63,571 research outputs found
Sialidase NEU4 is involved in glioblastoma stem cell renewal and survival
No full textGlioblastoma multiforme (GBM) is the most lethal primary brain tumor. GBM progression is strictly related to the malignant behavior of a cell subpopulation that shows stem characteristics. This subpopulation is known as GBM stem cells and is endowed with a great potential of self-renewal and resistance to radio/chemotherapy.
We demonstrated that GBM stem cells isolated from the cell line U87MG and from patients show a significant up-regulation of the sialidase NEU4, in comparison to GBM cells, which constitute the bulk of tumor. In order to understand the significance of the altered expression of NEU4, we stably silenced it by RNA interference in GBM stem cells isolated from the U87MG cell line. After silencing, GBM stem cell survival significantly decreased (69% after 15 days). The primary mechanism of cell death was assessed to be mitotic catastrophe, as demonstrated by the presence of multiple nuclei in single cells and by the block of cell cycle in G2/M phase with an increase of cyclin B1. A partial inhibition of key signaling pathways directly connected with GBM stem cell renewal came before cell death: in particular, we detected the increase of the active form of GSKβ3 that inhibits Sonic Hedgehog and Wnt/β catenin pathways and in parallel we recorded the decrease, as mRNA expression, of the transcriptional factors NANOG, OCT-4, SOX-2, GLI-1, β catenin. In addition, ganglioside GD3 content decreased because of Sp1 factors and GD3 synthase expression decrease. Ganglioside GD3 is severely implicated in GBM progression.1 It could be hypothesized that NEU4 could control GSKβ3 activity through the desialylation of particular glycoproteins, as previously described.2 Based on these results, NEU4 up-regulation could be considered an alteration significantly interconnected with GBM stem cell survival and could represent a novel cue for therapy.
1. Sa G et al (2009) Cancer Res. 69(7):3095-104
2. Tringali C et al (2012) Int J Cancer 131(8):1768-7
Stereochemistry and conformation of dolabellane diterpenes: an NMR and molecular mechanics study
No full textAntiangiogenic Resveratrol Analogues by Mild m-CPBA Aromatic Hydroxylation of 3,5-Dimethoxystilbenes
No full textA mild treatment of the resveratrol analogue 3,5,4'-trimethoxystilbene 2 with m-CPBA afforded two hydroxylated methoxystilbenes 5 and 6 by direct aromatic hydroxylation. A similar protocol was applied to other stilbenes bearing a 3,5-dimethoxy moiety, namely tetramethoxystilbenes 7 and 10 to obtain respectively the hydroxylated analogues 8, 9 and 11, 12. The Substrate 2 and the new compounds 5, 8 and 11 were evaluated as anti-angiogenic agents and proved significantly active in the range 1 - 100 mu M
A cumulative meta-analysis of endoscopic papillary balloon dilation versus endoscopic sphincterotomy for removal of common bile duct stones
No full textBackground Endoscopic papillary balloon dilation (EPBD)
was introduced to overcome the risk of adverse events
associated with endoscopic sphincterotomy in the removal
of common bile duct (CBD) stones. We performed a metaanalysis
of randomized controlled trials (RCTs) comparing
efficacy and safety of EPBD vs. endoscopic sphincterotomy,
focusing on stone size, balloon diameter, and balloon dilation
time.
Methods A multiple database search was performed, including
MEDLINE, EMBASE and Cochrane Library, from their
inception date until October 2017. RCTs comparing the efficacy
and safety of EPBD vs. endoscopic sphincterotomy in
the removal of CBD stones were included. Cumulative
meta-analyses over time, and subgroup analyses according
to stone size, and balloon diameter and dilation time were
carried out.
Results 25 RCTs met the inclusion criteria. Despite the cumulative
meta-analysis showing a trend over time in favor
of endoscopic sphincterotomy in studies published up to
2004, the conventional meta-analysis revealed that EPBD
was equally efficacious compared with endoscopic sphincterotomy
in stone removal at first attempt (odds ratio [OR]
0.95, 95% confidence interval [CI] 0.65 – 1.38). Endoscopic
sphincterotomy was superior to EPBD in terms of overall
stone clearance (OR 0.65, 95 %CI 0.43 – 0.99) in studies
published since 2002, but no differences emerged in studies
using large ( ≥ 10mm) balloons (OR 1.37, 95 %CI 0.72 –
2.62). No statistically significant difference in pancreatitis
occurrence emerged between EPBD and endoscopic
sphincterotomy (OR 1.35, 95 %CI 0.90 – 2.03). Pancreatitis
was more common with EPBD than with endoscopic sphincterotomy
in studies using balloons < 10mm (OR 1.78, 95%
CI 1.07 – 2.97), whereas no difference emerged in studies
using large balloons (OR 0.84, 95 %CI 0.46 – 1.53). EPBD
had lower rates of bleeding and cholecystitis.
Conclusions Our latest data confirm that EPBD is currently
inferior to endoscopic sphincterotomy in terms of overall
stone clearance. However, EPBD using large balloons
(≥ 10mm) was as effective as endoscopic sphincterotomy,
both in stone clearance and the need for endoscopic mechanical
lithotripsy, without carrying an increased risk of
pancreatitis
Covered versus uncovered metal stents for malignant gastric outlet obstruction : A systematic review and meta-analysis of RCTs
No full textBackground and aim: Self expandable metal stent are used for palliation of malignant gastric outlet obstruction (GOOD) in patients with gastric or pancreatic malignancy. Studies comparing C-SEMS and U-SEMS have led to inconclusive results. To date only a previous meta-analysis assessing together prospective and randomized studies with statistical criticism was published.
Aims: comparing efficacy and safety of FCSEMS vs USEMS in patients with GOOD.
