[Study on the direct economic burden and relevant influencing factors of 233 multidrug/rifampicin-resistant pulmonary tuberculosis patients in Jiangsu Province].

Objective: To explore the direct economic burden and factors affecting out-of-pocket direct costs of multidrug-/rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB) patients in Jiangsu Province. Methods: MDR/RR-PTB patients diagnosed and treated at 13 municipal tuberculosis (TB)-designated hospitals in Jiangsu Province between January 1, 2021, and December 31, 2022, were included, and basic information and direct economic costs were obtained through questionnaires and hospital information systems. Stepwise multiple linear regression was used to analyze the factors influencing patients' out-of-pocket direct costs. Results: The age of the 233 MDR/RR-PTB patients was (44.04±15.64) years. The M(Q1, Q3) direct medical expense of the patients was 134 051.00 (98 934.01,163 205.73) Yuan, of which the M(Q1,Q3) reimbursement by health insurance or policy reduction was 100 462.10 (78 120.00,130 816.00) Yuan, and the M(Q1,Q3) out-of-pocket direct medical expense was 21 694.62 (14 734.83,37 813.00) Yuan. The M(Q1,Q3) direct non-medical expense was 4 971.00 (3 138.00,7 870.00) Yuan. Age, registered residence location, TB resulting in divorce or separation from spouse or partner, drug resistance test results, and treatment regimens were the influencing factors associated with out-of-pocket direct costs for MDR/RR-PTB patients. Conclusions: The direct economic burden caused by MDR/RR-PTB in Jiangsu Province is heavy. It is necessary to emphasize psychological guidance and care for MDR/RR-PTB patients, improve the diagnosis, treatment, and management of MDR/RR-PTB, and effectively reduce the economic burden of MDR/RR-PTB patients.

[The variables affecting the time of B-cell reconstruction in children with steroid-sensitive nephrotic syndrome treated with rituximab].

Objective: To investigate the factors affecting the time taken for B cell reconstitution after rituximab (RTX) treatment in children with steroid-sensitive nephrotic syndrome. Methods: This was a retrospective cohort study. The clinical data of 42 children with SSNS who received treatment with RTX in Department of Nephrology, Rheumatology and Immunology, Children's Hospital Affiliated to Zhengzhou University between December 2019 and May 2023 were analyzed retrospectively. The data of demographics, immunosuppressant treatment and laboratory tests such as CD19+B cell count, urinary protein quantification were collected. The patients were divided into 2 groups, the early B cell reconstruction group and the late reconstruction group based on the average time of B cell reconstruction. A multivariate logistic regression model was used to analyze the factors impacting the timing of B cell reconstruction, and the predictive value of these factors was assessed by plotting the receiver operating characteristic (ROC) curve. Results: There were 42 children, with 35 males and 7 females. They were aged 3.5 (2.2, 5.9) years at the onset of PNS and (8.4±3.3) years at their first RTX treatment. The time for B cell reconstitution was (152±53) d. There were 20 children in the early reconstruction group and 22 children in the late reconstruction group. There were no statistically significant differences (all P>0.05) between the 2 groups in terms of the cumulative dose of steroids within 1 year before receiving RTX infusion (0.29 (0.16, 0.50) vs. 0.29 (0.19, 0.46) mg/(kg·d)), the percentage of children using tacrolimus before RTX (65%(13/20) vs. 45%(10/22)) and cumulative doses (0.04 (0.03, 0.05) vs. 0.03 (0.03, 0.06) mg/(kg·d)), the steroid doses at the time of RTX infusion (0.73 (0.49, 0.90) vs. 0.71 (0.58, 0.89) mg/(kg·d)), the percentage of children using tacrolimus at the initial RTX infusion (50% (10/20)vs. 41% (9/22)) and the doses (0.03 (0.02, 0.04) vs. 0.02 (0.01, 0.04) mg/(kg·d)), the discontinuation time of tacrolimus post-RTX infusion (71 (42, 91) vs. 64 (42, 91) d). A multivariate analysis revealed a correlation (OR=0.26, 95%CI 0.10-0.68, P=0.006) between B cell count following the second RTX infusion and the time taken for B cell reconstruction. The area under the ROC curve for B cell count after the RTX infusion in predicting the time to B cell reconstruction was 0.89 (95%CI 0.78-0.99, P<0.001) and the cut-off value was 0.925×106/L. Conclusions: The time of B cell reconstruction is not influenced by the previous or concurrent use of tacrolimus, regardless of its duration and the dosage of steroid and tacrolimus prior to the RTX infusion. Insteadly, the peripheral blood B cell count (0.925×106/L) following the second RTX infusion for SSNS is identified as an independent predictor of reconstruction time, allowing for a more precise prediction and early intervention to maintain disease remission.

