[Alteration and significance of serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma: a retrospective study based on LEGEND-2].

Objective: To explore the dynamic changes in serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma (R/R MM) based on LEGEND-2. Methods: The data of patients with R/R MM who underwent BCMA-CAR-T therapy at our hospital between March 30, 2016, and February 6, 2018, were retrospectively collected. Serum lipid levels, controlled nutritional status (CONUT) score, and other clinical indicators at different time points before and after CAR-T-cell infusion were compared and analyzed. The best cut-off value was determined by using the receiver operator characteristic (ROC) curve. The patients were divided into high-CONUT score (>6.5 points, malnutrition group) and low-CONUT score groups (≤6.5 points, good nutrition group), comparing the progression-free survival (PFS) and total survival (OS) of the two groups using Kaplan-Meier survival analysis. Results: Before the infusion of CAR-T-cells, excluding triglycerides (TG), patients' serum lipid levels were lower than normal on average. At 8-14 d after CAR-T-cell infusion, serum albumin (ALB), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and apolipoprotein A1 (Apo A1) levels dropped to the minimum, whereas CONUT scores reached the maximum. In addition to TG, apolipoprotein B (Apo B) levels increased compared with baseline. After CAR-T-cell therapy, the patients' serum lipid levels significantly increased with well-improved nutritional status. Spearman's related analysis showed that TC, HDL, and ApoA1 levels after CAR-T-cell injection were significantly negatively correlated with the grade of cytokine-release syndrome (CRS) (r=-0.548, P=0.003; r=-0.444, P=0.020; r=-0.589, P=0.001). Furthermore, survival analysis indicated that the CONUT score was unrelated to PFS, and the median OS of patients with R/R MM in the high-CONUT score group was shorter than that in the low-CONUT score group (P=0.046) . Conclusions: During CAR-T-cell therapy, hypolipidemia and poor nutritional status were aggravated, which is possibly related to CRS. The patients' serum lipid levels and nutritional status were significantly improved after CAR-T-cell treatment. The CONUT score affected the median OS in patients treated with CAR-T-cells. Therefore, specific screening and intervention for nutritional status in patients receiving CAR-T-cell therapy are required.

Heterologous expression of Escherichia coli fructose-1,6-bisphosphatase in Corynebacterium glutamicum and evaluating the effect on cell growth and L-lysine production.

Fructose-1,6-bisphosphatase (FBPase), which is mainly used to supply NADPH, has an important role in increasing L-lysine production by Corynebacterium glutamicum. However, C. glutamicum FBPase is negatively regulated at the metabolic level. Strains that overexpressed Escherichia coli fructose-1,6-bisphosphatase in C. glutamicum were constructed, and the effects of heterologous FBPase on cell growth and L-lysine production during growth on glucose, fructose, and sucrose were evaluated. The heterologous fructose-1,6-bisphosphatase is insensitive to fructose 1-phosphate and fructose 2,6-bisphosphate, whereas the homologous fructose-1,6-bisphosphatase is inhibited by fructose 1-phosphate and fructose 2,6-bisphosphate. The relative enzyme activity of heterologous fructose-1,6-bisphosphatase is 90.8% and 89.1% during supplement with 3 mM fructose 1-phosphate and fructose 2,6-bisphosphate, respectively. Phosphoenolpyruvate is an activator of heterologous fructose-1,6-bisphosphatase, whereas the homologous fructose-1,6-bisphosphatase is very sensitive to phosphoenolpyruvate. Overexpression of the heterologous fbp in wild-type C. glutamicum has no effect on L-lysine production, but fructose-1,6-bisphosphatase activities are increased 9- to 13-fold. Overexpression of the heterologous fructose-1,6-bisphosphatase increases L-lysine production in C. glutamicum lysC(T311I) by 57.3% on fructose, 48.7% on sucrose, and 43% on glucose. The dry cell weight (DCW) and maximal specific growth rate (µ) are increased by overexpression of heterologous fbp. A "funnel-cask" diagram is first proposed to explain the synergy between precursors supply and NADPH supply. These results lay a definite theoretical foundation for breeding high L-lysine producers via molecular target.

Correlation between oxidative stress and L-type calcium channel expression in the ventricular myocardia of selenium-deficient mice.

OBJECTIVE: Expression of the Cacna1c (calcium channel, voltage-dependent, L-type, α1C subunit) gene was studied to investigate the relationship between oxidative stress and L-type calcium channels in the myocardium of selenium-deficient mice. METHODS: Selenium levels in liver and heart tissue samples from mice fed normal or selenium-deficient diets were evaluated by fluorometry. In the same mice, glutathione peroxidase (GPx) and Cacna1c gene expression were analysed, malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured, oxidoreductase gene expression profiles were analysed (by DNA microarray), and myocardial structural changes were studied. RESULTS: In selenium-deficient versus control mice, GPx expression and SOD activity were decreased, and Cacna1c expression and MDA concentration were increased. Selenoprotein oxidoreductase and nonselenoprotein oxidoreductase gene expression differed significantly between selenium-deficient and control mice. In selenium-deficient mice, myocardial fibres were separated by loose collagenous tissue; electron microscopy showed shortened sarcomeres, dilated sarcoplasmic reticulum, scattered myofibril lysis and increased mitochondria with amorphous matrix densities. CONCLUSION: L-type calcium channels were involved in selenium deficiency-induced cardiomyocyte injury, which was positively related to oxidative stress.

