Driven Assembly of Lignin into Microcapsules for Storage and Delivery of Hydrophobic Molecules

Oil-filled microcapsules of kraft lignin were synthe- sized by first creating an oil in water emulsion followed by a high- intensity, ultrasound-assisted cross-linking of lignin at the water/oil interface. The rationale behind our approach is based on promoting documented lignin hydrophobic interactions within the oil phase, followed by locking the resulting spherical microsystems by covalent cross-linking using a high intensity ultrasound treatment. As further evidence in support of our rationale, confocal and optical microscopies demonstrated the uniformly spherical morphology of the created lignin microparticles. The detailed elucidation of the cross-linking processes was carried out using gel permeation chromatography (GPC) and quantitative 31P NMR analyses. The ability of lignin microcapsules to incorporate and release Coumarin-6 was evaluated in detail. In vitro studies and confocal laser scanning microscopy analysis were carried out to assess the internalization of capsules into Chinese hamster ovary (CHO) cells. This part of our work demonstrated that the lignin microcapsules are not cytotoxic and readily incorporated in the CHO cells

ФАРМАКОЭКОНОМИКА РАЗЛИЧНЫХ МЕТОДОВ ЛЕЧЕНИЯ СТЕРОИД-РЕФРАКТЕРНОЙ РЕАКЦИИ «ТРАНСПЛАНТАТ ПРОТИВ ХОЗЯИНА»: АНАЛИЗ РЕЗУЛЬТАТОВ ЛЕЧЕНИЯ В ОДНОЦЕНТРОВОМ ИССЛЕДОВАНИИ

Introduction. Steroid-refractory graft-versus-host disease (srGVHD) is one of the most severe and life-threatening complications of allogeneic hematopoietic stem cell transplantation. Currently, there is no standard treatment for this complication. In addition, there is no data on the pharmacoeconomics of various methods in the Russian Federation. The objective is to compare the effectiveness and cost of treatment of acute and chronic srGVHD, as well as the use of different approaches in therapy. Material and methods. We have conducted a pilot study in 12 srGVHD patients treated with ruxolitinib and in 24 patients of wellmatched historical control, who treated with etanercept for the acute srGVHD and with extracorporeal photopheresis for chronic srGVHD. Results. The 6-month therapy of acute GVHD was associated with significantly higher cost than therapy of chronic GVHD (4.138±2.672 vs 1.862±1.122 thd. rub., р=0.004). The major factors driving up the costs were bacterial infections (р=0.022), opportunistic viral infections (р<0.001), severity of GVHD at the start of a therapy (р=0.013) and GI involvement (р=0.006). There was no difference in 1-year failure-free survival in acute (50 % vs 67 %, р=0.9) and chronic GVHD (87.5 % vs 87.5 %, р=1.0) between ruxolitinib and the control group, although the overall response was faster in ruxolitinib group (100 % vs 71 %, р=0.035, when assessed at 28 days in acute and 12 weeks in chronic srGVHD). The mean 6-month overall costs in the ruxolitinib were higher compared to the control group (1534 thd. rub. higher for acute and 541 thd. rub. higher for chronic GVHD), however this might be attributed to higher number of previous lines in the ruxolitinib group. Conclusions. It is revealed that the treatment of acute srGVHD requires significantly higher economic costs than chronic srGVHD. The power of this study does not allow to draw conclusions regarding the efficacy of different methods. Further studies are required to determine the optimal therapy of srGVHD.Введение. Стероид-рефрактерная реакция «трансплантат против хозяина» (срРТПХ) – одно самых тяжелых и жизнеугрожающих осложнений аллогенной трансплантации гемопоэтических стволовых клеток. На сегодняшний день нет стандартов лечения этого осложнения, кроме того, в РФ отсутствуют данные о фармакоэкономике различных методов. Цель – сравнение эффективности и стоимости лечения острой и хронической срРТПХ, а также при использовании различных подходов в терапии. Материал и методы. В исследование включены 12 пациентов, получавших терапию Руксолитинибом по поводу срРТПХ, и 24 пациента сопоставимого исторического контроля, получивших Этанерцепт по поводу острой срРТПХ и экстракорпоральный фотоферез по поводу хронической. Результаты исследования. Выявлено, что 6 месяцев терапии острой РТПХ связаны с достоверно более высокими затратами, чем лечение хронической (4,138±2,672 против 1,862±1,122 тыс. р., р=0,004). Основными факторами, повышавшими стоимость лечения, были осложнения, связанные с развитием бактериальных инфекций (р=0,022), оппортунистических вирусных инфекций (р<0,001), тяжесть РТПХ на момент начала лечения (р=0,013) и наличие поражения желудочно-кишечного тракта (р=0,006). В исследовании не было получено различий между Руксолити- нибом и историческим контролем в годичной выживаемости без неудач лечения как для острой (50 и 67 %, р=0,9), так и для хронической РТПХ (87,5 и 87,5 %, р=1,0) соответственно, однако общий ответ в группе Руксолитиниба на- ступал раньше (100 против 71 %, р=0,035, в анализе через 28 дней и 12 недель лечения острой и хронической срРТПХ соответственно). Отмечено повышение стоимости 6 месяцев терапии в группе Руксолитиниба в среднем на 1534 тыс. р. при острой РТПХ и 541 тыс. р. при хронической РТПХ, что, однако, может быть связано с бóльшим количеством предшествующих линий терапии. Выводы. Выявлено, что лечение острой срРТПХ требует существенно бóльших экономических затрат, чем хрони- ческой. Размер выборки в данном исследовании не позволяет делать выводы об эффективности различных методов лечения. Требуются дальнейшие исследования для определения оптимального варианта терапии срРТПХ. Ключевые слова: аллогенная трансплантация гемопоэтических стволовых клеток, реакция «трансплантат против хозяина», стероид-резистентность, фармакоэкономика>< 0,001), тяжесть РТПХ на момент начала лечения (р=0,013) и наличие поражения желудочно-кишечного тракта (р=0,006). В исследовании не было получено различий между Руксолитинибом и историческим контролем в годичной выживаемости без неудач лечения как для острой (50 и 67 %, р=0,9), так и для хронической РТПХ (87,5 и 87,5 %, р=1,0) соответственно, однако общий ответ в группе Руксолитиниба наступал раньше (100 против 71 %, р=0,035, в анализе через 28 дней и 12 недель лечения острой и хронической срРТПХ соответственно). Отмечено повышение стоимости 6 месяцев терапии в группе Руксолитиниба в среднем на 1534 тыс. р. при острой РТПХ и 541 тыс. р. при хронической РТПХ, что, однако, может быть связано с бóльшим количеством предшествующих линий терапии. Выводы. Выявлено, что лечение острой срРТПХ требует существенно бóльших экономических затрат, чем хронической. Размер выборки в данном исследовании не позволяет делать выводы об эффективности различных методов лечения. Требуются дальнейшие исследования для определения оптимального варианта терапии срРТПХ

