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Background: Prolgolimab is the first Russian PD-1 inhibitor approved for the first-line treatment of unresectable or metastatic melanoma and advanced non-small cell lung cancer. It was approved in two weight-based regimens of 1 mg/kg Q2W and 3 mg/kg Q3W, but because of re-evaluation of weight-based dosing paradigm, studying of a fixed-dose regimen was considered perspective. Methods: We conducted a multicenter, single-arm, open-label efficacy, pharmacokinetics, and safety study to obtain data that would allow the approval of the new flat dosing regimen of prolgolimab in patients with previously untreated unresectable or metastatic melanoma (BCD-100-8/FLAT, NCT05783882). The primary objective was to prove the non-inferiority of prolgolimab 250 mg Q3W versus prolgolimab 1 mg/kg Q2W for the treatment of patients with unresectable or metastatic melanoma in terms of ORR according to RECIST 1.1. Patients from the MIRACULUM study (BCD-100-2/MIRACULUM, NCT03269565) comprised a historical control group. Results: One hundred fourteen patients received prolgolimab 250 mg Q3W, and 61 patients received prolgolimab (Prolgo) 1 mg/kg Q2W (historical control). Objective response was achieved by 33.3% [95% confidence interval (CI): 24.8, 42.8] of patients in the Prolgo 250 mg group compared with 32.8% (95% CI: 21.3, 46.0) of patients in the Prolgo 1 mg/kg group. Risk difference was 0.00, 95% CI (-0.12; NA), p = 0.0082. Both regimens were well tolerated, and safety profiles were comparable. The pharmacokinetic analysis (PK) showed that the regimen with the fixed dose of 250 mg Q3W was characterized by higher PK parameters. The immunogenicity study did not detect binding antibodies to prolgolimab in any of the subjects. Conclusion: The obtained results showed that the selected fixed dosing regimen of prolgolimab 250 mg Q3W is characterized by efficacy and safety parameters comparable to that observed for the 1 mg/kg Q2W regimen.
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Mesoporous polymer networks were prepared via the cross-linking radical copolymerization of non-toxic hydrophilic N-vinylpyrrolidone (VP) with triethylene glycol dimethacrylate (TEGDM) and poly(ethylene glycol) methyl ester methacrylate (PEGMMA) in bulk, using appropriate soluble and thermodynamically compatible macromolecular additives with a branched structure as porogens. The branched copolymers of various monomer compositions were obtained by radical copolymerization in toluene, controlled by 1-decanethiol, and these materials were characterized by a wide set of physical chemical methods. The specific surface areas and surface morphology of the polymer networks were determined by nitrogen low-temperature adsorption or Rose Bengal (RB) sorption, depending on the copolymer compositions and scanning electron microscopy. The electrochemical properties of RB before and after its encapsulation into a branched VP copolymer were studied on a glassy carbon electrode and the interaction between these substances was observed. Quantum chemical modeling of RB-VP or RB-copolymer complexes has been carried out and sufficiently strong hydrogen bonds were found in these systems. The experimental and modeling data demonstrate the high potency of such mesoporous polymer networks as precursors of molecularly imprinted polymers for the recognition of fluorescent dyes as nanomarkers for biomedical practice.
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In this work, we present a model of an autonomous three-mode ring generator based on the van der Pol oscillator, where periodic, two-frequency quasiperiodic, three-frequency quasiperiodic, and chaotic self-oscillations are observed. The transitions to chaos occur as a result of a sequence of torus doubling bifurcations. When the control parameters are varied, the resonant limit cycles appear on a two-dimensional torus, and two-dimensional tori appear on a three-dimensional torus as a result of synchronization. We used a time series of dynamic variables, projections of phase portraits, Poincaré sections, and spectra of Lyapunov characteristic exponents to study the dynamics of the ring generator.
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Hydrated copolymers of N-vinylpyrrolidone (VP) with triethylene glycol dimethacrylate as a promising platform for biologically active compounds (BAC) were investigated by different physical chemical methods (dynamic light scattering, infrared spectroscopy, thermal gravimetric analysis, and differential scanning calorimetry) and the quantum chemical modeling of water coordination by the copolymers in a solution. According to the quantum chemical simulation, one to two water molecules can coordinate on one O-atom of the lactam ring of VP units in the copolymer. Besides the usual terminal coordination, the water molecule can form bridges to bind two adjacent C=O groups of the lactam rings of VP units. In addition to the first hydration shell, the formation of a second one is also possible due to the chain addition of water molecules, and its structure depends on a mutual orientation of C=O groups. We showed that N,N-dimethylbiguanidine hydrochloride (metformin) as a frontline drug for the treatment of type 2 diabetes mellitus can be associated in aqueous solutions with free and hydrated C=O groups of the lactam rings of VP units in studied copolymers. Based on the characteristics of the H-bonds, we believe that the level of the copolymer hydration does not affect the behavior and biological activity of this drug, but the binding of metformin with the amphiphilic copolymer will delight in the penetration of a hydrophilic drug across a cell membrane to increase its bioavailability.