An improved method for generating human spinal cord neural stem cells.

Neural stem cells have exhibited efficacy in pre-clinical models of spinal cord injury (SCI) and are on a translational path to human testing. We recently reported that neural stem cells must be driven to a spinal cord fate to optimize host axonal regeneration into sites of implantation in the injured spinal cord, where they subsequently form neural relays across the lesion that support significant functional improvement. We also reported methods of deriving and culturing human spinal cord neural stem cells derived from embryonic stem cells that can be sustained over serial high passage numbers in vitro, providing a potentially optimized cell source for human clinical trials. We now report further optimization of methods for deriving and sustaining cultures of human spinal cord neural stem cell lines that result in improved karyotypic stability while retaining anatomical efficacy in vivo. This development improves prospects for safe human translation.

[Correlation between prognostic nutritional index and pleural thickness with survival time of epithelial malignant pleural mesothelioma patients].

Objective: To explore the role of prognostic nutritional index (PNI) and pleural thickness in the prognostic evaluation of patients with epithelial malignant pleural mesothelioma (MPM) . Methods: In April 2022, a retrospective analysis was conducted on the data and laboratory data of 41 patients with epithelial MPM admitted to the cardiothoracic surgery department of Chuxiong Yi Autonomous Prefecture People's Hospital from January 2018 to May 2021. Univariate and multivariate analysis were used to evaluate the relationships between total survival time, clinical characteristics, PNI and pleural thickness in patients. Results: The 41 patients were mostly male (26 cases, 63.4%) , with a median age of 55 years old. The main clinical manifestations were chest pain (53.7%) , bloody pleural effusion (75.6%) , and chest pain combined with bloody pleural effusion (36.6%) . The median survival time of patients with different TNM stage, efficacy after 4 cycles of chemotherapy, PNI, maximum pleural thickness after chemotherapy (post max) , sum of post max in 3 zones after chemotherapy (post sum) were statistically different (χ(2)=3.89, 14.51, 15.33, 4.33, 12.05, P<0.05) . Compared with patients with high PNI and post sum<32.26 mm, MPM patients with low PNI and post sum≥32.26 mm have higher risk of death, and the differences were statistically significant (HR=1.52, 95%CI: 1.75-11.93, P=0.002; HR=1.70, 95%CI: 1.84-16.23, P=0.002) . Conclusion: PNI and post sum can be used to predict the prognosis of patients with epithelial MPM.

Effect and mechanism of recombinant human fibroblast growth factor 18 on osteoporosis in OVX mice.

OBJECTIVES: This study aimed to investigate the effect and the mechanism of recombinant human fibroblast growth factor 18 (rhFGF18) on postmenopausal osteoporosis. METHODS: The effect of rhFGF18 on the proliferation and apoptosis of osteoblasts and the mechanism underlying such an effect was evaluated using an oxidative stress model of the MC3T3-E1 cell line. Furthermore, ovariectomy was performed on ICR mice to imitate estrogen-deficiency postmenopausal osteoporosis. Bone metabolism and bone morphological parameters in the ovariectomized (OVX) mice were evaluated. RESULTS: The results obtained from the cell model showed that FGF18 promoted MC3T3-E1 cell proliferation by activating the extracellular signal-regulated kinase (ERK) and p38 instead of c-Jun N-terminal kinase (JNK). FGF18 also prevented cells from damage inflicted by oxidative stress via inhibition of apoptosis. After FGF18 administration, the expression level of anti-apoptotic protein Bcl-2 in the mice was upregulated, whereas those of the pro-apoptotic proteins Bax and caspase-3 were downregulated. Administering FGF18 also improved bone metabolism and bone morphological parameters in OVX mice. CONCLUSIONS: FGF18 could effectively prevent bone loss in OVX mice by enhancing osteoblastogenesis and protecting osteoblasts from oxidative stress-induced apoptosis.

Correlation between angiotensin and acute kidney injury in patients with sepsis.

