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  • Abstract Chronic myeloid leukemia (CML) results from a t(9;22) (q34; q11) translocation, also called Philadelphia chromosome (Ph). This reciprocal translocation causes a constitutively-activated tyrosine kinase BCR-ABL fusion gene. By comparing imatinib-sensitive and -resistant CML cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential (MMP) and increase of cytosolic free Ca2+ levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by N-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box (HMGB1) demonstrating the immunological cell death markers by TMQ0153. We validated the anti-cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models. Conclusion: Our findings indicate that TMQ0153-induced ROS act as a rheostat determining the onset of apoptotic- or autophagy-related controlled necrotic cell death in CML.
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  • Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase (FLT)3-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show here that petromurin C, isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, which was isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether our results suggest that petromurin C could act as an anti-leukemic agent alone or in combination with gilteritinib.
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  • Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities such as prevention of neoplastic growth on an array of different cancer cell lines. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess anti-proliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests as well as analysis of differential toxicity in non-cancerous RPMI 1788 cells, we identified EE-84 as a promising novel drug candidate against myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five and was responsible for cell cycle dysregulation in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells likewise underwent morphological changes suggesting mitochondrial dysfunction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor, A-1210477, against K562 cells, highlighting the inhibition of anti-apoptotic Bcl-2 proteins as a promising therapeutic approach against myeloid leukemia in combination with EE-84.
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  • Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show here that petromurin C, isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, which was isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether our results suggest that petromurin C could act as an anti-leukemic agent alone or in combination with gilteritinib.
    Data Types:
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  • Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show here that petromurin C, isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, which was isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether our results suggest that petromurin C could act as an anti-leukemic agent alone or in combination with gilteritinib.
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  • ROTATION ANALYSIS In order to understand freight facilities demand in the city center and characterize the operation, rotation counts of freight operations were developed based following on-street parking analysis methodology presented in Cardenas & Cal y Mayor (2007). LEVEL OF SERVICE Loading and unloading performance analysis methodology found in Alho & Silva (2014) was selected as the most appropriate for this context, due to there is a high dependence on bay infrastructure for loading and loading operations and because this methodology was developed in a context of low data availability. STAKEHOLDER ANALYSIS Multi-Actor Multi-Criteria Analysis – MAMCA (Macharis et al., 2010) permitted to conclude that a combined set of strategies for loading and uploading operations in city centers should be implemented to raise parking offer and adapt to different demand conditions in terms of schedules and vehicles sizes. Some strategies requires a strong set of public incentives, including tax benefits and land price controls for logistic use. For this MAMCA analysis the surveys were completed as follows: 10 from Shippers/Carriers, 101 from receivers (Question PRO application used), 6 from authorities, 3 from residents (community leaders) and 2 from academics. According to the Cali Economic Census (DANE, 2006) there are approximately 4222 economic units in Cali city center, of which 23% belong to the retail trading sector for food, drinks and tobacco, the biggest group (CIIU Code 5211 of Chamber of Commerce). We decided to start our research with this type of commerce (971 units) and we have obtained responses from approximately 13% of them, so this represents a statistical confidence level of 90% (Torres, Paz, & Salazar, 2006). We developed 9 questionnaires for the enterprises that can represent approximately the 18% of the total shipper size in Cali city center (Bavaria, Coca-Cola, Productos Cárnicos, Productos Enrico, Distribuidora Colombina, Distribuidora Alpina, Pollos El Galpón, Quesos la Florida, Nutresa). We also interviewed 9 trade leaders and managers of parcel transport companies, (Cavasa, Andi, Adicomex, Sociedad Portuaria, Gids, Posey (International Freight Forwarders), Fedetranscol, Concretesa (Project’s Manager), Fenalco, Grecocentro).
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  • MCDS is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA was subjected to whole-exome sequencing and Sanger sequencing in all available family members. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Based on these, we found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. We draw the conclusion that two novel mutations were identified in the present work, which will further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.
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  • Dataset related to the paper of the same title submitted for publication in the journal iScience. The abstract is as follows.
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  • Materials for the stress-judgement task and exposure phases as described in "How intonational contours, exposure, and variety affect lexical stress judgements" (Submitted to LabPhon, Nov. 2019)
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  • Little is known about the pathophysiological linkages between altered ceramide profiles in the stratum corneum (SC) of patients with atopic dermatitis (AD) and their impaired skin barrier and water-holding functions. We studied that pathophysiological linkage by microanalysis of ceramides using NPLC-ESI Mass Spectrometry comparing before and after topical application of a designed synthetic pseudo-ceramide (pCer). Four weeks of treatment with pCer significantly reduced skin symptoms, accompanied by significant decreases in trans-epidermal water loss (TEWL) and increases in water content. In the SC ceramide profiles, Cer[NH/NP] increased and Cer[NS/AS] decreased with larger alkyl chain lengths in Cer[NS], distinctly representing a switch from an AD to a healthy skin phenotype. The levels of pCer that penetrated into the SC were significantly correlated with the SC water content but not with TEWL. The levels of Cer[NS] and the average carbon chain length of Cer[NS] were closely correlated with the pCer level in the SC. These findings indicate that the penetrated pCer contributes to shift the ceramide profile from an AD to a healthy skin phenotype. Taken together, the observed clinical efficacy of treatment with pCer provides a deep insight into the pathogenesis of AD as a ceramide-deficient disease.
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