Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC. Experimental design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features. Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169). Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets

Синтез рH-чувствительных гидрогелей модифицированного декстрана с фосфорнокислыми и карбаматными группами

The synthesis of gelling dextran esters with phosphate and carbamate groups in the dextran - phosphoric acid - urea system has been described. The effect of reaction time on hydrogels' gel fraction yield, their functional composition and the degree of equilibrium swelling has been studied. Swelling of hydrogels in the wide range of pH has been studied. The obtained hydrogels may be used as drugs delivery systems.В системе декстран-ортофосфорная кислота-мочевина синтезированы гелеобразующие смешанные эфиры дек-страна с фосфорнокислыми и карбаматными группами. Изучено влияние продолжительности реакции на выход гель-фракции гидрогелей, их функциональный состав и степень равновесного набухания. Набухание гидрогелей изучено в широком диапазоне pH. Полученные гидрогели могут быть использованы в качестве систем для доставки лекарственных веществ

Реологические свойства и гидролитическая устойчивость in vitro композиции карбоксиметилцеллюлоза–диоксидин

The composition of carboxymethylcellulose–dioxydine was obtained and its structural, morphological and rheological characteristics in the processes of heat treatment and chemical hydrolysis were studied. Using IR spectroscopy, scanning electron microscopy, and viscometry, it has been established that the introduction of dioxidine into a solution of carboxymethylcellulose sodium salt with different molecular weights leads to partial disordering of hydrogen bonds between macromolecules, promotes thermal destruction of the polysaccharide and a decrease in the dynamic viscosity of solutions. Experimental kinetic curves of carboxymethylcellulose hydrolysis in the presence and absence of dioxidine were obtained, and it was shown that they could be described using a first-order equation. The hydrolysis rate coefficients were calculated, and it was shown that, as a result of heat treatment, as well as in the presence of an active substance, the rate of carboxymethylcellulose hydrolysis increased. The change in the rheological properties of carboxymethylcellulose sodium salt solutions with different degrees of polymerization in the presence of an antimicrobial substance should be taken into account when choosing the composition of viscous prolonged forms of biologically active substances. Получена композиция карбоксиметилцеллюлоза–диоксидин и изучены ее структурно-морфологические и реологические характеристики в условиях термообработки и химического гидролиза в фосфатном буферном растворе с рН 7,4. Методами ИК-спектроскопии, сканирующей электронной микроскопии, вискозиметрии установлено, что введение диоксидина в раствор натриевой соли карбоксиметилцеллюлозы с разной молекулярной массой приводит к частичному разупорядочиванию водородных связей между макромолекулами, способствует термодеструкции полиcахарида, понижению динамической вязкости растворов. Получены экспериментальные кинетические кривые гидролиза карбоксиметилцеллюлозы в присутствии и в отсутствие диоксидина и установлено, что они могут быть описаны с помощью уравнения первого порядка. Рассчитаны константы скорости гидролиза и показано, что в результате термообработки, а также в присутствии активного вещества скорость процесса гидролиза карбоксиметилцеллюлозы в условиях in vitro увеличивается. Изменение реологических свойств растворов натриевой соли карбоксиметилцеллюлозы с разной степенью полимеризации в присутствии антимикробного вещества следует учитывать в выборе состава вязких пролонгированных форм биологически активных веществ