Prognostic significance of miR-34a in Ewing sarcoma is associated with cyclin D1 and ki-67 expression

BACKGROUND: At diagnosis, identification of reliable biological indicators of prognosis to allow stratification of patients according to different risks is an important but still unresolved aspect in the treatment of Ewing sarcoma (EWS) patients. This study aimed to explore the role of miR-34A expression on prognosis of EWS patients.PATIENTS AND METHODS: Specimens from 109 patients with non-metastatic EWS treated at the Rizzoli Institute with neoadjuvant chemotherapy (protocols ISG/SSGIII, EW-1, EW-2, EW-REN2, EW-REN3, EW-PILOT) and 17 metastases were studied. Sixty-eight patients (62%) remained disease-free and 41 (38%) relapsed (median follow-up: 67 months, range 9-241 months). Expression of miR-34a and of some of its targets (cyclin D1, bcl-2, SIRT1 and YY1) was evaluated by qRT-PCR using TaqMan MicroRNA Assays and/or by immunohistochemistry on tissue microarrays from the same patients.RESULTS: High expression of miR-34a in localized tumors was significantly related to better event-free and overall survival (P = 0.004). Relevance of miR-34a was confirmed by using different calibrators (normal mesenchymal stem cells and different normal tissues). By multivariate Cox regression analysis, low miR-34a expression as well as nontotal necrosis and high levels of lactate dehydrogenase were all confirmed as independent risk factors associated with poor outcome. Expression of miR-34a was lower in metastases than in primary tumors. It inversely correlated with expression of cyclin D1 and Ki-67.CONCLUSIONS: By demonstrating its relationship with clinical outcome, we propose evaluation of miR-34a at diagnosis of EWS patients to allow early risk stratification. Validation of these results would nonetheless ultimately need a prospective assessment

The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR-221&222-c-FOS pathway.

Cutaneous melanoma is the fastest increasing cancer worldwide. Although several molecular abnormalities have been associated with melanoma progression, the underlying mechanisms are still largely unknown and few targeted therapies are under evaluation. Here we show that the HOXB7/PBX2 dimer acts as a positive transcriptional regulator of the oncogenic microRNA-221 and -222. In addition, demonstrating c-FOS as a direct target of miR-221&222, we identify a HOXB7/PBX2→miR-221&222 →c-FOS regulatory link, whereby the abrogation of functional HOXB7/PBX2 dimers leads to reduced miR-221&222 transcription and elevated c-FOS expression with consequent cell death. Taking advantage of the treatment with the peptide HXR9, an antagonist of HOX/PBX dimerization, we recognize miR-221&222 as effectors of its action, in turn confirming the HXR9 efficacy in the treatment of human melanoma malignancy, whilst sparing normal human melanocytes. Our findings, besides suggesting the potential therapeutic of HXR9 or its derivatives in malignant melanoma, suggest the disruption of the HOXB7/PBX2 complexes, miR-221&222 inhibition or even better their combination, as innovative therapeutic approaches

Ecological and environmental factors affecting the risk of tick-borne encephalitis in Europe, 2017 to 2021

Background: Tick-borne encephalitis (TBE) is a disease which can lead to severe neurological symptoms, caused by the TBE virus (TBEV). The natural transmission cycle occurs in foci and involves ticks as vectors and several key hosts that act as reservoirs and amplifiers of the infection spread. Recently, the incidence of TBE in Europe has been rising in both endemic and new regions. Aim: In this study we want to provide comprehensive understanding of the main ecological and environmental factors that affect TBE spread across Europe. Methods: We searched available literature on covariates linked with the circulation of TBEV in Europe. We then assessed the best predictors for TBE incidence in 11 European countries by means of statistical regression, using data on human infections provided by the European Surveillance System (TESSy), averaged between 2017 and 2021. Results: We retrieved data from 62 full-text articles and identified 31 different covariates associated with TBE occurrence. Finally, we selected eight variables from the best model, including factors linked to vegetation cover, climate, and the presence of tick hosts. Discussion: The existing literature is heterogeneous, both in study design and covariate types. Here, we summarised and statistically validated the covariates affecting the variability of TBEV across Europe. The analysis of the factors enhancing disease emergence is a fundamental step towards the identification of potential hotspots of viral circulation. Hence, our results can support modelling efforts to estimate the risk of TBEV infections and help decision-makers implement surveillance and prevention campaigns

A Search for Coincident Neutrino Emission from Fast Radio Bursts with Seven Years of IceCube Cascade Events

This paper presents the results of a search for neutrinos that are spatially and temporally coincident with 22 unique, nonrepeating fast radio bursts (FRBs) and one repeating FRB (FRB 121102). FRBs are a rapidly growing class of Galactic and extragalactic astrophysical objects that are considered a potential source of high-energy neutrinos. The IceCube Neutrino Observatory\u27s previous FRB analyses have solely used track events. This search utilizes seven years of IceCube cascade events which are statistically independent of track events. This event selection allows probing of a longer range of extended timescales due to the low background rate. No statistically significant clustering of neutrinos was observed. Upper limits are set on the time-integrated neutrino flux emitted by FRBs for a range of extended time windows

