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It has been proposed that the increased severity of sleep apnea frequently observed in heart failure (HF) patients with Cheyne-Stokes respiration (CSR) when sleeping in the supine compared to the lateral position, may be caused by the concomitant reduction in functional residual capacity (FRC). We assessed positional changes in FRC in patients with CSR and investigated the relationship between these changes in the laboratory and corresponding changes in CSR severity during sleep.After a diagnostic polysomnography, 18 HF patients with dominant CSR and an apnea-hypopnea index (AHI)≥15 events/h underwent a standard pulmonary function test in the sitting position. Measurements were repeated in the supine, left lateral and right lateral. The latter two measurements were averaged to obtain a single lateral measurement.The FRC in the seated position was 3.0 ± 0.5 L (85 ± 13% of predicted), decreased to 2.3 ± 0.3 L (-21 ± 8%, p 0.0001) in the supine position, and increased to 2.8 ± 0.4 L (+21 ± 12%, p 0.0001) from the supine to the lateral position (-5±8% vs seated, p = 0.013). During sleep, the AHI and the apnea index (AI) decreased from 47 ± 15 events/h to 26 ± 12 events/h (-46 ± 20%, p 0.0001) and from 29 ± 21 events/h to 12 ± 10 events/h (-61 ± 40%, p 0.001) from the supine to the lateral position. Changes in the AI were significantly correlated with corresponding changes in FRC (ρ = -0.55, p = 0.032).In patients with HF and CSR, lying in the supine position causes a significant reduction in FRC in the context of a chronically reduced FRC. The negative correlation between postural changes in FRC and AI supports the hypothesis that the reduction in lung gas stores in the supine position may promote/exacerbate respiratory control instability.

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.

The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies, such as Chronic Lymphocytic Leukaemia (CLL) and Non-Hodgkin’s Lymphomas (NHL) including Diffuse Large B-cell Lymphomas (DLBCL). Small molecule inhibitors of key signaling kinases involved in the BCR pathway, such as the Btk inhibitor ibrutinib and the PI3Kdelta inhibitor idelalisib, have already demonstrated significant clinical activity. Spleen tyrosine kinase (Syk) is a non-receptor cytoplasmic tyrosine kinase that plays a fundamental role in BCR signaling initiation thus representing an additional potential therapeutic target for the inhibition of the BCR pathway. Here, we report the discovery and characterization of NMS-0963, a novel potent, selective and orally available Syk inhibitor, identified through an integrated medicinal chemistry and rational design approach. NMS-0963 showed potent inhibitory effect on Syk in an in vitro biochemical assay and displayed a good selectivity profile on a broad panel of kinases. On-target potency was confirmed in a cell-based assay using BaF3 cells engineered to express constitutively activated Syk, showing potent inhibition of Syk activity resulting in antiproliferative effect with IC50s in the low nanomolar range. Effective inhibition of BCR-mediated signaling pathway was observed in DLBCL-derived cell lines. NMS-0963 showed favourable ADME profile and good in vivo pharmacokinetic profiles after oral administration in mouse, rat and dog. Furthermore, NMS-963 demonstrated striking in vivo efficacy in tumor models of CD79/Myd88 mutated DLBCL, superior to competitors. Together with a permissive preclinical safety profile, these results support a rational for clinical development of NMS-0963 in DLBCL. Citation Format: Grazia Saturno, Michele Modugno, Paolo Orsini, Giovanni Cervi, Laura Buffa, Ilaria Motto, Nilla Avanzi, Marisa Montemartini, Fabio Gasparri, Gemma Texido, Arturo Galvani, Antonella Isacchi. NMS-0963 is a novel potent, selective and orally available Syk inhibitor with promising preclinical activity in diffuse large B-cell lymphoma. [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 4036.

