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The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.

Drug discovery is a challenging task, characterized by a protracted period of time between initial development and market release, with a high rate of attrition at each stage. Computational virtual screening, powered by machine learning algorithms, has emerged as a promising approach for predicting therapeutic efficacy. However, the complex relationships between features learned by these algorithms can be challenging to decipher. We have devised a neural network model for the prediction of drug sensitivity, which employs a biologically-informed visible neural network (VNN), enabling a greater level of interpretability. The trained model can be scrutinized to investigate the biological pathways that play a fundamental role in prediction, as well as the chemical properties of drugs that influence sensitivity. The model leverages multi-omics data obtained from diverse tumor tissue sources and molecular descriptors that encode drug properties. We have extended the model to predict drug synergy, resulting in favorable outcomes while retaining interpretability. Given the often imbalanced nature of publicly available drug screening datasets, our model demonstrates superior performance compared to state-of-the-art visible machine learning algorithms.

In this article we study a theory of support varieties over a skew complete intersection $R$, i.e. a skew polynomial ring modulo an ideal generated by a sequence of regular normal elements. We compute the derived braided Hochschild cohomology of $R$ relative to the skew polynomial ring and show its action on $\mathrm{Ext}_R(M,N)$ is noetherian for finitely generated $R$-modules $M$ and $N$ respecting the braiding of $R$. When the parameters defining the skew polynomial ring are roots of unity we use this action to define a support theory. In this setting applications include a proof of the Generalized Auslander-Reiten Conjecture and that $R$ possesses symmetric complexity.

DNA hypomethylating agents (DHA) combined with immune-checkpoint inhibitors (ICI) is a promising strategy to improve the effect of immunotherapy. Providing initial support to this notion, the phase Ib NIBIT-M4 study, a dose-escalation trial of the DHA guadecitabine plus ipilimumab, has shown this regimen to be safe, tolerable and with promising immunomodulatory and anti-tumor activity in advanced melanoma. Here we report the 5-year clinical outcome of NIBIT-M4 patients and its correlation with an integrated multi-omic analysis. The NIBIT-M4 enrolled unresectable Stage III or IV cutaneous melanoma patients. Median Overall Survival (OS), Progression Free Survival (PFS), 5-year OS and PFS rate, and median Duration of Response (DoR) were assessed. Tumor biopsies were performed at baseline and at week 4 and 12 on-treatment. RNA-seq, whole exome sequencing (WES), RRBS methylation profiling, and tumor immune contexture data generated by immunohistochemistry (IHC), were integratively analyzed and correlated with clinical outcome. Patients were classified as responder (R) or non-responder (NR) based on Disease Control. Nineteen patients were enrolled in the NIBIT-M4 study between October 2015, and August 2018. As of July 1, 2022, median OS was 25.6 months (mo) (95% CI, 0.0-52.9), median PFS was 5.2 mo (95% CI, 4.0-6.4); 5-year OS rate was 28.9% and 5-year PFS rate was 5.3 %; median DoR was 20.6 mo (95% CI, 12.4-28.8). Tumor biopsies for correlative analyses were available from 14 patients. Compared to NR, R patients showed higher mutation frequency in NRAS, while NR patients harbored more frequent somatic alterations in genes involved in Epithelial to Mesenchymal Transition (EMT) and chromatin organization pathways. By tumor transcriptome analysis, NR patients showed enrichment for proliferation/differentiation/EMT pathways associated with suppression of INF-ɣ/HLA-II/immune-related transcriptional modules. R patients displayed a dynamic pattern of activated immune signatures related to CD8+ Tex cells, B cells, tertiary lymphoid structures, TFH cells and IFN-ɣ, reaching highest expression levels in week 12 biopsies. Deconvolution of transcriptomic data showed higher CD8+ and NK cell content and higher correlation of TCRB clonality with CD8+ content in R patients. By integration of a genetic immunoediting index (GIE) with an adaptive immunity signature (ICR) lesions were stratified into four distinct subsets. Interestingly, the ICR/GIE classification discriminated 5-year OS and PFS while the classification based on response groups did not. Moreover, patients with a “high ICR/non-GIE” (i.e., without immunoediting) showed lower expression of antigen presentation and processing-related genes associated with defective HLA-class I expression in the lesions, in spite of high CD8+ content. Citation Format: Teresa Noviello, Anna Maria Di Giacomo, Francesca Pia Caruso, Alessia Covre, Giovanni Scala, Luigi Ferraro, Sandra Coral, Wolf H. Fridman, Catherine Sautes-Fridman, Roberta Mortarini, Elena Simonetti, Maria Fortunata Lofiego, Davide Bedognetti, Andrea Anichini, Michele Ceccarelli, Michele Maio. Guadecitabine plus ipilimumab in unresectable melanoma: Five-year follow-up and correlation with integrated, multi-omic analysis in the NIBIT-M4 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3273.