Constraining High-energy Neutrino Emission from Supernovae with IceCube

Core-collapse supernovae are a promising potential high-energy neutrino source class. We test for correlation between seven years of IceCube neutrino data and a catalog containing more than 1000 core-collapse supernovae of types IIn and IIP and a sample of stripped-envelope supernovae. We search both for neutrino emission from individual supernovae as well as for combined emission from the whole supernova sample, through a stacking analysis. No significant spatial or temporal correlation of neutrinos with the cataloged supernovae was found. All scenarios were tested against the background expectation and together yield an overall p-value of 93%; therefore, they show consistency with the background only. The derived upper limits on the total energy emitted in neutrinos are 1.7 × 1048 erg for stripped-envelope supernovae, 2.8 × 1048 erg for type IIP, and 1.3 × 1049 erg for type IIn SNe, the latter disfavoring models with optimistic assumptions for neutrino production in interacting supernovae. We conclude that stripped-envelope supernovae and supernovae of type IIn do not contribute more than 14.6% and 33.9%, respectively, to the diffuse neutrino flux in the energy range of about [ 103-105] GeV, assuming that the neutrino energy spectrum follows a power-law with an index of −2.5. Under the same assumption, we can only constrain the contribution of type IIP SNe to no more than 59.9%. Thus, core-collapse supernovae of types IIn and stripped-envelope supernovae can both be ruled out as the dominant source of the diffuse neutrino flux under the given assumptions

Synergy between vitamin D and sex hormones in respiratory functionality of patients affected by COVID-19

The outcome of COVID-19 appears to be influenced by vitamin D status of population. Although epidemiological data indicate that COVID-19 produces more severe symptoms and higher mortality in elderly in comparison to young patients and in men in comparison to women to date sex and age differences in vitamin D status in infected patients have not been evaluated yet. In this study we evaluated the levels of circulating 25(OH)D in patients hospitalized for COVID-19 divided accordingly to their sex and age. We also correlated 25(OH)D levels with patient’s respiratory status (i.e., PaO2/FiO2 ratio) and with sex hormones plasma levels to analyze the potential relationship of these parameters. We found no significant differences in plasma levels of 25(OH)D between pre- and post-menopausal female patients and age matched male patients. Interestingly, the 25(OH)D plasma levels positively correlated to PaO2/FiO2 ratio only in young patients, regardless of their sex. We also found a significantly positive correlation between 17β-estradiol and 25(OH)D in elderly women and between testosterone and 25(OH)D in elderly men, supporting the role of sex hormones in maintaining 25(OH)D levels. In conclusion, we suggest that a synergy between vitamin D and sex hormones could contribute to the age-related outcome of COVID-19

AP2α controls the dynamic balance between miR-126&126∗ and miR-221&222 during melanoma progression

Accumulating evidences have shown the association between aberrantly expressed microRNAs (miRs) and cancer, where these small regulatory RNAs appear to dictate the cell fate by regulating all the main biological processes. We demonstrated the responsibility of the circuitry connecting the oncomiR-221&222 with the tumor suppressors miR-126&126∗ in melanoma development and progression. According to the inverse correlation between endogenous miR-221&222 and miR-126&126∗, respectively increasing or decreasing with malignancy, their enforced expression or silencing was sufficient for a reciprocal regulation. In line with the opposite roles of these miRs, protein analyses confirmed the reverse expression pattern of miR-126&126∗-targeted genes that were induced by miR-221&222. Looking for a central player in this complex network, we revealed the dual regulation of AP2α, on one side directly targeted by miR-221&222 and on the other a transcriptional activator of miR-126&126∗. We showed the chance of restoring miR-126&126∗ expression in metastatic melanoma to reduce the amount of mature intracellular heparin-binding EGF like growth factor, thus preventing promyelocytic leukemia zinc finger delocalization and maintaining its repression on miR-221&222 promoter. Thus, the low-residual quantity of these two miRs assures the release of AP2α expression, which in turn binds to and induces miR-126&126∗ transcription. All together these results point to an unbalanced ratio functional to melanoma malignancy between these two couples of miRs. During progression this balance gradually moves from miR-126&126∗ toward miR-221&222. This circuitry, besides confirming the central role of AP2α in orchestrating melanoma development and/or progression, further displays the significance of these miRs in cancer and the option of utilizing them for novel therapeutics

A Search for Coincident Neutrino Emission from Fast Radio Bursts with Seven Years of IceCube Cascade Events

This paper presents the results of a search for neutrinos that are spatially and temporally coincident with 22 unique, nonrepeating fast radio bursts (FRBs) and one repeating FRB (FRB 121102). FRBs are a rapidly growing class of Galactic and extragalactic astrophysical objects that are considered a potential source of high-energy neutrinos. The IceCube Neutrino Observatory\u27s previous FRB analyses have solely used track events. This search utilizes seven years of IceCube cascade events which are statistically independent of track events. This event selection allows probing of a longer range of extended timescales due to the low background rate. No statistically significant clustering of neutrinos was observed. Upper limits are set on the time-integrated neutrino flux emitted by FRBs for a range of extended time windows