Targeting of H19/cell adhesion molecules circuitry by GSK-J4 epidrug inhibits metastatic progression in prostate cancer.

BACKGROUND: About 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer. Previously, we showed a transcriptional down-regulation of H19 under combined pro-tumoral estrogen and hypoxia treatment in PCa cells that, in turn, induced both E-cadherin and ß4 integrin expression. H19, indeed, acts as transcriptional repressor of cell adhesion molecules affecting the PCa metastatic properties. Here, we investigated the role of H19/cell adhesion molecules circuitry on in vivo PCa experimental tumor growth and metastatic dissemination models. METHODS: H19 was silenced in luciferase-positive PC-3 and 22Rv1 cells and in vitro effect was evaluated by gene expression, proliferation and invasion assays before and after treatment with the histone lysine demethylase inhibitor, GSK-J4. In vivo tumor growth and metastasis dissemination, in the presence or absence of GSK-J4, were analyzed in two models of human tumor in immunodeficient mice by in vivo bioluminescent imaging and immunohistochemistry (IHC) on explanted tissues. Organotypic Slice Cultures (OSCs) from fresh PCa-explant were used as ex vivo model to test GSK-J4 effects. RESULTS: H19 silencing in both PC-3 and 22Rv1 cells increased: i) E-cadherin and ß4 integrin expression as well as proliferation and invasion, ii) in vivo tumor growth, and iii) metastasis formation at bone, lung, and liver. Of note, treatment with GSK-J4 reduced lesions. In parallel, GSK-J4 efficiently induced cell death in PCa-derived OSCs. CONCLUSIONS: Our findings underscore the potential of the H19/cell adhesion molecules circuitry as a targeted approach in PCa treatment. Modulating this interaction has proven effective in inhibiting tumor growth and metastasis, presenting a logical foundation for targeted therapy.

A joint Bayesian framework for missing data and measurement error using integrated nested Laplace approximations.

Measurement error (ME) and missing values in covariates are often unavoidable in disciplines that deal with data, and both problems have separately received considerable attention during the past decades. However, while most researchers are familiar with methods for treating missing data, accounting for ME in covariates of regression models is less common. In addition, ME and missing data are typically treated as two separate problems, despite practical and theoretical similarities. Here, we exploit the fact that missing data in a continuous covariate is an extreme case of classical ME, allowing us to use existing methodology that accounts for ME via a Bayesian framework that employs integrated nested Laplace approximations (INLA) and thus to simultaneously account for both ME and missing data in the same covariate. As a useful by-product, we present an approach to handle missing data in INLA since this corresponds to the special case when no ME is present. In addition, we show how to account for Berkson ME in the same framework. In its broadest generality, the proposed joint Bayesian framework can thus account for Berkson ME, classical ME, and missing data, or any combination of these in the same or different continuous covariates of the family of regression models that are feasible with INLA. The approach is exemplified using both simulated and real data. We provide extensive and fully reproducible Supporting Information with thoroughly documented examples using R-INLA and inlabru.

microRNA Detection via Nanostructured Biochips for Early Cancer Diagnostics.

MicroRNA (miRNA) are constituted of approximately 22 nucleotides and play an important role in the regulation of many physiological functions and diseases. In the last 10 years, an increasing interest has been recorded in studying the expression profile of miRNAs in cancer. Real time-quantitative polymerase chain reaction (RT-qPCR), microarrays, and small RNA sequencing represent the gold standard techniques used in the last 30 years as detection methods. The advent of nanotechnology has allowed the fabrication of nanostructured biosensors which are widely exploited in the diagnostic field. Nanostructured biosensors offer many advantages: (i) their small size allows the construction of portable, wearable, and low-cost products; (ii) the large surface-volume ratio enables the loading of a great number of biorecognition elements (e.g., probes, receptors); and (iii) direct contact of the recognition element with the analyte increases the sensitivity and specificity inducing low limits of detection (LOD). In this review, the role of nanostructured biosensors in miRNA detection is explored, focusing on electrochemical and optical sensing. In particular, four types of nanomaterials (metallic nanoparticles, graphene oxide, quantum dots, and nanostructured polymers) are reported for both detection strategies with the aim to show their distinct properties and applications.

ZnO Tetrapods for Label-Free Optical Biosensing: Physicochemical Characterization and Functionalization Strategies.

In this study, we fabricated three different ZnO tetrapodal nanostructures (ZnO-Ts) by a combustion process and studied their physicochemical properties by different techniques to evaluate their potentiality for label-free biosensing purposes. Then, we explored the chemical reactivity of ZnO-Ts by quantifying the available functional hydroxyl groups (-OH) on the transducer surface necessary for biosensor development. The best ZnO-T sample was chemically modified and bioconjugated with biotin as a model bioprobe by a multi-step procedure based on silanization and carbodiimide chemistry. The results demonstrated that the ZnO-Ts could be easily and efficiently biomodified, and sensing experiments based on the streptavidin target detection confirmed these structures' suitability for biosensing applications.

