Real world effectiveness and safety of nivolumab in patients with relapsed or refractory classical hodgkin lymphoma. / Efectividad y seguridad en vida real de nivolumab en pacientes con linfoma de hodgkin clásico en recaída o refractario.

OBJECTIVE: The primary objective is to describe the real-life effectiveness and safety of nivolumab treatment in patients with relapsed or refractory classical Hodgkin's lymphoma. The secondary objective is to describe the therapeutic management after nivolumab monotherapy. METHOD: Observational, retrospective, multidisciplinary study including all patients with relapsed or refractory classical Hodgkin's lymphoma treated with nivolumab monotherapy from November 2015 to March 2023. Patient and treatment-related variables were collected. Effectiveness was measured as overall response rate, progression-free survival and overall survival. Safety was measured as percentage of patients with adverse effects and severity. RESULTS: Thirteen patients were included, median age 37.5 years (RIQ: 25.3-54.7), 84.6% male. The median number of previous lines of therapy was 3 (RIQ: 2.0-4.5), including autologous hematopoietic stem cell transplantation (84.6%) and brentuximab vedotin (100%). All received nivolumab 3 mg/kg/14 days, with a median of 11 cycles (RIQ: 6.5-20.5) per patient. Median time on treatment was 4.9 months (RIQ: 3.0-9.6) and median follow-up time was 9.2 months (RIQ: 5.6-32.3). Complete response was achieved by 3 patients (23.1%), partial response by 3 (23.1%), stable disease by 3 (23.1%) and progression by 4 (30.8%). The objective response rate was 46.2%. Median progression-free survival was 23.9 months (95%CI: 0-49.1), median overall survival was not reached. At the study cutoff date, five patients had died (38.5%), four were in complete remission without active treatment (30.8%) and four were continuing treatment (30.8%). Adverse events occurred in 76.9% of patients, 44% of severity ≥3, the most frequent being hypothyroidism and hepatotoxicity. One patient discontinued treatment due to pneumonitis, two suffered treatment delays (thrombocytopenia and hypertransaminemia) and one changed the regimen to monthly (pulmonary toxicity). CONCLUSIONS: Nivolumab in the treatment of relapsed or refractory classical Hodgkin's lymphoma has confirmed in the study sample favorable effectiveness data, expressed as objective response rate of 46.2% and clinical benefit of 69.2%. Safety was acceptable, manageable, and consistent with that described in the literature.

Ionic Conductivity, Diffusion Coefficients, and Degree of Dissociation in Lithium Electrolytes, Ionic Liquids, and Hydrogel Polyelectrolytes.

The conductive and diffusional behavior of electrolytes in media with different dielectric and viscoelastic properties is investigated. A revised model to separate the contribution of dissociated and nondissociated species to the diffusion coefficients determined with NMR is proposed. Impedance spectroscopy is used to measure the ionic conductivity of lithium salts in aqueous medium, ionic liquids in aprotic solvents, and hydrogel polyelectrolytes. The diffusion coefficients of the species of interest in those systems are determined with multinuclear pulsed-gradient spin-echo (PGSE) NMR. The results are analyzed using the revised model. It is shown that the degree of ionization could be determined directly from measurements of ionic conductivity and diffusion coefficients in very different types of electrolytes and in a wide range of concentrations. Furthermore, these findings support the original Arrhenius hypothesis about electrolytes and show that the assumption of a complete dissociation is not required to describe their conductive behavior. The reduced conductivity observed in hydrogels, at or near swelling equilibrium, compared to that in solutions could be attributed mainly to the hindered ionic mobility caused by the network structure.

BRCA1 Alternative splicing landscape in breast tissue samples.

BACKGROUND: BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples. METHODS: BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal. RESULTS: 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689). CONCLUSIONS: Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.

Surface modification of sepiolite in aqueous gels by using methoxysilanes and its impact on the nanofiber dispersion ability.

Surface modification reactions on needle-like sepiolite using alkyl and functional silanes have been carried out in the form of aqueous gels. In contrast with modifications in organic solvents, reactions in water make it possible to modify the surface of almost-individual sepiolite fibers and produce either a continuous coating or a nanotexturization of the sepiolite fiber surface, depending on the reaction conditions. This clean procedure substitutes advantageously organic solvent surface modifications and allows the tuning of surface properties such as specific surface area, wetting behavior, and chemical functionalization. A consequence of such tuning is, for example, the excellent dispersion of modified sepiolite nanofibers in a great variety of polymers by routine compounding and processing techniques.

Microwave versus conventional heating in the grafting of alkyltrimethoxysilanes onto silica particles.

The scope of this work is the comparative analysis in terms of grafting rate, structure of the grafted layer, and wetting behavior of three series of silica nanoparticles modified with alkyltrimethoxysilanes by using conventional heating with and without acid catalysis, and microwave irradiation. A comprehensive characterization of the grafted layer by means of Fourier transform infrared (FTIR), microanalysis, and solid state NMR techniques has shown that microwave irradiation provokes a pronounced increase in the loading rate compared to conventional heating. This microwave effect is outstanding in the case of the reactions with methyltrimethoxysilane, because of the acceleration of the condensation rate. Moreover, solid state NMR spectra ((29)Si and (13)C) strongly suggest structural differences in the grafted layer obtained by the two heating sources. The wetting behavior of the modified nanoparticles was studied, concluding that these changes in the structure of the grafted layer induced by the synthetic procedure do not determine the values of the dynamic water contact angles.

Use of p-toluenesulfonic acid for the controlled grafting of alkoxysilanes onto silanol containing surfaces: preparation of tunable hydrophilic, hydrophobic, and super-hydrophobic silica.

The modification of Aerosil 200 has been carried out using methoxysilanes in toluene reflux, with p-toluenesulfonic acid as the catalyst. Both trimethoxyalkyl silanes (methyl, ethyl, propyl, butyl, hexyl, octyl, and octadecyl) and trialkylmethoxy silanes (trimethyl and dimethyloctyl) have been used. The surface has been studied by 29Si NMR, 13C NMR, elemental analysis, thermogravimetry, water contact angle, and BET analysis. When incorporating trimethoxysilanes, a plateau of modification was achieved after 1 h of reflux, while when using trialkylmethoxy silanes, a longer time of about 7 h was required. The average number of molecules incorporated in both cases has been well above those reported by other authors in similar reactions and in much shorter times. Depending on the modification agent and on the experimental conditions, the resulting organosilicas are in seven cases superhydrophobic, in three cases hydrophobic, and in two cases hydrophilic. Two structural origins for superhydrophobicity have been identified in these samples: almost complete disappearance of water accessible surface silanols (smallest methoxysilanes) and shielding of would-be water accessible surface silanols by long aliphatic tails. These features can be very precisely controlled.

Studies on aromatic compounds: inhibition of calpain I by biphenyl derivatives and peptide-biphenyl hybrids.

With the objective to understand structural features responsible for the biological activity, novel nonelectrophilic biphenyl derivatives and peptide-biphenyl hybrids have been synthesized and evaluated as calpain I inhibitors. The preliminary results indicate that the presence of additional aromatic rings (besides the biphenyl system) makes these compounds potent calpain inhibitors with IC50 values in the nanomolar range.