Nucleosome reorganisation in breast cancer tissues.

Background Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Results We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5-10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. Conclusions Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring

PHARMACOECONOMIC ANALYSIS OF DIFFERENT METHODS FOR THE TREATMENT OF STEROID-REFRACTORY GRAFT-VERUS-HOST DISEASE: SINGLE-CENTER STUDY

Introduction. Steroid-refractory graft-versus-host disease (srGVHD) is one of the most severe and life-threatening complications of allogeneic hematopoietic stem cell transplantation. Currently, there is no standard treatment for this complication. In addition, there is no data on the pharmacoeconomics of various methods in the Russian Federation. The objective is to compare the effectiveness and cost of treatment of acute and chronic srGVHD, as well as the use of different approaches in therapy. Material and methods. We have conducted a pilot study in 12 srGVHD patients treated with ruxolitinib and in 24 patients of wellmatched historical control, who treated with etanercept for the acute srGVHD and with extracorporeal photopheresis for chronic srGVHD. Results. The 6-month therapy of acute GVHD was associated with significantly higher cost than therapy of chronic GVHD (4.138±2.672 vs 1.862±1.122 thd. rub., р=0.004). The major factors driving up the costs were bacterial infections (р=0.022), opportunistic viral infections (р<0.001), severity of GVHD at the start of a therapy (р=0.013) and GI involvement (р=0.006). There was no difference in 1-year failure-free survival in acute (50 % vs 67 %, р=0.9) and chronic GVHD (87.5 % vs 87.5 %, р=1.0) between ruxolitinib and the control group, although the overall response was faster in ruxolitinib group (100 % vs 71 %, р=0.035, when assessed at 28 days in acute and 12 weeks in chronic srGVHD). The mean 6-month overall costs in the ruxolitinib were higher compared to the control group (1534 thd. rub. higher for acute and 541 thd. rub. higher for chronic GVHD), however this might be attributed to higher number of previous lines in the ruxolitinib group. Conclusions. It is revealed that the treatment of acute srGVHD requires significantly higher economic costs than chronic srGVHD. The power of this study does not allow to draw conclusions regarding the efficacy of different methods. Further studies are required to determine the optimal therapy of srGVHD