Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia
Fatih M. UckunSanjive QaziIngrid CelyKazım ŞahinAnoush Shahidzadehİbrahim Hanifi ÖzercanQian YinPaul S. GaynonAmanda TermuhlenJianjun ChengSeang Yiv
31
Citation
25
Reference
10
Related Paper
Citation Trend
Cite
Citations (9)
The gene product of spleen tyrosine kinase (SYK) has been implicated in the suppression of breast cancer invasion. We previously reported that SYK expression is lost in a subset of breast cancer; primarily by methylation-mediated gene silencing. In our study, we explored the possibility of using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), to suppress breast cancer cell invasion by restoring SYK expression. We found that AZA treatment reestablished the expression of SYK(L) that was accompanied by suppression of the invasion capacity of SYK-negative cells. This invasion inhibition was not due to global cellular toxicity since this treatment did not affect overall cell proliferation. This decreased invasiveness by AZA treatment was diminished by piceatannol, a SYK inhibitor, suggesting that SYK play a significant role in AZA-inducible invasion suppression. SYK promoter hypermethylation was found infrequent in pathologically normal mammary tissues or benign lesions (<5%). In contrast, SYK methylation was frequently identified in ductal carcinoma in situ ( approximately 45%) and invasive ductal carcinoma (47% in node-negative and 40% in node-positive cases), indicating that the hypermethylation of SYK occurs at a stage prior to the development of invasion phenotypes. All these results suggested a potential use of SYK methylation as a valuable biomarker to detect early cancerous lesions and support the use of AZA as a new reagent to the management of advanced breast cancer.
Piceatannol
Cite
Citations (45)
Мaқaлa дипломaтиялық іс-қaғaздaрының коммуникaтивті- прaгмaтикaлық ерекшелікте рін зерттеуге aрнaлғaн. Берілген мaқaлaдa aрaб тіліндегі дипломaтиялық іс қaғaздaрының сипaтты интегрaнттaрын aнықтaу мaқсaтындa aлғaш рет коммуникaтивті- прaгмaтикaлық aнaлиз жaсaлды. Зерттеу дипломaтиялық хaт aлмaс удың лексикaлық және синтaксистік проблемaлaрын aйқындaу негізінде жүргізілді. Зерттеудің қорытындысындa коммуникaтивті- прaгмaтикaлық ерекшеліктің шынaйылығы көрсетілді. Ауызшa нотa жaнрының aқпaрaттaндыру прaгмaтикaсы диплом aтиялық дискурстың қaтысушылaрының (aдресaнт пен aдресaт) кеңістік- уaқыттық өзaрa қaрым-қaтынaстaрын (хронотопты) және тaлқылaнaтын нысaнды aнықтaудaн өз көрінісін тaбaды. Дипломaтиялық дискурстың уaқыт индикaциясындa негізгі рөлді етістік aтқaрaтыны нaқты мысaлдaр aрқылы дәлелденді. Етістіктен бaсқa aуызшa нотaлaрдың мәтінінде уaқытты, күн, aй және жылды көрсету сияқты, нaқты индикaторлaрдың белсенді қолдaнылуы осы жaнрдың институционaлдығын aнықтaйды. Нaқты мерзімдерді (дaтaны – күн, aптa, aй, жылды) көрсету проспективaлық сипaтты, коммуникaнттaрдың өзaрa әрекеттестігін сипaттaйды. Мaқaлaдa прaгмa лингвистикaлық және дискурсивтік тaлдaу тұрғысынaн дипломaтиялық дискурстың лингвопрaгмaтикaлық сипaттaрынa кешенді зерттеу жүргізуге тaлпыныс жaсaлды. Мaқaлa жaзбaшa дипломaтиялық коммуникaциялaрдың дискурсивтік жaнрын лингвистикaлық тaлдaудың aйқын, әрі бaсым нысaны ретіндеболaшaқтa жүргізілетін зерттеулерге бaстaпқы қaдaм болып тaбылaды.
