124 research outputs found
Features of bismuth and silicon oxides synthesis by pulsed laser ablation in water
Semiconductor nanomaterials are widely used in photocatalysis due to a number of advantages such as efficient electron separation and flexible choice of semiconductor with desired band gap for efficient light absorption. Bismuth silicates (BSO) are promising new photocatalytic materials for organic decomposition and hydrogen production [1]. Currently mainly chemical methods of synthesis are used to obtain BSO materials. In this work for the first time complex oxides BSO were prepared via pulsed laser ablation (PLA) in a liquid. PLA was performed by exposing Si and Bi targets to Nd:YAG laser radiation (1064 nm, 7 ns). Separately synthesized nanocolloids were mixed and subjected to additional laser irradiation and then dried. Using different Si/Bi ratios, as well as temperature treatment of the resulting powders, BSO of various compositions were synthesized, including monophases of the compounds Bi2SiO5, Bi4Si3O12 and Bi12SiO20. The photocatalytic activity of the samples was estimated by the decomposition of Rhodamine B under LED source irradiation with rad = 375 nm. The effect extra irradiation of colloids mixture on the formation of the structure of complex oxides BSO at different Si/Bi ratios has been studied. The correlations between the optical properties, composition and structure of catalysts and their photocatalytic properties has been established. It was shown that the best photocatalytic activity exhibits Bi12SiO20 powders
PLA synthesis and photocatalytic properties of bismuth silicates
In this work, bismuth silicates were obtained by pulsed laser ablation in a liquid (PLA)
Bismuth silicates: preparation by pulsed laser ablation and photocatalytic activity
Pulsed laser ablation (PLA) in liquid is advanced method for obtaining active nanoparticles in pure solvents without the use of chemical precursors. In this work, an original approach to the synthesis of complex oxides of bismuth and silicon (BSO) is proposed. The initial colloids obtained by PLA (Nd:YAG laser, 1064 nm, 7 ns) of Bi and Si targets in water were mixed and subjected to additional irradiation with the same laser parameters. Laser treatment stimulated the formation of complex oxides. Then the colloids were dried in air and nanopowders obtained were studied by X-ray diffraction (XRD), transmission electron microscopy (TEM) and UV-Vis spectroscopy. The photocatalytic activity of the materials was examined in the Rhodamine B degradation under LED source irradiation (375 nm)
FAK overexpression and p53 mutations are highly correlated in human breast cancer
Focal Adhesion Kinase (FAK) is overexpressed in a number of tumors, including breast cancer. Another marker of breast cancer tumorigenesis is the tumor suppressor gene p53 that is frequently mutated in breast cancer. In the present study, our aim was to find a correlation between FAK overexpression, p53 expression and mutation status in a population-based series of invasive breast cancer tumors from the Carolina Breast Cancer Study. Immunohistochemical analyses of 622 breast cancer tumors revealed that expression of FAK and p53 were highly correlated (P = 0.0002) and FAK positive tumors were 1.8 times more likely to be p53 positive compared to FAK negative tumors [odds ratio (OR) = 1.8; 95% Confidence Interval (CI) 1.2 – 2.8, adjusted for age, race and stage at diagnosis]. Tumors positive for p53 expression showed higher intensity of FAK staining (P<0.0001) and higher percent of FAK positive staining (P<0.0005). From the same study, we evaluated 596 breast tumors for mutations in the p53 gene, using SSCP (single strand conformational polymorphism) and sequencing. Statistical analyses were performed to determine the correlation between p53 mutation status and FAK expression in these tumors. We found that FAK expression and p53 mutation were positively correlated (P<0.0001) and FAK positive tumors were 2.5 times more likely to be p53 mutation positive compared to FAK negative tumors [adjusted OR = 2.5, 95% CI 1.6–3.9]. This is the first analysis demonstrating a high correlation between FAK expression and p53 mutations in a population-based series of breast tumors
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
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
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
Specific induction of pp125 focal adhesion kinase in human breast cancer
The pp125 focal adhesion kinase (FAK) is involved in integrin-mediated cell signalling and overexpressed in a variety of solid tumours. Focal adhesion kinase expression has been correlated to invasion and metastasis, but the data on breast cancer are inconclusive. We analysed FAK mRNA, protein levels and expression patterns in primary breast cancer and normal breast tissue. FAK expression on the functional protein level and mRNA was determined in 55 matched pairs of breast cancer and corresponding normal tissue by Western blot, immunohistochemistry and RT–PCR. Using a score ranging from 0 to +5 for Western blots, we determined in normal breast tissue a score of 1.51±0.84 (mean±standard deviation), which was strongly induced to 2.91 (±1.22) in breast cancers (P<0.001). Overall, 45 out of 55 tissue pairs (81.8%) showed this upregulation of FAK protein in tumours in comparison to normal tissue. Immunohistochemistry confirmed these findings with a significant higher score for tumours vs physiological tissue (1.0±0.63 vs 2.27±0.91; P=0.001). Interestingly, no overall significant difference in the mRNA levels (P=0.359) was observed. In conclusion, expression levels of the FAK protein are specifically upregulated in breast cancer in comparison to matched normal breast tissue supporting its pivotal role in neoplastic signal transduction and representing a potential marker for malignant transformation
Using Functional Signatures to Identify Repositioned Drugs for Breast, Myelogenous Leukemia and Prostate Cancer
The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine
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