Glass fiber reinforced epoxy (GFRE) composite materials are prone to suffer from water absorption due to their heterogeneous structure. The main process governing water absorption is diffusion of water molecules through the epoxy matrix. However, hydrolytic degradation may also take place during components service life specially due high temperatures. In order to mitigate the effects of the water diffusive processes in the deterioration of in-service behavior of epoxy matrix composites, the use of chemically modified nanoclays as an additive has been proposed and studied in previous works [1]. In this work, an Artificial Neural Network (ANN) model was developed for better understanding and predicting the influence of modified and unmodified bentonite addition on the water absorption behavior of epoxy-anhydride systems. An excellent correlation between model and experimental data was found. The ANN model allowed the identification of critical points like the precise temperature at which a particular system?s water uptake goes beyond a predefined threshold, or which system will resist an immersion longer than a particular time. Fil: Capiel, Guillermina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Arrosio, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Montemartini, Pablo Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Morán, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina

PIM1 is over-expressed in multiple tumors, including prostate cancer (PCa). PIM1 upregulation is mediated by direct binding of the ERG transcription factor to its promoter. About 50% of PCa cases are characterized by the presence of the TMPRSS2/ERG fusion, leading to ERG over-expression and thus to PIM1 transcriptional activation. PIM kinases are considered as weak oncogenes, but when combined with additional genetic alterations can induce strong transforming effects. Here we show anti-proliferative activity of the newly described PIM1 inhibitor NMS-P645 in combination with the PI3K inhibitor GDC-0941 in TMPRSS2/ERG positive and negative PCa cells. Treatment with NMS-P645 alone can reverse PIM1-mediated pro-survival signals in prostate cells, such as activation of STAT3 through Tyr705 phosphorylation and resistance to taxane-based treatments, but does not exert a strong anti-tumoral effect. However, the simultaneous treatment with NMS-P645 and GDC-0941 induces a significant anti-proliferative response in PCa cells. These results support the use of combination strategies with PIM and PI3K inhibitors as effective treatment for PCa cases.

Epoxy–anhydride-based polymers are commonly used as a matrix in pipeline systems exposed to water during their in-service life. Water absorption at moderate temperatures and/or at long exposure times could lead to irreversible hydrolysis reaction decreasing considerably the polymer overall performance. A strategy to enhance the barrier properties of epoxy resins is to add nanofillers to traditional matrices. In this work, we added bentonite and chemically modified bentonite to this purpose. Water absorption of the resulting materials at three different temperatures (22°C, 80°C, and 93°C) was studied, and simultaneously, the evolution during the immersion tests of glass transition temperature and flexural modulus was recorded. Long-term gravimetric results showed that composites with chemically modified bentonite produce a delay on the hydrolysis of epoxy–anhydride matrix, which is a relevant result, because of the tough application and uses of the system, from the technological point of view. Copyright © 2016 John Wiley & Sons, Ltd.

Background Inspiratory resistive breathing (IRB) challenges affect respiratory muscle endurance in healthy individuals, which is considered to be an interleukin 6 (IL-6)–dependent mechanism. Whether nonpharmacological thermal therapies promote the endurance of loaded inspiratory muscles in chronic obstructive pulmonary disease (COPD) is unclear. The objectives of this study were to compare the effects of two thermal interventions on endurance time (ET) and plasma IL-6 concentration following an IRB challenge. Methods This study was a randomized, parallel-group, unblinded clinical trial in a single-center setting. Forty-two patients (aged 42–76 years) suffering from mild to severe COPD participated in this study. Both groups completed 12 sessions of the mud bath therapy (MBT) (n=22) or leisure thermal activity (LTA) (n=19) in a thermal spa center in Italy. Pre- and postintervention spirometry, maximum inspiratory pressure, and plasma mediators were obtained and ET and endurance oxygen expenditure (VO2Endur) were measured following IRB challenge at 40% of maximum inspiratory pressure. Results There was no difference in ΔIL-6 between the intervention groups. But, IRB challenge increased cytokine IL-6 plasma levels systematically. The effect size was small. A statistically significant treatment by IRB challenge effect existed in ET, which significantly increased in the MBT group (P=0.003). In analysis of covariance treatment by IRB challenge analysis with LnVO2Endur as the dependent variable, ΔIL-6 after intervention predicted LnVO2Endur in the MBT group, but not in the LTA group. Adverse events occurred in two individuals in the MBT group, but they were mainly transient. One patient in the LTA group dropped out. Conclusion MBT model improves ET upon a moderate IRB challenge, indicating the occurrence of a training effect. The LnVO2Endur/ΔIL-6 suggests a physiologic adaptive mechanism in respiratory muscles of COPD patients allocated to treatment. Both thermal interventions are safe., Video abstract