Let k be an algebraically closed field and A a Z -graded finitely generated simple k -algebra which is a domain of Gelfand–Kirillov dimension 2. We show that the category of Z -graded right A-modules is equivalent to the category of quasicoherent sheaves on a certain quotient stack. The theory of these simple algebras is closely related to that of a class of generalized Weyl algebras (GWAs). We prove a translation principle for the noncommutative schemes of these GWAs, shedding new light on the classical translation principle for the infinite-dimensional primitive quotients of U ( sl 2 ) .

Purpose: Triple X syndrome, is an often undiagnosed chromosomal abnormality with an incidence of 1/1000 females. Main associated disorders are urogenital malformations, premature ovarian failure or primary amen-orrhea, gastrointestinal problems, psychiatric disorders and epilepsy. To date, triple X is not related to a specific epileptic syndrome. Therefore, the purpose of this clinical series is to analyze seizure semiology, electroen-cephalogram features and the long-term outcome of 13 patients with epilepsy and triple X syndrome.Methods: We retrospectively evaluated the long-term seizure outcome in patients with triple X syndrome who had been referred to 11 Epilepsy Centers in Italy. A close electroclinical follow-up was made for at least 2 years and outcomes were reported.Results: Our case series confirms that epilepsy is not an occasional finding but part of the phenotypic spectrum of this syndrome. The seizure semiology shows an higher prevalence of focal seizures in 62% of patients. EEG findings of focal epileptic activity were reported in 85% of patients. Anti-seizure medications were successful in all our patients whom in most cases were responsive to monotherapy.Conclusion: According to our case series most successful drugs were VPA and LEV. Long term prognosis of epi-lepsy in our case series was good. Our experience suggests that all triple X patients achieve good seizure control and in 69% of cases normalization of the EEG.

Introduction:The spread of Covid-19 has worsened the prognosis of oncology patients, interrupting or delaying life-saving therapies and contextually increasing the risk of severe SARS-CoV-2 infections. Acute lymphoblastic leukemia (ALL) is the most frequent cancer in pediatric age and the management of this disease with concomitant SARS-COV-2 infection represents a challenging situation.Case presentation:We present the case of a 6-year-old female newly diagnosed with ALL during a documented SARS-CoV-2 infection. Our patient was admitted 20 days after SARS-CoV-2 detection for evening-rise fever. Laboratory testing showed severe neutropenia while chest x-ray detected moderate pulmonary involvement. Acute lymphoblastic leukemia diagnosis was made through morphological and molecular analysis on bone marrow aspirate. Given the stability of the blood count and clinical conditions, antiviral therapy with Remdesivir and Convalescent Plasma was started before antileukemic treatment, obtaining a rapid resolution of the infection.Conclusion:In our experience, the treatment with Remdesivir and Convalescent Plasma led to a rapid resolution of Sars-Cov-2 infection. Our case did not present any adverse event to the therapy. Thus, this treatment could be considered in patients with malignancies, in order to accelerate the resolution of the infection and begin immunosuppressive treatment safely. Further studies are required to confirm this hypothesis.

Nella pronuncia del 5 maggio 2020 il Bundesverfassungsgericht ha giudicato il Public Sector Purchase Programme (PSPP) quale atto ultra vires, poiché è stato adottato dalla Banca centrale europea in violazione dei limiti della politica monetaria, invadendo illegittimamente la sfera della politica economica che invece rientra nella competenza degli Stati membri. In questo modo il Bundestag non è più pienamente responsabile del bilancio dello Stato tedesco, con un’evidente violazione del principio democratico, riconosciuto nella Legge fondamentale anche come controlimite al processo di integrazione europea e, quindi, nucleo essenziale dell’identità costituzionale della Germania. Alla luce di ciò, pure nella prospettiva del recente Pandemic Emergency Purchase Programme (PEPP), il contributo intende evidenziare, nelle motivazioni della sentenza in commento, l’assenza del richiamo al carattere solidaristico del PSPP, con la conseguente emersione di taluni profili problematici nel percorso argomentativo seguito dalla Corte di Karlsruhe.

