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.

Objective: To examine the developmental trajectory of fine motor ability in schoolage children with attention deficit hyperactivity disorder (ADHD) for two years, so as to provide scientific evidence to promote motor development in ADHD children. Methods: From April to June 2019, 31 children aged 6-8 years old were selected from a public elementary school. They were diagnosed with ADHD by two psychiatric professionals according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. Additionally, 31 typical developmental children, matched for age, sex and IQ with the ADHD group, were recruited as the control group. Fine motor ability was assessed with tasks of hand manual dexterity in Movement Assessment Battery for Children-2 (MACB-2), and a followup assessment was conducted from April to June 2021. The development changes of fine motor ability between two groups of children were compared by using t test and repeated measures analysis of variance. Results: Between baseline and followup periods after two years, the total score of hand fine motor in the ADHD group did not show significant improvement (7.4±3.0, 8.0±3.4; t=-1.05, P>0.05), while there was a small effect size improvement in typically developing control group (9.5±2.1, 10.5±2.4; t=-2.12, effect size=0.38, P<0.05). Followup after two years, coin/peg throwing scores with dominant hand improved between ADHD group and control group (7.0±3.3, 9.5±3.2; 8.4±2.8, 11.6±1.6) (t=-3.74, -6.33, P<0.01; effect size=0.67, 1.14), with a smaller improvement in the ADHD group. The score for threading beads/threads decreased in between ADHD group and control group (7.9±2.4, 5.8±3.1; 9.2±1.1, 8.2±1.9) (t=3.89, 2.78, P<0.01; effect size=0.70, 0.50), with a greater decrease in the ADHD group. Conclusions The development speed of fine motor ability in children with ADHD aged 6-8 is slow and continues to lag behind normal developmental children. Fine motor development in children with ADHD should be closely monitored, and targeted interventions should be implemented when necessary.

Objective:To investigate the clinical significance of tumor budding as an indicator of postoperative distant organ metastasis after radical gastrectomy in elderly patients diagnosed with gastric cancer.Methods:The clinical and pathological data of 124 elderly patients who experienced metastasis after undergoing radical gastrectomy were retrospectively analyzed.The analysis was conducted from March 2015 to June 2022, focusing on the clinicopathological factors that influenced the occurrence of postoperative distant metastasis in these patients.Tumor budding in gastric cancer tissues was assessed using hematoxylin-eosin staining, and its clinical significance was analyzed.Results:The tumor budding grade of gastric cancer tissues showed a significant correlation with vascular invasion( χ2=6.731, P=0.009), the number of lymph node metastases( rs=0.481, P<0.001), and the time of distant metastasis( rs=-0.450, P<0.001).In the univariate analysis, factors such as tumor budding grade, tumor size, vascular invasion, postoperative chemotherapy, cancerous nodule, preoperative serum carbohydrate antigen 125, and the number of lymph node metastases were found to influence distant metastasis-free survival after radical gastrectomy in elderly patients(all P<0.05).The multifactorial analysis also indicated that tumour outgrowth grade was an important independent prognostic factor for postoperative distant metastasis in elderly gastric cancer patients( HR=3.731, P<0.001). Conclusions:The findings of this study indicate that tumor budding may serve as a potential marker for predicting distant organ metastasis in elderly patients who have undergone radical gastrectomy.This discovery holds significant clinical implications.

Objective:To observe the effects of warming needle therapy combined with the modified Hua Tan Tong Luo Tang(decoction for dissipating phlegm and unblocking collaterals)on post-stroke cognitive impairment due to obstruction of wind-phlegm. Methods:A total of 78 patients who met the inclusion criteria were randomly assigned to an observation group and a control group,with 39 patients in each group.Both groups received conventional treatment.The control group was additionally treated with the modified Hua Tan Tong Luo Tang,while the observation group received warming needle therapy in addition to the treatment given to the control group.Scores on the mini-mental state examination(MMSE),Montreal cognitive assessment(MoCA),and activities of daily living(ADL)were assessed before and after treatment.Adverse reactions and clinical efficacy were analyzed and compared between the two groups after treatment. Results:The total effective rate was 82.1%in the observation group and 61.5%in the control group,showing statistical significance between the two groups(P<0.05).After treatment,the MMSE,MoCA,and ADL scores of both groups were significantly higher than those before treatment within each group(P<0.05).Notably,the scores in the observation group were higher than those in the control group(P<0.05).No adverse reactions occurred in either group during the treatment period. Conclusion:Based on the conventional treatment,compared to modified Hua Tan Tong Luo Tang alone,warming needle therapy combined with the modified Hua Tan Tong Luo Tang showed superior clinical efficacy in treating post-stroke cognitive impairment due to obstruction of wind-phlegm,and this combined therapy also showed high safety.

