Chronic Myeloid Leukemia Patients Sensitive and Resistant to Imatinib Treatment Show Different Metabolic Responses

The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML). However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. The untreated CML patients (UCML) showed different metabolic patterns from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. After imatinib treatment, patients sensitive to imatinib (SCML) and patients resistant to imatinib (RCML) had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA). In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients' sensitivity or resistance to drug intervention

Laser-assisted synthesis of two-dimensional transition metal dichalcogenides: a mini review

The atomically thin two-dimensional (2D) transition metal dichalcogenides (TMDCs) have attracted the researcher’s interest in the field of flexible electronics due to their high mobility, tunable bandgaps, and mechanical flexibility. As an emerging technique, laser-assisted direct writing has been used for the synthesis of TMDCs due to its extremely high preparation accuracy, rich light–matter interaction mechanism, dynamic properties, fast preparation speed, and minimal thermal effects. Currently, this technology has been focused on the synthesis of 2D graphene, while there are few literatures that summarize the progress in direct laser writing technology in the synthesis of 2D TMDCs. Therefore, in this mini-review, the synthetic strategies of applying laser to the fabrication of 2D TMDCs have been briefly summarized and discussed, which are divided into top-down and bottom-up methods. The detailed fabrication steps, main characteristics, and mechanism of both methods are discussed. Finally, prospects and further opportunities in the booming field of laser-assisted synthesis of 2D TMDCs are addressed

A Rapid Flp-In System for Expression of Secreted H5N1 Influenza Hemagglutinin Vaccine Immunogen in Mammalian Cells

Continuing transmissions of highly pathogenic H5N1 viruses in poultry and humans underscores the need for a rapid response to potential pandemic in the form of vaccine. Recombinant technologies for production of immunogenic hemagglutinin (HA) could provide an advantage over the traditional inactivated vaccine manufacturing process. Generation of stably transfected mammalian cells secreting properly folded HA proteins is important for scalable controlled manufacturing.We have developed a Flp-In based 293 stable cell lines through targeted site-specific recombination for expression of secreted hemagglutinin (HA) proteins and evaluated their immunogenicity. H5N1 globular domain HA1(1-330) and HA0(1-500) proteins were purified from the supernatants of 293 Flp-In stable cell lines. Both proteins were properly folded as confirmed by binding to H5N1-neutralizing conformation-dependent human monoclonal antibodies. The HA0 (with unmodified cleavage site) was monomeric, while the HA1 contained oligomeric forms. Upon rabbit immunization, both HA proteins elicited neutralizing antibodies against the homologous virus (A/Vietnam/1203/2004, clade 1) as well as cross-neutralizing antibodies against heterologous H5N1 clade 2 strains, including A/Indonesia/5/2005. These results exceeded the human antibody responses against the inactivated sub-virion H5N1 vaccine.Our data suggest that the 293 Flp-In system could serve as a platform for rapid expression of HA immunogens in mammalian cells from emerging influenza strains

Farmers’ Preference for Participating in Rural Solid Waste Management: A Case Study from Shaanxi Province, China

Rural solid waste management is an important method to improve rural living environments. Farmers’ participation in rural solid waste management plays an essential role in sustainable waste management. Based on the micro-survey data of 592 farmers in Shaanxi province, a multinomial logit model was applied to explore farmers’ preferences for participating in rural solid waste management. The empirical results show that both institutional and interpersonal trust have significant positive effects on farmers’ payment participation, and labor and payment participation. Among environmental awareness, farmers with pro-environmental behavior prefer labor participation, and labor and payment participation; the more environmental knowledge farmers have, the stronger their preferences for payment participation, labor and payment participation, and labor participation; farmers concerned about environmental problems are more inclined to adopt labor and payment participation or payment participation. For socio-demographic characteristics, gender has no significant influence, while agricultural net income and education can significantly increase farmers’ willingness to participate; farmers who have migrant work experience prefer to participate in payment; there are obvious intergenerational differences in the influence of social trust and environmental awareness on farmers’ participation preference. Therefore, providing diversified participation modes, creating a good social trust environment, and enhancing farmers’ awareness of environmental care are important in promoting rural solid waste management

Associations of serum and urinary magnesium with the pre-diabetes, diabetes and diabetic complications in the Chinese Northeast population.

The effect of magnesium (Mg) deficiency on the prevalence of diabetes and diabetic complications has received a great attention. The present study investigated the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications. From January 2010 to October 2011, patients with type 1 diabetes (T1D, n = 25), type 2 diabetes (T2D, n = 137), impaired fasting glucose (IFG, n = 12) or impaired glucose tolerance (IGT, n = 15), and age/gender matched control (n = 50) were enrolled in the First Hospital of Jilin University. In T2D group, there were 24, 34, and 50 patients with nephropathy, retinopathy or peripheral neuropathy. Serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control. There was no difference for these two changes among T2D with and without complications; In addition, there was a significantly positive correlation of serum Mg levels with serum Ca levels only in T2D patients, and also a significantly positive correlation of urinary Mg levels with urinary Ca levels in control, IGT patients, and T2D patients. Simvastatin treatment in T2D patients selectively reduced serum Ca levels and urinary Mg levels. These results suggest that the potential impact of Mg deficiency on metabolic syndrome, diabetes and diabetic complications needs to be received special attention

Study on Mechanical Failure Behavior of Steel-Wire Wound Reinforced Thermoplastic Pipe under Combined Internal Pressure and Soil Landslide Conditions

A steel-wire wound reinforced thermoplastic pipe (SWW-RTP) has been widely utilized in many industrial areas, and a soil landslide is an inevitable hazardous extreme condition for the SWW-RTP as it is usually buried underground. It is imperative to study the mechanical failure behavior and the failure criterion of the SWW-RTP under the combination of internal pressure and soil landslide conditions, and this paper is the first study to investigate the topic. In this paper, groups of stress–strain curves of high-density polyethylene (HDPE) and steel wires were obtained by uniaxial tensile tests at different strain rates, with the help of a Digital Image Correlation device (DIC). A rate-dependent constitutive model was employed to represent the mechanical behavior of the HDPE and to help deduce the stress–strain curve of the HDPE under the required strain rate, estimated from the static simplification of the dynamic soil landslide. Afterwards, a finite element model of the SWW-RTP, embedded in a cubic of soil, was established with the software ABAQUS. The SWW-RTP model was composed of HDPE solid elements, embedded with steel-wire truss elements, and the soil was characterized with the extended Drucker–Prager model. A quartic polynomial displacement distribution was applied to the soil model to represent the soil landslide. Then, the mechanical response of the SWW-RTP was analyzed. It was found that the failure criterion of the HDPE yield was more suitable for the pipe subjected to internal pressure and soil landslide conditions, instead of the steel-wire strength failure criterion always used in traditional research on the SWW-RTP. Further, the influence of landslide width, internal pressure and steel-wire number were discussed. The larger the width of the landslide area, the gentler the deformation of the pipeline; this resulted in an increase in the maximum landslide and a decrease in the maximum curvature with the width of the landslide area. The relatively high internal pressure was beneficial to the safety of the SWW-RTP under landslide, because the internal pressure could increase the stiffness of the pipeline. The number of steel wires had a limited influence on the maximum landslide required for the SWW-RTP’s failure. This work can be useful for the design and safe assessment of the SWW-RTP under internal pressure and soil landslide conditions

Extramedullary Manifestation in Multiple Myeloma Bears High Incidence of Poor Cytogenetic Aberration and Novel Agents Resistance

Extramedullary disease (EMD) in multiple myeloma (MM) patients is an uncommon event and more attention was directed toward the feature of these patients. Cytogenetic aberration is an important characteristic of MM and is associated with patients’ outcome. In this study, we aimed to compare the cytogenetic abnormality of patients with and without extramedullary manifestation, and to analyze the clinical outcomes of novel agents in EMD patients. We retrospectively investigated data from 41 MM patients. Our analyses showed del(17p13) in 31% of EMD versus 13% of medullary disease (P=0.03) and amp(1q21) in 55% versus 32% (P=0.019). No differences were shown in del(13q14) and t(4;14). 24/27 patients with EMD at diagnosis responded to the novel agents-containing regimens. However, when relapsed, 70% of patients did not benefit from the sequential use of novel agents as salvage therapy. In 14 patients who developed EMD at relapse phase, only 2 patients responded to novel agents therapy. Median overall survival of patients with extramedullary manifestations was 30 months, in comparison to 104 months for patients without EMD (P=0.002). Patients with extramedullary manifestation bore high incidence of poor cytogenetic aberration and novel agents resistance

Correlation between Mg with Ca in T2D patients.

<p>Correlations between serum Mg and serum Ca in T2D patients (r = 0.652, <i>P</i><0.000, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056750#pone-0056750-g003" target="_blank">Fig. 3A</a>). Correlations between urinary Mg and urinary Ca in T2D patients (r = 0.647, <i>P</i><0.000, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056750#pone-0056750-g003" target="_blank">Fig. 3B</a>).</p