1,720,978 research outputs found
Blockade of Aurora kinases activity enhances APO2L/TRAIL sensitivity in multiple myeloma
No full textThe Pharmacological Blockade of Phosphodiesterase IV Potentiates the Anti-Tumor Effects of Arsenic Trioxide (ATO) in Acute Myelogenous Leukemia Cells through Multiple Signaling Pathways
No full textPreclinical in vitro and in vivo studies showed that Arsenic Trioxide (ATO) has antileukemic effects both as a single agent and in combination with conventional therapies or with other molecularly targeted agents . Furthermore, analogs of cAMP have been shown to enhance the therapeutic effects of ATRA and ATO in APL cells. Because cAMP pathway is modulated by various Inhibitiors of phosphodiesterase IV (PDEIV), some of which are already in the clinics for the treatment of asthma, the aim of this study was to investigate whether the pharmacological inhibition of PDEIV potentiates the cytodifferentiating and/or proapoptotic activities of ATO in acute myelogenous leukemia (AML) cells. We found that PDEIV inhibitors induced the upregulation of the myeloid markers (CD38 and CD11b), and potentiated the cytodifferentiating action of ATO in APL cells via induction of cAMP; the cytodifferentiating effects of the PDEIV inhibitors /ATO combination in leukemic cells was also confirmed by nitro blue tetrazolium reductase activity assay. Accordingly, we also found that the inhibition of PDEIV accelerated the ATO-induced degradation of PML-retinoic acid receptor α (PML-RARα) oncoprotein in NB4 cells, thus removing the PML-RARα-induced maturation blocks. Furthermore we also demonstrated that PDEIV inhibitors synergized with ATO to induce apoptosis in both APL NB4 and non-APL HL-60, MOLM-13 and OCI-AML-3 AML cell lines and significantly (P<.01) potentiated the ATO-induced cell death of fresh purified leukemic blasts in 8 out of 10 AML patients analyzed with different genetic abnormalities; in contrast, no significant cytotoxicity in peripheral blood mononuclear cells from 3 healthy volunteers was observed after PDEIV inhibitors/ATO treatment. We consistently found that the inhibition of PDEIV strongly potentiated the ATO-induced activation of caspase-3 and PARP fragmentation in all the tested cell lines as well as in primary AML blasts from patients, and, by using a peptide inhibitor approach, we demonstrated that caspase activity was indispensable for PDEIV inhibitors / ATO-induced apoptosis. Furthermore, siRNA knockdown of endogenous PDE4A and PDE4B gene expression recapitulated the ability of PDEIV inhibitors to sensitize leukemic cells to ATO, thereby confirming the significant role of these enzymes in mediating ATO sensitization of leukemic cells to PDEIV inhibitors /ATO-induced apoptosis. Interestingly, by using cAMP analogs and cAMP competitors we demonstrated that PDEIV inhibitors /ATO -induced apoptosis was cAMP independent. In order to investigate the molecular effectors involved in PDEIV inhibitors /ATO-induced apoptosis we first evaluated the effects of the combined treatment on Bcl-2 and p53 family proteins and their biologic relevance in the synergism observed between PDEIV inhibitors and ATO. By western blot analysis we demonstrated that co-treatment with PDEIV inhibitors and ATO increased protein expression of pro-apoptotic of Bax, Bak and/or Puma and decrease anti-apoptotic Mcl-1, A1/Bfl1 and/or Bcl-2; in agreement with the biochemical findings indicating the activation of the mitochondrial apoptotic pathway, we found that combined treatment with PDEIV inhibitors and ATO strongly potentiated mitochondrial depolarization induced by ATO alone in all the tested cell lines. Preliminary data indicate the involvement of p73 pathway which is consistent with the observed upregulation of Bax, Bak and/or Puma in AML cells; ongoing experiment are in progress to evaluate whether p53 pathway is activated by the combined treatment in MOLM-13 and OCI-AML-3 AML cell lines as well as in fresh purified leukemic blasts. Additionally, we found that co-treatment with PDEIV inhibitors and ATO also induced prosurvival signals by increasing ERK and Bad phosphorylation and the expression of anti-apoptotic Bcl-xL, and the pharmacological or genetic disruption of ERK or Bcl-xL consistently and significantly potentiated the cytotoxic effects of the combination PDEIV inhibitors /ATO. Altogether these findings suggest to extend the study to more patients and strongly support the rationale for testing these promising combinations in clinically relevant in vivo mouse models of drug-resistant leukemia
Uveiti Infantili : incidenza delle varie forme e correlazione con le malattie sistemiche
No full textLa patogenesi delle uveiti è ancora poco conosciuta e può essere diversa nei casi associati a malattie sistemiche.
Gli Autori descrivono varie forme di uveite dell'infanzia da loro osservate.I problemi della diagnosi, degli esami e del trattamento sono discussi.
L'eziologia e la patogenesi di molti casi risultano non completamente definit
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Natural history of an early diagnosed retinocytoma: case report and literature review
No full textPurpose To study the ophtahlmoscopic evolution of a retinocytoma diagnosed in a 8 months old boy.
Methods The patient was referred at the Referral Center for Retinoblastoma of the University of Siena, with the suspect of unilateral retinoblastoma. The boy was diagnosed as having retinocytoma based on ophthalmoscopic appearance. Monthly ophthalmoscopic and ecographic evaluation were recommended. Detailed fundus drawings and fundus photographs and descriptions of the retinocytoma were collected. The little boy underwent also MRI, genetic testing and fluorangiography.
Results Throughout the months, we observed a tumor regression from avascular mass with fish‐flesh appearance and microscopic calcifications to a retinal transparent mass with calcifications, retinal cysts and surrounded by chorioretinal atrophy.
Conclusion Retinocytoma is a rare benign retinal tumor with characteristic clinical features. Usually diagnosed in parents of retinoblastoma children, “silent” retinocytoma diagnosis is more rare in babies. In our case, we observed a natural “regression” of a retinocytoma in a 8 months old boy kept under close RETCAM follow‐up for the risk of malignant transformation
Pan-aurora kinase inhibitor MK-0457 synergistically potentiates Apo2l/TRAIL cytotoxicity in Multiple Mieloma cells sensitive and resistant to bortezomib
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Use of amniotic membrane transplantation in isolated conjunctival Bowen disease: a case report
No full textPURPOSE: To report a case of isolated conjunctival Bowen disease treated with surgical resection and amniotic membrane transplantation.
METHODS: Interventional case report.
RESULTS: A 70-year-old man was admitted to our clinic with a large conjunctival verrucous plaque well-demarcated in the correspondence of the bulbar conjunctiva in the superior quadrant of the left eye with involved limbal and corneal surface. Ophthalmologic examination on slit-lamp examination and color fundus photographs were carried out before surgery and the results were evaluated.
CONCLUSIONS: Treatment options and treatment studies of Bowen disease are difficult because there are a variety of different protocols and the success of the management depends on several factors (body site, lesion size, number of lesions, and thickness). In the conjunctival localization of the lesion, amniotic membrane transplantation appears to be a useful therapeutic choice after surgical resection of the lesion used to reconstruct ocular and conjunctival surfac
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