A New Chapter in the Treatment of Patients with Heart Failure. The Role of Sodium-Glucose Co-transporter Type 2 Inhibitors

Heart failure (HF) remains one of the major social and medical public health problems worldwide. Despite new advances in the treatment of patients with HF, the prognosis is still poor. According to the European Cardiology Society guidelines for the diagnosis and treatment of acute and chronic heart failure (CHF) 2021, a new class of drugs related to hypoglycemic has been confirmed to be effective in influencing the survival of patients with heart failure with low ejection fraction (HFpEF), regardless of the presence of disorders of carbohydrate metabolism. We are talking about inhibitors of the sodium-glucose co-transporter type 2 (iSGLT-2) or gliflozins. The article presents the results of the latest large clinical trials on the effective use of SGLT-2 in patients with HF, not only with low, but also with intact ejection fraction (HFpEF), for which there is no evidence base at the present stage. The review article presents the results of experimental studies that explored the potential mechanisms of action of gliflozins with an emphasis on new ones that are of fundamental importance for patients with heart failure, and also describes controversial and little-studied issues. Currently, there is no therapy that improves outcomes in patients with acute heart failure. The article presents the results of small analyzes of the use of iSGLT-2 in this category of patients, which are the basis for the hypothesis of their potentially effective and safe use in the case of acute decompensation of CHF, however, the role of gliflozins in this category of patients requires further in-depth study

Clinical Efficacy and Safety of Empagliflozin in Patients with Acute Heart Failure from the First Day of Hospitalization

Aim. Evaluation of the safety, clinical and hemodynamic effects of empagliflozin in patients with acute decompensated heart failure (ADHF) from the first day of hospitalization in the absence of signs of hemodynamic instability.Material and methods. A prospective, comparative, randomized study included 46 patients admitted to the hospital in connection with ADHF in the absence of signs of hemodynamic instability. Inclusion in the study and randomization to receive empagliflozin was carried out in the first 24 hours from the moment of admission to the hospital. The main group (n=23) from the first day of hospitalization and the entire subsequent follow-up period took empagliflozin at a daily dose of 10 and 25 mg (for patients with type 2 diabetes mellitus) in addition to basic therapy, the control group (n=23) received standard therapy without gliflozines. The observation period was 3 months and included 3 control points: 1st day of hospitalization, 7th-12th day, 3rd month of observation. Clinical, anamnestic and instrumental data were evaluated at all control points.Results. In the hospital period, by the 7th-12th day, only in the main group there was an improvement in all clinical indicators (p<0.01), an increase in the rate of diuresis (p><0.01), a decrease in the daily dose of the parenteral diuretic furosemide from 54 mg to 26 mg (p><0.01). A decrease in systolic blood pressure (SBP) occurred in both groups (p><0.01), but it was more pronounced in the comparison group [from 141 (110; 160) to 110 (90; 120) mm Hg) compared to the main group [from 140 (120; 160) to 120 (110; 130) mm Hg]. According to echocardiography data in the main group, there was a decrease in the indexed volume of the right atrium, the end-systolic volume of the left ventricle (LV ESV) and systolic pressure in the pulmonary artery, an increase in the LV ejection fraction (LV EF) (p><0.05). In the comparison group, only an increase in LV ESV was noted (p=0.04). The index of the indexed volume of the left atrium did not show significant dynamics in the main group (p=0.79), but showed a significant decrease>˂0.01), a decrease in the daily dose of the parenteral diuretic furosemide from 54 mg to 26 mg (p<0.01). A decrease in systolic blood pressure (SBP) occurred in both groups (p>˂0.01), but it was more pronounced in the comparison group [from 141 (110; 160) to 110 (90; 120) mm Hg) compared to the main group [from 140 (120; 160) to 120 (110; 130) mm Hg]. According to echocardiography data in the main group, there was a decrease in the indexed volume of the right atrium, the end-systolic volume of the left ventricle (LV ESV) and systolic pressure in the pulmonary artery, an increase in the LV ejection fraction (LV EF) (p˂0.05). In the comparison group, only an increase in LV ESV was noted (p=0.04). The index of the indexed volume of the left atrium did not show significant dynamics in the main group (p=0.79), but showed a significant decrease in the 2nd and 3rd control points compared to the control group (p=0.01 and p=0.02). Complications, against the background of taking empagliflozin, were not noted: there were no episodes of hypotension (SBP˂90 mm Hg), hypoglycemia, acute kidney injury.Conclusion. The results obtained indicate the safety of empagliflozin in patients with ADHF, regardless of the status of carbohydrate metabolism and LV EF, as well as taking into account the clinical (more intense positive dynamics of clinical symptoms of ADHF) and hemodynamic (smooth decrease in SBP, increased diuretic effect) effects of empagliflozin, this drug should be considered as an effective and safe supplement to the main therapy from the first day of hospitalization in patients with stable hemodynamic parameters