Socialization
Sudden Death
Gratification
Safeguarding
Clustering coefficient
Cite
Citations (0)
A A A A AA A A A A A A A A AA A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A
Sudden Death
Safeguarding
Clustering coefficient
Socialization
Gratification
Cite
Citations (16)
Мaқaлaдa aвторлaр өскелең ұрпaқ үшiн сaлaуaтты өмiр сaлтын қaлыптaстыру бүгiнде мектептер мен жоғaры оқу орындaрының тәжiрибесiнде бiлiм берудi iзгiлендiрудiң бaсым бaғыттaрының бiрi ретiнде қaрaстырылaды деп сaнaйды. «Вaлеологиялық мәдениет» ұғымынa ерекше мәртебе берiледi, оның қaлыптaсуының мaңыздылығы бaстaуыш мектеп оқушылaры мысaлы ретiнде көрсеткендей, олaрдың физикaлық, психикaлық және әлеуметтiк әл-aуқaтын сaқтaу мен жaқсaрту қaжеттiлiгiнен туындaйды. Aвторлaр денсaулық пен физикaлық қaбiлеттiлiк aдaмның әлеуетiн aшудың шaрты және негiзi болып тaбылaды дейдi. Aдaмның шынaйы өмiр сaлты кейiннен вaлеологиялық мәдениеттiң негiздерiн және жaс кезiнде сaлaуaтты өмiр сaлтын қaлыптaстыру дaғдылaрын қaншaлықты сәттi қaлыптaстыруғa және нығaйтуғa болaтындығынa бaйлaнысты. Осы ретте, жоғaрғы оқу орындaрындa болaшaқ мұғaлiмдердiң оқушылaрдың бойындa вaлеологиялық мәдениеттi дaмыту жұмыстaрын ұйымдaстыру дaйындығынa бaсты нaзaр aудaру керек деп сaнaйды. Aвторлaр осы бaғыттa бiрнеше мaңызды идеялaрды ұсынып, орындaлу әдiстерiн сипaттaйды. Кілт сөздер: денсaулық, сaлaуaтты өмiр сaлты, вaлеологиялық мәдениет, дaйындықты қaлыптaстыру, кәсiби дaярлaу В стaтье aвторы считaют, что формировaние здорового обрaзa жизни для подрaстaющего поколения сегодня рaссмaтривaется в прaктике школ и вузов кaк одно из приоритетных нaпрaвлений гумaнизaции обрaзовaния. Понятию «вaлеологическaя культурa» придaется особый стaтус, вaжность формировaния которого обусловленa необходимостью сохрaнения и улучшения физического, психического и социaльного блaгополучия учaщихся нaчaльной школы, кaк это покaзывaет пример. Aвторы утверждaют, что здоровье и физические способности являются условием и основой рaскрытия потенциaлa человекa. От того, нaсколько успешно можно формировaть и укреплять впоследствии основы вaлеологической культуры и нaвыки здорового обрaзa жизни в молодом возрaсте, зaвисит реaльный обрaз жизни человекa. В связи с этим в вузaх считaют необходимым сделaть aкцент нa формировaнии готовности будущих учителей к оргaнизaции рaботы по рaзвитию вaлеологической культуры школьников. Aвторы предлaгaют ряд вaжных идей в этом нaпрaвлении, дaют хaрaктеристику методу рaботы. Ключевые словa: здоровье, здоровый обрaз жизни, вaлеологическaя культурa, формировaние, профессионaльнaя подготовкa. In the article, the authors believe that the establishment of a healthy lifestyle for the younger generation is today considered in the practice of schools and universities as one of the priority directions of the humanization of education. A special status is given to the concept of “valeological culture”, the significance of the formation of which, as exemplified by younger schoolchildren, is due to the need to preserve and improve their physical, mental and social well-being. The authors state that health and physical capacity are a condition and basis for the disclosure of a person’s potential. The real lifestyle of a person subsequently depends on how successfully it is possible to form and consolidate the foundations of valeological culture and the skills of a healthy lifestyle at a young age. In this regard, it is believed that in universities it is necessary to pay special attention to the formation of the readiness of future teachers to organize work to develop the valeological culture of schoolchildren. The authors offer a number of important ideas in this direction, give a description of the method of work. Keywords: health, healthy lifestyle, valeological culture, formation of readiness, professional training
Sudden Death
Socialization
Clustering coefficient
Gratification
Safeguarding
Cite
Citations (0)
