The purpose of this study was to investigate the effect of salt substitutes on the textural, microstructural and sensory properties in low-cost frankfurter sausages produced using mechanically ...deboned poultry meat (MDPM) as a potential strategy to reduce sodium in this meat product. In nine treatments, blends of calcium, sodium and potassium chloride were used to substitute 25% or 50% of the NaCl in sausages (at the same ionic strength and molar basis equivalent to 2% NaCl). When NaCl was partially replaced by 50% CaCl2 (F6), the batter presented the highest total liquid released, and the corresponding final product showed increased hardness when compared to the control formulation (100% NaCl, C1). Its respective microstructural analysis revealed numerous pores arranged in a noncompacted matrix, which could be explained by the lowest emulsion stability reported for samples with 50% CaCl2 and 50% NaCl. Frankfurter sausages produced using blends containing 25% CaCl2 (F2, F4) and 25 and 50% KCl (F4, F5) did not exhibit differences in the pH, aw and objective color in the frankfurters (p<0.05). The overall acceptability and flavor of the frankfurters containing 50% NaCl without salt substitution (C3), 25% CaCl2, 25% KCl (F4), and 50% KCl (F5) showed the worst scores compared to those of the control formulation (C1). These results may be useful to select salt blends containing KCl, CaCl2 and NaCl to reduce the sodium in sausages containing high concentrations of MPDM at an ionic equivalent strength to the NaCl commonly used in traditional formulations.
•NaCl was partially replaced by KCl or CaCl2 to reduce Na in frankfurters.•CaCl2 decreases the emulsion stability and the texture of low Na frankfurters.•Blends of 25% CaCl2 and 25% KCl can substitute 50% NaCl in frankfurters.•Blends of 50% KCl and 50% NaCl do not change the textural properties of frankfurters.
High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL ...has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m
) or Id-MTX (0.5 g/m
). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.
Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development ...and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR-ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan.
Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease entity with the peculiar characteristic that tumor cells proliferate within vessels. Despite recent advances in understanding the ...disease from clinical aspects, the underlying pathogenesis remains unknown. Here we demonstrate analyses of IVLBCL biology using four xenograft mouse models established from primary IVLBCL samples. In all four models, the main characteristic of IVLBCL tumor cell proliferation within vessels was retained. Time-lapse engraftment analyses revealed that the tumor cells initially engrafted and proliferated in the sinusoids and vessels in the liver and then engrafted and proliferated in multiple organs. Intriguingly, serial passage of tumor cells from the adrenal gland of a transplanted mouse developed from primary patient bone marrow cells into a second mouse showed that the tumor cells mainly distributed into the adrenal gland in the second mouse, implying the existence of clonal selection and/or evolution at engraftment of a specific organ. Gene expression profiling analyses demonstrated that the gene set associated with cell migration was enriched for normal peripheral blood B cells, indicating that inhibition of cell migration might be involved in IVLBCL pathogenesis. In conclusion, the mouse xenograft models described here are essential tools for uncovering IVLBCL biology.
The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U ...protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.
PAX5 is a transcription factor required for B-cell development and maintenance. PML is a tumor suppressor and a pro-apoptotic factor. A fusion gene, PAX5-PML, was found in acute lymphoblastic ...leukemia (ALL) with chromosomal translocation t(9;15)(p13;q24), but no functional analysis has been reported. Here, we demonstrate that PAX5-PML had a dominant-negative effect on both PAX5 and PML. PAX5-PML dominant negatively inhibited PAX5 transcriptional activity in the luciferase reporter assay and suppressed the expression of the PAX5 transcriptional targets in B-lymphoid cell line. Surprisingly, PAX5-PML hardly showed DNA-binding activity in vitro although it retained the DNA-binding domain of PAX5. Additional experiments, including chromatin immunoprecipitation (ChIP) assay, suggested that PAX5-PML bound to the promoter through the association with PAX5 on the promoter. On the other hand, coexpression of PAX5-PML inhibited PML sumoylation, disrupted PML nuclear bodies (NBs), and conferred apoptosis resistance on HeLa cells. Furthermore, treatment with arsenic trioxide (ATO) induced PML sumoylation and reconstitution of PML NBs, and overcame the anti-apoptotic effect of PAX5-PML in HeLa cells. These data suggest the possible involvement of this fusion protein in the leukemogenesis of B-ALL in a dual dominant-negative manner and the possibility that ALL with PAX5-PML can be treated with ATO.
Fms-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells. An internal tandem duplication (ITD) of FLT3 (FLT3/ITD) is the most frequent mutation in human adult acute myeloid ...leukemia (AML). FLT3/ITD contributes to the constitutive activation of FLT3 itself and its downstream signal components, mitogen-activated protein kinase and signal transducers and activators of transcription 5 (STAT5), and enables interleukin (IL)-3-dependent cell lines to grow autonomously. In the present study, we showed the specific association of FLT3/ITD with Lyn, which led to the phosphorylation of Lyn in vivo. We also demonstrated that FLT3/ITD receptors displayed a higher affinity to bind to Lyn than wild-type FLT3 receptors in vitro and that this affinity was relative to the intensity of tyrosil phosphorylation of the receptor. Both treatment with small interfering RNA (siRNA) targeting Lyn and the Src family kinase inhibitor PP2 suppressed the IL-3-independent growth of FLT3/ITD-expressing 32D cells (FLT3/ITD-32D), reducing the constitutive phosphorylation of Lyn and STAT5. PP2 treatment of mice transplanted with FLT3/ITD-32D cells blocked the onset of tumors and decreased the size of established tumors. These results demonstrate that Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.
The precise clinical characteristics of acute encephalopathy with bilateral reduced diffusion are not fully understood. We compared clinical, laboratory, and neuroimaging findings according to the ...patterns of brain lesions among children with reduced diffusion in the bilateral hemispheres.
Nine patients were analyzed. The patterns of brain lesions were divided into diffuse lesions and central-sparing lesions. Diffuse lesions were defined as reduced diffusion in the whole cortex and/or subcortical white matter. Central-sparing lesions were defined as the lack of reduced diffusion in the areas around the bilateral Sylvian fissures. Clinical, laboratory, and neuroimaging findings were compared between groups.
Five patients showed diffuse lesions and 4 showed central-sparing lesions. Coma was significantly more common in patients with diffuse lesions, whereas a biphasic clinical course was more common in those with central-sparing lesions. Outcome was worse in patients with diffuse lesions. Maximal aspartate aminotransferase, alanine aminotransferase, and kinase levels were also significantly higher in patients with diffuse lesions. In 2 patients with diffuse lesions, diffusion-weighted images during the acute phase revealed reduced diffusion in the bilateral frontal and occipital areas, followed by diffuse lesions. No patient with central-sparing lesions showed MR imaging abnormalities during the acute phase.
Clinical manifestations in patients with diffuse lesions were severe, whereas those in patients with central-sparing lesions were relatively mild.
AIMS To clarify the features of the background electroencephalographic (EEG) activities in clinically well preterm infants born at less than 27 weeks gestation and to outline their chronological ...changes with increasing postconceptional age (PCA). METHODS EEGs of clinically well premature infants born at less than 27 weeks gestation were recorded during the early postnatal period. The infants were separated into three groups according to their PCA at the time of EEG recording (21–22 weeks PCA, 23–24 weeks PCA, and 25–26 weeks PCA). The mean and maximum duration of interburst intervals (IBIs), the mean duration of bursts, and the percentage of continuous and discontinuous patterns in each PCA group were evaluated. RESULTS There were three infants at 21–22 weeks PCA, seven at 23–24 weeks PCA, and five at 25–26 weeks PCA. Eighteen EEG recordings were obtained. The mean and maximum IBI duration decreased with increasing PCA. The percentage of continuous patterns increased with increasing PCA. Conversely, the percentage of discontinuous patterns decreased with increasing PCA. CONCLUSIONS In premature infants born at less than 27 weeks gestation, the characteristics of the background EEG activities were similar to those of older premature infants. These changes reflect the development of the central nervous system in this period. Key messages At less than 27 weeks gestational age, the characteristics of background EEG activities were found to be as follows: the mean and maximum IBI duration decreased with increasing PCA the percentage of continuous patterns increased with increasing PCA the percentage of discontinuous patterns increased with increasing PCA the mean burst duration during discontinuous patterns increased as PCA increased
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