Following the Formation of Synaptonemal Complex Formation in Wheat and Barley by High-Resolution Microscopy

International audienceWheat and barley have large genomes of 15 Gb and 5.1 Gb, respectively, which is much larger than the human genome (3.3 Gb). The release of their respective genomes has been a tremendous advance the understanding of the genome organization and the ability for deeper functional analysis in particular meiosis. Meiosis is the cell division required during sexual reproduction. One major event of meiosis is called recombination, or the formation of crossing over, a tight link between homologous chromosomes, ensuring gene exchange and faithful chromosome segregation. Recombination is a major driver of genetic diversity but in these large genome crops, the vast majority of these events is constrained at the end of their chromosomes. It is estimated that in barley, about 30% of the genes are located within the poor recombining centromeric regions, making important traits, such as resistance to pest and disease for example, difficult to access. Increasing recombination in these crops has the potential to speed up breeding program and requires a good understand of the meiotic mechanism. However, most research on recombination in plant has been carried in Arabidopsis thaliana which despite many of the advantages it brings for plant research, has a small genome and more spread out of recombination compare to barley or wheat. Advance in microscopy and cytological procedures have emerged in the last few years, allowing to follow meiotic events in these crops. This protocol provides the steps required for cytological preparation of barley and wheat pollen mother cells for light microscopy, highlighting some of the differences between the two cereals

The direct effect of Focal Adhesion Kinase (FAK), dominant-negative FAK, FAK-CD and FAK siRNA on gene expression and human MCF-7 breast cancer cell tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in survival signaling. FAK has been shown to be overexpressed in breast cancer tumors at early stages of tumorigenesis.</p> <p>Methods</p> <p>To study the direct effect of FAK on breast tumorigenesis, we developed Tet-ON (tetracycline-inducible) system of MCF-7 breast cancer cells stably transfected with FAK or dominant-negative, C-terminal domain of FAK (FAK-CD), and also FAKsiRNA with silenced FAK MCF-7 stable cell line. Increased expression of FAK in isogenic Tet-inducible MCF-7 cells caused increased cell growth, adhesion and soft agar colony formation <it>in vitro</it>, while expression of dominant-negative FAK inhibitor caused inhibition of these cellular processes. To study the role of induced FAK and FAK-CD <it>in vivo</it>, we inoculated these Tet-inducible cells in nude mice to generate tumors in the presence or absence of doxycycline in the drinking water. FAKsiRNA-MCF-7 cells were also injected into nude mice to generate xenograft tumors.</p> <p>Results</p> <p>Induction of FAK resulted in significant increased tumorigenesis, while induced FAK-CD resulted in decreased tumorigenesis. Taq Man Low Density Array assay demonstrated specific induction of FAKmRNA in MCF-7-Tet-ON-FAK cells. DMP1, encoding cyclin D binding myb-like protein 1 was one of the genes specifically affected by Tet-inducible FAK or FAK-CD in breast xenograft tumors. In addition, silencing of FAK in MCF-7 cells with FAK siRNA caused increased cell rounding, decreased cell viability <it>in vitro </it>and inhibited tumorigenesis <it>in vivo</it>. Importantly, Affymetrix microarray gene profiling analysis using Human Genome U133A GeneChips revealed >4300 genes, known to be involved in apoptosis, cell cycle, and adhesion that were significantly down- or up-regulated (p < 0.05) by FAKsiRNA.</p> <p>Conclusion</p> <p>Thus, these data for the first time demonstrate the direct effect of FAK expression and function on MCF-7 breast cancer tumorigenesis <it>in vivo </it>and reveal specific expression of genes affected by silencing of FAK.</p

Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular Vesicles Sequestering Photosensitive Chemotherapeutics

Multidrug resistance (MDR) remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs) and topotecan resulted in intravesicular formation of reactive oxygen species (ROS) and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently preventing lysosomal photodestruction of normal breast epithelial cells. Thus, MDR modalities including ABCG2-dependent drug sequestration within EVs can be rationally converted to a pharmacologically lethal Trojan horse to selectively eradicate MDR cancer cells

Частота, факторы риска и клиническая характеристика облитерирующего бронхиолита после аллогенной трансплантации гемопоэтических стволовых клеток

Bronchiolitis obliterans (BO) is a severe form of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aim. The aim of current study was to evaluate the incidence, risk factors, and clinical manifestation of BO after allo-HSCT. Methods. The study included 1189 adult patients who received allo-HSCT at R.M.Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Academician I.P.Pavlov First Federal Saint-Petersburg State Medical University, Healthcare Ministry of Russia in 2008 – 2019. BO was diagnosed according to the US National Institutes of Health criteria (2014), including pulmonary function test (PFT) and high-resolution computed tomography (HRCT) of the chest. We analyzed the cumulative incidence of BO with competing events, risk factors in the Fine – Gray regression model, clinical symptoms, BO severity, and bronchial obstruction formation dynamics. Results. BO was diagnosed in 42 (3.5%) patients. Cumulative incidence of BO was 1.8% (95% CI, 1.2 – 2.7), 3.9 (95% CI, 2.8 – 5.2) и 4.5% (95% CI, 3.2 – 6.1) at 1, 3, and 5 years after allo-HSCT, respectively. The median time of BO onset and diagnosis was 321 (86 – 1 771) and 371 (161 – 2 134) days, respectively. Risk factors were HLAmismatched unrelated and haploidentical donor (ОР – 2.301, 95% CI, 1.247 – 4.246; p = 0.0076), myeloablative conditioning (ОР – 2.544, 95% CI, 1.384 – 4.674; p = 0.0026) and GVHD prophylaxis without posttransplant cyclophosphamide (ОР – 2.152, 95% CI, 1.154 – 4.013; p = 0.0160). The clinical manifestation included cough (88 %) and shortness of breath (90%). Bronchial wall thickening (95%) and expiratory air trapping (79%) were frequent chest HRCT findings. Mild, moderate, and severe BO was identified in 9 (21%), 12 (29%), and 21 (50%) patients, respectively. The median forced expiratory volume in 1 second (FEV1 ) was 39% (20 – 74). The most significant loss of bronchial conductivity was between day + 100 and 1 year after allo-HSCT. Conclusion. The large cohort study provided details on current incidence, risk factors, and clinical features of BO after HSCT. The results create the basis for predicting and early diagnosis of BO after allo-HSCTОблитерирующий бронхиолит (ОБ) является тяжелой формой хронической реакции «трансплантат против хозяина» (хРТПХ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью исследования явилось изучение частоты, факторов риска и клинической манифестации ОБ после алло-ТГСК. Материалы и методы. В исследование включены взрослые больные (n = 1 189), госпитализированные в стационар Научно-исследовательского института детской онкологии, гематологии и трансплантологии имени Р.М.Горбачевой Федерального государственного бюджетного образовательного учреждения высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П.Павлова» Министерства здравоохранения Российской Федерации и получившие алло-ТГСК в 2008–2019 гг. Диагностика ОБ проводилась согласно критериям Национальных институтов здоровья США (2014), включающим показатели функции внешнего дыхания и компьютерной томографии высокого разрешения (КТВР) органов грудной клетки (ОГК). Проводился анализ кумулятивной частоты ОБ с учетом конкурирующих событий, факторов риска в регрессионной модели Fine–Gray, клинических симптомов и степени тяжести, динамики формирования бронхообструкции. Результаты. ОБ диагностирован у 42 (3,5 %) больных. Кумулятивная частота ОБ составила 1,8 % (95%-ный доверительный интервал (ДИ) – 1,2–2,7), 3,9 (95%-ный ДИ – 2,8–5,2) и 4,5 % (95%-ный ДИ – 3,2–6,1) через 1 год, 3 и 5 лет после алло-ТГСК соответственно. Медиана (Me) времени манифестации и выявления ОБ составила 321 (86–1 771) и 371 (161–2 134) день соответственно. Факторами риска явились неродственный частично совместимый и гаплоидентичный донор (относительный риск (ОР) – 2,301; 95%-ный ДИ – 1,247–4,246; p = 0,0076), миелоаблативное кондиционирование (ОР – 2,544; 95%-ный ДИ – 1,384–4,674; p = 0,0026), профилактика РТПХ без посттрансплантационного циклофосфамида (ОР – 2,152; 95%-ный ДИ – 1,154–4,013; p = 0,016). При клинической манифестации ОБ отмечались кашель (88 %) и одышка (90 %). По данным КТВР ОГК чаще всего (95 %) выявлялись утолщения бронхиальных стенок и «воздушные ловушки» в фазе выдоха (79 %). ОБ легкой, средней и тяжелой степени установлены у 9 (21 %), 12 (29 %) и 21 (50 %) пациентов соответственно. Me объема форсированного выдоха за 1-ю секунду составила 39 % (20–74). Наиболее значимый компонент утраты бронхиальной проводимости формировался в период между 100-м днем («день + 100») и 1 годом после алло-ТГСК. Заключение. По данным крупного когортного исследования детализирована частота развития, факторы риска и клинические особенности ОБ на современном этапе развития алло-ТГСК. Полученные данные позволят прогнозировать развитие и своевременно диагностировать ОБ