Epoxy-anhydride networks have been analyzed in terms of water uptake and degradation behavior by means of broadband dielectric spectroscopy and atomic force microscopy. It has been found that water absorption produces a chemical reaction in the polymer networks, in turn causing a plasticizing effect and changing their mechanical properties. We demonstrate that a non invasive dielectric spectroscopy analysis of the segmental dynamics can be performed in order to quantitatively describe the degradation effects, as well as their influence in the mechanical properties at the nanoscale., This work was partially Supported by the Spanish Ministry “Ministerio de Economía y Competitividad”, code: MAT2015-63704-P (MINECO/FEDER, UE) and by the Argentine government funded scholarship program, BEC.AR.

Epoxy-anhydride based polymers are commonly used as a matrix in pipeline systemsexposed to water during their in-service life. Water absorption at moderatetemperatures and/or at long exposure times could lead to irreversible hydrolysisreaction decreasing considerably the polymer overall performance. A strategy toenhance the barrier properties of epoxy resins is to add nano-fillers to traditional matrices. In this work, we added bentonite and chemically modified bentonite to this purpose. Water absorption of the resulting materials at three different temperatures (22°C, 80 °C and 93 °C) was studied and simultaneously, the evolution during the immersion tests of glass transition temperature and flexural modulus was recorded.Long-term gravimetric results showed that composites with chemically modified bentonite produce a delay on the hydrolysis of epoxy-anhydride matrix, which is a relevant result, due to the tough application and uses of the system, from the technological point of view. Fil: Capiel, Guillermina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Uicich, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Montemartini, Pablo Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina

Simonetta Baldi,1 Paul E Jose,2 Claudio Bruschi,1 Gian Domenico Pinna,3 Roberto Maestri,3 Antonella Rezzani,1 Ezio Bellinzona,1 Claudio Fracchia,1 Elena Dacosto,1 Paola Crotti,1 Silvia Montemartini1 1Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy; 2School of Psychology, Victoria University, Wellington, New Zealand; 3Department of Biomedical Engineering, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, ItalyObjectives: To explore the mediating role of protein interleukin-6 (IL-6) on the relationship between forced expiratory volume in 1 second (FEV1) and 6-minute walk distance (6MWD) and, further, to determine whether status variables (such as age, sex, and body mass index [BMI]) operate as moderators of this mediation relationship.Design: Moderated mediation model.Setting: An inpatient pulmonary rehabilitation center in Italy.Participants: All 153 patients involved in the screening of a randomized controlled clinical trial (ClinicalTrials.gov identifier: NCT01253941) were included in this study. All patients were Global initiative for chronic Obstructive Lung Disease (GOLD) stages I–IV and were aged 70.1±9.1 years.Measurements: At run-in phase of the protocol, clinical and functional screening included BMI, fasting plasma levels of protein (IL-6), spirometry, and standardized 6-minute walking test, measured at the start of the respiratory rehabilitation program.Methods: The size of the indirect effect of the initial variable (FEV1) upon the outcome variable (6MWD) through the intervening variable (IL-6) was computed and tested for statistical significance. Moderated mediation analyses were subsequently conducted with age, sex, and BMI.Results: FEV1 averaged 53.4%±21.2%, and 6MWD 66.4%±41.3% of predicted. Median protein IL-6 was 6.68 pg/mL (interquartile range: 5.96). A bootstrapped mediation test supported the predicted indirect pathway (P=0.003). The indirect effect through IL-6 log units accounted for 17% of the total effect between FEV1 and 6MWD. Age functioned as a significant moderator of the mediational pattern. For individuals aged 70 years it was not significant (0.04, 95% CI: –0.010 to 0.142, P=0.10).Conclusion: This moderated mediation result based on concurrent data suggests, but does not prove, a causal role of systemic inflammatory syndrome on progression from functional impairment to “frailty” status and substantial disability in aging chronic obstructive pulmonary disease. Keywords: COPD, chronic airflow obstruction, aging, mediation analysis