Objective:To investigate the MRI features of fibro-adipose vascular anomaly (FAVA).Methods:The clinical, pathological and MRI data of the FAVA patients confirmed clinically and pathologically in Henan Provincial People’s Hospital from January 2016 to June 2021 were retrospectively analyzed, including 17 females and 13 males, aged 4-53 (18.5±12.8) years.Through the analysis of the MRI images of FAVA performance, including the lesion area, shape, signal, the degree of reinforcement, inner structure, outer structure and other image characteristics, summarize the MRI features.Results:The lesions located at the lower leg (12 cases), thigh (12 cases), upper arm (4 cases), forearm (1 case) and trunk (1 case). Twenty-four case of lower limbs. All cases involved the muscular layer, including 21 cases of superficial muscle layer, 7 cases of deep muscle layer, and 2 cases of both. Twenty-three cases of superficial muscle layer. Most of the affected muscles were quadriceps femoris and gastrocnemius. Morphology: all lesions were intramuscular solid masses growing parallel to the long axis of the muscle. There were 11 cases of focal type, 11 cases of locally infiltrating type, and 8 cases of diffuse type. MRI findings: all lesions showed mixed signal. On T1WI, 28 cases showed cloud-like, band-like and patchy high signal on the background of medium and high signal. On T2WI-FS, all the 30 cases showed low to medium signal areas on the background of high signal, which were dendrimer, ribbon and cloud-like. The lesions showed moderate to obvious heterogeneous progressive enhancement. Twenty-seven lesions had different shapes of vascular shadow, and 28 lesions had drainage vein shadow adjacent to the lesions, 24 of which were located at the proximal end of the lesions. Fascial tail sign was found at the periphery of the lesions in 26 cases, of which 23 cases were located at the upper and lower ends of the lesions.Conclusion:FAVA is a complex vascular malformation with unclear pathological classification. MRI usually shows a solid mass in the superficial muscle layer of the lower limbs parallel to the long axis of the muscle, with cloud-like, band-like, and patchy hyperintensity on the background of high signal on T1WI, and dendritic, band-like, and cloud-like hypointensity on the background of high signal on T2WI-FS, which is helpful for the diagnosis of FAVA. Combined with the data of fascial tail sign, draining vein and clinical manifestations, the diagnosis of FAVA can be confirmed to a certain extent, which can provide reference and basis for clinical decision making.

Objective:To investigate the MRI features of fibro-adipose vascular anomaly (FAVA).Methods:The clinical, pathological and MRI data of the FAVA patients confirmed clinically and pathologically in Henan Provincial People’s Hospital from January 2016 to June 2021 were retrospectively analyzed, including 17 females and 13 males, aged 4-53 (18.5±12.8) years.Through the analysis of the MRI images of FAVA performance, including the lesion area, shape, signal, the degree of reinforcement, inner structure, outer structure and other image characteristics, summarize the MRI features.Results:The lesions located at the lower leg (12 cases), thigh (12 cases), upper arm (4 cases), forearm (1 case) and trunk (1 case). Twenty-four case of lower limbs. All cases involved the muscular layer, including 21 cases of superficial muscle layer, 7 cases of deep muscle layer, and 2 cases of both. Twenty-three cases of superficial muscle layer. Most of the affected muscles were quadriceps femoris and gastrocnemius. Morphology: all lesions were intramuscular solid masses growing parallel to the long axis of the muscle. There were 11 cases of focal type, 11 cases of locally infiltrating type, and 8 cases of diffuse type. MRI findings: all lesions showed mixed signal. On T1WI, 28 cases showed cloud-like, band-like and patchy high signal on the background of medium and high signal. On T2WI-FS, all the 30 cases showed low to medium signal areas on the background of high signal, which were dendrimer, ribbon and cloud-like. The lesions showed moderate to obvious heterogeneous progressive enhancement. Twenty-seven lesions had different shapes of vascular shadow, and 28 lesions had drainage vein shadow adjacent to the lesions, 24 of which were located at the proximal end of the lesions. Fascial tail sign was found at the periphery of the lesions in 26 cases, of which 23 cases were located at the upper and lower ends of the lesions.Conclusion:FAVA is a complex vascular malformation with unclear pathological classification. MRI usually shows a solid mass in the superficial muscle layer of the lower limbs parallel to the long axis of the muscle, with cloud-like, band-like, and patchy hyperintensity on the background of high signal on T1WI, and dendritic, band-like, and cloud-like hypointensity on the background of high signal on T2WI-FS, which is helpful for the diagnosis of FAVA. Combined with the data of fascial tail sign, draining vein and clinical manifestations, the diagnosis of FAVA can be confirmed to a certain extent, which can provide reference and basis for clinical decision making.

Claudin18.2(CLDN18.2)is a tight junction protein that is overexpressed in a variety of solid tumors such as gastrointestinal cancer and oesophageal cancer.It has been identified as a promising target and a potential biomarker to diagnose tumor,evaluate efficacy,and determine patient prognosis.TST001 is a recombinant humanized CLDN18.2 antibody that selectively binds to the extracellular loop of human Claudin18.2.In this study,we constructed a solid target radionuclide zirconium-89(89Zr)labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines.The[89Zr]Zr-des-ferrioxamine(DFO)-TST001 showed high radiochemical purity(RCP,＞99％)and specific activity(24.15±1.34 GBq/μmol),and was stable in 5％human serum albumin,and phosphate buffer saline(＞85％RCP at 96 h).The EC50 values of TST001 and DFO-TST001 were as high as 0.413±0.055 and 0.361±0.058 nM(P＞0.05),respectively.The radiotracer had a significantly higher average standard uptake values in CLDN18.2-positive tumors than in CLDN18.2-negative tumors(1.11±0.02 vs.0.49±0.03,P=0.0016)2 days post injection(p.i.).BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96 h p.i.with[89Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups.Immunohistochemistry results showed that BGC823CLDN18.2 tumors were highly positive(+++)for CLDN18.2,while those in the BGC823 group did not express CLDN18.2(-).The results of ex vivo biodistribution studies showed that there was a higher distribution in the BGC823CLDN18.2 tumor bearing mice(2.05±0.16％ID/g)than BGC823 mice(0.69±0.02％ID/g)and blocking group(0.72±0.02％ID/g).A dosimetry estimation study showed that the effective dose of[89Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq,which is within the range of acceptable doses for nuclear medicine research.Taken together,these re-sults suggest that Good Manufacturing Practices produced by this immuno-positron emission tomog-raphy probe can detect CLDN18.2-overexpressing tumors.

