Discovery and optimization of 4-pyrazolyl-2-aminopyrimidine derivatives as potent spleen tyrosine kinase (SYK) inhibitors.

Spleen tyrosine kinase (Syk) is a key signal transduction mediator of the B cell receptor (BCR) signaling pathway. Abnormal BCR signaling plays a key role in initiation and development of B-cell-derived hematological malignancies, therefore, Syk represents a potential target for inhibiting the BCR signaling resulting in a therapeutic effect in these cancers. Herein, we describe a novel series of SYK inhibitors with 4-(3'-pyrazolyl)-2-amino-pyrimidine scaffold.

Temporal trends in the starting of insulin therapy in type 2 diabetes in Italy: data from the AMD Annals initiative.

Aims: Opportunities and needs for starting insulin therapy in Type 2 diabetes (T2D) have changed overtime. We evaluated clinical characteristics of T2D subjects undergoing the first insulin prescription during a 15-year-observation period in the large cohort of the AMD Annals Initiative in Italy.

Methods: Data on clinical and laboratory variables, complications and concomitant therapies and the effects on glucose control after 12 months were evaluated in T2D patients starting basal insulin as add-on to oral/non-insulin injectable agents, and in those starting fast-acting in add-on to basal insulin therapy in three 5-year periods (2005-2019).

Effectiveness, Safety, and Appropriateness in the Use of the Fixed-Ratio Combination of Insulin Glargine and Lixisenatide in Type 2 Diabetes: The ENSURE Retrospective Real-World Study.

Introduction: Pivotal trials documented glycemic benefits of fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi), with no weight gain and low hypoglycemia risk in type 2 diabetes (T2D). This study aimed at assessing effectiveness and patterns of use of iGlarLixi in a real-world setting.

Methods: This was a retrospective, multicenter, study, based on electronic medical records.

Solitons in Inhomogeneous Gauge Potentials: Integrable and Nonintegrable Dynamics.

We introduce an exactly integrable nonlinear model describing the dynamics of spinor solitons in space-dependent matrix gauge potentials of rather general types. The model is shown to be gauge equivalent to the integrable system of vector nonlinear Schrödinger equations known as the Manakov model. As an example we consider a self-attractive Bose-Einstein condensate with random spin-orbit coupling (SOC).

Self-Bound Quantum Droplets of Atomic Mixtures in Free Space.

Self-bound quantum droplets are a newly discovered phase in the context of ultracold atoms. In this Letter, we report their experimental realization following the original proposal by Petrov [Phys. Rev.

Dynamics of Spin-Orbit Coupled Bose-Einstein Condensates in a Random Potential.

Disorder plays a crucial role in spin dynamics in solids and condensed matter systems. We demonstrate that for a spin-orbit coupled Bose-Einstein condensate in a random potential two mechanisms of spin evolution that can be characterized as "precessional" and "anomalous" are at work simultaneously. The precessional mechanism, typical for solids, is due to the condensate displacement.

Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers.

Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types.

Optimization of diarylthiazole B-raf inhibitors: identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect.

Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R(1) and R(2) groups of the scaffold.

New resistance mechanisms for small molecule kinase inhibitors of Abl kinase.

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with Imatinib in patients with chronic myelogenous leukaemia (CML). Second generation Bcr-Abl inhibitors, such as Nilotinib and Dasatinib, are able to overcome most Imatinib- resistant mutants, with the exception of the T315I substitution. Structural studies of Abl wild-type and T315I mutant have provided better understanding of how this mutation leads to resistance and have been used to support the drug design process for the development of inhibitors able to target the T315I substitution.

Vibrational mode multiplexing of ultracold atoms.

Sending multiple messages on qubits encoded in different vibrational modes of cold atoms or ions along a transmission waveguide requires us to merge first and then separate the modes at input and output ends. Similarly, different qubits can be stored in the modes of a trap and be separated later. We design the fast splitting of a harmonic trap into an asymmetric double well so that the initial ground vibrational state becomes the ground state of one of two final wells, and the initial first excited state becomes the ground state of the other well.

Fault-tolerant almost exact state transmission.

We show that a category of one-dimensional XY-type models may enable high-fidelity quantum state transmissions, regardless of details of coupling configurations. This observation leads to a fault-tolerant design of a state transmission setup. The setup is fault-tolerant, with specified thresholds, against engineering failures of coupling configurations, fabrication imperfections or defects, and even time-dependent noises.

Identification of a phenylacylsulfonamide series of dual Bcl-2/Bcl-xL antagonists.

A series of phenylacylsulfonamides has been prepared as antagonists of Bcl-2/Bcl-xL. In addition to potent binding affinities for both Bcl-2 and Bcl-xL, these compounds were shown to induce classical markers of apoptosis in isolated mitochondria. Overall weak cellular potency was improved by the incorporation of polar functionality resulting in compounds with moderate antiproliferative activity.

Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode.

Observation of subdiffusion in a disordered interacting system.

We study the transport dynamics of matter-waves in the presence of disorder and nonlinearity. An atomic Bose-Einstein condensate that is localized in a quasiperiodic lattice in the absence of atom-atom interaction shows instead a slow expansion with a subdiffusive behavior when a controlled repulsive interaction is added. The measured features of the subdiffusion are compared to numerical simulations and a heuristic model.

Identification of Myb-binding protein 1A (MYBBP1A) as a novel substrate for aurora B kinase.

Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers.

Results by motor cortex stimulation in treatment of focal dystonia, Parkinson's disease and post-ictal spasticity. The experience of the Italian Study Group of the Italian Neurosurgical Society.

Extradural motor cortex stimulation has been employed in cases of Parkinson's disease (PD), fixed dystonia (FD) and spastic hemiparesis (SH) following cerebral stroke. Symptoms of PD are improved by EMCS: results were evaluated on the basis of the UPDRS and statistically analysed. In PD EMCS is less efficacious than bilateral subthalamic nucleus (STN) stimulation, but it may be safely employed in patients not eligible for deep brain stimulation (DBS).

Anderson localization of a non-interacting Bose-Einstein condensate.

Anderson localization of waves in disordered media was originally predicted fifty years ago, in the context of transport of electrons in crystals. The phenomenon is much more general and has been observed in a variety of systems, including light waves. However, Anderson localization has not been observed directly for matter waves.

Atom interferometry with a weakly interacting Bose-Einstein condensate.

We demonstrate the operation of an atom interferometer based on a weakly interacting Bose-Einstein condensate. We strongly reduce the interaction induced decoherence that usually limits interferometers based on trapped condensates by tuning the s-wave scattering length almost to zero via a magnetic Feshbach resonance. We employ a 39K condensate trapped in an optical lattice, where Bloch oscillations are forced by gravity.

Spatial interference of coherent atomic waves by manipulation of the internal quantum state.

A trapped >(87)Rb Bose-Einstein condensate is initially put into a superposition of two internal states. Under the effect of gravity and by means of a second transition, we prepare two vertically displaced condensates in the same internal state. These constitute two coherent sources of matter waves with adjustable spatial separation.

Development of an aciclovir implant for the effective long-term control of herpes simplex virus type-1 infection in Vero cells and in experimentally infected SKH-1 mice.

Human herpes simplex virus type-1 (HSV-1) is treatable with oral doses of an antiviral agent such as aciclovir (ACV), a drug that has poor bioavailability. An alternative for delivering ACV would employ a long-lived subcutaneous implant that would allow for near zero-order drug delivery kinetics. This study aimed to develop an implant composed of a matrix of silicone and ACV that is capable of sustained long-term release of ACV.

Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358.

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with imatinib in patients with chronic myelogenous leukemia (CML). Second-generation Bcr-Abl inhibitors are able to overcome most imatinib-resistant mutants, with the exception of the frequent T315I substitution, which is emerging as a major cause of resistance to these drugs in CML patients. Structural studies could be used to support the drug design process for the development of inhibitors able to target the T315I substitution, but until now no crystal structure of the T315I Abl mutant has been solved.

39K Bose-Einstein condensate with tunable interactions.

We produce a Bose-Einstein condensate of 39K atoms. Condensation of this species with a naturally small and negative scattering length is achieved by a combination of sympathetic cooling with 87Rb and direct evaporation, exploiting the magnetic tuning of both inter- and intraspecies interactions at Feshbach resonances. We explore the tunability of the self-interactions by studying the expansion and the stability of the condensate.

A combination of docking/dynamics simulations and pharmacophoric modeling to discover new dual c-Src/Abl kinase inhibitors.

A computational protocol was applied to identify molecular scaffolds untested toward the c-Src tyrosine kinase. A combination of docking and dynamics calculations allowed us to build three-dimensional models of the complexes between Src and several of its known inhibitors. Interactions most contributing to activity of the inhibitors, in terms of hydrogen bonds and hydrophobic contacts, were codified into pharmacophoric models that were in turn applied to perform a search of commercially available compounds within the Asinex database.

Pyrazolo[3,4-d]pyrimidines as potent antiproliferative and proapoptotic agents toward A431 and 8701-BC cells in culture via inhibition of c-Src phosphorylation.

We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src.

Effect of optical disorder and single defects on the expansion of a Bose-Einstein condensate in a one-dimensional waveguide.

We investigate the one-dimensional expansion of a Bose-Einstein condensate in an optical guide in the presence of a random potential created with optical speckles. With the speckle the expansion of the condensate is strongly inhibited. A detailed investigation has been carried out varying the experimental conditions and checking the expansion when a single optical defect is present.