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Background: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach. Objectives: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. Methods: Observational retrospective multi-centers Italian cohort study. Results: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion (p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU (p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). Conclusions: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) diagnosis are based on the presence of serological and magnetic resonance imaging (MRI) biomarkers. Diffusion tensor imaging (DTI), neurites orientation dispersion and density imaging (NODDI), and the Spherical Mean Technique (SMT) may be helpful to provide a microstructural characterization of the different types of white matter lesions and give an insight about their different pathological mechanisms. The aim of the study was to characterize microstructural differences between brain typical lesions (TLs) and nontypical lesions (nTLs). Methods: A total of 17 NMOSD and MOGAD patients [9 Aquaporin4 (AQP4) + NMO, 2 seronegative‐NMO, 6 MOGAD] underwent MRI scans on a 3 Tesla MAGNETON PRISMA. Diffusion parameters (fractional anisotropy; mean diffusivity [MD]; intracellular volume fraction [ICVF]; extra‐neurite transverse diffusivity; and extra‐neurite MD; neurite signal fraction) were obtained using DTI, NODDI, and SMT. Microstructural parameters within lesions were compared through a generalized linear model using age, sex, and total lesion volume as covariates. Results: In NMOSD/MOGAD whole cohort (total lesions = 477), TLs showed increased MD and decreased ICVF compared to nTLs (p <.05), indicating higher inflammation and axonal loss. Similar results were found also in the AQP4 + NMO subgroup (decreased ICVF, p <.05). Furthermore, in NMOSD/MOGAD whole cohort and in AQP4 + NMO subgroup, TLs showed a trend toward higher EXRATRANS than nTLs, suggesting a more severe degree of demyelination within TLs. Conclusions: TLs and nTLs in NMOSD/MOGAD showed different diffusion MRI‐derived microstructural features, with TLs showing a more severe degree of inflammation and fiber disruption with respect to nTLs. [ABSTRACT FROM AUTHOR]

In this paper, we consider multi-objective optimization problems with a sparsity constraint on the vector of variables. For this class of problems, inspired by the homonymous necessary optimality condition for sparse single-objective optimization, we define the concept of L-stationarity and we analyze its relationships with other existing conditions and Pareto optimality concepts. We then propose two novel algorithmic approaches: the first one is an iterative hard thresholding method aiming to find a single L-stationary solution, while the second one is a two-stage algorithm designed to construct an approximation of the whole Pareto front. Both methods are characterized by theoretical properties of convergence to points satisfying necessary conditions for Pareto optimality. Moreover, we report numerical results establishing the practical effectiveness of the proposed methodologies. [ABSTRACT FROM AUTHOR]

Metastatic prostate cancer is a major health burden worldwide, necessitating the continuous development of effective treatment strategies. Androgen deprivation therapy remains the cornerstone of prostate cancer treatment, but novel approaches are needed for metastatic castration-resistant prostate cancer (mCRPC). Recent studies have highlighted the prevalence of mutations in DNA repair genes, including BRCA1 and BRCA2, in mCRPC patients, rendering them more susceptible to platinum-based chemotherapy and Poly (ADP-ribose) polymerase (PARP) inhibitors. Platinum-based chemotherapy, particularly in combination with taxanes, has demonstrated encouraging activity in mCRPC, as well as homologous recombination gene alterations have shown increased sensitivity to platinum compounds in these patients. The combination of platinum-based chemotherapy with PARP inhibitors represents a novel and potentially effective therapeutic strategy for this subgroup of patients. However, the optimal sequence of administering these agents and the potential for cross-resistance and cross-toxicities remain areas requiring further investigation. Prospective randomized studies are essential to elucidate the most effective treatment approach for this challenging patient population. This review aims to explore the potential of platinum-based chemotherapy in the context of prostate cancer, and more in detail in homologous recombination repair (HRR) mutated patients. We discuss the synergistic effects of combining platinum compounds with PARP inhibitors and the potential benefits of adopting specific therapeutic sequences. [ABSTRACT FROM AUTHOR]

Understanding and monitoring the ecological quality of coastal waters is crucial for preserving marine ecosystems. Eutrophication is one of the major problems affecting the ecological state of coastal marine waters. For this reason, the control of the trophic conditions of aquatic ecosystems is needed for the evaluation of their ecological quality. This study leverages space-based Sentinel-3 Ocean and Land Color Instrument imagery (OLCI) to assess the ecological quality of Mediterranean coastal waters using the Trophic Index (TRIX) key indicator. In particular, we explore the feasibility of coupling remote sensing and machine learning techniques to estimate the TRIX levels in the Ligurian, Tyrrhenian, and Ionian coastal regions of Italy. Our research reveals distinct geographical patterns in TRIX values across the study area, with some regions exhibiting eutrophic conditions near estuaries and others showing oligotrophic characteristics. We employ the Random Forest Regression algorithm, optimizing calibration parameters to predict TRIX levels. Feature importance analysis highlights the significance of latitude, longitude, and specific spectral bands in TRIX prediction. A final statistical assessment validates our model's performance, demonstrating a moderate level of error (MAE of 0.51) and explanatory power (R2 of 0.37). These results highlight the potential of Sentinel-3 OLCI imagery in assessing ecological quality, contributing to our understanding of coastal water ecology. They also underscore the importance of merging remote sensing and machine learning in environmental monitoring and management. Future research should refine methodologies and expand datasets to enhance TRIX monitoring capabilities from space. [ABSTRACT FROM AUTHOR]

