Hypoxia-dependent expression of ADAM8 in human pancreatic cancer cell lines

One of the most characteristic features of malignant tissue is the high level of intratumoral hypoxia, which is considered as a powerful factor for induction of tumor aggressiveness and malignant progression. Pancreatic cancer (PC) is a near fatal disease with very unfavorable clinical outcome despite the application of different treatment regimes. It was shown that PC is characterized by high level of hypoxia. Aim: To clarify the correlation between tumor hypoxia and ADAM8 protein expression. Materials and Methods: ASPC-1, Panc-1, BxPC-3, Capan-1, MiaPaCa-2, Colo-357, Su8686 and T3M4 cell lines were used in the study. Expression of mRNA ADAM8 was evaluated by real-time quantitative polymerase chain reaction method. Immunoblot analysis was used to evaluate the expression of ADAM8 protein. Results: Hypoxia induced a 2.5–5.9-fold increase of ADAM8 mRNA levels of in the examined pancreatic cancer cell lines except Panc-1 (p = 0.046). On the protein level, hypoxia induced a 1.2–5.9-fold increase of the ADAM8 prodomain removal form (90 kDa) in 5/8 pancreatic cancer cells. Moreover, hypoxia induced a 1.3–2.0-fold increase of the remnant form ADAM8 (60 kDa) in 4/8 pancreatic cancer cell lines: Aspc-1, Colo-357, Panc-1, T3M4. Conclusion: It was observed the clear tendency in the increase both of ADAM8 mRNA and ADAM8 protein levels in pancreatic cancer cell lines under hypoxia compared to normal conditions of oxygenation. A potential role of ADAM8 as a hypoxia-dependent protein in the pathogenesis and evolution of pancreatic cancer that is characterized by high level of intratumoral hypoxia can be suggested.Введение: известно, что характерной чертой злокачественных опухолей является внутриопухолевая гипоксия, положительно влияющая на злокачественную прогрессию. Рак поджелудочной железы (РПЖ) является очень агрессивной опухолью, обладающей высокой способностью к инвазии в близлежащие ткани и органы, что обусловливает неудовлетворительные результаты лечения. Показано при этом, что РПЖ относится к новообразованиям с высокой степенью гипоксии. Цель: установление возможной зависимости экспрессии белка АДАМ8 и его мРНК от уровня оксигенации клеток. Материалы и методы: использовали клеточные линии РПЖ человека. Экспрессию мРНК и белка ADAM8 определяли методами qRTPCR и вестерн-блот-анализа соответственно. Результаты: установлено, что гипоксия индуцировала повышение уровня мРНК АDAM8 в 2,5–5,9 раза в исследованных клеточных линиях РПЖ, за исключением клеток линии Panc-1. В клетках линий BxPC-3, Capan-1 и Su8686 выявлено наиболее значительное возрастание уровня экспрессии мРНК ADAM8 при гипоксии (p = 0,046). С помощью вестерн-блот-анализа показано, что экспрессия удаляемой формы продомена ADAM8 (90 kDa) усиливалась в несколько раз при гипоксии в 5 из 8 изученных клеточных линий РПЖ. Гипоксия индуцировала повышение экспрессии остаточной формы ADAM8 (60 kDa) в 4 из 8 клеточных линий РПЖ: Aspc-1, Colo-357, Panc-1, T3M4, хотя изменения оказались умеренно выраженными. Выводы: в клеточных линиях РПЖ человека отмечается четкая тенденция к повышению при гипоксии уровня экспрессии, как мРНК, так и белка ADAM8, что позволяет предположить зависимость экспрессии от уровня оксигенации и потенциальную роль ADAM8 в развитии и прогрессии РПЖ, который отличается высокой степенью внутриопухолевой гипоксии

INFLUENCE OF SECONDARY HYPERPARATHYROIDISM ON THE CALCIFICATION OF HEART VALVES IN PATIENTS WITH CHRONIC KIDNEY DISEASE VD STAGE

