Background::B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy yield remarkable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in the distribution and genetic variations in R/RMM.Methods::Herein, the ctDNA of 108 peripheral blood plasma samples from patients with R/RMM at the First Affiliated Hospital, School of Medicine, Zhejiang University was thoroughly investigated before administration of anti-BCMA CAR-T therapy to establish its predictive potential. Flow cytometry is used primarily to detect subgroups of T cells or CAR-T cells.Results::In this study, several tumor and T cell effector-mediated factors were considered to be related to treatment failure by an integrat analysis, including higher percentages of multiple myeloma (MM) cells in the bone marrow ( P = 0.0125), lower percentages of CAR-T cells in the peripheral blood at peak ( P = 0.0375), and higher percentages of CD8 + T cells ( P = 0.0340). Furthermore, there is a substantial correlation between high ctDNA level (>143 ng/mL) and shorter progression-free survival (PFS) ( P = 0.007). Multivariate Cox regression analysis showed that high levels of ctDNA (>143 ng/mL), MM-driven high-risk mutations (including IGLL5 [ P = 0.004], IRF4 [ P = 0.024], and CREBBP [ P = 0.041]), number of multisite mutations, and resistance-related mutation ( ERBB4, P = 0.040) were independent risk factors for PFS. Conclusion::Finally, a ctDNA-based risk model was built based on the above independent risk factors, which serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy.

Objective:To analyze trends in urticaria incidence among children aged 0 - 14 years in China from 1990 to 2021, to explore its changing patterns in different age, period, and cohort groups, and to investigate the impact of age and air pollutants on the incidence trends.Methods:Data were obtained from the Global Burden of Disease Database (GBD2021) , including the number of urticaria cases, crude incidence rates, and age-standardized incidence rates among children aged 0 - 14 years of different genders in China from 1990 to 2021. The Joinpoint regression model was used to calculate the annual percentage change (APC) and average annual percentage change (AAPC) to assess temporal trends in incidence rates. An age-period-cohort model was applied to assess the effects of age, period, and cohort on urticaria incidence. Data on the annual emissions of 4 air pollutants (SO 2, CO, PM 2.5, and PM 10) in China from 1990 to 2021 were obtained from the Emissions Database for Global Atmospheric Research (EDGAR) , and a multivariable meta-regression model was used to explore the relationship between air pollutants and urticaria incidence. Results:From 1990 to 2021, the age-standardized incidence rate of urticaria among children aged 0 - 14 years in China demonstrated a slight overall downward trend (AAPC = -0.03%, P < 0.01) . The incidence rate was generally higher in female children than in male children, and the decline in incidence rates was greater in female children than in male children (female AAPC = -0.02%, male AAPC = -0.01%, both P < 0.01) . The age-period-cohort model indicated that the risk of urticaria decreased with advancing age: with the age group of 0 - 4 years as the reference ( RR = 1.000) , the risk of urticaria significantly decreased in the age group of 5 - 9 years ( RR = 0.790, 95% CI: 0.789 - 0.791) and further declined in the age group of 10 - 14 years ( RR = 0.711, 95% CI: 0.710 - 0.711) ; the period effect analysis showed that the risk of urticaria gradually decreased after the baseline period of 1992 - 1996 ( RR = 1.000) , and dropped to 0.995 (95% CI: 0.994 - 0.997) in the period of 2017 - 2021; in the cohort effect analysis of the overall population aged 0 - 14 years, with the 1988 - 1992 birth cohort as the base cohort, an earlier birth cohort 1978 - 1982 exhibited the highest risk of urticaria ( RR = 1.006, 95% CI: 1.004 - 1.009) , while the 2013 - 2017 cohort showed the lowest risk ( RR = 0.996, 95% CI: 0.994 - 0.997) . The multivariable meta-regression analysis indicated a significant association between PM 2.5 exposure and urticaria incidence ( β = 0.319, 95% CI: 0.022 - 0.616, P = 0.033) , although this association was not statistically significant in different age groups. Conclusions:From 1990 to 2021, children aged 0 - 4 years in China were the highest-risk group for urticaria; the decline in the incidence rate of urticaria was more pronounced in female children than in male children, and earlier birth cohorts exhibited higher risks of urticaria. Exposure to PM 2.5 appeared to be associated with the incidence of urticaria.

Objective:To analyze trends in urticaria incidence among children aged 0 - 14 years in China from 1990 to 2021, to explore its changing patterns in different age, period, and cohort groups, and to investigate the impact of age and air pollutants on the incidence trends.Methods:Data were obtained from the Global Burden of Disease Database (GBD2021) , including the number of urticaria cases, crude incidence rates, and age-standardized incidence rates among children aged 0 - 14 years of different genders in China from 1990 to 2021. The Joinpoint regression model was used to calculate the annual percentage change (APC) and average annual percentage change (AAPC) to assess temporal trends in incidence rates. An age-period-cohort model was applied to assess the effects of age, period, and cohort on urticaria incidence. Data on the annual emissions of 4 air pollutants (SO 2, CO, PM 2.5, and PM 10) in China from 1990 to 2021 were obtained from the Emissions Database for Global Atmospheric Research (EDGAR) , and a multivariable meta-regression model was used to explore the relationship between air pollutants and urticaria incidence. Results:From 1990 to 2021, the age-standardized incidence rate of urticaria among children aged 0 - 14 years in China demonstrated a slight overall downward trend (AAPC = -0.03%, P < 0.01) . The incidence rate was generally higher in female children than in male children, and the decline in incidence rates was greater in female children than in male children (female AAPC = -0.02%, male AAPC = -0.01%, both P < 0.01) . The age-period-cohort model indicated that the risk of urticaria decreased with advancing age: with the age group of 0 - 4 years as the reference ( RR = 1.000) , the risk of urticaria significantly decreased in the age group of 5 - 9 years ( RR = 0.790, 95% CI: 0.789 - 0.791) and further declined in the age group of 10 - 14 years ( RR = 0.711, 95% CI: 0.710 - 0.711) ; the period effect analysis showed that the risk of urticaria gradually decreased after the baseline period of 1992 - 1996 ( RR = 1.000) , and dropped to 0.995 (95% CI: 0.994 - 0.997) in the period of 2017 - 2021; in the cohort effect analysis of the overall population aged 0 - 14 years, with the 1988 - 1992 birth cohort as the base cohort, an earlier birth cohort 1978 - 1982 exhibited the highest risk of urticaria ( RR = 1.006, 95% CI: 1.004 - 1.009) , while the 2013 - 2017 cohort showed the lowest risk ( RR = 0.996, 95% CI: 0.994 - 0.997) . The multivariable meta-regression analysis indicated a significant association between PM 2.5 exposure and urticaria incidence ( β = 0.319, 95% CI: 0.022 - 0.616, P = 0.033) , although this association was not statistically significant in different age groups. Conclusions:From 1990 to 2021, children aged 0 - 4 years in China were the highest-risk group for urticaria; the decline in the incidence rate of urticaria was more pronounced in female children than in male children, and earlier birth cohorts exhibited higher risks of urticaria. Exposure to PM 2.5 appeared to be associated with the incidence of urticaria.

Objective:To predict and analyze the T/B combined epitope of EM10 protein in Echinococcus multilocularis, and identify the expressed products of the biosynthetic EM10 multi epitopes. Methods:The gene-related information of EM10 protein was obtained through NCBI GenBank public database. Bioinformatics technique was used to predict and analyze the T/B binding epitopes of EM10 protein. The prokaryotic expession recombinant plasmid pET30a-EM10 (epitope) was synthesized, and transformed into host bacteria Ecoli. BL21 (DE3). The expression of EM10 recombinant multi-epitope protein was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting after induced expression by isopropyl thiogalactopyranoside (IPTG). Results:The total length of EM10 gene was 1 759 bp (GenBank registration number: U05573), and its protein amino acid sequence (GenBank registration number: AAA50580.1) was 559 amino acids. By using Phyre software for homology modeling, the tertiary structure of EM10 protein was obtained, and the T/B combined epitope of EM10 protein was successfully predicted, the dominant epitope was located at 46 - 61, 133 - 183, 239 - 255 and 442 - 475 amino acid sites. The (GGGGS)n linker sequence was used to connect the epitopes to form an EM10 recombinant multi-epitope protein with a total of 206 amino acid. The size of the DNA fragment was 618 bp and the relative molecular weight of the protein was 22.66 × 10 3. The prokaryotic expession recombinant plasmid was validated by enzyme digestion, the results showed that the plasmid size was between 5 000 and 6 000 bp, which was consistent with the length of the constructed plasmid (5 854 bp). SDS-PAGE showed that the target protein was expressed in the supernatant induced by IPTG at 37 ℃ and the effect was the best. The relative molecular weight of the protein was 22.66 × 10 3 by Western blotting, which was consistent with the constructed plasmid. Conclusions:The combined epitope of EM10 T/B is successfully designed and predicted using bioinformatics technology. A prokaryotic expression recombinant plasmid is constructed, the expression of EM10 recombinant multi-epitope protein is verified through experiments, providing an experimental basis for the construction of an EM10 dominant epitope diagnostic kit.

Objective To investigate the potential of a two-component model combining T2 and diffusion weighted imaging(T2-DWI)in the diagnosis of prostate cancer.Methods Thirty-two prostate cancer patients and twenty prostatic hyperplasia patients underwent combined T2-DWI,with TE values set at 50 ms and 70 ms and b values at 50 s/mm2 and 800 s/mm2,respectively.This provided four measurements for each voxel.The signal fractions were calculated from the slow component(SFslow)extracted from the two-component model of T2-DWI,which was fitted with two free parameters.The results were compared with the traditional single exponential apparent diffusion coefficient(ADC)model.Results A significant difference was observed between SFslow(0.77±0.14 vs 0.35±0.10)and ADC[(0.91±0.24)μm2/ms vs(1.98±0.32)μm2/ms]in region of interest(ROI)between peripheral zone tumors and normal prostate tissue(P＜0.001).No significant difference was found between SFslow(0.75±0.13 vs 0.68±0.11)and ADC[(0.88±0.18)μm2/ms vs(0.97±0.13)μm2/ms]in ROI between non-peripheral zone tumors and prostatic hyperplasia.The area under the curve(AUC)of the receiver operating characteristic(ROC)for distinguishing tumors from prostate voxels was 0.962 for two-component SFslow and 0.940 for single exponential ADC models.The Spearman correlation coefficients between tumor SFslow and ADC with Gleason scores were 0.631 and-0.558,respectively.Conclusion SF estimation based on T2-DWI two-component model can effectively differentiate tumors from normal prostate tissue,showing potential in diagnosing prostate cancer.

miR-135 is a highly conserved miRNA in mammals and includes miR-135a and miR-135b.Recent studies have shown that miR-135b is a key regulatory factor in cardio-cerebrovascular diseases.It is involved in regulating the pathological process of myocardial infarction,myocardial ischemia/reperfusion injury,cardiac hypertrophy,atrial fibrillation,diabetic cardiomyopathy,atherosclerosis,pulmonary hyperten-sion,cerebral ischemia/reperfusion injury,Parkinson's disease,and Alzheimer's disease.Obviously,miR-135b is an emerging player in cardio-cerebrovascular diseases and is expected to be an important target for the treatment of cardio-cerebrovascular diseases.However,the crucial role of miR-135b in cardio-cerebrovascular diseases and its underlying mechanism of action has not been reviewed.Therefore,in this review,we aimed to comprehensively summarize the role of miR-135b and the signaling pathway mediated by miR-135b in cardio-cerebrovascular diseases.Drugs targeting miR-135b for the treatment of diseases and related patents,highlighting the importance of this target and its utility as a therapeutic target for cardio-cerebrovascular diseases,have been discussed.

Background Arsenic, cobalt, barium, and other individual metal exposure have been confirmed to be associated with the incidence of kidney stones. However, there are few studies on the association between mixed metal exposure and kidney stones, especially in occupational groups. Objective To investigate the association between mixed metal exposure and kidney stones in an occupational population from a metal smelting plant. Methods A questionnaire survey was conducted to collect sociodemographic characteristics, medical history, and lifestyle information of 1158 mixed metal-exposed workers in a metal smelting plant in Guangdong Province from July 2021 to January 2022. Midstream morning urine samples were collected from the workers, the concentrations of 18 metals including lithium, vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, strontium, molybdenum, cadmium, cesium, barium, tungsten, titanium, and lead were measured by inductively coupled plasma mass spectrometry, and the urinary mercury levels were measured by cold atomic absorption spectroscopy. Based on predetermined inclusion criteria, a total of 919 mixed metal-exposed workers were included in the study, including 117 workers in the kidney stone group and 802 workers in the non-kidney stone group. With a detection rate of urinary metals greater than 80% as entry criterion, 16 eligible metals were finally included for further analysis. Parametric or non-parametric methods were used to compare the differences between continuous or categorical variables of the non-kidney stone group and the kidney stone group. Logistic regression models were constructed to explore the association between individual metal exposures and kidney stones. Weighted quantile sum (WQS) regression models were used to evaluate the association between mixed metal exposure and kidney stones, as well as the weights of each metal on kidney stones. Then Bayesian kernel machine regression (BKMR) models were used to explore the overall effect of mixed metal exposure on renal calculi and the potential interactions between metals. Results We found that there were significant differences in sex, age, length of service, and body mass Index (BMI) between the non-kidney stone group and the kidney stone group (P<0.05). The urinary concentrations of molybdenum and barium in the kidney stone group were higher than those in the non-kidney stone group, and the differences were statistically significant (P<0.05). The logistic regression models demonstrated that urinary cobalt, arsenic, molybdenum, and barium were positively correlated with the risk of kidney stones (P_trend<0.05). The WQS regression models showed that the mixed exposure to vanadium, cobalt, arsenic, molybdenum, and barium was positively associated with the risk of kidney stones (P<0.05). Among them, molybdenum, arsenic, and barium accounted for 0.391, 0.337, and 0.154, respectively. The BKMR results revealed a positive association between metal mixture exposure and the risk of kidney stones (P<0.05). When other metals were fixed at the 25th, 50th, or 75th percentile, arsenic, molybdenum, cobalt, and barium exhibited significant positive effects on the risk of kidney stones (P<0.05), while vanadium showed a significant negative effect (P<0.05). The interaction analysis demonstrated interactions between barium and cobalt, as well as between vanadium and cobalt (P<0.05). Conclusion In the occupational population of this smelter, occupational mixed metal exposure could increase the risk of kidney stones, and the main metals are molybdenum, arsenic, barium, and cobalt.

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy yield remarkable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in the distribution and genetic variations in R/RMM. METHODS: Herein, the ctDNA of 108 peripheral blood plasma samples from patients with R/RMM was thoroughly investigated before administration of anti-BCMA CAR-T therapy to establish its predictive potential. Flow cytometry is used primarily to detect subgroups of T cells or CAR-T cells. RESULTS: In this study, several tumor and T cell effector-mediated factors were considered to be related to treatment failure by an integrat analysis, including higher percentages of multiple myeloma (MM) cells in the bone marrow (P = 0.013), lower percentages of CAR-T cells in the peripheral blood at peak (P = 0.037), and higher percentages of CD8+ T cells (P = 0.034). Furthermore, there is a substantial correlation between high ctDNA level (>143 ng/mL) and shorter progression-free survival (PFS) (P = 0.007). Multivariate Cox regression analysis showed that high levels of ctDNA (>143 ng/mL), MM-driven high-risk mutations (including IGLL5 [P = 0.004], IRF4 [P = 0.024], and CREBBP [P = 0.041]), number of multisite mutations, and resistance-related mutation (ERBB4, P = 0.040) were independent risk factors for PFS. CONCLUSION: Finally, a ctDNA-based risk model was built based on the above independent risk factors, which serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy. REGISTERATION Chinese Clinical Trial Registry (ChiCTR2100046474) and National Clinical Trial (NCT04670055, NCT05430945).

Diabetes mellitus(DM)is a major metabolic disease endangering global health,with diabetic ne-phropathy(DN)as a primary complication lacking curative therapy.Sporoderm-broken spores of Ganoderma lucidum(GLP),an herbal medicine,has been used for the treatment of metabolic disorders.In this study,DN was induced in Sprague-Dawley rats using streptozotocin(STZ)and a high-fat diet(HFD),and the protective mechanisms of GLP were investigated through transcriptomic,metabolomic,and network pharmacology(NP)analyses.0ur results demonstrated that GLP intervention ameliorated renal damage and inflammation levels in DN rats.Integrative metabolomic and transcriptomic analysis revealed that GLP treatment modulated glucose and cellular energy metabolisms by regulating relevant genes.GLP significantly suppressed the inflammations by impacting glucose and energy metabolism-related gene expression(Igfbp1 and Angptl4)and enhanced metabolic biomarkers of 4-Aminocatechol.In addition,NP analysis further indicated that GLP may efficiently alleviate DN via immune-related pathways.In conclusion,this study provides supportive evidence of the anti-inflammatory effects of GLP supplements,highlighting their potential for promising clinical applications in treating DN.

Urate oxidase (Uox) plays a pivotal role in uric acid (UA) degradation, and it has been applied in controlling serum UA level in clinical treatment of hyperuricemia (HUA). However, because Uox is a heterogenous protein to the human body, the immune rejections typically occur after intravenous administration, which greatly hampers the application of Uox-based agents. In this study, we used Lactococcus lactis NZ9000, a food-grade bacterium, as a host to express exogenous Uox genes, to generate the Uox-expressing engineered strains to treat HUA. Aspergillus flavus-derived Uox (aUox) and the "resurrected" human-derived Uox (hUox) were cloned into vector and expressed in NZ9000, to generate engineered strains, respectively. The engineered NZ9000 strains were confirmed to express Uox and showed UA-lowering activity in a time-dependent manner in vitro. Next, in an HUA mice model established by oral gavage of yeast paste, the UA levels were increased by 85.4% and 106.2% at day 7 and day 14. By contrast, in mice fed with NZ9000-aUox, the UA levels were increased by 39.5% and 48.3% while in mice fed with NZ9000-hUox were increased by 57.0% and 82.9%, suggesting a UA-lowering activity of both engineered strains. Furthermore, compared with allopurinol, the first-line agent for HUA treatment, mice fed with NZ9000-aUox exhibited comparable liver safety but better kidney safety than allopurinol, indicating that the use of engineered NZ9000 strains not only alleviated kidney injury caused by HUA, but could also avoided the risk of kidney injury elicited by using allopurinol. Collectively, our study offers an effective and safe therapeutic approach for HUA long-term treatment and controlling.
Animals ; Lactococcus lactis/metabolism* ; Urate Oxidase/genetics* ; Mice ; Uric Acid/blood* ; Hyperuricemia ; Humans ; Administration, Oral ; Aspergillus flavus/genetics* ; Male