected by the BC administration were Clostridia UCG-014, Barnesiellaceae, and Eggerthellaceae. A trend was also found for Lachnospiraceae, Akkermansiaceae, and Bacteroidaceae. A functional prediction has revealed several altered pathways in BC groups, with particular reference to amino acids and lactose metabolism. Firmicutes:Bacteroidetes ratio decreased in caecum luminal samples of the 2.5% BC group. These findings suggest that BC supplementation could positively affect the intestinal microbiota. However, further research is needed to establish the optimal administration dose

A functional gene expression analysis in epithelial sinonasal cancer: Biology and clinical relevance behind three histological subtypes

Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics. We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses. The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8 + effector memory cells, in SNUC) and \u201cother cells\u201d: keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic \u3b2-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples. Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities

Formazione di giovani leader di sanità pubblica: un’esperienza sperimentale dell’Accademia Lombarda di Sanità Pubblica

Introduzione L’Accademia Lombarda di Sanità Pubblica (ALSP), Associazione no-profit fondata nel 2017, ha come obiettivo quello di promuovere il progresso in Sanità Pubblica (SP) attraverso il coinvolgimento di studiosi impegnati a vario titolo nei molteplici ambiti della SP come quello dell’igiene, dell’epidemiologia, della prevenzione, dell’ambiente, della direzione sanitarie, dell’edilizia sanitaria, del management, del diritto e dell’economia sanitaria. A tale scopo l’Accademia ha promosso, all’inizio del 2019, l’iniziativa Academy of Young Leader in Public Health (AYLPH). Si tratta di un percorso didattico-scientifico di un anno rivolto a 10 giovani con background formativo differente, fortemente motivati a sviluppare competenze di leadership in SP e già avviati a carriere professionali e di ricerca. Metodi Questo percorso formativo per i 10 giovani, selezionati con bando competitivo aperto ai soci, basa il suo metodo didattico-formativo su incontri con riconosciuti leader nazionali e internazionali di SP; visite a istituzioni; collaborazione a progetti di ricerca; training specifico sulla scrittura di lavori scientifici; opportunità di partecipare a convegni nazionali internazionali e a corsi brevi ad hoc. Risultati A metà programma, le attività condotte sono state: esperienza di team building in località montana; incontro con alcune importanti figure impegnate, a vari livelli, nella sanità pubblica come l’ex Ministro della salute Beatrice Lorenzin, l’Editor-in-chief della rivista European Journal of Public Health Peter Allebeck, il Presidente EUPHA Natasha Azzopardi-Muscat oltre ai past-Presidenti EUPHA Walter Ricciardi e Martin Mc Kee. Ha fatto seguito un corso intensivo sulle revisioni sistematiche che ha visto l’attivazione di 6 gruppi di ricerca coinvolti in altrettanti progetti di revisione sistematica della letteratura. Ulteriori attività sono state: la partecipazione all’Assemblea Generale dell’Organizzazione Mondiale della Sanità, la partecipazione al Deans’ and Directos’ Retreat dell’ASPHER e al Congresso Americano di Sanità Pubblica (APHA). Sono in programma anche un corso di Public speaking, presso l’Università di Pisa ed alcuni incontri ad hoc. Conclusioni Nel contesto attuale, in cui la salute delle persone è minata da un senso di sfiducia nei confronti delle Istituzioni, dalla mancata equità nell’accesso alle cure e da stili di vita scorretti, la SP ha necessità di formare nuovi leaders in grado di promuovere valori e guidare al cambiamento individuale, organizzativo e politico. La AYLPH rappresenta un’occasione formativa di alto livello per giovani professionisti interessati a conoscere e attuare strategie di leadership in SP

Genetic Interaction between MTMR2 and FIG4 Phospholipid Phosphatases Involved in Charcot-Marie-Tooth Neuropathies

We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT) type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2) in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5)P2, thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor) mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5)P2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5)P2 homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5)P2 is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro

Adamantinoma-like Ewing sarcoma of the salivary glands: a case report and systematic literature review

Adamantinoma-like Ewing sarcoma (ALES) of the salivary glands is an exceedingly rare malignancy defined by the t(11,22) EWSR1::FLI1 fusion, with complex epithelial differentiation. To identify features that can allow for better recognition of this disease entity, we reviewed all published reports of molecularly confirmed ALES of the salivary glands and explored epidemiological, clinical, radiological, pathological, and therapeutic characteristics of a population of 21 patients including a single newly reported patient from our group. We searched the English-language literature indexed in PubMed, Medline, Scopus, and Web of Science using the keyword ‘Adamantinoma-like Ewing sarcoma’ published up to June 2022. The median age at diagnosis was 46 years, and a slight female sex predilection was observed. Most tumors originated in the parotid gland (86%) and presented as a painless palpable mass with a median diameter of 3.6 cm. Metastatic dissemination was reported only in one patient (5%), and after a median follow-up of 13 months the 1-year overall survival rate was 92%. Salivary gland ALES were frequently misdiagnosed at presentation (62% of cases) and were pathologically characterized by the presence of highly monomorphic small round blue cells with infiltrative pattern and positive immunostaining for CD99 and high- and low-molecular weight cytokeratins. Epidemiological and clinical features of salivary gland ALES raise questions on the incorporation of this malignancy in the Ewing sarcoma family tumor group

Magnetic Resonance Planimetry in the Differential Diagnosis between Parkinson’s Disease and Progressive Supranuclear Palsy

The clinical differential diagnosis between Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) is often challenging. The description of milder PSP phenotypes strongly resembling PD, such as PSP-Parkinsonism, further increased the diagnostic challenge and the need for reliable neuroimaging biomarkers to enhance the diagnostic certainty. This review aims to summarize the contribution of a relatively simple and widely available imaging technique such as MR planimetry in the differential diagnosis between PD and PSP, focusing on the recent advancements in this field. The development of accurate MR planimetric biomarkers, together with the implementation of automated algorithms, led to robust and objective measures for the differential diagnosis of PSP and PD at the individual level. Evidence from longitudinal studies also suggests a role of MR planimetry in predicting the development of the PSP clinical signs, allowing to identify PSP patients before they meet diagnostic criteria when their clinical phenotype can be indistinguishable from PD. Finally, promising evidence exists on the possible association between MR planimetric measures and the underlying pathology, with important implications for trials with new disease-modifying target therapies