Objective: The objective of this study was to assess the position of the conus medullaris (CM) at the first trimester 3D ultrasound in a cohort of structurally normal fetuses. Methods: This was a multicenter prospective study involving a consecutive series of structurally normal fetuses between 11 and 13 weeks of gestation (CRL between 45 and 84 mm). All fetuses were submitted to 3D transvaginal ultrasound using a sagittal view of the spine as the starting plane of acquisition. At offline analysis, the position of the CM was evaluated by 2 independent operators with a quantitative and a qualitative method: (1) the distance between the most caudal part of the CM and the distal end of the coccyx (CMCd) was measured; (2) a line perpendicular to the fetal spine joining the tip of the CM to the anterior abdominal wall was traced to determine the level of this line in relation to the umbilical cord insertion (conus to abdomen line, CAL). Interobserver agreement for the CCMd was evaluated. Linear regression analysis was used to determine the association between the CMCd and CRL, and a normal range was computed based on the best-fit model. The absence of congenital anomalies was confirmed in all cases after birth. Results: In the study period between December 2019 and March 2020, 143 fetuses were recruited. In 130 fetuses (90.9%), the visualization of the CM was feasible. The mean value of the CMCd was 1.09 ± 0.16 cm. The 95% limits of agreement for the interobserver variability in measurement of the CMCd were 0.24 and 0.26 cm. The interobserver variability based on the intra-class correlation coefficient (ICC) for the CCMd was good (ICC = 0.81). We found a positive linear relationship between the CCMd and CRL. In all these fetuses, the CAL encountered the abdominal wall at or above the level of the cord insertion. Conclusion: In normal fetuses, the assessment of the CM position is feasible at the first trimester 3D ultrasound with a good interobserver agreement. The CM level was never found below the fetal umbilical cord insertion, while the CMCd was noted to increase according to the gestational age, confirming the “ascension” of the CM during fetal life.

This paper is based on Computational Biology with an eye towards medicine. In fact our aim is to identify new indications for existing drugs with a computational approach using Systems Biology, in order to speed up the market entry, avoiding some phases of drug development (for example toxicity tests) and with a lower cost.The method that we will discuss exploits the concept of Random Walk in a heterogeneous network, formed by a drug-drug and disease-disease similarity and known drug-disease associations. This is done by combining different types of data in order to connect more effectively two drugs or two diseases with a similarity score. At the end we integrate the known associations between drugs and diseases with the purpose of finding similarity values of new couples.

La recente formazione del governo Sánchez merita una particolare attenzione poiché si tratta del primo esecutivo spagnolo di coalizione. Il contributo analizza in termini problematici le prospettive future della forma di governo in Spagna, dopo aver richiamato i caratteri fondamentali del parlamentarismo spagnolo e la sua evoluzione nella prassi alla luce di taluni istituti attivati recentemente, come lo scioglimento automatico delle Cortes Generales e la mozione di sfiducia costruttiva

We present two noncommutative algebras over a field of characteristic zero that each posses a family of actions by cyclic groups of order $2n$, represented in $n \times n$ matrices, requiring generators of degree $3n$.

For each nontrivial semisimple Hopf algebra $H$ of dimension sixteen over $\mathbb{C}$, the smallest dimension inner-faithful representation of $H$ acting on a quadratic AS regular algebra $A$ of dimension 2 or 3, homogeneously and preserving the grading, is determined. Each invariant subring $A^H$ is determined. When $A^H$ is also AS regular, thus providing a generalization of the Chevalley-Shephard-Todd Theorem, we say that $H$ is a reflection Hopf algebra for $A$., Revised version. To appear in Algebras and Representation Theory

Differential graded algebra techniques have played a crucial role in the development of homological algebra, especially in the study of homological properties of commutative rings carried out by Serre, Tate, Gulliksen, Avramov, and others. In this article, we extend the construction of the Koszul complex and acyclic closure to a more general setting. As an application of our constructions, we shine some light on the structure of the Ext algebra of quotients of skew polynomial rings by ideals generated by normal elements. As a consequence, we give a presentation of the Ext algebra when the elements generating the ideal form a regular sequence, generalizing a theorem of Bergh and Oppermann. It follows that in this case the Ext algebra is noetherian, providing a partial answer to a question of Kirkman, Kuzmanovich, and Zhang.