Material and methods: A computerized medical search was performed by using MEDLINE, EMBASE, Cochrane Library, from 2000 to September 2017 aimed at identifying available randomized trials comparing C-SEMS versus U-SEMS in patients with GOOD. Primary outcomes were stent survival and patient survival, while secondary outcomes were clinical and technical success, adverse events, stent occlusion and migration Pooled estimates were computed using the random effects models.
Results: Overall 7 RCTs were identified including 635 patients were included. Stent and patient survival did not statistically significantly differ between C-SEMS and U-SEMS groups (HR=0.93, 95% CI: 0.66–1.31; HR=0.87, 95% CI: 0.64–1.19, respectively). Clinical success and technical success were not statistical difference between two groups (OR=1.44 95%, CI: 0.68–3.05, OR=1.17, 95% CI: 0.39–3.52). U-SEMS was associated with lower risk of adverse events (OR=2.20, 95% CI: 1.37–3.54) but with higher risk of tumor ingrowth (OR=0.30, 95% CI: 0.18–0.49). C-SEMS was associated with higher risk of migration (OR=5.24, 95% CI: 2.26–2.12).
Conclusions: C-SEMS did not show statistically significant differences in terms of stent and patient survival as compared to U-SEMS although U-SEMS was associated with higher risk of tumor ingrowth and C-SEMS with migration. Further studies using new C-SEMS with anti migration system are needed
Chain-breaking antioxidant activity of hydroxylated and methoxylated magnolol derivatives: The role of H-bonds
No full textChemical modification of magnolol, an uncommon dimeric neolignan contained in Magnolia genus trees, provides a unique array of polyphenols having interesting biological activity potentially related to radical scavenging. The chain-breaking antioxidant activity of four new hydroxylated and methoxylated magnolol derivatives was explored by experimental and computational methods. The measurement of the rate constant of the reaction with ROO center dot radicals (k(inh)) in an apolar solvent showed that the introduction of hydroxyl groups ortho to the phenolic OH in magnolol increased the k(inh) value, being 2.4 x 10(5) M-1 s(-1) and 3.3 x 10(5) M-1 s(-1) for the mono and the dihydroxy derivatives respectively (k(inh) of magnolol is 6.1 x 10(4) M-1 s(-1)). The di-methoxylated derivative is less reactive than magnolol (k(inh) = 1.1 x 10(4) M-1 s(-1)), while the insertion of both hydroxyl and methoxyl groups showed no effect (6.0 x 10(4) M-1 s(-1)). Infrared spectroscopy and theoretical calculations allowed a rationalization of these results and pointed out the crucial role of intramolecular H-bonds. We also show that a correct estimation of the rate constant of the reaction with ROO center dot radicals, by using BDE(OH) calculations, requires that the geometry of the radical is as close as possible to that of the parent phenol
Three further dolabellane diterpenoids from Dictyota SP.
No full textA brown alga of the genus Dictyota has yielded three new dolabellane diterpenoids the structures of which were elucidated mainly by spectroscopic methods
Proteasome as a New Target for Bio-Inspired Benzo[k,l]xanthene Lignans
No full textMass spectrometry-based chemical proteomics is a powerful tool for the target discovery of small molecules. Here, the application of this approach is presented to define the target profile of bio-inspired synthetic benzo[k,l]xanthene lignans endowed with interesting biological properties. Proteasome has been identified as a new main interactor for this class of compounds. A combination of molecular docking with in vitro and in cell fluorescence assays gave insights on the molecular mechanism of the interaction, highlighting the tendency of these lignans to inhibit the proteasome
Primary cultures of microglial cells for testing toxicity of anticancer drugs
No full textToxicity of anticancer agents on normal neural cells during chemotherapy of primary or secondary brain tumors is a clinical problem of increasing relevance and concern. In this perspective, here we used primary cultures of rat cortical microglia as an in vitro paradigm of normal glia to investigate the neurotoxicity of anticancer agents. The effects of two compounds frequently used for treatment of brain tumors, methotrexate (MTX) and temozolomide (TMZ), were compared to those of a known microglial activator, bacterial lipopolysaccharide (LPS); cell viability and metabolism was assessed by the MTS assay. We found that LPS, in the low-intermediate range of concentrations, strongly activates microglia cells, but a highly significant decrease in viability was observed from 100 ng/ml onward. TMZ has no effect at concentrations of clinical interest, whereas MTX significantly increases cell metabolism at 30 muM, a phenomenon possibly reflecting MTX neurotoxicity observed in patients. (C) 2004 Elsevier Ireland Ltd. All rights reserved
Challenges and opportunities of water quality monitoring and multi-stakeholder management in small islands: the case of Santa Cruz, Galápagos (Ecuador)
No full textSustainable water resources management roots in monitoring data reliability and a full engagement of all institutions involved in the water sector. When competences and interests are overlapping, however, coordination may be difficult, thus hampering cooperative actions. This is the case of Santa Cruz Island (Galápagos, Ecuador). A comprehensive assessment on water quality data (physico-chemical parameters, major elements, trace elements and coliforms) collected since 1985 revealed the need of optimizing monitoring efforts to fill knowledge gaps and to better target decision-making processes. A Water Committee (Comité de la gestión del Agua) was established to foster the coordinated action among stakeholders and to pave the way for joint monitoring in the island that can optimize the efforts for water quality assessment and protection. Shared procedures for data collection, sample analysis, evaluation and data assessment by an open-access geodatabase were proposed and implemented for the first time as a prototype in order to improve accountability and outreach towards civil society and water users. The overall results reveal the high potential of a well-structured and effective joint monitoring approach within a complex, multi-stakeholder framework.publishedVersio
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