In this paper, we consider the optimization problem of minimizing a continuously differentiable function subject to both convex constraints and sparsity constraints. By exploiting a mixed-integer reformulation from the literature, we define a necessary optimality condition based on a tailored neighborhood that allows to take into account potential changes of the support set. We then propose an algorithmic framework to tackle the considered class of problems and prove its convergence to points satisfying the newly introduced concept of stationarity. We further show that, by suitably choosing the neighborhood, other well-known optimality conditions from the literature can be recovered at the limit points of the sequence produced by the algorithm. Finally, we analyze the computational impact of the neighborhood size within our framework and in the comparison with some state-of-the-art algorithms, namely, the Penalty Decomposition method and the Greedy Sparse-Simplex method. The algorithms have been tested using a benchmark related to sparse logistic regression problems. [ABSTRACT FROM AUTHOR]

The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment. [ABSTRACT FROM AUTHOR]

The central vein sign (CVS) has been proposed as a biomarker of multiple sclerosis (MS). In adult-onset MS (AOMS), 40%-threshold of CVS positive (+) lesions demonstrated high accuracy for MS diagnosis. However, CVS+ lesions' performance has not been characterized in paediatric-onset (POMS) yet. We compared the CVS contribution to MS diagnosis in 10 POMS and 12 disease-duration-matched AOMS patients. Three POMS patients did not meet the 40%-threshold, while all AOMS patients were correctly diagnosed as having MS. The high proportion of periventricular confluent lesions, excluded from the CVS assessment, seemed to impair CVS sensitivity in POMS diagnosis. [ABSTRACT FROM AUTHOR]

In this manuscript, we consider multi-objective optimization problems with a cardinality constraint on the vector of decision variables and additional linear constraints. For this class of problems, we analyse necessary and sufficient conditions of Pareto optimality. We afterwards propose a Penalty Decomposition type algorithm, exploiting multi-objective descent methods, to tackle the aforementioned family of problems. We conduct a rigorous convergence analysis for the proposed method, where we prove that the produced sequence of points has limit points, each one being feasible and satisfying first-order optimality conditions. Numerical computational experiments, carried out on instances of relevant real-world problems such as sparse mean/variance portfolio selection and sparse regularized logistic regression, in their multi-objective formulation, show that the proposed procedure is effective at finding solutions forming good Pareto sets approximations. [ABSTRACT FROM AUTHOR]

Inner macular layers are the most involved in the retinal distortion caused by idiopathic epiretinal membrane (iERM). They represent the anatomical structures in which the superficial (SCP) and deep (DCP) capillary plexus are embedded. We quantified flow signal (FS) in these capillary plexuses using Swept Source OCT angiography to identify possible markers for postoperative outcome. The software ImageJ was used to quantify the FS in a 150 µm radius area around each point analyzed by MAIA microperimeter. In 16 patients with unilateral iERM, focal light sensitivity (FLS) in the para- and perimacular areas was measured to evaluate macular function in 24 points overlapping macular plexuses and compared with normal fellow eyes (FEs). t-Test for independent samples iERM eyes (iERMEs) vs. fellow eyes (FEs) and Pearson correlation coefficient of FS vs. FLS in each point were calculated. A level of p < 0.05 was accepted as statistically significant. As a whole, FLS was significantly higher in FEs vs. ERMEs (p < 0.001); FS in both SCP and DCP was not significantly different between ERMEs and FEs (p = 0.827, p = 0.791). Correlation in focal retinal areas between FLS and FS in ERMEs was significant in SCP (p = 0.002) and not significant in DCP (p = 0.205); in FEs was significant in both SCP (p < 0.001) and DCP (p = 0.022). As previously described, these defective areas were located mainly in sites of distortion of retinal layers; therefore, it can be hypothesized that a focal change in FS, occurring mostly in SCP, could be involved in the onset of the functional defect. [ABSTRACT FROM AUTHOR]

Background and Purpose: Double inversion recovery (DIR) imaging is used in multiple sclerosis (MS) clinical protocols to improve the detection of cortical and juxtacortical gray matter lesions by nulling confounding signals originating from the cerebrospinal fluid and white matter. Achieving a high isotropic spatial resolution, to depict the neocortex and its typically small lesions, is challenged by the reduced signal‐to‐noise ratio (SNR) determined by multiple tissue signal nulling. Here, we evaluate both conventional and optimized DIR implementations to improve tissue contrast (TC), SNR, and MS lesion conspicuity. Methods: DIR images were obtained from MS patients and healthy controls using both conventional and prototype implementations featuring a T2‐preparation module (T2P), to improve SNR and TC, as well as an image reconstruction routine with iterative denoising (ID). We obtained quantitative measures of SNR and TC, and evaluated the visibility of MS cortical, cervical cord, and optic nerve lesions in the different DIR images. Results: DIR implementations adopting T2P and ID enabled improving the SNR and TC of conventional DIR. In MS patients, 34% of cortical, optic nerve, and cervical cord lesions were visible only in DIR images acquired with T2P, and not in conventional DIR images. In the studied cases, image reconstruction with ID did not improve lesion conspicuity. Conclusions: DIR with T2P should be preferred to conventional DIR imaging in protocols studying MS patients, as it improves SNR and TC and determines an improvement in cortical, optic nerve, and cervical cord lesion conspicuity. [ABSTRACT FROM AUTHOR]

