siRNA-mediated off-target gene silencing triggered by a 7 nt complementation

A growing body of evidence suggests that siRNA could generate off-target effects through different mechanisms. However, the full impact of off-target gene regulation on phenotypic induction and accordingly on data interpretation in the context of large-scale siRNA library screen has not been reported. Here we report on off-target gene silencing effects observed in a large-scale knockdown experiment designed to identify novel regulators of the HIF-1 pathway. All of the three ‘top hits’ from our screen have been demonstrated to result from off-target gene silencing. Two of the three ‘siRNA hits’ were found to directly trigger down-regulation of hif-1α mRNA through a 7 nt motif, AGGCAGT, that is present in both the hif-1α mRNA and the siRNAs. Further analysis revealed that the generation of off-target gene silencing via this 7 nt motif depends on the characteristics of the target mRNA, including the sequence context surrounding the complementary region, the position of the complementary region in the mRNA and the copy number of the complementary region. Interestingly, the off-target siRNA against hif-1α was also shown to trigger mRNA degradation with high probability of other genes that possess multiple copies of the AGGCAGT motif in the 3′-untranslated region. Lessons learned from this study will be a valuable asset to aid in designing siRNAs with more stringent target selectivity and improving ‘hits-follow-up’ strategies for future large-scale knockdown experiments

Рутений: прошлое и настоящее

This article provides information on one of the most interesting elements in the D.I. Mendeleev Periodic Table - ruthenium, discovered 175 years ago by the outstanding Russian chemist Karl Karlovich Klaus. Its most important physical properties, a variety of oxidation states, and a tendency to form countless compounds have been noted, mocking it unique and indispensable in all areas of science, technology, and in society. We have taken into consideration the structure of ruthenium consumption today as well as a few prospects for its future use.В представленной статье приведена информация об одном из интереснейших элементов Периодической системы Д.И. Менделеева - рутении, открытом 175 лет назад выдающимся русским химиком Карлом Карловичем Клаусом Отмечены его важнейшие физические свойства, многообразие степеней окисления, склонность к образованию бесчисленного количества соединений, что обусловило его уникальность и сделало незаменимым во всех сферах науки, техники и в социальной сфере. Рассмотрена структура потребления рутения в наши дни, а также некоторые перспективы применения в будущем

Dedifferentiated liposarcoma with leukocytosis. A case report of G-CSF-producing soft-tissue tumors, possible association with undifferentiated liposarcoma lineage

<p>Abstract</p> <p>Background</p> <p>Granulocyte-colony-stimulating factor (G-CSF) functions as a hematopoietic growth factor and it is responsible for leukocytosis. G-CSF-producing tumors associated with leukocytosis include various types of malignancies.</p> <p>Case presentation</p> <p>We report the case of a 72-year-old man with dedifferentiated liposarcoma characterized by dedifferentiated components of malignant fibrous histiocytoma (MFH)-like features in addition to well-differentiated lipoma-like liposarcoma, arising from his upper arm. Preoperative laboratory data showed leukocytosis (103,700/μl). The serum level of G-CSF was also elevated (620 pg/ml [normal, <8 pg/ml]). Nine days after the surgery, the leukocytosis was relieved (WBC; 6,920/μl) and the elevated serum G-CSF level was significantly decreased (G-CSF; 12 pg/ml). One month after the surgery, leukocytosis gradually began to appear again. Three months after the surgery metastatic lung lesions were confirmed, and the patient subsequently died of respiratory problems. In the English literature regarding soft-tissue tumors with leukocytosis, including the current case, we could review a total of 6 cases of liposarcoma with leukocytosis. The subtype of these 6 liposarcoma cases was undifferentiated liposarcoma, comprising dedifferentiated liposarcoma in 4 cases and pleomorphic liposarcoma in 2 cases.</p> <p>Conclusion</p> <p>Since the only other soft-tissue tumor that was associated with leukocytosis was MFH, and since MFH is characterized by the absence of any specific differentiation, we would like to propose a possible association between G-CSF-producing soft-tissue tumors and an undifferentiated liposarcoma lineage, such as dedifferentiated liposarcoma or pleomorphic liposarcoma.</p

Modern NMR spectroscopy of proteins and peptides in solution and its relevance to drug design

The knowledge of the three-dimensional (3D) structures and conformational dynamics of proteins and peptides is important for the understanding of biochemical and genetic data derived for these molecules. This understanding can ultimately be of help in drug design. We describe here the role of Nuclear Magnetic Resonance (NMR) spectroscopy in this process for three distinct situations: for small proteins, where relatively simple NMR methods can be used for full 3D structure determination; for larger proteins that require multinuclear multidimensional NMR but for which full 3D structures can still be obtained; and for small peptides that are studied in interaction with macromolecules (receptors) using specialized NMR techniques. A fourth situation, pertaining to large systems where only partial structural information can be obtained from NMR data, is briefly discussed. Molecules of interest to the biomedical field (C5a and stromelysin) are discussed as examples.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43356/1/11091_2005_Article_BF02174537.pd

СЛУЧАЙ ПЕРВИЧНО-МНОЖЕСТВЕННЫХ СИНХРОННЫХ ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ: АДЕНОКАРЦИНОМЫ ШЕЙКИ МАТКИ И СИНХРОННОГО ПЛОСКОКЛЕТОЧНОГО РАКА ЯИЧНИКОВ

A rare clinical case of synchronous cervical adenocarcinoma and primary squamous cell ovarian carcinoma has been presented. Epidemiological and treatment aspects have been analyzed.Представлен редкий клинический случай сочетания аденокарциномы шейки матки и первичного плоскоклеточного рака яичников, рассмотрены вопросы эпидемиологии данных нозологий, тактика лечения