BACKGROUND Iodine is an essential micronutrient for intellectual development in children. Information on iodine intakes based on 24-h urinary iodine excretion (UIE) is scant, because iodine status is only assessed by the measurement of urinary iodine concentration (UIC) in spot urine samples. OBJECTIVES The aim of our study was to evaluate the iodine intake of school-age children and adolescents, using UIE measurement in 24-h urine collections. METHODS The study population included 1270 healthy subjects (677 boys, 593 girls) aged 6-18 y (mean age ± SD: 10.3 ± 2.9) from 10 Italian regions. Daily iodine intake was estimated as UIE/0.92, based on the notion that $\sim$92% of the dietary iodine intake is absorbed. The adequacy of intakes was assessed according to the Dietary Reference Values for iodine of the European Food Safety Authority (EFSA). Body mass index (BMI) and UIC were also measured for each subject. RESULTS Based on the scientific opinion of EFSA, 600 of 1270 subjects (47.2%) had a lower than adequate iodine intake, with a higher prevalence among girls (54.6%) compared with boys (40.2%) (P

In seguito allo sviluppo della crisi economica sono state adottate misure di carattere emergenziale, sia a livello europeo che interno. Il riferimento è, ad esempio, al Quantitative easing in sede UE, mentre in Italia si è dovuti ricorrere al Governo tecnico, alla rielezione del Capo dello Stato, all’ampio utilizzo dei decreti legge e alla riforma dell’art. 81 Cost. Queste due ultime misure sono state adottate anche dalla Spagna, costretta ad introdurre in Costituzione, in meno di due settimane, il principio della stabilità di bilancio per riconquistare la fiducia dell’Europa e dei mercati. In Francia, in una situazione meno grave di Italia e Spagna, la crisi economica ha invece inciso soprattutto sul sistema partitico della V Repubblica. L’indagine comparata è servita allora ad esaminare le tensioni che si sono prodotte nella forma di governo in Italia. Il carattere contingente di un contesto di grave crisi sembra essere la linea di confine entro cui poterle contenere: se la crisi ha una durata limitata nel tempo, l’elasticità dell’assetto parlamentare e la sua debole razionalizzazione consentono di assorbire lo stato di tensione all’interno di questo modello.

In this work, we prove that if a graded, commutative algebra $R$ over a field $k$ is not Koszul then, denoting by $\mathfrak{m}$ the maximal homogeneous ideal of $R$ and by $M$ a finitely generated graded $R$-module, the nonzero modules of the form $\mathfrak{m} M$ have infinite Castelnuovo-Mumford regularity. We also prove that over complete intersections which are not Koszul, a nonzero direct summand of a syzygy of $k$ has infinite regularity. Finally, we relate the vanishing of the graded deviations of $R$ to having a nonzero direct summand of a syzygy of $k$ of finite regularity.

Stable cohomology is a generalization of Tate cohomology to associative rings, first defined by Pierre Vogel. For a commutative local ring R with residue field k, stable cohomology modules Ext ˆ R n ( k , k ) , defined for n ∈ Z , have been studied by Avramov and Veliche. Stable cohomology carries a structure of Z -graded k-algebra. One of the main goals of this paper is to prove that, for a class of Gorenstein rings, this algebra is a trivial extension of absolute cohomology Ext R ( k , k ) and a shift of Hom k ( Ext R ( k , k ) , k ) . We use this information to characterize the rings R for which stable cohomology is graded-commutative. Stable cohomology is connected through an exact sequence to bounded cohomology. We use this connection to understand the algebra structure of Ext ˆ R ( k , k ) by investigating the structure of bounded cohomology Ext ‾ R ( k , k ) as a graded Ext R ( k , k ) -bimodule.

Let $H$ be a semisimple Hopf algebra acting on an Artin-Schelter regular algebra $A$, homogeneously, inner-faithfully, preserving the grading on $A$, and so that $A$ is an $H$-module algebra. When the fixed subring $A^H$ is also AS regular, thus providing a generalization of the Chevalley-Shephard-Todd Theorem, we say that $H$ is a reflection Hopf algebra for $A$. We show that each of the semisimple Hopf algebras $H_{2n^2}$ of Pansera, and $\mathcal{A}_{4m}$ and $\mathcal{B}_{4m}$ of Masuoka is a reflection Hopf algebra for an AS regular algebra of dimension 2 or 3., Comment: Some minor corrections

Aspergillus myofasciitis is a rare infection of the muscles and their fascial sheaths that has been reported in patients with immune deficiencies of various kinds but, until now, not with chronic granulomatous disease (CGD). Patients affected by CGD are at high risk of invasive aspergillus infections. The case described involves a 14-year-old boy with a severe autosomal recessive CGD who was admitted to hospital with an Aspergillus myofasciitis of the left forearm. He was treated with liposomal amphotericin for 14 days and then with oral voriconazole for three months with an excellent clinical outcome. He did not evidence any recurrence in the following 30 months using itraconazole prophylaxis.

Goals The goal of this study was to evaluate the clinical efficacy of an intake of Lactobacillus salivarius LS01 (DSM 22775) for the treatment of atopic dermatitis (AD) in children. Background AD is an inflammatory and pruritic chronic relapsing skin disorder with multifactorial etiopathology. Some evidence suggests that probiotics may improve AD by modulating the immune system and the composition of intestinal microbiota. Study A total of 43 patients aged from 0 to 11 years were enrolled in the study (M/F ratio=1:1) and treated with the probiotic strain L. salivarius LS01. Clinical efficacy of probiotic treatment was assessed from baseline by changes in itch index and in the objective SCORAD/SCORAD index. Results Patients being given probiotic treatment showed a significant improvement in clinical parameters (SCORAD and itch values) from baseline. The reduction in SCORAD and itch index observed after 4 weeks of treatment also persisted after the cessation of probiotic supplementation. Conclusions L. salivarius LS01 seems to be able to improve the quality of life of children affected by AD and, as a consequence, it may have promising clinical and research implications.

This study aims to highlight some elements such as: the rural novel in Giovanni Verga and the relation between land and national character in Unamuno’s En torno al Casticismo on Castile and Castilian men. Special attention will be put to intrahistory in the works of the two authors and how a relation may be set up between Vergas’s Cavalleria Rusticana and Unamuno’s characters Augusto Perez and Abel Sanchez, which, on the one hand, reveal epic names (Augusto and Abel) and on the other hand, the ordinary and common surnames (Perez and Sanchez), showing thus that we are all partly epic heroes and partly common human beings. Moreover, there is another element that makes Unamuno —in his first intellectual period (1884-1897)— very similar to Verga: Ruralism . Paz en la Guerra deals with Bilbao, but Unamuno highlights the popular aspect of the city. The main characters, Pedro Antonio and Ignacia, come from the fields. Their son Ignacio spends a lot of time in the country, where lives his uncle, a country priest. In all these aspects, the rural Biscay has many things in common with the Sicily of I Malavoglia .

s / Digestive and Liver Disease 46 (2014) e85–e127 e95 4.5±0.6pg/ml, mean FT4 1.2± .4 ng/dl. TSH levels were above cutoff laboratory range in 10% of our population and the 2 patients (0.2%) of the whole population presented TSH≥10 UI/ml. We found a significant positive correlation between TSH levels and BMI z-score (rho=0.121, p=0.001), even after adjustment for age and sex (r=0.117, p=0.001); a positive correlation was also observed between FT3 and BMI z-score (rho=0.161, p

Il C.I.R.B. (Centro Interuniversitario di Ricerca Bioetica), cui aderiscono tutte le Universita campane, e un organismo di ricerca nel quale – con metodo rigorosamente scientifico, grazie al concorso di qualificati cultori delle varie discipline interessate e in un clima di costante e costruttivo dialogo con i rappresentanti delle diverse posizioni culturali – e possibile delineare le trame di una serena e ponderata riflessione comune su tematiche che coinvolgono l’identita stessa della persona umana e il destino delle generazioni future.