The aim of this work was to study the relationship of elevated levels of parathyroid hormone (PTH) with cardiovascular changes (calcification of the heart valves) and to identify possible risk factors of calcification in the group of patients receiving renal replacement therapy. Materials and methods. The study included 96 patients with ESRD: 1-st group receives the treatment of peritoneal dialysis (PD) (45 patients), 2-nd group haemodialysis (HD) (51 patients). In serum determined concentration of calcium, phosphorus, PTH. All patients underwent echocardiographic examination. Results. The prevalence of secondary hyperparathyroidism in PD-patients reached 72%, in HD-patients 83%. Calcification of heart valves in both groups occurred in patients with high PTH level (greater than 400 PG/ml). Patients in both groups were significantly more frequent in the combined mitrale-aortic calcification. Isolated mitral calcification was detected more often aortic. Predictors of progression of calcification of heart valves in patients on PD is the age, in patients on HD - level average BP and the duration of dialysis therapy. Conclusions. Echocardiological data and clinical and laboratory examination of patients with ESRD allowed us to estimate the prevalence and structure of mitrale-aortic calcification and its relationship with secondary hyperparathyroidism

From the experience of organization of pupils’ project activities in the line of health care

This article contains organization questions about the process of pupils’ project activities in the line of Health care and social-oriented work. It has the summarizing of many years teachers’ work on creating of the system of organization of pupils’ project activities in 5-10 forms. There are also successful totals of teachers and pupils cooperationСтатья посвящена вопросам организации проектно-исследовательской деятельности школьников в области социально-ориентированных проектов и здоровьесбережения. Обобщен опыт многолетней работы педагогов по созданию системы организации проектной деятельности в среднем звене с 5 по 10 класс. Отмечены успешные итоги интеграции усилий педагогов и учащихс

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Peer reviewe

ADAM8 in squamous cell carcinoma of the head and neck: a retrospective study

<p>Abstract</p> <p>Background</p> <p>A disintegrin and metalloproteinase (ADAMs) have been associated with multiple malignancies. ADAMs are involved in cell fusion, cell migration, membrane protein shedding and proteolysis. ADAM8 has been found to be overexpressed in squamous cell carcinomas of the lung. A new study showed that ADAM8 is significantly overexpressed in metastasis of squamous cell carcinomas of the head and neck (HNSCC).</p> <p>Methods</p> <p>We determined ADAM8 levels in the serum of 79 HNSCC patients at the time of diagnosis, in 35 patients 3 months after treatment and in 10 patients 1 year after therapy and compared the results to the sera of 31 healthy volunteers. We also constructed tissue microarrays to detect ADAM8 immunohistochemically in 100 patients. The results were correlated with the survival data of the patients to determine the diagnostic and prognostic value.</p> <p>Results</p> <p>The data demonstrated that patients with high ADAM8 expression in the tumor have worse survival rates. We found that high ADAM8 serum levels correlated with high ADAM8 expression in tumor samples. Soluble ADAM8 levels did not show any prognostic or diagnostic properties.</p> <p>Conclusion</p> <p>In summary ADAM8 expression is a prognostic factor for survival of patients with head and neck squamous cell carcinoma.</p

Study protocol of DIVERGE, the first genetic epidemiological study of major depressive disorder in Pakistan

INTRODUCTION: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan. METHODS: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology. RESULTS AND DISCUSSION: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings. CONCLUSION: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research

Deficiency of the Metalloproteinase-Disintegrin ADAM8 Is Associated with Thymic Hyper-Cellularity

Thymopoiesis requires thymocyte-stroma interactions and proteases that promote cell migration by degrading extracellular matrix and releasing essential cytokines and chemokines. A role for several members of the A Disintegrin and Metalloprotease (ADAM) family in T cell development has been reported in the past

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q  Conclusions Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings