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In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the “MIPI-genetic” (“MIPI- g”). The “MIPI-g” improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. (Trial registered at clinicaltrials.gov identifier: NCT02354313).

We are devoted with singular integro-differential abstract Cauchyproblems. Required conditions on spaces and operators are givenguaranteeing existence and uniqueness of solutions. Applications from partial differential equations are given to illustrate the abstract singular integro-differential problem.

Let \begin{document}$ \left(H, \langle \cdot, \cdot \rangle \right) $\end{document} be a separable Hilbert space and \begin{document}$ A_{i}:D(A_i) \to H $\end{document} (\begin{document}$ i = 1, \cdots, n $\end{document}) be a family of nonnegative selfadjoint operators mutually commuting. We study the inverse problem consisting in the identification of the function \begin{document}$ u:[0, T] \to H $\end{document} and \begin{document}$ n $\end{document} time-dependent diffusion coefficients \begin{document}$ \alpha_{1}, \cdots, \alpha_{n}:[s, T] \to {\mathbb{R}}_+ $\end{document} that fulfill the initial-value problem \begin{document}$ u'(t) + \alpha_{1}(t) A_{1}u(t) + \cdots + \alpha_{n}(t) A_{n}u(t) = 0, \quad s \leq t \leq T, \quad u(s) = x, $\end{document} and the additional conditions \begin{document}$ \langle A_{1} u(t), u(t)\rangle = \varphi_{1}(t), \quad \cdots \quad, \langle A_{n} u(t), u(t)\rangle = \varphi_{n}(t), \quad s \leq t \leq T. $\end{document} Under suitable assumptions on the operators \begin{document}$ A_i $\end{document}, \begin{document}$ i = 1, \cdots, n $\end{document}, on the initial data \begin{document}$ x\in H $\end{document} and on the given functions \begin{document}$ \varphi_i $\end{document}, \begin{document}$ i = 1, \cdots, n $\end{document}, we shall prove that the solution of such a problem exists, is unique and depends continuously on the data. We apply the abstract result to the identification of diffusion coefficients in a heat equation and of the Lamé parameters in an elasticity problem on a plate.

Although previous research has corroborated the independent contributions of parent personality and adolescent temperament in predicting adolescents' externalizing behavior problems (EXT), few studies have examined their joint contribution to predict EXT in adolescence. In the present longitudinal study, first we examined the developmental trajectory of EXT from ages 12 to 14, and, next, we investigated the joint effects of mothers' irritability and adolescents' inhibitory control (IC) in predicting the developmental trajectory of EXT. Altogether, 106 mothers from Rome provided data annually for three years (Mage of child in wave 1 = 12.34 years, SD = 0.77; 53% boys). Mothers rated their irritability, adolescents' IC, and adolescents' EXT. Multilevel modeling indicated that EXT followed a quadratic trajectory with an increase from age 12 through age 13 followed by a slight downturn by age 14. Interactive effects emerged between mothers' irritability and adolescents' IC in predicting the developmental trajectory of EXT. IC buffered the detrimental effect of mothers' irritability on the development of adolescents' EXT. The practical implications of these findings are discussed.

During adolescence, some personality characteristics may represent vulnerabilities to adolescents' adjustment. Adopting a person-centered approach, the aims of this study were (a) to examine the relations of early adolescents' personality profiles to internalizing (i.e., anxious/depressed, withdrawal, and somatic complaints) and externalizing (i.e., aggressive and rule breaking behavior) problems three years later, and (b) to explore the moderating role of gender in these relations. Six hundred fifteen Italian preadolescents (mean age = 12.5) completed the Big Five Questionnaire for Children at age 12 and the Youth Self-Report at age 12 and three years later. Four personality types were identified using Latent Profile Analysis: Resilient, Moderate, Undercontrolled and Vulnerable. In multiple-group path analysis, after controlling for the stability of the outcomes, for both genders, Resilient reported low levels of externalizing problems three years later, whereas Vulnerable youths reported high levels of internalizing problems. Finally, Undercontrolled reported high levels of subsequent externalizing problems. The present study corroborated the unique and specific prediction by personality profiles of different types of subsequent maladjustment.

We are concerned with a general abstract equation that allows to handle various degenerate first and second order differential equations in Banach spaces. We indicate sufficient conditions for existence and uniqueness of a solution. Periodic conditions are assumed to improve previous approaches on the abstract problem to work on $$(-\infty ,\infty )$$ . Related inverse problems are discussed, too. All general results are applied to some systems of partial differential equations. Inverse problems for degenerate evolution integro-differential equations might be described, too.

Synovial sarcoma (SS) is an aggressive tumor with propensity for lung metastases which significantly impact patients' prognosis. New therapeutic approaches are needed to improve treatment outcome. Targeting the heparanase/heparan sulfate proteoglycan system by heparin derivatives which act as heparanase inhibitors/heparan sulfate mimetics is emerging as a therapeutic approach that can sensitize the tumor response to chemotherapy. We investigated the therapeutic potential of a supersulfated low molecular weight heparin (ssLMWH) in preclinical models of SS. ssLMWH showed a potent anti-heparanase activity, dose-dependently inhibited SS colony growth and cell invasion, and downregulated the activation of receptor tyrosine kinases including IGF1R and IR. The combination of ssLMWH and the IGF1R/IR inhibitor BMS754807 synergistically inhibited proliferation of cells exhibiting IGF1R hyperactivation, also abrogating cell motility and promoting apoptosis in association with PI3K/AKT pathway inhibition. The drug combination strongly enhanced the antitumor effect against the CME-1 model, as compared to single agent treatment, abrogating orthotopic tumor growth and significantly repressing spontaneous lung metastatic dissemination in treated mice. These findings provide a strong preclinical rationale for developing drug regimens combining heparanase inhibitors/HS mimetics with IGF1R antagonists for treatment of metastatic SS.

We study the initial-boundary value problem for a Laplace reaction-diffusion equation. After constructing local solutions by using the theory of abstract degenerate evolution equations of parabolic type, we show global existence under suitable assumptions on the reaction function. We also show that the problem generates a dynamical system in a suitably set universal space and that this dynamical system possesses a Lyapunov function.

A degenerate identification problem in Hilbert space is considered. An application to second order evolution equations of hyperbolic type is also provided. The abstract results are applied to concrete differential problems., Bruno Pini Mathematical Analysis Seminar, Seminars 2017

We study nonsymmetric second order elliptic operators with Wentzell boundary conditions in general domains with sufficiently smooth boundary. The ambient space is a space of $L^p$- type, $1\le p\le \infty$. We prove the existence of analytic quasicontractive $(C_0)$-semigroups generated by the closures of such operators, for any $1< p< \infty$. Moreover, we extend a previous result concerning the continuous dependence of these semigroups on the coefficients of the boundary condition. We also specify precisely the domains of the generators explicitly in the case of bounded domains and $1 < p < \infty$, when all the ingredients of the problem, including the boundary of the domain, the coefficients, and the initial condition, are of class $C^{\infty}$.

Sobolev type equations now constitute a vast area of non-classical equations of mathematical physics. They include equations of mathematical physics, whose representation in the form of equations or systems of partial differential equations does not fit any of the classical types (elliptic, parabolic or hyperbolic). By the properties of the operators involved, the considered Sobolev type equation has a degenerate solving semigroup of class C 0 in suitable Banach spaces. We consider a Sobolev type stochastic equation in the spaces of random processes. The concepts previously introduced for the spaces of differentiable “noises” using the Nelson–Gliklikh derivative are carried over to the case of complex-valued “noises”. We construct a solution to the weakened Showalter–Sidorov problem for Sobolev type equation with relatively p-radial operator in a space of complex-valued processes.

In this paper we study an inverse problem with time dependent operator-coefficients. We indicate sufficient conditions for the existence and the uniqueness of a solution to this problem. A number of concrete applications to partial differential equations is described.

Sobolev type equation theory has been an object of interest in recent years, with much attention being devoted to deterministic equations and systems. Still, there are also mathematical models containing random perturbation, such as white noise; these models are often used in natural experiments and have recently driven a large amount of research on stochastic differential equations. A new concept of ``white noise", originally constructed for finite dimensional spaces, is extended here to the case of infinite dimensional spaces. The main purpose is to develop stochastic higher-order Sobolev type equation theory and provide some practical applications. The main idea is to construct ``noise" spaces using the Nelson -- Gliklikh derivative. Abstract results are applied to the Boussinesq -- Love model with additive ``white noise" within Sobolev type equation theory. Because of their usefulness, we mainly focus on Sobolev type equations with relatively p-bounded operators. We also use well-known methods in the investigation of Sobolev type equations, such as the phase space method, which reduces a singular equation to a regular one, as defined on some subspace of the initial space.