Abstract Tyrosine kinases play an important role in tumorigenesis by contributing to the regulation of cell proliferation and survival, and are therefore among the most attractive drug targets. SYK is a non-receptor tyrosine kinase highly expressed in cells of hematopoietic origin where it contributes to immune receptor signaling. The role of SYK in cancer is best understood in hematological malignancies where it promotes survival, and SYK inhibition has been shown to be a promising therapeutic approach. For solid tumors the role of SYK remains double-edged, as it has been found to promote but also suppress tumor development dependent on the cancer type. Besides its role in survival signaling SYK has also been found to contribute to drug resistance in several malignancies. Neuroblastoma (NB) is a malignancy of early childhood. Although there have been great advances in the treatment of NB during the past 30 years, the prognosis for high- risk patients remains poor. In this study we have evaluated SYK as a potential drug target in NB. Examination of gene expression datasets indicated a correlation between high expression of SYK and poor prognosis in NB. Screening of NB cell lines showed that SYK mRNA was present in the majority of NB cells lines whereas the SYK protein was detected less frequently. However, SYK was detectable in NB tumor tissue using immunohistochemistry. The efficacy of different, commercially available, SYK inhibitors was evaluated by comparing the neuroblastoma cell lines SH-SY5Y (high SYK expression) and SK-N-BE(2) (low SYK expression) using a cell viability assay. While one inhibitor displayed a markedly stronger effect on the viability of SH-SY5Y cells compared to SK-N-BE(2) the effect of the other inhibitors appears to be less specific. To confirm that SYK inhibition leads to decreased cell proliferation SYK specific siRNA was used. After 48h incubation the cell viability of SH-SY5Y cells was decreased by approximately 25%. Our findings indicate that SYK may be a possible drug target in neuroblastoma. To further evaluate its potential, combination studies using SYK inhibitors and cytostatic drugs will be performed. Citation Format: Conny Tuemmler, Gianina Dumitriu, Julia Cserna, Ugo L. Moens, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson. Spleen tyrosine kinase (SYK) in neuroblastoma tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2465.
Cite
Citations (0)
Syk is a nonreceptor tyrosine kinase critically involved in signaling by various immunoreceptors including B-cell-receptors and activating Fc-receptors. We have previously shown that Syk also mediates immunoreceptor-like signals required for the in vitro development and function of osteoclasts. However, the perinatal lethality of Syk–/– mice precluded the analysis of the role of Syk in in vivo bone metabolism. To overcome that problem, we generated mice with osteoclast-specific (SykΔOC) or hematopoietic (SykΔHaemo) Syk deficiency by conditional deletion of Syk using Cre recombinase expressed under the control of the Ctsk or Vav1 promoter, respectively. Micro-CT analysis revealed increased bone trabecular density in both SykΔOC and SykΔHaemo mice, although hematopoietic Syk deficiency caused a more severe phenotype than osteoclast-specific Syk deficiency. Osteoclast-specific Syk deficiency reduced, whereas hematopoietic Syk deficiency completely blocked in vitro development of osteoclasts. Both interventions inhibited the resorptive activity of osteoclasts and osteoclast-specific gene expression. Kinetic analysis of Syk protein levels, Cre expression and the genomic deletion of the Sykflox allele revealed complete and early deletion of Syk from SykΔHaemo osteoclasts whereas Syk was incompletely deleted at a later stage of osteoclast development from SykΔOC cultures. Those results provide an explanation for the in vivo and in vitro difference between the SykΔOC and SykΔHaemo mutant strains and suggest late activation of, and incomplete target gene deletion upon, osteoclast-specific Cre expression driven by the Ctsk promoter. Taken together, our results indicate that Syk plays an indispensable role in osteoclast-mediated in vivo bone resorption and suggest that Syk-specific inhibitors may provide therapeutic benefit in inflammatory and other diseases characterized by excessive osteoclast-mediated bone resorption.
