PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion.

BACKGROUND: Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach. METHODS: In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients. RESULTS: Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity. CONCLUSIONS: Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

A dual system platform for drug metabolism: Nalbuphine as a model compound.

Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450s (CYPs), while not considering phase II metabolism. Therefore, the morphinan analgesic, nalbuphine, primarily metabolized in the liver via CYPs and UDP-glucuronosyltransferases (UGTs), was selected as a model drug to establish a dual-phase platform to elucidate its comprehensive metabolic pathway. Enzyme kinetics was studied using 8 common recombinant (r)CYPs, 10 rUGTs, and pooled human liver microsomes. The overall fraction of nalbuphine metabolized by each isozyme was evaluated by determining parent drug depletion. Finally, in vitro-in vivo correlation was validated in animal studies. Fluconazole, a specific UGT2B7 inhibitor, was administered orally to rats to determine the pharmacokinetic effects on nalbuphine and nalbuphine metabolites. Seventy-five percent and 25% of nalbuphine was metabolized by UGTs and CYPs, respectively. UGT2B7, UGT1A3, and UGT1A9 were primarily responsible for nalbuphine glucuronidation; only UGT2B7 produced nalbuphine-6-glucuronide. CYP2C9 and CYP2C19 were the two CYP isozymes that produced 3'-hydroxylnalbuphine and 4'-hydroxylnalbuphine. In vivo, the maximum serum concentration (Cmax) and area under the curve (AUC) of nalbuphine increased 12.4-fold and 13.2-fold, respectively, with fluconazole co-administration. A dual system platform for drug metabolism was successfully established in this study and was used to generate a complete metabolic scheme for nalbuphine. This platform has been verified by in vivo evaluations and can be utilized to study drugs that undergo multisystem metabolism.

[Estimation Models for Jujube Leaf Pigment Concentration with Hyperspectrum Data at Canopy Scale].

Plant canopy pigment concentration is a critical variable for agricultural remote sensing due to its close relationship to leaf nitrogen content. The aims of this study were to: (1) compare the prediction performances on chlorophyll, chlorophyll-a and b, and carotenoid concentration in jujube leaf at canopy scale between partial least squares regression (PLSR) and support vector machine (SVM), (2) develop quantitative models to estimate pigment concentration in jujube canopy using hyperspectral data and provide theoretical and technical support for rapidly, non-destructive, less expensive and eco-friendly measuring the concentration. Results from correlation analysis showed that jujube canopy pigment concentration correlated strongly with hyperspectral data. What's more, the hyperspectral data was better correlated by chlorophyll and chlorophyll-a than chlorophyll-b and carotenoid. Results of independent samples tested in predicting performance indicated that both of the PLSR and SVM models could effectively estimate pigment concentration, however, with different prediction precisions. Additionally, the precision of SVM outperformed PLSR for predicting chlorophyll and carotenoid. Whereas chlorophyll-a and chlorophyll-b were better predicted using PLSR than SVM. Compared among all the pigments' prediction precisions with corresponding optimal inversion models showed that prediction precisions on chlorophyll, chlorophyll-a and carotenoid were superior to chlorophyll-b. The determination coefficients and residual prediction deviation from predicting chlorophyll, chlorophyll-a and carotenoid were higher than 0.8 and 2.0, respectively, while the mean relative error values were lower than 13%. And the corresponding values from predicting chlorophyll-b were 0.60%, 20.79% and 1.79% respectively.

[Effect of Foliar Dustfall Content (FDC) on High Spectral Characteristics of Pear Leaves and Remote Sensing Quantitative Inversion of FDC].

The precipitation of floating and sinking dust on leaves of plants is called as foliar dustfall. To monitor foliar dustfall, it will provide fundamental basis for environmental assessment and agricultural disaster evaluation of dust area. Therefore, the aim of this work to (1) study the effect of foliar dustfall content (FDC) on high spectral characteristics of pear leaves, (2) analyze the relationship between reflectances and FDC, and (3) establish high spectral remote sensing quantitative inversion model of FDC. The results showed that FDC increased reflectances of visible band (400~700 nrn) with maximum band of 666 nm. Absolute and relative rates of change were -10. 50% and -62. 89%, respectively. The FDC decreased reflectances of near infrared band (701 ~ 1 050 nm) with maximum band of 758 nm. Absolute and relative rates of change were 12. 04% and 41. 75%, respectively. After dustfall was removed, reflection peak of green light and absorption valley of red and blue light became prominent, and slope of 500~750 nm wake band increased when FDC was more than 20 g . m-2. While FDC just slightly affected shape and area of reflection peak of green light when FDC was less than 20 g . m-2. FDC were positive and negative correlated with reflectances of visible band and near infrared band, respectively. Maximum correlation coefficient (0. 61) showed at 663 nm. All of 7 inversion models, the model based on the first-order differential of logarithm of the reciprocal had better stability and predictive ability. The coefficient of determination(R2), root mean square error (RMSE) and relative percent deviation (RPD) of this model were 0. 78, 3. 37 and 2. 09, respectively. The results of this study can provide a certain reference basis for hyperspectral remote sensing of FDC.

[Comparative study on hyperspectral inversion accuracy of soil salt content and electrical conductivity].

The objective of the present article is to ascertain the mechanism of hyperspectral remote sensing monitoring for soil salinization, which is of great importance for improving the accuracy of hyperspectral remote sensing monitoring. Paddy soils in Wensu, Hetian and Baicheng counties of the southern Xinjiang were selected. Hyperspectral data of soils were obtained. Soil salt content (S(t)) an electrical conductivity of 1:5 soil-to-water extracts (EC(1:5)) were determined. Relationships between S(t) and EC(1:5) were studied. Correlations between hyperspectral indices and S(t), and EC(1:5) were analyzed. The inversion accuracy of S(t) using hyperspectral technique was compared with that of EC(1:5). Results showed that: significant (p<0.01) relationships were found between S(t) and EC(1:5) for soils in Wensu and Hetian counties, and correlation coefficients were 0.86 and 0.45, respectively; there was no significant relationship between S(t) and EC(1:5) for soils in Baicheng county. Therefore, the correlations between S(t) and EC(1:5) varied with studied sites. S(t) and EC(1:5) were significantly related with spectral reflectance, first derivative reflectance and continuum-removed reflectance, respectively; but correlation coefficients between S(t) and spectral indices were higher than those between EC(1:5) and spectral indices, which was obvious in some sensitive bands for soil salinization such as 660, 35, 1229, 1414, 1721, 1738, 1772, 2309 nm, and so on. Prediction equations of St and EC(1:5) were established using multivariate linear regression, principal component regression and partial least-squares regression methods, respectively. Coefficients of determination, determination coefficients of prediction, and relative analytical errors of these equations were analyzed. Coefficients of determination and relative analytical errors of equations between S(t) and spectral indices were higher than those of equations between EC(1:5) and spectral indices. Therefore, the responses of high spectral information to St were more sensitive than those of high spectral information to EC(1:5). Accuracy of St predicted from high spectral data was higher than that of EC(1:5) estimated from high spectral data. The results of this study can provide a theoretical basis to improve hyperspectral remote sensing monitoring accuracy of soil salinization.

[Antihypertensive effect of metformin in essential hypertensive patients with hyperinsulinemia.].

OBJECTIVE: To investigate the possibility and utility of metformin alone or in combination with fosinopril to reduce blood pressure in patients with essential hypertension. METHODS: A total of 140 cases of non-diabetic essential hypertension with hyperinsulinemia were recruited and randomly assigned to two groups: a group of 68 treated with metformin 500 mg tid and a group of 72 treated with fosinopril 10 mg qd. The duration of the treatment was 8 weeks. Combination therapy with the two drugs was used after 4 weeks of treatment if needed. If the target goals of systolic blood pressure (SBP) < 140 mm Hg (1 mm Hg = 0.133 kPa) and/or diastolic blood pressure (DBP) < 90 mm Hg were not attained 4 weeks, combination therapy with two drugs was used in either group in the next 4 weeks. The changes of blood pressure and insulin sensitivity of the two groups were observed before and after treatment. RESULTS: (1) After 4 weeks of treatment, SBP in metformin group and fosinopril group decreased by (13.0 +/- 1.2) mm Hg and (15.4 +/- 1.4) mm Hg, and DBP decreased by (9.0 +/- 1.0) mm Hg and (10.4 +/- 1.1) mm Hg respectively. After 8 weeks of treatment, SBP in metformin group and fosinopril group decreased by (17.8 +/- 1.5) mm Hg and (20.9 +/- 1.5) mm Hg, and DBP decreased by (13.2 +/- 0.9) mm Hg and (15.3 +/- 1.1) mm Hg respectively. There was no significant difference in the decline of blood pressure between the two groups (P > 0.05). The rates of combination therapy were both 54% in the two groups. (2) Fasting insulin as well as 30 min and 120 min insulin levels after oral glucose tolerance test and insulin area under the curve in the metformin group were significantly reduced after 4 and 8 weeks of treatment as compared with those of baseline (P < 0.05 and P < 0.01). In the fosinopril group, however, they decreased only after 8 weeks treatment (P < 0.05). The insulin action index in the metformin group was higher than that in the fosinopril group after 4 weeks of treatment (P < 0.05), but there was no significant difference between the two groups after 8 weeks of treatment (P > 0.05). CONCLUSION: Metformin and fosinopril have similar antihypertensive effect and a good synergy in essential hypertension with hyperinsulinemia.

Surface-ascension of discrete liquid drops via experimental reactive wetting and lattice Boltzmann simulation.

The reactive-wetting technique is employed to move liquid against gravitational force. Experiments have shown that the velocity of an ascending liquid drop is constant, unlike the gradual decrease intuitively linked to objects against gravitation. The ascending velocity decreases for increasing slope. The maximum inclination, or stopping, angle for this particular setup is >25 degrees . Computer simulation of a reactive-wetting drop using the lattice Boltzmann method is also performed. The results indicate that the method employed is suitable for the task, producing most experimentally observable responses. The mass flow of a liquid drop under reactive wetting was studied through simulation results, and a general description of the reactive-wetting phenomenon was deduced.