In this manuscript, we consider the problem of minimizing a smooth function with cardinality constraint, i.e., the constraint requiring that the -norm of the vector of variables cannot exceed a given threshold value. A well-known approach of the literature is represented by the class of penalty decomposition methods, where a sequence of penalty subproblems, depending on the original variables and new variables, are inexactly solved by a two-block decomposition method. The inner iterates of the decomposition method require to perform exact minimizations with respect to the two blocks of variables. The computation of the global minimum with respect to the original variables may be prohibitive in the case of nonconvex objective function. In order to overcome this nontrivial issue, we propose a modified penalty decomposition method, where the exact minimizations with respect to the original variables are replaced by suitable line searches along gradient-related directions. We also present a derivative-free penalty decomposition algorithm for black-box optimization. We state convergence results of the proposed methods, and we report the results of preliminary computational experiments. [ABSTRACT FROM AUTHOR]

In this work we present a novel way to solve the sub-problems that originate when using decomposition algorithms to train Support Vector Machines (SVMs). State-of-the-art Sequential Minimization Optimization (SMO) solvers reduce the original problem to a sequence of sub-problems of two variables for which the solution is analytical. Although considering more than two variables at a time usually results in a lower number of iterations needed to train an SVM model, solving the sub-problem becomes much harder and the overall computational gains are limited, if any. We propose to apply the two-variables decomposition method to solve the sub-problems themselves and experimentally show that it is a viable and efficient way to deal with sub-problems of up to 50 variables. As a second contribution we explore different ways to select the working set and its size, combining firstorder and second-order working set selection rules together with a strategy for exploiting cached elements of the Hessian matrix. An extensive numerical comparison shows that the method performs considerably better than state-of-the-art software. [ABSTRACT FROM AUTHOR]

Background and purpose: The best therapeutic approach for aggressive relapsing–remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing–remitting multiple sclerosis. Methods: The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6‐month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24. Results: Fifty‐seven patients treated with aHSCT (n = 25) or alemtuzumab (n = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P < 0.001), higher ARR (mean ARR 3.2 vs. 1.7; P = 0.001) and a higher number of baseline T1 gadolinium‐enhancing lesions on MRI (mean number 15.5 vs. 1.6; P < 0.001). NEDA‐3 (no evidence of disease activity) status was more frequently achieved in aHSCT‐treated patients than in alemtuzumab‐treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.08–0.84; P = 0.023]. aHSCT significantly reduced the risk of relapse (relapse‐free survival 84% vs. 69%; HR 0.13, 95% CI 0.02–0.63; P = 0.012) and MRI activity (MRI‐activity‐free survival 85% vs. 59%; HR 0.13, 95% CI 0.03–0.59; P = 0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs. 0.35, P = 0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (P = 0.035). Conclusions: Alemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short‐term disability improvement. [ABSTRACT FROM AUTHOR]

Objectives: To retrospectively evaluate the different performances of T1-SE and T1-GE sequences in detecting hypointense lesions in multiple sclerosis (MS), to quantify the degree of microstructural damage within lesions and to correlate them with patient clinical status.Methods: Sixty clinically isolated syndrome (CIS) and MS patients underwent brain magnetic resonance imaging (MRI) on 1.5-T and 3-T scanners. We identified T2 fluid-attenuated inversion recovery hyperintense lesions with no hypointense signal on T1-SE/T1-GE (a), hypointense lesions only on T1-GE (b), and hypointense lesions on both T1-SE and T1-GE sequences (c). We compared mean lesion number (LN) and volume (LV) identified on T1-SE and T1-GE sequences, correlating them with Expanded Disability Status Scale (EDSS); fractional anisotropy (FA) and mean diffusivity (MD) values inside each lesion type were extracted and normal-appearing white matter (NAWM).Results: Thirty-five patients were female. Mean age was 39.2 (± 7.8); median EDSS was 3 (± 2). There were 23 CIS, 21 relapsing-remitting (RR), and 16 progressive MS. T1-GE and T1-SE LN and LV were significantly different (p < 0.001), both correlating with EDSS. Both FA and MD metrics resulted significantly different among the three lesion groups and NAWM (p < 0.001). FA and MD values extracted from (b) and (c) showed statistically significant differences (p < 0.001), while for (a) and (b), the differences were not significant (p = 0.31 for FA and p = 0.62 for MD).Conclusion: T1-SE hypointense lesions demonstrated a more pronounced degree of microstructural damage. T1-weighted sequence type must be more carefully evaluated in clinical and research settings.Key Points: • T1-weighted spin-echo (T1-SE) images detect chronic hypointense lesions (so called black holes) associated with more severe microstructural changes. • In the last years, three-dimensional (3D) T1-weighted gradient-echo (T1-GE) sequences are often utilized in lieu of T1-SE acquisition, more so at 3 T or higher fields. • T1-weighted sequence type must be more carefully evaluated in clinical and research settings in the definition of "black holes" in MS, in order to avoid the overestimation of the effective severe tissue damage. [ABSTRACT FROM AUTHOR]

We consider the problem of minimizing a smooth nonconvex function over a structured convex feasible set, that is, defined by two sets of constraints that are easy to treat when considered separately. In order to exploit the structure of the problem, we define an equivalent formulation by duplicating the variables and we consider the augmented Lagrangian of this latter formulation. Following the idea of the Alternating Direction Method of Multipliers (ADMM), we propose an algorithm where a two-blocks decomposition method is embedded within an augmented Lagrangian framework. The peculiarities of the proposed algorithm are the following: (1) the computation of the exact solution of a possibly nonconvex subproblem is not required; (2) the penalty parameter is iteratively updated once an approximated stationary point of the augmented Lagrangian is determined. Global convergence results are stated under mild assumptions and without requiring convexity of the objective function. Although the primary aim of the paper is theoretical, we perform numerical experiments on a nonconvex problem arising in machine learning, and the obtained results show the practical advantages of the proposed approach with respect to classical ADMM. [ABSTRACT FROM AUTHOR]

ATP Binding Cassette (ABC) transporters, widely studied in cancer for their role in drug resistance, have been more recently also considered for their contribution to cancer cell biology. To date, many data provide evidences for their potential role in all the phases of cancer development from cancer susceptibility, tumor initiation, tumor progression and metastasis. Although many evidences are based on correlative analyses, data describing a direct or indirect role of ABC transporters in cancer biology are increasing. Overall, current available information suggests a relevant molecular effector role of some ABC transporters in cancer invasion and metastasis as reported in experimental tumor models. From a therapeutic point of view, due to the physiological relevant roles that ABC transporters play in the organism, the capability to selectively inhibit the function or the expression of ABC transporters in cancer stem cells or other tumor cells, represents the main challenge for researcher scientists. A detailed and updated description of the current knowledge on the role of ABC transporters in cancer biology is provided. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusion Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T‐MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months.Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0‐2)] underwent 3 Tesla‐MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3‐dimensional (3D)‐segmented echo‐planar‐imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow‐up were computed using high‐resolution 3D T1‐weighted images.Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty‐four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM‐iso‐/hypo‐intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM‐hyperintense WMLs showed a positive correlation with total brain volume reduction at follow‐up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow‐up.Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso‐/hypo‐intense lesions was found, which could account for the higher remyelination potential in pediatric MS. [ABSTRACT FROM AUTHOR]

Transcriptional deregulation emerges as a key pathogenetic mechanism in ALS pathogenesis, and non-class-specific histone deacetylase (HDACs) inhibitors proved of therapeutic efficacy in preclinical models of ALS. When tested in patients, however, these drugs failed, probably because of a lack of selectivity toward pathogenetic HDACs. Here, we studied the effects of MC1568, an inhibitor of Class-II HDACs which have been reported to contribute to ALS pathogenesis. We focused on transcriptional regulation of glutamate transporter EAAT2, whose reduced expression may contribute to motor neuron degeneration in ALS. We report that MC1568 highly increased EAAT2 transcripts in primary cultures of mouse glia, but these increases did not correlate with increased glutamate uptake capacity. Accordingly, we found that MC1568 augmented protein expression of EAAT2 together with its sumoylation, a post-translational modification typically altering protein function and localization. When tested in SOD1G93A mice, however, MC1568 fully restored the reduced spinal cord expression of EAAT2 and glutamate uptake up to control levels. A prolonged treatment with MC1568 (from onset to end stage) was unable to prolong survival of mice. Data reveal a key role of Class-II HDACs in expression and function of glutamate transporter, further corroborating preclinical and clinical evidence that the sole restoration of glutamate uptake is not of therapeutic relevance to ALS therapy. [ABSTRACT FROM AUTHOR]

The olive species ( Olea europaea L.) is characterized by significant phenotypic and genetic variability the genetic matrix has a strong influence on several important extra virgin olive oil (EVOO) chemical components. Four clones from cultivars autochthonous of the Emilia Romagna region were selected for their notable performance in terms of agronomical characteristics, and the quality of the olive oil produced was studied in detail. In particular, we analyzed the fatty acid composition, the phenolic profile and the sensory analysis of the oils from these clones and compared them with the oils from the respective cultivars. Most of the new clones, all already provided with a genetic and sanitary certification, exhibited overall higher qualitative standards than the cultivars, producing monovarietal oils interesting both nutritionally and from a sensory point of view, and furthermore with a beneficial effect on health. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to present a new method for fetal Kell genotyping by means of the allelic discrimination of K1 and K2 in real-time polymerase chain reaction ( PCR). Methods Real-time quantitative polymerase chain reaction incorporating an allele-specific primer was developed for detecting the K allele of KEL. Results By means of this method, the K1/K2 genotype was able to be determined in all blood samples analyzed. Results using cell-free fetal DNA (cff DNA) from two Kell-negative pregnant women confirmed the Kell-positive genotype of fetuses. The real-time PCR analysis also allowed the determination of the fetal fraction using the quantification of Kell-positive DNA. Conclusion An efficient and reliable strategy for Kell genotyping is herein presented. The method was optimized on cff DNA to create a non-invasive prenatal test which could be routinely used for the prevention of hemolytic disease of the fetus and the newborn ( HDFN). [ABSTRACT FROM AUTHOR]