Effects of diet, packaging, and irradiation on protein oxidation, lipid oxidation, and color of raw broiler thigh meat during refrigerated storage.

This study was designed to evaluate the effects of dietary treatment, packaging, and irradiation singly or in combination on the oxidative stability of broiler chicken thigh meat. A total of 120 four-week-old chickens were divided into 12 pens (10 birds/pen), and 4 pens of broilers were randomly assigned to a control oxidized diet (5% oxidized oil) or an antioxidant-added diet [500 IU of vitamin E + 200 mg/kg of butylated hydroxyanisole (BHA)] and fed for 2 wk. After slaughter, thigh meats were separated, ground, packaged in either oxygen-permeable or oxygen-impermeable vacuum bags, and irradiated at 0 or 3 kGy. Lipid oxidation (TBA-reactive substances), protein oxidation (carbonyl), and color of the meat were measured at 1, 4, and 7 d of refrigerated storage. The lipid and protein oxidation of thigh meats from birds fed the diet supplemented with antioxidants (vitamin E + BHA) was significantly lower than the lipid and protein oxidation of birds fed the control diet, whereas the lipid and protein oxidation of broilers fed the oxidized oil diet was higher than that of birds fed the control diet. Vacuum packaging slowed, but irradiation accelerated, the lipid and protein oxidation of thigh meat during storage. Dietary antioxidants (vitamin E + BHA) and irradiation treatments showed a stronger effect on lipid oxidation than on protein oxidation. A significant correlation between lipid and protein oxidation in meat was found during storage. Dietary supplementation of vitamin E + BHA and the irradiation treatment increased the lightness and redness of thigh meat, respectively. It is suggested that appropriate use of dietary antioxidants in combination with packaging could be effective in minimizing oxidative changes in irradiated raw chicken thigh meat.

Effect of Salvia miltiorrhiza Bunge injection on anticardiolipin antibody production induced by beta2 glycoprotein.

AIM: To explore the therapeutic effect and the mechanism of Chinese herbs on antiphospholipid syndrome (APS) by observing the effect of Salvia miltiorrhiza Bunge injectio (SmBI) on anticardiolipin antibody (aCL) induced by beta2 glycoprotein I (beta2-GP I). METHODS: Sixty female mice randomly fell into 6 groups: group A, B, C, D was injected through abdominal cavity with different dosage of SmBI daily; after 14 d, group A, B, C, E was immunized with 150 microg of purified human beta2-GP I in complete Freund's adjuvant subcutaneously; group F as control. The titre of aCL were detected by enzyme linked immunosorbent assay; subsets of T cell were grouped by streptavidin-biotin complex technique; and the activity of IL-2 was measured by MTT chromatometry. RESULTS: (1) Compared with group E, the absorbance (A) of aCL in group A, B, and C was decreased (P < 0.05 or P < 0.01). By linear correlation, the dosage is negatively correlated with the A values of aCL in 1, 2, and 3 weeks (P < 0.01). (2) Compared with group E, TH/TS ratio was reduced in group A, B, and C (P < 0.05 or P < 0.01); there is no significant differences between group D and F (P>0.05). By linear correlation, the dosage is negatively correlated with TH/TS ratio (P < 0.01). (3) Compared with E, the activity of IL-2 in group B and C decreased significantly (P < 0.01). By linear correlation, there is negative correlation between dosage and IL-2 activity (P < 0.01). There is no significant difference between D and F (P > 0.05). (4) There is positive correlation between TH/TS ratio and IL-2 activity in different dilutions (P<0.01). CONCLUSION: The mechanism of suppressive effect of SmBI on aCL induced by beta2-GP I may be realized by resuming the elevated TH/TS ratio and IL-2 activity. The state that SmBI have no effect on normal mice indicates that SmBI has selective immunoregulative functive.

mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer.

The mammalian target of rapamycin (mTOR) is a central regulator of G1 cell cycle protein synthesis that precedes commitment to normal cellular replication. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a rapamycin ester that inhibits mTOR function, on the proliferation of a panel of breast cancer cell lines. Six of eight lines studied were sensitive (IC(50)< or = 50 nM) and two lines were resistant (IC(50)>1.0 microM) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549), and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lines (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM) inhibited mTOR function in both a sensitive and a resistant line. In nu/nu mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779 resulted in a decrease in D-type cyclin and c-myc levels and an increase in p27(kip-1) levels. There was good correlation between activation of the Akt pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6 kinase, which is downstream of Akt, may also have conferred CCI-779 sensitivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.

[The mechanism of topical applied ion supplemented acidulated phosphate fluoride gel effects on dental enamel demineralization: an in vitro study].

The present study was carried out on dental enamel to describe surface changes in the scanning electron microscope and crystallites changes in the high-resolution transmitted electron microscope as related to treatments of topical applied ion supplemented acidulated phosphate fluoride (APFI) gel and artificial caries agent demineralization in vitro, which imitated in vivo with pH- cycling condition. Our data suggest that topical application of APFI gel produce some CaF2 spheres on the surface of enamel and some fluoride-containing apatites in dental enamel. The latter are considered as result of F- and CaHPO4 or hydroxyapatites. The essence of chemical reactions are discussed. The results confirm that enamel treated with APFI gel becomes more resistant to artificial caries agent and electron radiation damage.