MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib

Untreated chronic myeloid leukemia (CML) progresses from chronic phase to blastic crisis (BC). Increased genomic instability, deregulated proliferation, and loss of differentiation appear associated to BC, but the molecular alterations underlying the progression of CML are poorly characterized. MYC oncogene is frequently deregulated in human cancer, often associated with tumor progression. Genomic instability and induction of aberrant DNA replication are described as effects of MYC. In this report, we studied MYC activities in CML cell lines with conditional MYC expression with and without exposure to imatinib, the front-line drug in CML therapy. In cells with conditional MYC expression, MYC did not rescue the proliferation arrest mediated by imatinib but provoked aberrant DNA synthesis and accumulation of cells with 4C content. We studied MYC mRNA expression in 66 CML patients at different phases of the disease, and we found that MYC expression was higher in CML patients at diagnosis than control bone marrows or in patients responding to imatinib. Further, high MYC levels at diagnosis correlated with a poor response to imatinib. MYC expression did not directly correlate with BCR-ABL levels in patients treated with imatinib. Overall our study suggests that, as in other tumor models, MYC-induced aberrant DNA synthesis in CML cells is consistent with MYC overexpression in untreated CML patients and nonresponding patients and supports a role for MYC in CML progression, possibly through promotion of genomic instability.     

Heuristic estimation of the α/β ratio for a cohort of Mexican patients with prostate cancer treated with external radiotherapy techniques

BackgroundThe aim of the study was to Estimate and compare the radiobiological ratio α/β with the heuristic method for a cohort of Mexican patients with prostate cancer (PCa) who were treated with external radiotherapy (RT) techniques at three Hospital Institutions in Mexico City. With the Kaplan-Meier technique and the Cox proportional hazards model, the biochemical relapse-free survival (bRFS) is determined and characterized for cohorts of Mexican patients with PCa who received treatment with external RT. Using these clinical outcomes, the radiobiological parameter α/β is determined using the heuristic methodology of Pedicini et. al.Materials and methodsThe α/β is calculated from the survival curves for different treatment schemes implemented at three distinct hospitals. The Pedicini’s techniques allow to determine the parameters α/β, k and N₀ when treatments are not radiobiologically equivalent, therefore, are built up of a set of curved pairs for the biologically effective dose (BED) versus the ratio α/β, where the ratio is given by the intersection for each pair of curves.ResultsSix different values of α/β were found: the first α/β = 2.46 Gy, the second α/β = 3.30 Gy, the third for α/β = 3.25 Gy, the fourth α/β = 3.24 Gy, the fifth α/β = 3.38 Gy and the last α/β = 4.08 Gy. These values can be explained as follows: a) The bRFS of the schemes presents a statistical variation; b) The absorbed doses given to the patient present uncertainties on the physical dosimetry that are not on the modeling; c) Finally, in the model for the bRFS of Eq. (3), there are parameters that have to be considered, such as: the number of clonogenic tumor cells N₀, the overall treatment time (OTT), the kick-off time for tumor repopulation T_k and the repopulation doubling time. Therefore, the mean value to α/β for all schemes has an average value of 3.29 (± 0.52) Gy.ConclusionsThe value of α/β¯=3.29 (±0.52) Gy is determined from cohorts of Mexican patients with PC a treated with external radiotherapy using the time-dependent LQ model, which is a higher value with respect to the “dogma” value of α/β 1.5 Gy obtained with the LQ model without temporal dependence. Therefore, there is a possibility of optimizing treatments radiobiologically and improving the results of bRFS in Mexican patients with PCa treated with external radiotherapy.     

Exploring anaerobic environments for cyanide and cyano-derivatives microbial degradation

Applied Microbiology and Biotechnology - Cyanide is one of the most toxic chemicals for living organisms described so far. Its toxicity is mainly based on the high affinity that cyanide presents...     

Rapid Diagnosis of Bloodstream Infections with PCR Followed by Mass Spectrometry

Achieving a rapid microbiological diagnosis is crucial for decreasing morbidity and mortality of patients with a bloodstream infection, as it leads to the administration of an appropriate empiric antimicrobial therapy. Molecular methods may offer a rapid alternative to conventional microbiological diagnosis involving blood culture. In this study, the performance of a new technology that uses broad-spectrum PCR coupled with mass spectrometry (PCR/ESI-MS) was evaluated for the detection of microorganisms directly from whole blood. A total of 247 whole blood samples and paired blood cultures were prospectively obtained from 175 patients with a suspicion of sepsis. Both sample types were analyzed using the PCR/ESI-MS technology, and the results were compared with those obtained by conventional identification methods. The overall agreement between conventional methods and PCR/ESI-MS performed in blood culture aliquots was 94.2% with 96.8% sensitivity and 98.5% specificity for the molecular method. When comparing conventional methods with PCR/ESI-MS performed in whole blood specimens, the overall agreement was 77.1% with 50% sensitivity and 93.8% specificity for the molecular method. Interestingly, the PCR/ESI-MS technology led to the additional identification of 13 pathogens that were not found by conventional methods. Using the PCR/ESI-MS technology the microbiological diagnosis of bloodstream infections could be anticipated in about half of the patients in our setting, including a small but significant proportion of patients newly diagnosed. Thus, this promising technology could be very useful for the rapid diagnosis of sepsis in combination with traditional methods.     

Luminescent thermometer based on Eu3+/Tb3+‐organic‐functionalized mesoporous silica

In this work we investigate a mesoporous silica (MS) decorated with dipyridyl‐pyridazine (dppz) ligands and further grafted with a mixture of Eu³⁺/Tb³⁺ ions (28.45%:71.55%), which was investigated as a potential thermometer in the 10–360 K temperature range. The MS material was prepared employing a hetero Diels–Alder reaction: 3,6‐di(2‐pyridyl)‐1,2,4,5‐tetrazine was reacted with the double bonds of vinyl‐silica (vSilica) followed by an oxidation procedure. We explore using the dppz‐vSilica material to obtain visible emitting luminescent materials and for obtaining a luminescent thermometer when grafted with Eu³⁺/Tb³⁺ ions. For the dppz‐vSilica@Eu,Tb material absolute sensitivity S_a of 0.011 K^?1 (210 K) and relative sensitivity S_r of 1.32 %K^?1 (260 K) were calculated showing good sensing capability of the material. Upon temperature change from 10 K to 360 K the emission color of the material changed gradually from yellow to red.     

τ Protein from Alzheimer's Disease Patients Is Glycated at Its Tubulin-Binding Domain

Abstract: Glycated residues of τ protein from paired helical filaments isolated from the brains of Alzheimer's disease patients were localized by doing a proteolytic cleavage of the protein, fractionation of the resulting peptides, and identification of those peptides using specific antibodies. The most suitable residues for glycation, lysines, present at the tubulin-binding motif of τ protein, seem to be preferentially modified compared with those lysines present at other regions. Among these modified lysines, those located in the sequence comprising residues 318–336 (in the largest human τ isoform) were found to be glycated, as determined by the reaction with an antibody that recognizes a glycated peptide containing this sequence. Because those lysines are present in a tubulin binding motif of τ protein, its modification could result in a decrease in the interaction of τ with tubulin.