Among the enzymes involved in NAD homeostasis, nicotinamide mononucleotide adenylyltransferases (NMNAT1-3) are central to intracellular NAD formation. Although NMNAT3 is postulated to be a mitochondrial enzyme contributing to NAD-dependent organelle functioning, information on endogenous proteins is lacking. We report that in human cells a single gene nmnat3 localized on chromosome 3 codes for two mRNA splice variants NMNATv1 and FKSG76, whereas the previously reported NMNAT3v2 transcript is not present. However, NMNAT3v1 and FKSG76 proteins are not detectable, consistent with the finding that an upstream ORF in their mRNAs negatively regulates translation. NMNAT3v1 transfection demonstrates that the protein is cytosolic and inactive, whereas FKSG76 is mitochondrial but operates NAD cleavage rather than synthesis. In keeping with the lack of NMNAT3, we show that extracellular NAD, but not its metabolic precursors, sustains mitochondrial NAD pool in an ATP-independent manner. Data of the present study modify the scenario of the origin of mitochondrial NAD by showing that, in human cells, NMNAT3 is absent in mitochondria, and, akin to plants and yeast, cytosolic NAD maintains the mitochondrial NAD pool. [ABSTRACT FROM AUTHOR]

Abstract: The results of numerical simulations are reported modeling the behavior of a unidimensional Hybrid Stable–Unstable Resonator (HSUR) in strongly non-confocal configurations. Our analysis shows that such a resonator setup can produce cavity losses consistent with our design requirements and extract a Beam with Propagation Parameter better than 3mm mrad. [ABSTRACT FROM AUTHOR]

The human antiapoptotic bcl-2 gene has been discovered in t(14;18) B-cell leukemias/lymphomas because of its overexpression caused at a transcriptional control level by the bcl-2/IgH fusion gene. We were the first to disclose the post-transcriptional control of bcl-2 expression mediated by interactions of an adenine + uracil (AU)-rich element (ARE) in the 3'-UTR of bcl-2 mRNA with AU-binding proteins (AUBPs). Here, we identify and characterize ζ-crystallin as a new bcl-2 AUBP, whose silencing or overexpression has impact on bcl-2 mRNA stability. An increased Bcl-2 level observed in normal phytohemagglutinin (PHA)-activated T lymphocytes, acute lymphatic leukemia (ALL) T-cell lines, and T cells of patients with leukemia in comparison with normal non-PHA-activated T lymphocytes was concomitant with an increase in ζ-crystallin level. The specific association of ζ-crystallin with the bcl-2 ARE was significantly enhanced in T cells of patients with ALL, which accounts for the higher stability of bcl-2 mRNA and suggests a possible contribution of ζ-crystallin to bcl-2 overexpression occurring in this leukemia. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to investigate the antitumour impact of synthesized naphthyridine derivatives. The study conducted various methods such as thin-layer chromatography (TLC), nuclear magnetic resonance (NMR) spectroscopy, and elemental analyses. Results suggest that the said derivatives have the potential use in cancer research.

Usually, towed hydrophone arrays are instrumented with a set of compasses. Data from these sensors are utilized while beamforming the acoustic signal for target bearing estimation. However, elements of the hydrophone array mounted in the neighborhood of a compass can affect the Earth's magnetic field detection. The effects depend upon the materials and magnetic environment present in the vicinity of the platform hosting the compass. If the disturbances are constant in time, they can be compensated for by means of a magnetic calibration procedure. This process is commonly known as soft and hard iron compensation. In this paper, a solution is presented for carrying out the magnetic calibration of a COTS (Commercial Off the Shelf) digital compass without sensor motion. This approach is particularly suited in applications where a physical rotation of the platform that hosts the sensor is unfeasible. In our case, the platform consists in an assembled and operational towed hydrophone array. A standard calibration process relies on physical rotation of the platform and thus on the use of the geomagnetic field as a reference during the compensation. As a variation on this approach, we generate an artificial reference magnetic field to simulate the impractical physical rotation. We obtain this by using a tri-axial Helmholtz coil, which enables programmability of the reference magnetic field and assures the required field uniformity. In our work, the simulated geomagnetic field is characterized in terms of its uncertainty. The analysis indicates that our method and experimental set-up represent a suitably accurate approach for the soft and hard iron compensation of the compasses equipped in the hydrophone array under test. [ABSTRACT FROM AUTHOR]

The present pilot study investigates whether an abnormal miRNA profile in NIPT plasma samples can explain the finding of a low cell-free DNA (cfDNA) fetal fraction (cfDNAff) in euploid fetuses and non-obese women. Twelve women who underwent neoBona® NIPT with a normal fetal karyotype were studied. Six with a cfDNAff < 4% were matched with a control group with normal levels of cfDNAff > 4%. Samples were processed using the nanostring nCounter® platform with a panel of 800 miRNAs. Four of the maternal miRNAs, miR-579, miR-612, miR-3144 and miR-6721, had a significant abnormal expression in patients. A data filtering analysis showed that miR-579, miR-612, miR-3144 and miR-6721 targeted 169, 1, 48 and 136 placenta-specific genes, respectively. miR-579, miR-3144 and miR-6721 shared placenta-specific targeted genes involved in trophoblast invasion and migration pathways (IGF2R, PTCD2, SATB2, PLAC8). Moreover, the miRNA target genes encoded proteins localized in the placenta and involved in the pathogenesis of pre-eclampsia, including chorion-specific transcription factor GCMa, PRG2, Lin-28 Homolog B and IGFBP1. In conclusion, aberrant maternal miRNA expression in circulating plasma could be a source of dysregulating trophoblast invasion and migration and could represent a novel cause of a low cfDNAff in the sera of pregnant women at the time of NIPT analysis. [ABSTRACT FROM AUTHOR]