OBJECTIVE: The aim of the study was to analyze the changes in angiotensin (Ang) levels in patients with sepsis complicated with acute kidney injury (AKI) and evaluate the relationship between Ang and AKI. PATIENTS AND METHODS: Prospective research methods were used in this study. A total of 66 sepsis patients admitted to the Intensive care Unit (ICU) of the First Hospital of Hebei Medical University from October 2020 to January 2021 were enrolled. According to the occurrence of AKI, patients were divided into the sepsis-associated AKI (SA-AKI) group and the non-AKI group. The levels of Ang-1 and Ang-2 were compared between the two groups. The relationship between Ang and glomerular filtration rate (GFR) in sepsis patients was studied by correlation analysis. RESULTS: Plasma Ang-1 in the SA-AKI group was significantly higher than that in the non-AKI group (0.39±1.05 ng/ml vs. 0.10±0.24 ng/ml, p=0.039). The Ang-2/Ang-1 in the SA-AKI group was lower than that in the non-AKI group with a significant difference (52.55±191.38 vs. 349.50±327.49, p=0.001). Correlation analysis indicated that Ang-1 was negatively correlated with GFR (r=-0.12, p=0.031), while Ang-2/Ang-1 was positively correlated with GFR (r=0.21, p<0.001). The Ang-2 was positively correlated with GFR (r=0.204, p<0.001) CONCLUSIONS: Plasma Ang-1 and Ang-2 levels are suggestive for assessing the risk of AKI in patients with sepsis.

Predictive values of cervix length measurement based on transvaginal ultrasonography combined with pathological examination of placenta for premature delivery and correlation between premature delivery and infection.

OBJECTIVE: The predictive values of cervix length (CL) measurement based on transvaginal ultrasonography (TVUS) and pathological examination of placenta for premature delivery (PTD) were investigated, and the correlation between PTD and infection was analyzed. PATIENTS AND METHODS: A total of 120 pregnant women with PTD or high-risk factors for PTD admitted to Hengyang Maternal and Child Health Hospital, between February 2020 and March 2022 were included in this retrospective study. There were 36 subjects in the PTD group and 84 in the normal delivery group (control group). They underwent pathological examination of the placenta and TVUS for CL measurement. The final gestational age was set as the standard for the evaluation of the predictive values of pathological examination of the placenta and TVUS. Moreover, a pathological examination of the placenta was used to analyze the correlation between PTD and infection. RESULTS: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of joint inspection were remarkably superior to those of single CL or pathological examination of the placenta (p<0.05). The proportion of pregnant women with CL ≤30 mm and positive placental pathology was higher than that of pregnant women with CL >30 mm and negative placental pathology (p<0.05). In addition, the incidence of Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), and chorioamnionitis (CA) in the vaginal discharge of the PTD group was markedly superior to that of the control group (p<0.05). CONCLUSIONS: The combination of CL ≤30 mm and positive placental pathology could effectively predict PTD, and placental infection was notably correlated with the occurrence of PTD.

[Heterogeneity analysis of pancreatic cancer and identification of molecular subtypes of tumor cells based on CEACAM5, LGALS1 and CENPF gene expression].

OBJECTIVE: To explore the heterogeneity of pancreatic cancer and new methods for tumor cell molecular subtyping and identify the signature genes in pancreatic cancer progression. METHODS: Based on the single-cell sequencing data of 16 pancreatic cancer tissues from the GSE155698 dataset, the single pancreatic cancer cells were classified according to EPCAM gene expression after preliminary clustering, re-clustering, and subgrouping to identify the signature genes, followed by pathway enrichment analysis and pseudo-time analysis. The key genes identified were validated using the clinical and tissue gene and protein expression data from 179 pancreatic cancer patients and 171 healthy controls. The impact of CEACAM5, LGALS1, and CENPF on proliferation, migration and invasion of pancreatic cancer cells were analyzed. RESULTS: Analysis of 48 570 cells from 16 pancreatic cancer samples revealed a total of 22 clusters, including 5 clusters of pancreatic cancer cells, which were classified into Subtype 1, Subtype 2, and Subtype 3, each exhibiting distinct gene expression patterns and functions. The signature genes were enriched in negatively regulated protein metabolic processes, ferroptosis, and antigen processing and presentation-related pathways in Subtype 1 pancreatic cancer cells; in peptide synthesis processes, translation, and ribosome-related pathways in Subtype 2; and in ATP metabolic processes, glycolysis/gluconeogenesis, and cell cyclerelated pathways in Subtype 3. Subtypes 2 and 3 were potentially derived from Subtype 1, and Subtype 3 possibly represented the final developmental stage of pancreatic cancer cells. The key signature genes (CEACAM5, LGALS1, and CENPF) also exhibited different expression patterns in the developmental trajectory and showed high expressions in pancreatic cancer in association with poor prognoses. In pancreatic cancer cells, downregulation of CEACAM5, LGALS1, and CENPF significantly inhibited the proliferation, migration, and invasion abilities of the cells (P<0.05). CONCLUSION: Pancreatic cancer cells exhibit significant heterogeneity, and CEACAM5, LGALS1, and CENPF gene expressions, which affect pancreatic cancer cell proliferation, invasion, and metastasis, can be used to identify distinct molecular subtypes during tumor cell development.

[Progress in research of prophylactic therapy in contacts of rifampicin-resistant tuberculosis patients].

Tuberculosis (TB) prophylactic therapy for latent infection, which can reduce the risk for the development of active TB, is an important measure in TB control. China recommends prophylactic therapy for latent tuberculosis infection (LTBI) in some key populations to reduce the risk for TB. Contacts of patients with multi-drug and rifampicin-resistant TB (MDR/RR-TB) are at high risk for the infection with drug-resistant pathogen, however, no unified prophylactic therapy regimen has been recommended for LTBI due to exposure to MDR/RR-TB patients. This paper summarizes the current MDR/RR-TB prophylactic therapy regimen and its protection effect based on the results of the retrieval of literature, guidelines, expert consensus and technical specifications to provide reference for the prevention and control of LTBI.

[Predictive value of CONUT score and dialysis age for peritoneal dialysis-associated peritonitis].

Objective: To explore the predictive value of controlling nutritional status (CONUT) score and dialysis age for peritoneal dialysis-associated peritonitis (PDAP). Methods: This study was a follow-up study. Patients with end-stage renal disease who received peritoneal dialysis (PD) for the first time in the Department of Nephrology, the Third Affiliated Hospital of Suzhou University from January 2010 to December 2020 were enrolled in the study. Patients were divided into non-peritonitis group, mono group (only once PDAP occurred in one year) and frequent group (twice or more PDAP occurred in one year) according to the occurrence and frequency of PDAP during follow-up. The demographic, clinical and laboratory data of patients were collected, and the body mass index and CONUT score were recorded after half a year. Cox regression analysis was used to screen the relevant factors, and receiver operating characteristic (ROC) curve was used to analyze the predictive value of CONUT score and dialysis age for PDAP. Results: A total of 324 PD patients were included, with 188 males (58.0%) and 136 females (42.0%), and aged［M（Q1，Q3）］48 (37, 60) years old. The follow-up time was 33 (19, 56) months. PDAP occurred in 112 patients (34.6%), including 63 patients (19.4%) in mono group and 49 patients (15.1%) in frequent group. Multivariate Cox regression analysis showed that half-year CONUT score (HR=1.159, 95%CI: 1.047-1.283, P=0.004) was a risk factor for PDAP, and the baseline CONUT score (HR=1.194, 95%CI: 1.012-1.408, P=0.036) was a risk factor for frequent peritonitis. The area under ROC curve of baseline CONUT score combined with dialysis age in predicting PDAP and frequent peritonitis was 0.682 (95%CI: 0.628-0.733) and 0.676 (95%CI: 0.622-0.727), respectively. Conclusion: CONUT score and dialysis age have certain predictive value for PDAP, and the predictive value of combined diagnosis is higher, which may be used as a potential predictor for PDAP in PD patients.

Molecular epidemiology and antifungal susceptibilities of Aspergillus species isolated from patients with invasive aspergillosis

SUMMARY OBJECTIVE: The aim of this study was to evaluate the demographic data, molecular epidemiology, and in vitro antifungal susceptibility results of patients with Aspergillus isolated from various clinical specimens. METHODS: A total of 44 Aspergillus strains were studied. The definition of invasive aspergillosis in patients was made according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Strains were phenotypically and molecularly identified. Demographic characteristics of patients and genotypes of strains were evaluated. Phylogenetic analysis was done by the The Unweighted Pair-Group Method with Arithmetic Mean (UPGMA). Antifungal susceptibility of strains was determined according to The Clinical and Laboratory Standards Institute (CLSI)-M61-Ed2 and The European Committee on Antimicrobial Susceptibility Testing (EUCAST). RESULTS: A total of 11 patients were classified as proven and 33 as probable invasive aspergillosis. There was a statistically significant difference in age groups, subdisease, neutropenic, and receiving chemotherapy between groups. A total of 23 strains were identified as Aspergillus fumigatus, 12 as Aspergillus niger, 6 as Aspergillus flavus, and 3 as Aspergillus terreus. Phylogenetic analysis revealed five different genotypes. No statistical difference was found in the comparisons between patients groups and genotype groups. There was a statistically significant difference between genotype groups and voriconazole, posaconazole, and itraconazole Minimum Inhibition Concentration (MIC). CONCLUSION: Accurate identification of strains and antifungal susceptibility studies should be performed due to azole and amphotericin B resistance. Genotyping studies are important in infection control due to identifying sources of infection and transmission routes.

[Accuracy of the China-PAR and WHO risk models in predicting the ten-year risks of cardiovascular disease in the Chinese population].

Objective: To externally validate and compare the accuracy of the China-PAR (Prediction for ASCVD Risk in China) model and the 2019 World Health Organization (WHO) cardiovascular disease risk charts for East Asian in predicting a 10-year cardiovascular disease in a general Chinese population. Methods: Participants aged 40-79 years without prior cardiovascular disease at baseline in the CHinese Electronic health Records Research in Yinzhou (CHERRY) were analyzed. The Kaplan-Meier analysis estimated the observed cardiovascular events (including non-fatal myocardial infarction, fatal coronary heart disease, and non-fatal or fatal stroke) rate within ten years. The expected risks were calculated using the WHO risk charts for East Asia (including the laboratory-based and non-laboratory-based models) and the China-PAR model. The expected-observed ratios were calculated to evaluate the overestimation or underestimation of the models in the cohort. Model accuracy was assessed by discrimination C-index, calibration χ2 value, and calibration plots. Results: During a median of 7.26 years of follow-up, 13 301 cardiovascular events were identified among 225 811 participants. The C-index for the China-PAR model, WHO laboratory-based model and WHO non-laboratory-based model were 0.741 (0.735-0.747), 0.747 (0.740-0.753), and 0.739 (0.733-0.746) for men, and 0.782 (0.776-0.788), 0.789 (0.783-0.795), and 0.782 (0.776-0.787) for women, respectively. The WHO laboratory-based model and non-laboratory-based model underestimated the 10-year ASCVD risk by around 15% in women and underestimated by 0.8% and 4.4% in men, respectively. The China-PAR model underestimated the risks by 19.5% and 42.3% for men and women. Conclusions: The China-PAR and WHO models all have pretty good discriminations for 10-year cardiovascular risk assessment in this general Chinese population. However, the accuracy should be improved in the highest-risk groups, suggesting further specific models are still needed for those with the highest risk, such as patients with diabetes or older persons.

[Applications of the NDR and DIAL models for risk prediction on cardiovascular disease in patients with type 2 diabetes in Ningbo].

Objective: To validate the performance of cardiovascular risk prediction models based on the Sweden National Diabetes Register (NDR) and Diabetes Lifetime-perspective prediction (DIAL) model for assessing risks of 5-year and 10-year cardiovascular disease (CVD) among Chinese patients with type 2 diabetes. Methods: Based on the Chinese Electronic Health Records Research in Yinzhou study, 83 503 patients with type 2 diabetes aged 30-75 years without a history of CVD at baseline were included from January 1, 2010 to December 31, 2020. Recalibrated NDR model was used to estimate 5-year risk, while the recalibrated DIAL model was used to predict 5-year and 10-year risks. The competing events adjusted Kaplan-Meier analysis was used to obtain the observed cardiovascular events. Discrimination C statistics evaluated model accuracy, calibration χ2 value, and calibration plots. Results: Through a median follow-up of 7.0 years, 7 326 cardiovascular events, and 2 937 non-vascular deaths were identified among a total of 83 503 subjects. The recalibrated NDR model overestimated 5-year risk by 39.4% in men and 8.6% in women, whereas the overestimation for the recalibrated DIAL model was 14.6% in men and 50.1% in women. The DIAL model had a better discriminative ability (C-statistic=0.681, 95%CI: 0.672-0.690) than NDR model (C-statistic=0.667, 95%CI: 0.657-0.677) in 5-year risk prediction for men, and the models had a similar ability for women (C-statistic=0.699, 95%CI: 0.690-0.708 for NDR and C-statistic=0.698, 95%CI: 0.689-0.706 for DIAL). The prediction accuracy of the DIAL model was improved in the 10-year risk, with the underestimation being 1.6% for men and the overestimation being 12.8% for women. Conclusions: Both recalibrated NDR and DIAL models overestimated 5-year cardiovascular risk in Chinese patients with type 2 diabetes, while the higher overestimation was shown using the DIAL model. However, the improvement was found in predicting 10-year CVD risk using the DIAL model, which suggested the value of lifetime risk prediction and indicated the need for research on the lifetime risk prediction model for cardiovascular risk assessment in Chinese patients with type 2 diabetes.

Dietary Protein Intake in Relation to the Risk of Osteoporosis in Middle-Aged and Older Individuals: A Cross-Sectional Study.

OBJECTIVES: Dietary protein intake is of great significance for the bone health of middle-aged and elderly people. This study is aimed to explore the relationships between dietary protein intake and the risk of osteoporosis in middle-aged and older individuals among US population. METHODS: Based on the National Health and Nutrition Examination Survey (NHANES), this study includes a total of 20497 participants during 2005-2008, and identify 4707 middle-aged and older people aged 45 years or above. Demographic data and relevant dietary intake information are acquired through in-home management questionnaires. The logistic regression models are established to identify the odds ratio (OR) and 95% confidence interval (CI) of OP in each quartile category of energy-adjusted dietary protein intake. The receiver operating characteristic (ROC) curve is applied to explore the optimal cut-off value of daily dietary protein intake for predicting risk of OP. RESULTS: 442 participants with OP are identified among 4707 middle-aged and older people, and the dietary protein intake of OP group is significantly lower than that of non-OP group (P<0.001). The logistic regression analysis shows that with the increase of daily dietary protein intake, the prevalence of OP in each quartile category decreases gradually (P<0.001). This trend is not altered in univariate model (P<0.001), as well as the adjustments for the covariates of age and BMI (Model 1, P<0.001), the covariates of sex (Model 2, P=0.036), the covariates of smoking, drinking alcohol, education, ratio of family income to poverty, hypertension and diabetes (Model 3, P<0.001), and the covariates of dietary intake (Model 4, P=0.008). Moreover, we also identify that the daily dietary protein intake of 61.2g is the optimal cut-off value for predicting risk of OP. CONCLUSION: In general, among US population, the lower daily dietary protein intake is positively related to the ascending risk of OP in middle-aged and older individuals.

Exogenous citric acid enhances drought tolerance in tobacco (Nicotiana tabacum).

Organic acids play a pivotal role in improving plant response to long-term drought stress. External application of organic acids has been reported to improve drought resistance in several species. However, whether organic acids have similar effects in tobacco remains unknown. A screening study of the protective function of organic acids in tobacco and understanding the underlying molecular mechanism would be useful in developing a strategy for drought tolerance. Several physiological and molecular adaptations to drought including abscisic acid, stomatal closure, reactive oxygen species homeostasis, amino acid accumulation, and drought-responsive gene expression were observed by exogenous citric acid in tobacco plants. Exogenous application of 50 mm citric acid to tobacco plants resulted in higher chlorophyll content, net photosynthesis, relative water content, abscisic acid content and lower stomatal conductance, transpiration and water loss under drought conditions. Moreover, reactive oxygen species homeostasis was better maintained through increasing activity of antioxidant enzymes and decreasing hydrogen peroxide content after citric acid pretreatment under drought. Amino acids involved in the TCA cycle accumulated after external application of citric acid under drought stress. Furthermore, several drought stress-responsive genes also dramatically changed after application of citric acid. These data support the idea that external application of citric acid enhances drought resistance by affecting physiological and molecular regulation in tobacco. This study provides clear insights into mechanistic details of regulation of amino acid and stress-responsive gene expression by citric acid in tobacco in response to drought, which is promising for minimizing growth inhibition in agricultural fields.