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Biguanidas/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Polímeros/química , Pirrolidinonas/química , Biguanidas/química , Portadores de Fármacos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hipoglucemiantes/química , Estructura Molecular , Agua/químicaRESUMEN
Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Humanos , Ipilimumab , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Modelos de Riesgos ProporcionalesRESUMEN
Examination of material recently collected by the German-Russian deep-sea expeditions has revealed that new species occur regularly in macro- and meiobenthic samples of the North-Western (NW) Pacific. In this paper, we report three desmodorid species of the genera Desmodorella and Zalonema from the NW Pacific. They were studied and described using both scanning electron microscopy (SEM) and light microscopy. Desmodorella tenuispiculum (Allgen, 1928) was found at several locations in the Sea of Japan during the Russian-German expedition SoJaBio (Sea of Japan Biodiversity Studies) cruise of RV ''Akademik M.V. Lavrentyev'' in 2010, at water depths ranging between 515 and 1500 m. Zalonema granda sp. nov. and Z. kamchatkaensis sp. nov. are characterized by having a larger body size in comparison with other species of the genus. Zalonema kamchatkaensis sp. nov. is characterized by having a convex cephalic capsule, subcephalic setae (3-4 µm long) located in the middle and at the posterior region of the cephalic capsule, very large spiral amphidial fovea with 2.1-2.2 turns, sexual dimorphism in amphideal fovea size (larger in males, 39-45 µm, than in females, 37-43 µm). Zalonema granda sp. nov. is characterized by having a very long body (3.3-4.3 mm), curved elongate spicules (1.4-1.6 body diameter long), with blade broadening anteriorly towards the rounded capitulum, and pointed distally; weakly developed tubular gubernaculum, and absence of pre-cloacal supplements.
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Nematodos/anatomía & histología , Nematodos/clasificación , Animales , Femenino , Masculino , Océano Pacífico , Especificidad de la EspecieRESUMEN
Four new Campylaimus species are described from the deep-sea sediments of the Sea of Japan at depths of about 500â3400 m. Campylaimus orientalis sp. nov. is characterized by having a body of moderate length, clearly annulated cuticle, a small rhomboid mouth opening which is displaced on the dorsal side of body, a gap between the unequal limbs of the amphid, prominent narrow longitudinal alae and cephalated spicules. Campylaimus minutus sp. nov. is characterized by having a cylindrical body, very weak annulations, amphids with a short dorsal limb (25-44% of pharynx length) and a ventral limb completely fused with lateral alae of equal width; and lateral alae extending from the base of the amphid to the tail tip. Campylaimus amphidialis sp. nov. is characterized by having the combination of a very long amphidial fovea occupying nearly the entire length of the pharynx; and a well defined boundary between the ventral amphid limb and lateral alae. The distinctive feature of Campylaimus pulcher sp. nov. is the elongated loop-shaped amphid with nearly equal parallel limbs and prominent narrow longitudinal alae; and cephalated spicules without a gubernaculum. The diagnosis of the genus Campylaimus is emended and an identification key to species, based mainly on form and length of amphidial fovea, width of lateral alae, and copulatory apparatus is given. The genus Campylaimus now includes nineteen valid species. Two species are considered as species inquirendae, mainly because of incomplete descriptions.
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Distribución Animal , Nematodos/anatomía & histología , Nematodos/clasificación , Animales , Clasificación , Ecosistema , Femenino , Japón , Masculino , Nematodos/fisiología , Océano Pacífico , Especificidad de la EspecieRESUMEN
Structurally isomeric complexes formed between homopyrimidine bis-PNAs (T(2)JT(2)JT(4)-linker-T(4)CT(2)CT(2)) and single- and double-stranded DNA targets were investigated. These complexes are triplexes designated S1, S2 and S3 in order of increased mobility by polyacrylamide gel electrophoresis. It is shown that the S3 isomer is formed only on double-stranded DNA and possesses highest stability. Isomers S2 and S1 are formed upon binding of bis-PNA to double-stranded as well as to single-stranded DNA. It was found that the stability of the isomer S1 increases dramatically in the presence of excess single-stranded oligonucleotide complementary to the bis-PNA. The structure of the stabilized S1 isomer is proposed to consist of two bis-PNA/DNA triplexes. The relationship between the yield of the isomer S1 formed on single-stranded DNA and the bis-PNA concentration was investigated and a kinetic model of the formation of S1 is presented.