Predictive value of Tmax perfusion maps on final core in acute ischemic stroke: an observational single-center study.

PURPOSE: To assess utility of computed tomography perfusion (CTP) protocols for selection of patients with acute ischemic stroke (AIS) for reperfusive treatments and compare the diagnostic accuracy (ACC) in predicting follow-up infarction, using time-to-maximum (Tmax) maps. METHODS: We retrospectively reviewed consecutive AIS patients evaluated for reperfusive treatments at comprehensive stroke center, employing a multimodal computed tomography. To assess prognostic accuracy of CTP summary maps in predicting final infarct area (FIA) in AIS patients, we assumed the best correlation between non-viable tissue (NVT) and FIA in early and fully recanalized patients and/or in patients with favorable clinical response (FCR). On the other hand, the tissue at risk (TAR) should better correlate with FIA in untreated patients and in treatment failure. RESULTS: We enrolled 158 patients, for which CTP maps with Tmax thresholds of 9.5 s and 16 s, presented sensitivity of 82.5%, specificity of 74.6%, and ACC of 75.9%. In patients selected for perfusion deficit in anterior circulation territory, CTP-Tmax > 16 s has proven relatively reliable to identify NVT in FCR patients, with a tendency to overestimate NVT. Similarly, CTP-Tmax > 9.5 s was reliable for TAR, but it was overestimated comparing to FIA, in patients with unfavorable outcomes. CONCLUSIONS: In our experience, Tmax thresholds have proven sufficiently reliable to identify global hypoperfusion, with tendency to overestimate both NVT and TAR, not yielding satisfactory differentiation between true penumbra and benign oligoemia. In particular, the overestimation of NVT could have serious consequences in not selecting potential candidates for a reperfusion treatment.

A spatiotemporal analysis of NO 2 concentrations during the Italian 2020 COVID-19 lockdown.

When a new environmental policy or a specific intervention is taken in order to improve air quality, it is paramount to assess and quantify-in space and time-the effectiveness of the adopted strategy. The lockdown measures taken worldwide in 2020 to reduce the spread of the SARS-CoV-2 virus can be envisioned as a policy intervention with an indirect effect on air quality. In this paper we propose a statistical spatiotemporal model as a tool for intervention analysis, able to take into account the effect of weather and other confounding factor, as well as the spatial and temporal correlation existing in the data. In particular, we focus here on the 2019/2020 relative change in nitrogen dioxide (NO 2 ) concentrations in the north of Italy, for the period of March and April during which the lockdown measure was in force. We found that during March and April 2020 most of the studied area is characterized by negative relative changes (median values around - 25%), with the exception of the first week of March and the fourth week of April (median values around 5%). As these changes cannot be attributed to a weather effect, it is likely that they are a byproduct of the lockdown measures. There are two aspects of our research that are equally interesting. First, we provide a unique statistical perspective for calculating the relative change in the NO 2 by jointly modeling pollutant concentrations time series. Second, as an output we provide a collection of weekly continuous maps, describing the spatial pattern of the NO 2 2019/2020 relative changes.

Should Entanglement Measures be Monogamous or Faithful?

"Is entanglement monogamous?" asks the title of a popular article [B. Terhal, IBM J. Res. Dev. 48, 71 (2004)], celebrating C. H. Bennett's legacy on quantum information theory. While the answer is affirmative in the qualitative sense, the situation is less clear if monogamy is intended as a quantitative limitation on the distribution of bipartite entanglement in a multipartite system, given some particular measure of entanglement. Here, we formalize what it takes for a bipartite measure of entanglement to obey a general quantitative monogamy relation on all quantum states. We then prove that an important class of entanglement measures fail to be monogamous in this general sense of the term, with monogamy violations becoming generic with increasing dimension. In particular, we show that every additive and suitably normalized entanglement measure cannot satisfy any nontrivial general monogamy relation while at the same time faithfully capturing the geometric entanglement structure of the fully antisymmetric state in arbitrary dimension. Nevertheless, monogamy of such entanglement measures can be recovered if one allows for dimension-dependent relations, as we show explicitly with relevant examples.

Strong monogamy conjecture for multiqubit entanglement: the four-qubit case.

We investigate the distribution of bipartite and multipartite entanglement in multiqubit states. In particular, we define a set of monogamy inequalities sharpening the conventional Coffman-Kundu-Wootters constraints, and we provide analytical proofs of their validity for relevant classes of states. We present extensive numerical evidence validating the conjectured strong monogamy inequalities for arbitrary pure states of four qubits.