[Correlation between nUGT1A1 gene polymorphisms and adverse events of irinotecan plus S-1 for patients with recurrent or metastatic esophageal squamous cell carcinoma: a prospective, open-label, randomized controlled trial (ESWN 01)].

Objective: To investigate the correlation between UGT1A1 polymorphisms and the irinotecan plus S-1 regimen-induced toxicities in Chinese advanced esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 46 recurrent or metastatic ESCC patients selected from ESWN 01 trial were randomly assigned to irinotecan plus S-1 group [intravenous infusion of irinotecan (160 mg/m(2)) on day 1 and oral S-1 (80-120 mg) on days 1-10, repeated every 14 days]. Peripheral venous blood at baseline was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by polymerase chain reaction (PCR) amplification. Irinotecan plus S-1 regimen-induced toxicities of patients with different UGT1A1 polymorphisms were observed. The correlation between UGT1A1 polymorphisms and the adverse effects was analyzed. Results: Among the 46 patients, the numbers of UGT1A1*6 wild type genotype (GG), mutant heterozygote (GA) and mutant homozygote (AA) were 30, 15 and 1, while those with UGT1A1*28 wild type genotype (TA6/6), mutant heterozygote (TA6/7) and mutant homozygote (TA7/7) were 36, 8 and 2, respectively. Only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea, while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea. No neutropenia was observed in the patient with UGT1A1*6 AA genotype, however, both of the two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia. Patients with UGT1A1*28 genetic polymorphism (TA 6/7 or TA7/7) had a higher response rate compared with wild-type TA6/6 carriers. (55.6% versus 26.5%). Conclusions: The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 are rare (<5%) in Chinese ESCC population. Not all homozygous AA and TA7/7 carriers occur severe dose limited toxicities (DLT) when treated with irinotecan (160 mg/m(2)) plus S-1 regimen for 2 weeks. However, it's still necessary torigorously observe the occurrence of severe diarrhea and neutropenia in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7 and adjust the dose timely.

Tongxin formula protects H9c2 cardiomyocytes from cobalt chloride-induced hypoxic injury via inhibition of apoptosis.

In this study, the effect of the Tongxin formula (TXF) on the apoptosis of H9c2 cardiomyocytes induced by cobalt chloride (CoCl2) was investigated, and the potential mechanism was explored. A hypoxic injury model of H9c2 cardiomyocytes was established using CoCl2. The cell viability was measured using a Cell Counting Kit-8 assay. The lactate dehydrogenase (LDH) release and caspase-3 activity were measured using spectrophotometry. The apoptosis was measured via Annexin V-FITC/PI staining and flow cytometry. The changes in the mitochondrial membrane potential were examined using immunofluorescence microscopy following the loading of JC-1 probes. The expressions of apoptosis-related proteins and key proteins in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway were examined via immunoblotting. The different TXF concentrations studied significantly improved the percentage of viability of cardiomyocytes with hypoxic injury, and the LDH release, apoptotic rate, caspase-3 activity, and levels of cleaved caspase-3 protein were reduced in the injured cells. Additionally, the TXF group had increased mitochondrial membrane potential, upregulated expression of Bcl-2 and p-Akt proteins, and significantly reduced expression of cleaved caspase-3 protein in the cells with hypoxic injury. Moreover, in the TXF group, the treatment significantly reduced the BAX protein expression, but the difference was not statistically significant compared with the CoCl2 group. In this study, TXF regulated the expression of apoptosis-related proteins, inhibited apoptosis, increased the mitochondrial membrane potential, and alleviated damage to the mitochondrial membrane, thereby protecting the cardiomyocytes from hypoxic injury. The underlying mechanism could be related to activation of the PI3K/Akt signaling pathway and upregulation of the Bcl-2 protein.

Experimental realization of a π/2 vortex mode converter for electrons using a spherical aberration corrector.

In light optics, beams with orbital angular momentum (OAM) can be produced by employing a properly-tuned two-cylinder-lens arrangement, also called π/2 mode converter. It is not possible to convey this concept directly to the beam in an electron microscope due to the non-existence of cylinder lenses in commercial transmission electron microscopes (TEMs). A viable work-around are readily-available electron optical elements in the form of quadrupole lenses. In a proof-of-principle experiment in 2012, it has been shown that a single quadrupole in combination with a Hilbert phase-plate produces a spatially-confined, transient vortex mode. Here, an analogue to an optical π/2 mode converter is realized by repurposing a CEOS DCOR probe corrector in an aberration corrected TEM in a way that it resembles a dual cylinder lens using two quadrupoles. In order to verify the presence of OAM in the output beam, a fork dislocation grating is used as an OAM analyser. The possibility to use magnetic quadrupole fields instead of, e.g., prefabricated fork dislocation gratings to produce electron beams carrying OAM enhances the beam brightness by almost an order of magnitude and delivers switchable high-mode purity vortex beams without unwanted side-bands.