Presence of an in situ component is associated with reduced biological aggressiveness of size-matched invasive breast cancer

Background:The metastatic propensity of invasive ductal carcinoma (IDC) of the breast correlates with axillary node involvement and with expression of the proliferation antigen Ki-67, whereas ductal carcinoma in situ (DCIS) is non-metastasising. To clarify whether concomitant DCIS affects IDC prognosis, we compared Ki-67 expression and node status of size-matched IDC subgroups either with DCIS (IDC-DCIS) or without DCIS (pure IDC).Methods:We analysed data from 1355 breast cancer patients. End points were defined by the association of IDC (with or without DCIS) with grade, nodal status, Ki-67, and ER/HER2.Results: Size-matched IDC-DCIS was more likely than pure IDC to be screen detected (P0.03), to occur in pre-menopausal women (P0.002), and to be either ER-positive (P0.002) or HER2-positive (P0.0005), but less likely to be treated with breast-conserving surgery (P0.004). Grade and Ki-67 were lower in IDC-DCIS than in pure IDC (P0.02), and declined as the DCIS enlarged (P0.01). Node involvement and lymphovascular invasion in IDC-DCIS increased with the size ratio of IDC to DCIS (P0.01). A 60-month cancer-specific survival favoured IDC-DCIS over size-matched pure IDC (97.4 vs 96.0%).Conclusion:IDC co-existing with DCIS is characterised by lower proliferation and metastatic potential than size-matched pure IDC, especially if the ratio of DCIS to IDC size is high. We submit that IDC-DCIS is biologically distinct from pure IDC, and propose an incremental molecular pathogenesis of IDC-DCIS evolution involving an intermediate DCIS precursor that remains dependent for replication on upstream mitogens. © 2010 Cancer Research UK All rights reserved.published_or_final_versio

Sulforaphane Causes Epigenetic Repression of hTERT Expression in Human Breast Cancer Cell Lines

Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer. expression facilitated the induction of cellular apoptosis in human breast cancer cells.Collectively, our results provide novel insights into SFN-mediated epigenetic down-regulation of telomerase in breast cancer prevention and may open new avenues for approaches to SFN-mediated cancer prevention