Introduction: Choline kinase alpha (ChoKα), the first enzyme in the Kennedy pathway that catalyzes the phosphorylation of free choline to phosphocholine (PCho), is responsible for the de novo biosynthesis of phosphatidylcholine (PC), the major phospholipid of cellular membranes. Aberrant choline metabolic profiles and concomitant ChoKα upregulation have been described in most human malignancies (i.e. breast, lung, ovary, liver) and have been found to correlate with advanced histological tumour grade. ChoKα, depletion by siRNA or shRNA inhibits growth and migration of different tumor cell lines both in vitro and in vivo, which is not observed for the ChoKβ isoform. Choline mimetic inhibitors of ChoKα (i.e. MN58b) have been shown to have antitumor activity in preclinical models, although their efficacy is hampered by a significant toxicity, possibly due to cross-reactivity with other choline-dependent proteins (transporters, enzymes). At NMS a high throughput screening (HTS) was performed with the objective to identify ATP-mimetic ChoKα inhibitors potentially less toxic than choline-mimetic compounds. Methods: Hits from different classes were characterized for biochemical activity on ChoKα and ChoKβ and biochemical mechanism of inhibition. The binding site of selected ATP competitive inhibitors was confirmed by co-crystallization with ChoKα. On-target mechanism of action in cells was confirmed by analysing inhibition of PCho formation. Result: Structure-based chemical expansion of Hits from one of the prioritized classes resulted in compounds with biochemical potencies in the single digit nanomolar range displaying selectivity vs ChoKβ as well as a diverse panel of protein kinases. In several tumor cell lines, the compounds were able to inhibit the formation of PCho at a concentration in agreement with that required to achieve anti-proliferative activity. The most potent compounds were tested on a panel of 24 representative breast cancer cell lines which showed differential sensitivity towards ChoKα inhibition. Analysis of genomic (DNA and RNA) and proteomic (>50 markers) expression profiles of the breast cancer cell lines is ongoing to identify predictive biomarkers of response. Conclusion: Medicinal chemistry expansion of a novel class of compounds identified by HTS allowed the development of potent ChoKα ATP-mimetic inhibitors able to modulate PCho levels in cells, which can be used to identify preferential sensitivity contexts. Medicinal chemistry activities are ongoing to further improve their potency and optimize their ADME/PK properties. Citation Format: Paola Gnocchi, Francesca Quartieri, Alessandra Badari, Roberta Bosotti, Elena Casale, Emiliana Corti, Cinzia G. Cristiani, Ulisse Cucchi, Fabio Gasparri, Laura M. Gianellini, Laura M. Giorgini, Marisa Montemartini, Giuliana Mion, Marcella Nesi, Christian Orrenius, Claudia E. Re, Daniele Donati, Eduard R. Felder, Arturo Galvani, Antonella Isacchi. Identification and characterization of ATP-mimetic choline kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4790.

Halloysite nanotubes (HNTs) have attracted a technologic and scientific attention as reinforcements of epoxy-basednanocomposites. However, their reported interaction with epoxy matrices is varied and the controlled dispersion of HNTs is still a challenge. In this work, we study the effect of chemical reactions taking place in the dispersion process of halloysite and their possible influence in the composite?s properties. HNTs? surface was modified through an alkaline treatment and by grafting two aminosilanes withdifferent chain lengths and functionality numbers. Evidence of homopolymerization and degradation reactions was found, dependingon the surface treatment. The rheological study indicated that an interconnected network can be achieved in epoxy/HNTs blendsdepending on the surface chemical characteristics of the nanofillers and the blending method. The better dispersion was accomplishedwhen ultrasonicating with the aid of a solvent. Nevertheless, the mechanical properties of the nanocomposites are not warranted byselecting a dispersion method Fil: Sánchez, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina. Consejo Interuniversitario Nacional; Argentina Fil: Uicich, Julieta Fabienne. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Arenas, Gustavo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Científicas y Tecnológicas en Electrónica. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones Científicas y Tecnológicas en Electrónica; Argentina Fil: Rodriguez, Exequiel Santos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Montemartini, Pablo Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Penoff, Marcela Elisabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina