12 research outputs found
Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma
Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide. In detail, basal cell carcinoma (BCC) is the most frequent malignancy in the fair-skinned population. The incidence of BCC remains difficult to assess due to the poor registration practice; however, it has been increasing in the last few years. Approximately, 85% of sporadic BCCs carry mutations in Hedgehog pathway genes, especially in PTCH, SUFU and SMO genes, which lead to the aberrant activation of GLI transcriptional factors, typically silent in cells of adult individuals. The management of advanced BCC (aBCC), both metastatic (mBCC) and locally advanced BCC (laBCC), not candidates for surgical excision or radiotherapy, remains challenging. The discovery of mutations in the Hh signaling pathway has paved the way for the development of Hh pathway inhibiting agents, such as vismodegib and sonidegib, which have represented a breakthrough in the aBCC management. However, the use of these agents is limited by the frequent occurrence of adverse events or the development of drug resistance. In this review, we thoroughly describe the current knowledge regarding the available options for the pharmacological management of aBCCs and provide a forward-looking update on novel therapeutic strategies that could enrich the therapeutic armamentarium of BCC in the near future
Gut microbiota diversity and T1DM onset: Preliminary data of a case-control study
Type-1 diabetes incidence is increasing during the last decades. Recently, a role of microbiota alteration is proposed as pre-diabetic and diabetic risk factor. A bicentric case-control study is in progress in Northern Italy. Here preliminary results are shown. The microbiome clusterization showed a division between cases and controls even if fingerprint profiles are heterogenic. Methanobrevibacter smithii is highly present only in few patients. The diversity index and the microorganism sequenced in cases and controls, seems to be quite dissimilar. The conclusive results could show a significant predictive value for the bio-indicators evaluated. Keywords: Type 1 diabetes mellitus, Microbiota, Children, Methanobrevibacter smithii, qRT-PC
MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes
Oxidation processes in mitochondria and different environmental insults contribute to unwarranted accumulation of reactive oxygen species (ROS). These, in turn, rapidly damage intracellular lipids, proteins, and DNA, ultimately causing aging and several human diseases. Cells have developed different and very effective systems to control ROS levels. Among these, removal of excessive amounts is guaranteed by upregulated expression of various antioxidant enzymes, through activation of the NF-E2-Related Factor 2 (NRF2) protein. Here, we show that Mitogen Activated Protein Kinase 15 (MAPK15) controls the transactivating potential of NRF2 and, in turn, the expression of its downstream target genes. Specifically, upon oxidative stress, MAPK15 is necessary to increase NRF2 expression and nuclear translocation, by inducing its activating phosphorylation, ultimately supporting transactivation of cytoprotective antioxidant genes. Lungs are continuously exposed to oxidative damages induced by environmental insults such as air pollutants and cigarette smoke. Interestingly, we demonstrate that MAPK15 is very effective in supporting NRF2-dependent antioxidant transcriptional response to cigarette smoke of epithelial lung cells. Oxidative damage induced by cigarette smoke indeed represents a leading cause of disability and death worldwide by contributing to the pathogenesis of different chronic respiratory diseases and lung cancer. Therefore, the development of novel therapeutic strategies able to modulate cellular responses to oxidative stress would be highly beneficial. Our data contribute to the necessary understanding of the molecular mechanisms behind such responses and identify new potentially actionable targets
Risk factors for type 1 diabetes, including environmental, behavioural and gut microbial factors: a case–control study
Type 1 diabetes (T1D) is a common autoimmune disease that is characterized by insufficient insulin production. The onset of T1D is the result of gene-environment interactions. Sociodemographic and behavioural factors may contribute to T1D, and the gut microbiota is proposed to be a driving factor of T1D. An integrated preventive strategy for T1D is not available at present. This case-control study attempted to estimate the exposure linked to T1D to identify significant risk factors for healthy children. Forty children with T1D and 56 healthy controls were included in this study. Anthropometric, socio-economic, nutritional, behavioural, and clinical data were collected. Faecal bacteria were investigated by molecular methods. The findings showed, in multivariable model, that the risk factors for T1D include higher Firmicutes levels (OR 7.30; IC 2.26-23.54) and higher carbohydrate intake (OR 1.03; IC 1.01-1.05), whereas having a greater amount of Bifidobacterium in the gut (OR 0.13; IC 0.05 - 0.34) was a protective factor for T1D. These findings may facilitate the development of preventive strategies for T1D, such as performing genetic screening, characterizing the gut microbiota, and managing nutritional and social factors
Genetics and material culture support repeated expansions into Paleolithic Eurasia from a population Hub out of Africa
The population dynamics that followed the Out of Africa (OoA) expansion and the whereabouts of the early migrants before the differentiation that ultimately led to the formation of Oceanian, West and East Eurasian macropopulations have long been debated. Shedding light on these events may, in turn, provide clues to better understand the cultural evolution in Eurasia between 50 and 35 ka. Here, we analyze Eurasian Paleolithic DNA evidence to provide a comprehensive population model and validate it in light of available material culture. Leveraging on our integrated approach we propose the existence of a Eurasian population Hub, where Homo sapiens lived between the OoA and the broader colonization of Eurasia, which was characterized by multiple events of expansion and local extinction. A major population wave out of Hub, of which Ust’Ishim, Bacho Kiro, and Tianyuan are unadmixed representatives, is broadly associated with Initial Upper Paleolithic lithics and populated West and East Eurasia before or around 45 ka, before getting largely extinct in Europe. In this light, we suggest a parsimonious placement of Oase1 as an individual related to Bacho Kiro who experienced additional Neanderthal introgression. Another expansion, started before 38 ka, is broadly associated with Upper Paleolithic industries and repopulated Europe with sporadic admixtures with the previous wave (GoyetQ116-1) and more systematic ones, whereas moving through Siberia (Yana, Mal’ta). Before these events, we also confirm Zlatý Kůň as the most basal human lineage sequenced to date OoA, potentially representing an earlier wave of expansion out of the Hub
Network hubs revealed by “metabolic connectivity” mapping from [18F]FDG kinetic parameters
Growth rates and age at maturity of Mediterranean loggerhead sea turtles estimated from a single-population foraging ground
In sea turtles, somatic growth rates and Age at Sexual Maturity (ASM) are important parameters for investigating population dynamics. Moreover, ASM informs on the time lag needed to observe the effects of past environmental variables, threats and conservation measures acting at nesting beaches on future numbers of clutches or nesting females, that are the most monitored indices. Assessing ASM of mixed populations that share the same foraging areas is difficult, as in the case of the Mediterranean Sea that is frequented by turtles originating from both the Mediterranean and the Atlantic. Here we investigated growth rates of loggerhead sea turtles (Caretta caretta) foraging in the Adriatic Sea, known to be frequented only by individuals of Mediterranean origin. Capture-mark-recapture records of 79 turtles provided growth rates ranging from - 1.1 to 9.6 cm yr(-1) which were analyzed through Generalized Additive Models. When integrated with previous data on growth rates in the first years of life, results indicate a non-monotonic growth curve, likely due to an ontogenetic shift from oceanic to neritic areas. Using an integration equation, we estimated mean ASM to be 29.5 or 25.0 year based on mean nester size in Greece (83.4 cm curved carapace length, CCL) or across the Mediterranean (79.7 cm CCL), respectively. Growth rates and size-at-age are similar to the Atlantic population, but Mediterranean turtles mature earlier at a smaller size. The heterogenous growth rates and ASM reported so far in the Mediterranean are probably due, at least in part, to different foraging areas
Microbiota, epidemiological and nutritional factors related to ketoacidosis at the onset of type 1 diabetes
The incidence of type 1 diabetes has increased over the last decades. The pathological pathway is not yet clear, even if genetic and environmental risk factors are known. An early diagnosis can avoid ketoacidosis and its complications. This work aims to discuss the determinants of both ketoacidosis at the onset and access by hospital emergency departments without a suspected diagnosis
Behavioural plasticity in the use of a neritic foraging area by loggerhead sea turtles: insights from 37 years of capture–mark–recapture in the Adriatic Sea (Mediterranean Sea)
Assessing sea turtle movements and connectivity among different areas is pivotal to understanding their biology and implementing efficient conservation actions. In the Adriatic Sea, one of the most important sea turtle foraging areas in the Mediterranean, a total of 311 capture-mark-recapture (CMR) records (mostly bycatch) from 294 loggerhead turtles (Caretta caretta) in the period 1984-2021 were analysed. A general fidelity pattern to Adriatic subareas was indicated by a significantly shorter CMR distance than the potential dispersal distance and by the significantly higher proportion of re-encounters in the same area of release than expected. No seasonal pattern was detected between subareas, and shorter re-encounter distances were observed in turtles released and re-encountered in the same season, suggesting different winter and summer residential areas. Results suggest that turtles frequenting the Adriatic can go anywhere in the Mediterranean basin and may exhibit a wandering behaviour regardless of their size. A substantial connectivity with nesting sites in Greece was observed, confirming with empirical evidence that this is the most important breeding area for turtles foraging in the Adriatic Sea. This study highlights the value of cooperation among different groups and shows a main behavioural pattern of fidelity to neritic foraging grounds