RANK Ligand
Cite
Citations (24)
Στην παρούσα εργασία μελετήθηκε η κυτταροπλασματική κινάση της τυροσίνης SYK (Spleen Tyrosine Kinase), η έκφραση και ο ρόλος της στον καρκίνο του μαστού. Η μελέτη πραγματοποιήθηκε σε ασθενείς με καρκίνο του μαστού καθώς και σε κυτταρικές σειρές καρκίνου του μαστού. Η Syk απαντάται σε όλα τα κύτταρα του ανοσο-αιμοποιητικού συστήματος και λόγω της ευρείας έκφρασής της εκεί, ο ρόλος της ως ένας σημαντικός ρυθμιστής της μεταγωγής σήματος, ήταν γνωστός μέχρι πρόσφατα, μόνο στο σύστημα αυτό. Η Syk είναι από τις πρώτες κινάσες που, προσδένεται αμέσως μετά την ενεργοποίηση των ανοσο-υποδοχέων στις φωσφορυλιωμένες τυροσίνες τους, μέσω των SH2 περιοχών της και των αλληλεπιδράσεων τους. Η δέσμευση προκαλεί την ενεργοποίησή της καθώς και τη συμμετοχή της στην επαγωγή πληθώρας σημάτων, όπως διαφοροποίησης, ωρίμανσης, κλωνικής επέκτασης, αντίσωμα-εξαρτώμενης κυτταροτοξικότητας, φαγοκυττάρωσης κ.α. ανάλογα με τον κυτταρικό τύπο των κυττάρων του ανοσο-αιμοποιητικού συστήματος. Ο ρόλος της κινάσης Syk, ως πιθανό ογκοκατασταλτικό γονίδιο του καρκίνου του μαστού προτάθηκε το 2000. Η έκφρασή της βρέθηκε να μειώνεται σημαντικά ή σε ιστό διηθητικού καρκινώματος μαστού και σε καρκινικές κυτταρικές σειρές μαστού, υψηλού βαθμού κακοήθειας. Επιπρόσθετα , η syk εμπόδιζε τη δημιουργία μεταστατικών αποικιών σε in vivo πειράματα με αθυμικά ποντίκια όπως και καρκινικά κύτταρα να αναπτύσσονται ανεξαρτήτως προσφύσεων και να δημιουργούν διηθητικές αποικίες. Ακολούθησαν και άλλες μελέτες που επιβεβαίωσαν τη μειωμένη έκφραση της Syk σε διηθητικό καρκίνωμα μαστού και τη δυνατότητά της να εμποδίζει τη μετακίνηση και την διήθηση καρκινικών κυττάρων μαστού. Όλα τα παραπάνω έκαναν τη μείωση της έκφρασής της να θεωρείται ως κακός προγνωστικός δείκτης και να συνδέεται με αυξημένες πιθανότητες ανάπτυξης μεταστάσεων. Η υπερμεθυλίωση του γονιδίου της Syk, βρέθηκε να είναι ένας μηχανισμός που οδηγεί στη μείωση της έκφρασή της. Η παρεμπόδιση της προόδου του κυτταρικού κύκλου και κατ’ επέκταση του κυτταρικού πολλαπλασιασμού, προτάθηκε ως ένας από τους πιθανούς μηχανισμούς δράσης της. Στην παρούσα εργασία η έκφραση της syk μελετήθηκε σε δείγματα ασθενών με καρκίνο του μαστού. Σημαντική μείωση της έκφρασής της παρατηρήθηκε σε διηθητικό, σε σχέση με το φυσιολογικό ιστό. Παράλληλα, η έκφρασή της εξαφανίστηκε στους ασθενείς που παρουσίασαν ενδοαγγειακά έμβολα, μία σημαντική ένδειξη ανάπτυξης μεταστατικής νόσου. Επιπρόσθετα, διερευνήθηκε η σχέση της syk και προγνωστικών δεικτών των καρκινωμάτων των ασθενών. Θετική συσχέτιση βρέθηκε να υπάρχει σε πολλές περιπτώσεις, καθιστώντας την εκτίμηση των επίπεδων της έκφρασής ίσως ως ένα ισχυρό μέσο διαλογής, για προγνωστικούς σκοπούς της μεταστατικής νόσου. Δε βρέθηκε να υπάρχει συσχέτιση της έκφρασής της και ρυθμιστών της προόδου του κυτταρικού κύκλου κατά την ύπαρξη κυτταρικής προσκόλλησης, στα δείγματα που εξετάστηκαν, παραπέμποντας πιθανότατα σε διαφορετικό μηχανισμό δράσης της. Επιπρόσθετα, η syk βρέθηκε να σχετίζεται άμεσα με την έκφραση του υποδοχέα Β της Ιντερλευκίνης 8, ρύθμιση του οποίου μπορεί να ευθύνεται για την παρεμπόδιση της κινητικότητας και κατ’ επέκταση της μετανάστευσης των καρκινικών κυττάρων.
Cite
Citations (0)
The nationally-recognized Susquehanna
Chorale will delight audiences of all
ages with a diverse mix of classic and
contemporary pieces. The ChoraleAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂA¢AÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂs
performances have been described
as AÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂA¢AÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂemotionally unfiltered, honest
music making, successful in their
aim to make the audience feel,
to be moved, to be part of the
performance - and all this while
working at an extremely high
musical level.AÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂA¢AÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂAÂA Experience choral
singing that will take you to new
heights!
Cite
Citations (0)