Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Conventional 1.5T and 3.0T cardiac MRI(CMRI)had been widely used.The ultrahigh field MR behaved better in image resolution and signal-to-noise ratio.The domestic 5.0T whole-body ultrahigh field MRI had better balance between the field strength and quality in CMRI,which was expected to improve imaging quality and efficiency.The status challenges and future of 5.0T CMRI were reviewed in this paper.

Objective:To assess the changes of selenium nutrition of school-age children in Kashin-Beck disease (KBD) areas of Linzhou County, Lhasa City and Xietongmen County, Shigatse City in Tibet Autonomous Region (referred to as Tibet), and provide a scientific basis for evaluating the effectiveness of prevention and control measures.Methods:According to the historical condition of KBD, a total of 344 children's hair samples were collected to determine the content of selenium in Kazi (KBD area) and Jiangxia townships (non-KBD area) of Linzhou County in 2013 and 2021, Renqinze (KBD area) and Tongmen townships (non-KBD area) of Xietongmen County in 2015 and 2021.Results:Compared to 2013/2015, in 2021, the hair selenium level of children in the four townships increased ( P < 0.001). The selenium nutritional level of more than 90% of the children reached medium or above (hair selenium > 0.25 μg/g) in 2021. The hair selenium levels of girls in the two KBD areas (Kazi and Renqinze townships) were lower than those of boys ( Z = - 2.83, - 2.83, P < 0.05). Conclusions:The selenium nutrition level of school-age children in KBD areas in Linzhou and Xietongmen counties has increased rapidly in recent years. However, the selenium nutrition level of girls is significantly lower than that of boys. It is necessary to strengthen prevention, controlling and monitoring, and to further improve the dietary structure of school-age children through the joint efforts of families and schools, to increase the proportion of exogenous high selenium food intake.

Objective:To analyze the distribution of different SF3B1 genotypes in patients with myelodysplastic syndromes (MDS) and its prognostic value.Methods:Totally, 377MDS patients who were initially diagnosed in the First Affiliated Hospital of Nanjing Medical University from January 2014 to January 2022 were included in the retrospective analysis.The patients were divided into three different groups according to mutation stcote of SF3B1, including 317 patients with SF3B1 wild type (SF3B1 WT) (214 males and 103 females, 63(49, 71) years old),39 patients with SF3B1 K700E mutation(SF3B1 K700E(17 males and 22 females, 65(52, 73)years old)) and 21 patients with SF3B1 non-K700E mutation(SF3B1 non-K700E)(13 males and 8 females, 67(63, 73) years old). MDS-related 20 gene mutations were detected using targeted sequencing technology; Survival curves were constructed by the Kaplan-Meier method; Cox proportional hazards model was established to evaluate different factors at diagnosis on survival by univariate and multivariate analyses.. Results:Compared with SF3B1 non-K700E patients, SF3B1 K700E patients had a higher median absolute neutrophil count ( P=0.002) and were likely to be in the low/int-1 International Prognostic Scoring System (IPSS) categories ( P=0.023). A 20-gene targeted sequencing analysis showed that, compared with SF3B1 WT patients, SF3B1 K700E patients were associated with lower frequency of ASXL1 and U2AF1 mutations ( P=0.018 and P=0.003); while compared with SF3B1 non-K700E patients, the frequency of ASXL1 mutation was significantly lower in SF3B1 K700E cases ( P=0.029). Patients with SF3B1 K700E had better overall survival (OS) in comparison with SF3B1 WT and SF3B1 non-K700E in MDS patients ( P<0.001 and P=0.045, respectively). In comparison with SF3B1 WT patients, SF3B1 MUT patients had more favorable OS and progression-free survival (PFS) in MDS without excess blasts ( P<0.001 and P<0.001, respectively), but no significant difference was found in MDS with excess blasts ( P>0.05). Compared with SF3B1 WT patients, SF3B1 K700E patients had superior OS and PFS in the int-1 IPSS category ( P=0.010 and P=0.013, respectively). By multivariable analysis, the presence of SF3B1 K700Ewas an independent predictor of superior OS ( HR=0.461,95% CI 0.262-0.811, P=0.007). Conclusion:SF3B1 K700E and SF3B1 non-K700E patients had significantly improved OS in comparison with SF3B1 WT MDS patients. Furthermore, SF3B1 K700E patients were associated with a better OS compared with SF3B1 non-K700E MDS patients. SF3B1 mutation could not overcome the poor prognostic effect of excess blasts, which highlights the importance of the SF3B1 mutation subtype in risk assessment of MDS without excess blasts.