Background: Asthma is frequently found in athletes, often associated with rhinitis and allergy. Aim: To study the predictive value of allergy and pulmonary function tests for the diagnosis of asthma in athletes. Subjects and methods: Ninety-eight national preOlympic athletes underwent an accurate medical examination including a validated questionnaire for asthma and rhinitis, spirometric recordings and skin prick testing with a panel of the most frequent inhalant allergens. Bronchodilator and/or exercise challenge were also performed in asthmatic subjects. Results: Clinical asthma was present in 20.4% of athletes, rhinitis in 35.3% (in 21.4% of cases alone and in 13.9% associated with asthma). Positive prick tests were recorded in 44.4% of athletes (in 60.5% of asthmatics, in 95.2% of rhinitics and in 21.0% of nonasthmatic – nonrhinitic subjects). Mean spirometric values and distribution of abnormal values were not different among asthmatics, rhinitics and nonasthmatics – nonrhinitic patients. Skin-tests positivity was not related to the abnormal spirometric data found in individual cases. Provocation tests with bronchodilators or exercise did not appear sensitive enough to diagnose mild forms of asthma in subjects with normal basal spirometric values. Conclusions: Allergy testing and spirometry should be performed routinely in athletes because of the high prevalence of allergy, rhinitis and asthma in this population. However, the predictive value of these tests and of the bronchial provocation tests performed in this study seems too low to document mild or subclinical asthma in athletes. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan syndrome (LNS) is an X-Iinked genetic disorder resulting in hyperuricemia, choreoathetosis, mental retardation, and self-injurious behavior. It is caused by loss of activity of the ubiquitous enzyme hypoxanthine-guanine-phosphoribosyltransferase (HPRD. The biochemical analysis of residual HPRT activity in patients' red blood cells is the first step in LNS diagnosis, and it precedes molecular study to discover the specific mutation. Unfortunately, biochemical diagnosis of healthy carriers is difficult because HPRT enzymatic activity in blood cells is similar in LNS carriers and in healthy people; genetic tests can help reveal mutations at the genomic or cDNA level, whereas gross deletions involving the first or last exons of HPRT gene are not detectable, Until now, a test based on 6-thioguanine-resistant phenotype of HPRT mutant cells from LNS patients is the only method accepted for the diagnosis of any kind of mutation in carriers. In this work, we introduce a new approach to identify carriers of large deletions in HPRT gene using real- time PCR, Results were validated in a blinded manner with a linkage study and with results obtained in Italian families previously analyzed with selective medium test. Real-time PCR analysis clearly confirmed the results obtained by selective medium; linkage data strengthened real-time results, allowing us to follow the allele with the mutated HPRT through the family pedigree. We hope that the real-time PCR approach will provide a useful and reliable method to diagnose LNS carriers of large deletions in HPRT gene. [ABSTRACT FROM AUTHOR]

It has been shown that lung mast cells, eosinophils, and fibroblasts are receptive to the action of nerve growth factor (NGF) and that NGF is released in to the bloodstream of subjects affected by allergic inflammatory response. The role of NGF in lung inflammatory disorders is unclear because there is evidence suggesting that NGF can be involved in both proinflammatory and anti-inflammatory responses. Lung fibroblasts play a marked role in inflammation. In this study we investigated the effect of NGF, interleukin 1β (II-1β), and dexamethasone (DEX) on human lung fibroblasts in vitro. We found that II-1β, but not NGF. promotes fibroblasts' survival and that NGF stimulates trkA receptor expression, down regulates TFG-α, and has no effect on TNF-β immunoreactivity. Moreover. DEX exerts different effects on NGF release by fibroblasts pre-exposed to II-1β. Our findings suggest that the NGF released by lung flbroblast during inflammation is not associated with the increase of proinflammatory factors such as TNF-α and II-1β. [ABSTRACT FROM AUTHOR]

Modulation of mRNA stability by regulatory cis-acting AU-rich elements (AREs) and ARE-binding proteins is an important posttranscriptional mechanism of gene expression control. We previously demonstrated that the 3'-untranslated region of BCL-2 mRNA contains an ARE that accounts for rapid BCL-2 down-regulation in response to apoptotic stimuli. We also demonstrated that the BCL-2 ARE core interacts with a number of ARE-binding proteins, one of which is AU-rich factor 1/heterogeneous nuclear ribonucleoprotein D, known for its interaction with mRNA elements of others genes. In an attempt to search for other BCL-2 mRNA-binding proteins, we used the yeast RNA three-hybrid system assay and identified a novel human protein that interacts with BCL-2 ARE. We refer to it as TINO. The predicted protein sequence of TINO reveals two amino-terminal heterogeneous nuclear ribonucleoprotein K homology motifs for nucleic acid binding and a carboxyl-terminal RING domain, endowed with a putative E3 ubiquitinprotein ligase activity. In addition the novel protein is evolutionarily conserved; the two following orthologous proteins have been identified with protein-protein BLAST: posterior end mark-3 (PEM-3) of Ciona savignyi and muscle excess protein-3 (MEX-3) of Caenorhabditis elegans. Upon binding, TINO destabilizes a chimeric reporter construct containing the BCL-2 ARE sequence, revealing a negative regulatory action on BCL-2 gene expression at the posttranscriptional level. [ABSTRACT FROM AUTHOR]

Some N-phenyl- (7a–10a) and N-benzyl-substituted (7b–10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7–10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds (7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 μM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a–9a present steric hindrances which may prevent a good interaction with COX-2 active site. [Copyright &y& Elsevier]

In a previous study, we reported the synthesis of several 3-(methylenaminoxymethyl)-substituted piperidine derivatives and their ability to interfere with the transmission mediated by biogenic amines. The present study describes the preparation of some new oxime derivatives and their capacity to inhibit serotonin (SERT) and dopamine (DAT) transporters expressed at the level of the rabbit cortex and the striatal membranes, respectively. All the compounds showed Ki values in the micromolar range on both transporters. [Copyright &y& Elsevier]

Using the same radio-frequency excited slab device, we have comparatively studied two different optical schemes defining a stable multipass resonator and a hybrid stable–unstable resonator. A thorough analysis of the beams extracted from the two laser setups shows that the stable folded resonator can produce a quasi-TEM00 output, at a variance with the hybrid stable–unstable resonator which always generates undesired low-power side lobes. [Copyright &y& Elsevier]

The 5,6- (10a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-2′,5′-morpholine] (11a) and their N-isopropyl derivatives (10b and 11b) (DDSNMs), which can be viewed as the result of the combination of the structure of the 2-(3,4-dihydroxyphenyl)morpholine 5a or 5b (DPMs) with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy- (8a or 8b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-1-naphthalen-ol (9a or 9b) (1-AMDTNs) were synthesised. The new compounds DDSNMs 10a,b and 11a,b were assayed for their α- and β-adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described morpholine (5) and tetrahydronaphthalene (8, 9) derivatives. The affinity and activity indices thus obtained indicate in general a low ability of the new compounds 10 and 11 to interact with the α- and β-adrenoceptors, which, in all cases, was lower than that of the corresponding morpholine (5) and tetrahydronaphthalene (8, 9) analogues. [Copyright &y& Elsevier]

During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine. • Brief postponing of Ocrelizumab infusions appears to not impact on short-term efficacy and safety outcomes. • CD19+ cells monitoring may guide re-infusion in RRMS patients, preserving treatment efficacy against inflammatory activity. • Treatment naïve RRMS patients seems to present a faster repopulation rate in comparison with previously treated RRMS patients. • A positive correlation was found between CD19+ cells repopulation rate and the time interval from last ocrelizumab infusion. [ABSTRACT FROM AUTHOR]

Panorama Plus (Natera), a single-nucleotide polymorphism- (SNP-) based approach that relies on the identification of maternal and fetal allele distributions, allows the detection of common aneuploidies and also incorporates a panel of 5 microdeletions including Di George syndrome. We report here the first case of Di George syndrome detected by NIPT in Italy; blood was drawn at 12 weeks’ gestation. The patient had an amniocentesis to confirm the diagnosis by MLPA (multiplex ligation-dependent probe amplification) and an ultrasound aimed to detect the features associated with the syndrome. A right aortic arch and suspect of thymus atrophy were detected, but not other severe malformations typical of the disease. The patient terminated the pregnancy at 17 weeks. NIPT allowed an early screening of Di George syndrome. As the patient was at low risk, it is likely that an ultrasound would have missed the condition. [ABSTRACT FROM AUTHOR]

Provides an analysis on the discharge power distribution in radio frequency discharge of large-area diffusion-cooled CO2 lasers. How the distribution is determined; How efficient power extraction from radio frequency (RF) CO2 lasers can be obtained; Details on experiments conducted.

Could arterial spin labelling perfusion imaging uncover the invisible in N-methyl-d-aspartate receptor encephalitis? Few reports exist on the utility of magnetic resonance imaging (MRI) perfusion techniques in NMDAR encephalitis. Arterial spin labeling perfusion imaging demonstrates cerebral hyperperfusion in anti-NMDAR encephalitis. [Extracted from the article]

To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males. Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which contains only the WAC gene (WW-domain-containing adaptor with coiled coil). In this clinical case report, we report a 5-year-old girl, born from non-consanguineous parents, with a 10p11.22p11.21 microdeletion. She presents clinical features that overlap with other patients described in the literature, such as dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity), even though the WAC gene is not involved in the microdeletion. Our results are the first to highlight that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype but partially overlaps with the previous cases reported in the literature, even though the same genes are not involved. In particular, in this study, we speculate about the role of the WAC gene that seems to be associated with normal motor development. In fact, we found that our patient is the only one described in the literature with a large deletion in the 10p11.22p11.21 region without the involvement of the WAC gene deletion, and, interestingly, the patient did not have motor delay. [ABSTRACT FROM AUTHOR]