Редкое клиническое наблюдение пациента со смешанной нейроэндокринной-не-нейроэндокринной опухолью большого дуоденального соска

Background. Neuroendocrine tumors are rare neoplasias accounting for 1 % of all digestive malignancies. In 2010, mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) were classified by the World Health Organization This type of tumor is extremely rare and most commonly occurs in the appendix, colon, and rectum. To date, only 30 clinical cases of MINEN of the major duodenal papilla (MDP) have been described in the available world literature, while we have not found a description of this pathology in the domestic literature.Description of the clinical case. We present a case of a 64-year-old male patient with MiNEN MDP. The first clinical manifestation of the disease was obstructive jaundice. To eliminate the jaundice, papillosphincterotomy, transpapillary stenting of the choledochus with a plastic stent was performed. MDP tumor was verifed as adenocarcinoma by histological examination. The patient underwent gastropancreatoduodenal resection. Postoperative immunohistochemical examination showed the expression of antibodies in tumor cells: Synaptophysin (clone 27G12) +++, Chromogranin A (5H7) +, CD 57 (NK-1) ++, Ki 67 (Mib 1) 80 %.Conclusion: mixed neuroendocrine (G3) non-neuroendocrine carcinoma (G2) of the major duodenal papilla with growth within the wall of the duodenum; metastases of the neuroendocrine component in three lymph nodes, adenocarcinoma metastasis in 1 out of 15 lymph nodes examined; pT2N2M0, MiNEN high grade (classified by S. La Rosa). Conclusion. Mixed neuroendocrine-non-neuroendocrine tumors of MDP are an extremely rare pathology. The accuracy of preoperative morphological diagnostics is not high, therefore, this diagnosis can be easily missed at the preoperative stage. In the morphological study of malignant tumors of MDP, a pathologist should take into account the feasibility of a combination of a neuroendocrine tumor with adenocarcinoma. Актуальность. Нейроэндокринные опухоли являются редкими неоплазиями, которые встречаются в 1 % среди всех опухолевых поражений органов пищеварения. В 2010 г. в классификацию нейроэндокринных опухолей ВОЗ включены смешанные нейроэндокринно-не-нейроэндокринные опухоли (СННО). Данный вид опухоли является чрезвычайно редким и чаще всего встречается в червеобразном отростке, ободочной и прямой кишке. В доступной мировой литературе описано 30 клинических случаев СННО большого дуоденального соска (БДС), в отечественной литературе данная патология не описана.Описание клинического случая. Первым клиническим проявлением заболевания была механическая желтуха. Госпитализирован в дежурный хирургический стационар, проведена эзофагогастродуоденоскопия, выявлено объемное образование БДС. Для купирования желтухи выполнена папиллосфинктеротомия, транспапиллярное стентированиие холедоха пластиковым стентом. На фоне лечения желтуха купирована, получено гистологическое заключение – опухоль БДС верифицирована как аденокарцинома. Пациенту проведено оперативное лечение в объеме гастропанкреатодуоденальной резекции. По результатам послеоперационного иммуногистохимического исследования экспрессия в опухолевых клетках антител: Synaptophysin (клон 27G12) +++, Chromogranin A (5H7) +, CD 57 (NK-1) ++, Ki 67 (Mib 1) 80 %. Заключение: смешанная нейроэндокринная (G3) не-нейроэндокринная карцинома (G2) большого дуоденального соска с ростом в пределах стенки двенадцатиперстной кишки. Метастазы нейроэндокринного компонента в 3 лимфоузлах, метастаз аденокарциномы в 1 из 15 исследованных лимфоузлов; pT2N2M0, СННО high grade (по классификации S. La Rosa).Заключение. Смешанные нейроэндокринно-не-нейроэндокринные опухоли БДС являются крайне редкой патологией. Информативность предоперационной морфологической диагностики невысока. При морфологическом исследовании злокачественных опухолей БДС должна учитываться возможность сочетания нейроэндокринной опухоли с аденокарциномой

Sphingosine Kinase 1 Regulates the Akt/FOXO3a/Bim Pathway and Contributes to Apoptosis Resistance in Glioma Cells

The aim of this study was to investigate the mechanism through which Sphingosine kinase-1 (SPHK1) exerts its anti-apoptosis activity in glioma cancer cells. We here report that dysregulation of SPHK1 alters the sensitivity of glioma to apoptosis both in vitro and in vivo. Further mechanistic study examined the expression of Bcl-2 family members, including Bcl-2, Mcl-1, Bax and Bim, in SPHK1-overexpressing glioma cells and revealed that only pro-apoptotic Bim was downregulated by SPHK1. Moreover, the transcriptional level of Bim was also altered by SPHK1 in glioma cells. We next confirmed the correlation between SPHK1 and Bim expression in primary glioma specimens. Importantly, increasing SPHK1 expression in glioma cells markedly elevated Akt activity and phosphorylated inactivation of FOXO3a, which led to downregulation of Bim. A pharmacological approach showed that these effects of SPHK1 were dependent on phosphatidylinositol 3-kinase (PI3K). Furthermore, effects of SPHK1 on Akt/FOXO3a/Bim pathway could be reversed by SPHK1 specific RNA interference or SPHK1 inhibitor. Collectively, our results indicate that regulation of the Akt/FOXO3a/Bim pathway may be a novel mechanism by which SPHK1 protects glioma cells from apoptosis, thereby involved in glioma tumorigenesis