Biological Effects of Small Sized Graphene Oxide Nanosheets on Human Leukocytes.

Since the discovery of graphene, there has been a wide range of the literature dealing with its versatile structure and easy binding of biomolecules as well as its large loading capacity. In the emerging field of immunotherapy, graphene and its derivatives have potential uses as drug delivery platforms directly into tumour sites or as adjuvants in cancer vaccines, as they are internalized by monocytes which in turn may activate adaptive anti-tumoral immune responses. In this study, we expose cells of the innate immune system and a human acute monocytic leukemia cell line (THP-1) to low doses of small-sized GO nanosheets functionalized with bovine serum albumin (BSA) and fluorescein isothiocyanate (FITC), to study their acute response after internalization. We show by flow cytometry, uptake in cells of GO-BSA-FITC reaches 80% and cell viability and ROS production are both unaffected by exposure to nanoparticles. On the contrary, GO-BSA nanosheets seem to have an inhibitory effect on ROS production, probably due to their antioxidant properties. We also provided results on chemotaxis of macrophages derived from peripheral blood monocytes treated with GO-BSA. In conclusion, we showed the size of nanosheets, the concentration used and the degree of functionalization were important factors for biocompatibility of GO in immune cells. Its low cytotoxicity and high adaptability to the cells of the innate immune system make it a good candidate for deployment in immunotherapy, in particular for delivering protein antigens to monocytes which activate adaptive immunity.

Menarche and eating disorders.

160 undergraduate women (M age = 20.3, SD = 1.52) were assessed for depression, drug abuse, and eating disorders. The age of menarche was positively correlated with higher scores on a screening measure for eating disorders, a finding opposite to past studies for adolescent girls.

Blockage of autophagosome-lysosome fusion through SNAP29 O-GlcNAcylation promotes apoptosis via ROS production.

Macroautophagy/autophagy has been shown to exert a dual role in cancer i.e., promoting cell survival or cell death depending on the cellular context and the cancer stage. Therefore, development of potent autophagy modulators, with a clear mechanistic understanding of their target action, has paramount importance in both mechanistic and clinical studies. In the process of exploring the mechanism of action of a previously identified cytotoxic small molecule (SM15) designed to target microtubules and the interaction domain of microtubules and the kinetochore component NDC80/HEC1, we discovered that the molecule acts as a potent autophagy inhibitor. By using several biochemical and cell biology assays we demonstrated that SM15 blocks basal autophagic flux by inhibiting the fusion of correctly formed autophagosomes with lysosomes. SM15-induced autophagic flux blockage promoted apoptosis-mediated cell death associated with ROS production. Interestingly, autophagic flux blockage, apoptosis induction and ROS production were rescued by genetic or pharmacological inhibition of OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) or by expressing an O-GlcNAcylation-defective mutant of the SNARE fusion complex component SNAP29, pointing to SNAP29 as the molecular target of SM15 in autophagy. Accordingly, SM15 was found to enhance SNAP29 O-GlcNAcylation and, thereby, inhibit the formation of the SNARE fusion complex. In conclusion, these findings identify a new pathway in autophagy connecting O-GlcNAcylated SNAP29 to autophagic flux blockage and autophagosome accumulation, that, in turn, drives ROS production and apoptotic cell death. Consequently, modulation of SNAP29 activity may represent a new opportunity for therapeutic intervention in cancer and other autophagy-associated diseases.

Prevalence of unruptured intracranial aneurysms in patients with Marfan syndrome: A cross-sectional study and meta-analysis.

INTRODUCTION: Marfan syndrome (MFS) is the most common inherited connective tissue disorder and its association with intracranial aneurysms (ICAs) has been debated for more than two decades. Here, we report the prevalence of ICAs at screening neuroimaging in a population of genetically confirmed MFS patients and present the results of a meta-analysis including our cohort of patients and those of previous studies. PATIENTS AND METHODS: We enrolled 100 consecutive MFS patients, who underwent screening with brain magnetic resonance angiography at our tertiary center between August 2018 and May 2022. We did a PubMed and Web of Science search to retrieve all studies on the prevalence of ICAs in patients with MFS published before November, 2022. RESULTS: Of the 100 patients included in this study (94% Caucasians, 40% females, mean age 38.6 ± 14.6 years), three had an ICA. We pooled the current study with five previously published studies, including a total of 465 patients, 43 of which harbored at least one unruptured ICA, leading to an overall ICA prevalence of 8.9% (95% CI 5.8%-13.3%). DISCUSSION AND CONCLUSION: In our cohort of genetically confirmed MFS patients, the prevalence of ICAs was 3%, which is substantially lower compared to previous studies based on neuroimaging. The high frequency of ICA found in previous studies could be explained by selection bias and lack of genetic testing, which may have led to the inclusion of patients with different connective tissue disorders. Further studies, including several centers and a large number of patients with genetically confirmed MFS, are needed to confirm our results.

Non-Invasive Treatments for Failed Back Surgery Syndrome: A Systematic Review.

STUDY DESIGN: Systematic Review. OBJECTIVES: The aim of this systematic review is to evaluate the efficacy of non-invasive procedures in relieving chronic pain due to Failed Back Surgery Syndrome (FBSS). METHODS: Since patients who suffered from FBBS are often non-responders to analgesics, we compared Visual Analogical Scale for low back and leg pain, Oswestry Disability Index, trial success rate, adverse events and complications between conservative treatment groups and control groups. RESULTS: The included studies were 15. Spinal Cord Stimulation (SCS) was performed in 11 trials; 4 studies assessed the efficacy of different epidural injections; one study evaluated repetitive Transcranial Magnetic Stimulation. All the studies reported back and leg pain relief after treatment with SCS, with a significant superiority in high frequences (HFS) group, compared to low frequences (LFS) group. Moreover, disability decreased with each non-invasive treatment evaluated. Epidural injections of steroids and hyaluronidase have shown controversial results. Adverse events were described in 7 studies: lead migration, hardware-related events, infection and incisional pain were the most reported. Finally, trial success rate showed better outcomes for HFS. CONCLUSIONS: Our systematic review highlights the efficacy of conservative treatments in FBSS patients, with an improvement in pain scores and a decrease in disability index, especially after SCS with HFS. However, due to the lack of homogeneity among trials and population characteristics, further studies are needed to confirm the effectiveness of non-invasive interventions in patients affected by FBSS.

Bayesian spatial analysis of crash severity data with the INLA approach: Assessment of different identification constraints.

Multinomial logit models have been widely used in the analysis of categorical crash data. When the regional information of the data is available, the dependence structure needs to be incorporated into the model to accommodate for spatial heterogeneity. We consider a Bayesian multinomial structured additive regression model to analyze categorical spatial crash data and compare its performance with a fractional split multinomial model. We use the multinomial-Poisson transformation to apply the integrated nested Laplace approximation method for fitting the proposed model efficiently and fast. Moreover, we consider two different types of identifiability constraints to deal with the inherent identifiability problem of the multinomial models. The proposed models are studied through simulated examples and applied to a road traffic crash dataset from Mazandaran province, Iran.

MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer.

BACKGROUND: Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). METHODS: We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment. RESULTS: In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment. CONCLUSIONS: These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective.

Perceptions of visible piercings: a pilot study.

49 undergraduates were shown pictures of a man and a woman with piercings and with no piercings. The pierced model was judged to be less attractive and less normal than the nonpierced model. The pierced model was perceived as less intelligent, caring, generous, honest, and religious but more artistic and mysterious.

Magnetic resonance imaging findings in patients with non-ketotic hyperglycaemia and focal seizures.

We present the neuroimaging findings of three cases of non-ketotic hyperglycaemia (NKH) associated with focal seizures and a review of the previous cases and series reported in literature. NKH is a cause of seizures in both long-standing and newly diagnosed diabetic patients. They are usually focal motor seizures, rarely with a secondary generalisation. This condition does not fully respond to anticonvulsant therapy if glycaemic levels are not normalised. Of interest, magnetic resonance imaging (MRI) of NKH could be different from those observed during other kinds of seizures. Indeed, seizure-related MRI abnormalities mainly involve the cortical grey matter, while NKH-related seizures usually appear as reversible subcortical T2/fluid attenuation inversion recovery (FLAIR) hypointensity. This latter abnormality shows a good spatial correlation with the area of the ictal focus on electroencephalogram and could be associated with other more common post-ictal MRI changes (cortical grey matter T2/FLAIR hyperintensity, cortical or leptomeningeal enhancement). Although these abnormalities tend to be transient, a focal volume loss or gliosis can result on follow-up imaging. Our cases confirm T2/FLAIR subcortical hypointensity as a main neuroradiological hallmark of NKH-induced seizures.

Perceptions of a photograph of a woman with visible piercings.

To examine perceptions of people with visible piercings 105 undergraduate students from four different courses on campus (85 women, 20 men; M age=20.0 yr., SD=3.4) were randomly assigned to rate a photograph of a women with or without piercings on her eyebrow, ear, lip, and nose on 13 characteristics. Analysis indicated the model with visible piercings was rated less religious and more creative, artistic, and mysterious. These findings differ from previous findings on perception of tattoos. Implications and directions for research with different age groups are discussed.