Background: Indoleamine 2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) are the two principals enzymes involved in the catabolization of tryptophan (Trp) into kynurenine (Kyn). Despite their well-established role in the immune escape, their involvement in angiogenesis remains uncertain. We aimed to characterize TDO and IDO1 in human umbilical venular endothelial cells (HUVECs) and human endothelial colony-forming cells (ECFCs). Methods: qRT-PCR and immunofluorescence were used for TDO and IDO1 expression while their activity was measured using ELISA assays. Cell proliferation was examined via MTT tests and in in vitro angiogenesis by capillary morphogenesis. Results: HUVECs and ECFCs expressed TDO and IDO1. Treatment with the selective TDO inhibitor 680C91 significantly impaired HUVEC proliferation and 3D-tube formation in response to VEGF-A, while IDO1 inhibition showed no effect. VEGF-induced mTor phosphorylation and Kyn production were hindered by 680C91. ECFC morphogenesis was also inhibited by 680C91. Co-culturing HUVECs with A375 induced TDO up-regulation in both cell types, whose inhibition reduced MMP9 activity and prevented c-Myc and E2f1 upregulation. Conclusions: HUVECs and ECFCs express the key enzymes of the kynurenine pathway. Significantly, TDO emerges as a pivotal player in in vitro proliferation and capillary morphogenesis, suggesting a potential pathophysiological role in angiogenesis beyond its well-known immunomodulatory effects. [ABSTRACT FROM AUTHOR]

Examines impedance variations in large area radio frequency excited carbon dioxide CO[sub 2] lasers. Information on the impedance matching conditions and longitudinal power distributions of the lasers; Difference between CO[sub 2] laser plasma impedance and voltage distribution; Importance of parameters in designing matching networks and voltage smoothing schemes.

Examines the operation of a laser with large area discharges. Composition of the laser; Observation of locked emission due to distributed coupling of the three slabs; Results of the far-field pattern; Techniques used in handling far-field.

Background: In Europe, it is estimated that one third of women had experienced at least one physical or sexual violence after their 15. Taking into account the severe health consequences, the Emergency Department (ED), may offer an opportunity to recognize when an aggression is part of the spectrum of violence. This study applies Social Network analysis (SNA) to ED data in the Lazio region with the objective to identify patterns of diagnoses, within all the ED accesses of women experiencing an aggression, that are signals for gender-based violence against women. We aim to develop a risk assessment tool for ED professionals in order to strength their ability to manage victims of violence.Methods: A cohort of 124,691 women aged 15-70 with an ED visit for aggression between 2003 and 2015 was selected and, for each woman, the ED history of diagnoses and traumas was reconstructed. SNA was applied on all these diagnoses and traumas, including also 9 specific violence diagnoses. SNA community detection algorithms and network centrality measures were used to detect diagnostic patterns more strongly associated to violence. A logistic model was developed to validate the capability of these patterns to predict the odds for a woman of having an history of violence. Model results were summed up into a risk chart.Results: Among women experiencing an aggression, SNA identified four communities representing specific violence-related patterns of diagnoses. Diagnoses having a central role in the violence network were alcohol or substance abuse, pregnancy-related conditions and psychoses. These high-risk violence related patterns accounted for at most 20% of our cohort. The logistic model had good predictive accuracy and predictive power confirming that diagnosis patterns identified through the SNA are meaningful in the violence recognition.Conclusions: Routine ED data, analyzed using SNA, can be a first-line warning to recognize when an aggression related access is part of the spectrum of gender-based violence against women. Increasing the available number of predictors, such procedures may be proven to support ED staff in identifying early signs of violence to adequately support the victims and mitigate the harms. [ABSTRACT FROM AUTHOR]

Monitoring water quality changes in coastal waters is critical in response to the needs for sustainable development and also for mapping and monitoring ecosystems, species and threats to biodiversity. Consequently, there is a need for accurate, cost effective, frequent, and synoptic methods of characterizing and monitoring these zones of remarkable primary and secondary productivity, where complex ecosystems are found. This work describes the application of a remote sensing downscaling method via multi-sensor satellite data merging, aimed at water quality monitoring of environmentally sensitive coastal areas. The availability of high quality and high resolution satellite data from satellite platforms such as Sentinel-3 and especially Sentinel-2, allows an effective optical remote sensing in coastal and inland waters, until now negatively affected by the low spatial resolution of the former satellites (MODIS, VIIRS). It is then possible to observe and study ocean surface dynamics in coastal areas as well as some impacts of human activities close to shore and inside ports and estuaries. Many new opportunities are outlined using Landsat-8, Sentinel-2 and Pléiades (K. Ruddick, et al., 2016).Multi Spectral Instrument (MSI) Sentinel 2 sensor was developed for land observations, but it is turning out to be promising also for ocean observations (N. Pahlevan et al., 2017). Because of the high spatial resolution of the blue, green and red bands (10 m), this sensor is particularly suitable for complex coastal areas observations. The method (following Fu et al., 2018) consists of statistical bands downscaling. MSI Sentinel 2 data atmospheric correction was performed via ESA Sen2Cor processor. MODIS reflectance bands were downscaled from 1 km spatial resolution to 10 m on MSI Sentinel 2 reflectance bands. Curve fitting was used to derive the statistic relationships between MODIS and MSI bands. A coastal area north Elba Island (north Tyrrhenian Sea, Italy) was chosen as our test case, because of the steep rocky bottom slope, in order to minimize possible bottom effects. Preliminary results will be presented at the conference. [ABSTRACT FROM AUTHOR]