[CART therapy followed by allo-HSCT for patients with B-cell acute lymphoblastic leukemia relapsing after the first hematopoietic stem cell transplantation].

Objective: To study the clinical efficacy of chimeric antigen receptor T-cell (CART) treatment followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with B-cell acute lymphoblastic leukemia (ALL) who relapsed following the first HSCT. Methods: Retrospective analysis of the clinical characteristics and prognosis of 41 patients with B-cell ALL who received a second allo-HSCT from October 2015 to June 2020 in Hebei Yanda Lu Daopei Hospital. After the first HSCT, all patients received CD19-CART, or CD22-CART treatment following a relapse of bone marrow morphology or extramedullary leukemia. Results: A total of 41 patients (male, 21; female, 20) were included in this study. The median age at the second HSCT was 16 (3-46) years. There were 31 cases of bone marrow recurrence (75.6%) , 5 cases of extramedullary recurrence (12.2%) , and 5 cases of bone marrow and extramedullary recurrences (12.2%) . After relapse, 35 patients (85.4%) received CD19-CART treatment, 2 patients received CD22-CART treatment (4.9%) , and 4 patients received CD19-CART and CD22-CART treatments (9.8%) . The expected 3-year overall survival (OS) , leukemia-free survival, cumulative relapse incidence, and non-relapse mortality (NRM) of patients after the second HSCT were 48.9% (95%CI 23.0%-70.6%) , 41.8% (95%CI 17.3%-64.9%) , 8.8% (95%CI 2.9%-26.4%) , and 51.1% (95%CI 31.2%-83.6%) , respectively. The 1-year OS of patients who relapsed ≤6 months and >6 months after the first HSCT were 45.0% (95%CI 12.7%-73.5%) and 75.0% (95%CI 51.4% -88.8%) (P=0.017) , respectively. Conclusion: CART bridging in the second HSCT enables some B-cell ALL patients who relapsed after the first HSCT to achieve long-term survival. However, because of the high NRM, further modifications could help improve the outcome.

MDM2 inhibition improves cisplatin-induced renal injury in mice via inactivation of Notch/hes1 signaling pathway.

OBJECTIVE: To explore the potential function of MDM2-mediated Notch/hes1 signaling pathway in cisplatin-induced renal injury. METHODS: The acute renal injury models of mice after intraperitoneal injection of cisplatin in vivo, and the apoptotic models of human renal tubular epithelial (HK-2) cells induced by cisplatin in vitro, were conducted respectively. The renal function-related parameters were measured. The renal tissue pathological changes and apoptosis were observed by PAS staining and TUNEL staining, respectively. Cell viability and apoptosis were detected by MTT and flow cytometry. Notch/hes1 pathway-related proteins were tested by Western blotting. RESULTS: After mice injected by cisplatin, the levels of Cr, BUN, urine cystatin C, urine NGAL and urine ACR were increased and GFR was decreased with the elevation of renal tubular injury scores, the upregulation of the expressions of MDM2, N1ICD, Hes1 and Cleaved caspase-3, as well as the enhancement of cell apoptosis accompanying decreased ratio of Bcl-2/Bax. However, these cisplatin-induced renal injuries of mice have been improved by MDM2 inhibition. Besides, the declined viability, increased cytotoxicity, and enhanced apoptosis were observed in cisplatin-induced HK-2 cells, with the activated Notch/hes1 pathway. Notably, the phenomenon was alleviated in cisplatin-induced HK-2 cells transfected with MDM2 shRNA, but was severer in those co-treated with AdMDM2. Moreover, Notch1 siRNA can reverse the injury of AdMDM2 on HK-2 cells. CONCLUSION: Inhibiting MDM2 could reduce cell apoptosis through blocking Notch/hes1 signaling pathway, thus alleviating the acute renal injury caused by cisplatin.