Objective:To investigate the effect of sequential suture and adhesion on craniomaxillofacial skin contusion and laceration.Methods:A total of 189 patients with craniomaxillofacial skin contusion and laceration (CMFSCL) were randomly divided into three groups: 66 cases in SSA group, 63 cases in CS group and 60 cases in TS group. Operation time, visual analogue scale (VAS), Vancouver scar scale (VSS) and adverse reactions incidence were compared and analyzed between the three groups. Effect and satisfactory scale were evaluated.Results:Operation time in SSA group (10.67±1.26) min was significantly less than that in CS (18.91±1.38) min and TS group (17.96±1.43) min ( P<0.05). VAS in SSA group 24 h post-operation (3.11±1.01) was significantly lower than that in CS and TS group ( P<0.05). VSS in SSA group 6 months post-operation (1.18±0.21) was significantly lower than that in CS (3.78±1.01) ( P<0.05) and TS group (5.98±1.06) ( P<0.01). Total effective rate of SSA group (96.5%) was significantly higher than that in CS (85.7%) ( P<0.05) and TS group (56.1%) ( P<0.01); total effective rate in CS group was significantly higher than that in TS group ( P<0.05). Infection and dehiscence rates in SSA group were lower than those in CS and TS group ( P<0.01). Satisfactory rate of SSA group (99%) was significantly higher than that of CS (89.1%) and TS group (71.3%) ( P<0.05); the satisfactory rate of CS group was significantly higher than that of TS group ( P<0.05). Conclusions:Sequential suture and adhesion technique is simple and effective for craniomaxillofacial skin contusion and laceration, which is worthy of clinical promotion.

Bevacizumab, an anti-VEGF monoclonal antibody, has significantly improved the clinical outcomes of patients with advanced non-squamous NSCLC (ns-NSCLC). However, the safety and efficacy of bevacizumab for elderly patients with advanced NSCLC require further investigation. Thus, 59 patients were included in the present retrospective study, 22 patients in the bevacizumab plus pemetrexed and platinum (B + PP) group, and 37 patients in the pemetrexed and platinum (PP) group. For the entire cohort of patients, the median OS was 33.3 months, and the 1-year and 2-year overall survival rates were 88.5% and 67.8%, respectively. The median OS and 1-year and 2-year OS rates were 20.5 months, 70.3% and 0%, respectively, in the B + PP group and 33.4 months, 97.0% and 89.4%, respectively, in the PP group (P < 0.001). The incidence of grade ⩾ 3 adverse events was higher in the B + PP group than in the PP group (27.3% vs. 10.8%, respectively; P = 0.204). Univariate and multivariate analyses suggested that the receipt of ⩾ 5 cycles of first-line chemotherapy was an independent favorable prognostic factor for OS, whereas the addition of bevacizumab was an unfavorable prognostic factor. With increased toxicities, the addition of bevacizumab to PP does not improve the overall survival of elderly patients with advanced ns-NSCLC.
Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Bevacizumab/adverse effects* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Humans ; Lung Neoplasms/drug therapy* ; Pemetrexed/adverse effects* ; Platinum/therapeutic use* ; Retrospective Studies ; Treatment Outcome

Objective:To analyze the epidemiological trends and major risk attribution of pancreatic cancer in China, Japan and South Korea from 1990 to 2019.Methods:The descriptive epidemiological method was conducted. The overall incidence rate, mortality rate, age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) of pancreatic cancer in China, Japan and South Korea from 1990 to 2019 were collected from the Global Burden of Disease (GBD) Database. Age-standardized rates were calculated based on the worldwide standardized population structure provided by GBD Database 2019. Observation indicators: (1) incidence and motality of pancreatic cancer in China, Japan and South Korea in 2019; (2) age-period-cohort model analysis of incidence and mortality rates of pancreatic cancer in China, Japan and South Korea from 1990 to 2019; (3) trends of ASIR and ASMR of pancreatic cancer in China, Japan and South Korea from 1990 to 2019; (4) trends of major risk attribution of pancreatic cancer related death in China, Japan and South Korea from 1990 to 2019. Count data were represented as absolute numbers, percentages and ratios. Joinpoint V.4.7.0.0 software was used to calculate the annual percentage change (APC), the average annual percentage change (AAPC) of incidence and mortality rates of pancreatic cancer in different time periods and 95% confidence interval (95% CI). The age-period-cohort model in STATA V.15.0 software was used to analyze the influence of different ages, periods and birth cohorts on the risk of onset and death of pancreatic cancer after controlling the other two variables, with the risk effect size described as relative risk (95% CI). Results:(1) Incidence and motality of pancreatic cancer in China, Japan and South Korea in 2019. In 2019, the incidence rate of pancreatic cancer in China increased from 0.07/100,000 among 15-19 years old to 64.01/100,000 among 85-89 years old, with increasing from 0.09/100,000 to 94.71/100,000 in males and from 0.04/100,000 to 47.47/100,000 in females. The mortality rate of pancreatic cancer in China increased from 0.04/100,000 among 15-19 years old to 79.58/100,000 among 85-89 years old, with increasing from 0.05/100,000 to 116.50/100,000 in males and from 0.03/100,000 to 59.69/100,000 in females. The incidence rate of pancreatic cancer in Japan increased from 0.03/100,000 among 15-19 years old to 162.26/100,000 among 85-89 years old, with increasing from 0.03/100,000 to 177.67/100,000 in males and from 0.04/100,000 to 153.67/100,000 in females. The mortality rate of pancreatic cancer in Japan increased from 0.02/100,000 among 15-19 years old to 154.88/100,000 among 85-89 years old, with increasing from 0.02/100,000 to 170.93/100,000 in males and from 0.02/100,000 to 145.94/100,000 in females. The incidence rate of pancreatic cancer in South Korea increased from 0.04/100,000 among 15-19 years old to 136.78/100,000 among 85-89 years old, with increasing from 0.03/100,000 to 153.78/100,000 in males and from 0.04/100,000 to 129.73/100,000 in females. The mortality rate of pancreatic cancer in South Korea increased from 0.02/100,000 among 15-19 years old to 135.98/100,000 among 85-89 years old, with increasing from 0.02/100,000 to 156.21/100,000 in males and from 0.02/100,000 to 127.59/100,000 in females. The peak incidence and mortality of pancreatic cancer in China were found in males aged 65-69 years, and the overall incidence and mortality of males in different age groups were higher than those of females in the same age group. In Japan, the peak incidence of pancreatic cancer occurred in females aged 80-84 years and the peak mortality occurred in males aged 75-79 years. The morbidity and mortality of males aged <80 years were higher than those of females in the same age group, while the morbidity and mortality of males aged ≥80 years were lower than those of females in the same age group. In South Korea, the peak incidence of pancreatic cancer occurred in females aged 80-84 years, and the peak mortality occurred in males aged 70-74 years. The morbidity and mortality of males aged <75 years were higher than those of females in the same age group, while the morbidity and mortality of males aged ≥75 years were lower than those of females in the same age group. (2) Age-period-cohort model analysis of incidence and mortality rates of pancreatic cancer in China, Japan and South Korea from 1990 to 2019. Age effect: after adjustment for the period and cohort effects, the risk of incidence and mortality rates of pancreatic cancer in both males and females of China, Japan and South Korea increased with age, which is more obvious in females than males, and more obvious in Japanese than Chinese and Korean populations. Period effect: after adjustment for age and cohort effects, the risk of incidence and mortality rates of pancreatic cancer in both males and females of China, Japan and South Korea increased from 1990 to 2019, with the period effect more significant in the Chinese population. Cohort effect: after adjustment for age and period effects, the risk of morbidity and mortality rates of pancreatic cancer decreased with the passage of birth cohort in China, Japan and South Korea. (3) Trends of ASIR and ASMR of pancreatic cancer in China, Japan and South Korea from 1990 to 2019. The ASIR and ASMR of pancreatic cancer in China increased yearly from 1990 to 2019, and the ASIR and ASMR in 2019 were 1.82 times and 1.79 times those in 1990, respectively. The ASIR and ASMR of pancreatic cancer in Japan showed a slowly increasing trend, and the ASIR and ASMR in 2019 were 1.09 times and 1.05 times those in 1990, respectively. The ASIR and ASMR of pancreatic cancer in South Korea increased firstly, then decreased, and slowly increased. From 1990 to 2019, the AAPC of ASIR of pancreatic cancer in China was 2.08% (95% CI as 1.91% to 2.24%, P<0.05) and AAPC of ASMR was 2.02% (95% CI as 1.86% to 2.19%, P<0.05). The AAPC of ASIR of pancreatic cancer in Japan was 0.28% (95% CI as 0.15% to 0.42%, P<0.05) and AAPC of ASMR was 0.13% (95% CI as 0.03% to 0.24%, P<0.05). The AAPC of ASIR of pancreatic cancer in South Korea was 0.50% (95% CI as 0.21% to 0.80%, P<0.05) and AAPC of ASMR was 0.15% (95% CI as -0.10% to 0.40%, P>0.05). (4) Trends of major risk attribution of pancreatic cancer related death in China, Japan and South Korea from 1990 to 2019. The main risk factors for pancreatic cancer related death in China, Japan and South Korea from 1990 to 2019 were smoking, high fasting glucose and high body mass index (BMI). The trend of pancreatic cancer related death, mainly attributed to smoking, showed that the proportion of Chinese males increased from 31.4% in 1990 to 34.1% in 2000, then decreased to 31.1% in 2015, and then showed a slow increase to 31.7% in 2019. The proportion of Chinese females increased from 6.7% in 1990 to 10.4% in 2005 and then dropped to 8.7% in 2019. The proportion of Japanese males decreased from 38.8% in 1990 to 26.9% in 2019 and the proportion of Japanese females decreased from 20.9% in 1990 to 14.8% in 2019. The proportion of South Korean males decreased from 37.5% in 1990 to 30.3% in 2019 and the proportion of South Korean females decreased from 12.6% in 1990 to 10.0% in 2019. The trend of pancreatic cancer related death proportion, mainly attributed to high fasting blood glucose, showed that the proportion of Chinese males increased from 5.9% in 1990 to 7.1% in 2019 and the propor-tion of Chinese females increased from 6.2% in 1990 to 6.8% in 2019. The proportion of Japanese males increased from 7.0% in 1990 to 7.7% in 2019 and the proportion of females increased from 5.0% in 1990 to 5.5% in 2019. The proportion of South Korean males increased from 6.8% in 1990 to 9.7% in 2019 and the proportion of females increased from 6.1% in 1990 to 8.2% in 2019. The trend of pancreatic cancer related deaths proportion, attributed mainly to high BMI, showed that the proportion of Chinese males increased from 1.3% in 1990 to 3.0% in 2019 and the proportion of females increased from 2.1% in 1990 to 4.3% in 2019. The proportion of Japanese males increased from 2.0% in 1990 to 2.4% in 2019 and the proportion of females increased from 3.1% in 1990 to 3.4% in 2019. The proportion of South Korean males increased from 1.9% in 1990 to 3.1% in 2019 and the proportion of females increased from 3.4% in 1990 to 4.3% in 2019. Conclusions:The incidence of pancreatic cancer in China may continue to rise but to be stable in Japan and South Korea. The incidence of pancreatic cancer in females, especially elderly women, needs more attention. Smoking remains the most critical risk factor for pancreatic cancer. More attention should also be paid to the increased risk of pancreatic cancer associated with high BMI and high fasting plasma glucose.

Objective:To explore the correlation of CD49d expression patterns with molecular genetics and hotspot gene mutants in patients with chronic lymphocytic leukemia.Methods:The expression of CD49d was detected by flow cytometry and grouped into homogeneous, bimodal, negative and positive expression. Panel fluorescence in situ hybridization (FISH) was used for molecular genetics analysis and next-generation sequencing (NGS) was conducted for gene mutation detection.Results:There were 43 patients (23.89% ) with positive CD49d expression, 137 patients (76.11% ) with negative CD49d expression, 96 patients (53.33% ) with homogeneous CD49d expression and 84 patients (46.67% ) with bimodal CD49d expression. Compared with patients in the CD49d negative group, patients in the CD49d positive group had higher Rai stage ( P=0.048) and higher proportion of spleen enlargement ( P=0.030) . Compared with patients with homogeneous expression of CD49d, patients with bimodal expression of CD49d had a higher proportion of spleen enlargement ( P=0.009) . The expression rate of 11q22- in bimodal CD49d - group was significantly higher than that in homogeneous CD49d - group (24.29% vs 10.45% , P=0.043) . The incidence of +12 in homogeneous CD49d group was higher than that in bimodal CD49d group (16.67% vs 5.95% , P=0.035) . The incidence of +12 in homogeneous CD49d + group was higher than that in bimodal CD49d - group (17.24% vs 4.29% , P=0.045) . The incidence of +12 in homogeneous CD49d - group was higher than that in bimodal CD49d - group (16.42% vs 4.29% , P=0.024) . BIRC3 mutation rate in CD49d positive group was higher than that in CD49d negative group (11.63% vs 2.92% , P=0.037) . Conclusion:There were significant correlations between CD49d and 11q22-, +12 and BIRC3 gene mutation. Patients with bimodal CD49d were more correlated with poor prognosis indexes.

Objective:To analyze the differences in immunophenotype, cytogenetics, and molecular biology between typical and atypical immunophenotype chronic lymphocytic leukemia (CLL) , and explore the correlation of cytogenetic anomalies with gene mutations.Methods:This study included 488 patients diagnosed in the First Affiliated Hospital of Nanjing Medical University between November 2014 and May 2021. Of these, 382 patients scored 4-5 points, which was typical CLL (tCLL) , and 106 scored 3 points, which was atypical CLL (aCLL) as per the Royal Marsden Hospital Immunomarker Integral System. Peripheral blood cells were collected for immunophenotype by multiparameter flow cytometry in 488 patients, fluorescence in situ hybridization (FISH) was employed to detect cytogenetic anomalies in 359 patients, and gene mutations were detected by next-generation sequencing (NGS) in 330 patients.Results:The positive rates of CD10, CD22, CD49d, CD81, and FMC7 were significantly higher in the aCLL compared with the tCLL group ( P=0.020, P<0.001, P<0.001, P=0.027, and P<0.001, respectively) , while the positive rates of CD5, CD23, CD148, and CD200 were lower in the former compared to the latter ( P<0.001, P=0.017, P=0.041, and P<0.001, respectively) . aCLL exhibited a higher frequency of trisomy 12 and lower frequency of del (13q14) compared to the tCLL group ( P<0.001 and P<0.001, respectively) . Moreover, aCLL patients also showed a higher incidence of NOTCH1 mutations than the tCLL patients ( P=0.038) , while no statistically significant differences in other gene mutations occurred between the two groups. No significant differences in overall survival (OS) and treatment-free survival (TFS) occurred between aCLL and tCLL using Kaplan-Meier analysis ( P>0.05) . Conclusion:aCLL has characteristic immunophenotype, cytogenetic, and somatic mutation that differ from tCLL, and this can provide reliable information for the diagnosis and differential diagnosis between the two groups.