Objective:To observe the expression levels of Toll-like receptor 4 (TLR4) signaling pathway-related proteins and their phosphorylation in the liver tissues of rats with inorganic arsenic poisoning, and to explore the role of TLR4-mediated inflammatory signaling pathway in arsenic-induced liver fibrosis injury.Methods:Eighteen healthy weanling SD rats were divided into 3 groups according to their body weight (80 - 100 g) using a random number table (6 rats in each group, half males and half females). The control group was given 10 ml/kg of normal saline by gavage. The sodium arsenite (NaAsO 2) exposure group was given 10 mg/kg of NaAsO 2 by gavage. The TAK-242 intervention group was given 10 mg/kg of NaAsO 2 by gavage, and 0.5 mg/kg of TAK-242 was also administered intraperitoneally to inhibit TLR4 after 12 weeks. All rats were administered 6 days a week for 36 weeks. At the end of the treatment, the liver tissues and serum of the rats in each group were collected. HE and Masson staining were used to observe the pathological and fibrotic changes of the liver tissues. Automatic biochemical analyzer was used to detect serum liver function indexes of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Western blot was used to detect the expression changes of rat liver fibrosis protein α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), Vimentin and TLR4 signaling pathway-related proteins TLR4, nuclear factor κB (NF-κB)-p65 subunit (p65), NF-κB-p50 subunit (p50) and their phosphorylation p-p65 and p-p50 expression levels. Enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion levels of inflammatory related factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-10. Results:HE and Masson staining results showed that compared with the control group, the NaAsO 2 exposure group showed significant inflammatory cell infiltration, hepatocyte necrosis and collagen fibrous deposition, while the TAK-242 intervention group showed improvement of the inflammatory cell infiltration and reduction of collagen fibrous deposition compared with the NaAsO 2 exposure group. The results of serum liver function indexes showed that ALT, AST and ALP in NaAsO 2 exposure group were increased compared with the control group, but the TAK-242 intervention group was significantly decreased compared with the NaAsO 2 exposure group ( P < 0.05). Western bolt results showed that in NaAsO 2 exposure group, the expression levels of fibrosis protein α-SMA, TGF-β1 and Vimentin (1.04 ± 0.19, 0.92 ± 0.14, 1.20 ± 0.21) and TLR4 signaling pathway-related proteins and their phosphorylation TLR4, p50, p-p50 and p-p65 (1.16 ± 0.21, 0.95 ± 0.16, 1.24 ± 0.23, 1.56 ± 0.25) were higher than the control group (0.44 ± 0.08, 0.42 ± 0.08, 0.72 ± 0.07, 0.69 ± 0.15, 0.71 ± 0.11, 0.46 ± 0.07, 0.54 ± 0.11, P < 0.05), and the TAK-242 intervention group (0.60 ± 0.13, 0.59 ± 0.16, 0.49 ± 0.11, 0.47 ± 0.08, 0.86 ± 0.09, 0.79 ± 0.14, 1.02 ± 0.17) were lower than the NaAsO 2 exposure group ( P < 0.05). There was no significant difference in the expression level of TLR4 signal pathway-related protein p65 among the three groups ( F = 14.29, P = 0.053). ELISA results showed that the secretion levels of IL-6 and TNF-α [(98.89 ± 4.58), (83.25 ± 4.57) ng/g] in rats liver tissues of the NaAsO 2 exposure group were higher than the control group [(27.30 ± 3.92), (27.77 ± 1.83) ng/g, P < 0.05], while the secretion level of IL-10 [(36.88 ± 3.86) ng/g] was lower than the control group [(77.96 ± 7.87) ng/g, P < 0.05]. In TAK-242 intervention group, IL-6 and TNF-α secretion levels [(44.32 ± 3.60), (36.51 ± 2.93) ng/g] were lower and IL-10 secretion level [(60.40 ± 4.94) ng/g] was higher compared with the NaAsO 2 exposure group ( P < 0.05). Conclusion:TLR4-mediated inflammatory signaling pathway-related proteins and their phosphorylation are highly expressed in the liver tissues of rats with inorganic arsenic poisoning, and inhibition of TLR4 signaling pathway could significantly reduce the degree of liver fibrosis injury caused by inorganic arsenic in rats.

OBJECTIVE: To validate the effectiveness of a novel comprehensive classification for intertrochanteric fracture (ITF). METHODS: The study included 616 patients with ITF, including 279 males (45.29%) and 337 females (54.71%); the age ranged from 23 to 100 years, with an average of 72.5 years. Two orthopaedic residents (observers Ⅰ and Ⅱ) and two senior orthopaedic surgeons (observers Ⅲ and Ⅳ) were selected to classify the CT imaging data of 616 patients in a random order by using the AO/Orthopaedic Trauma Association (AO/OTA) classification of 1996/2007 edition, the AO/OTA classification of 2018 edition, and the novel comprehensive classification method at an interval of 1 month. Kappa consistency test was used to evaluate the intra-observer and inter-observer consistency of the three ITF classification systems. RESULTS: The inter-observer consistency of the three classification systems evaluated by 4 observers twice showed that the 3 classification systems had strong inter-observer consistency. Among them, the κ value of the novel comprehensive classification was higher than that of the AO/OTA classification of 1996/2007 edition and 2018 edition, and the experience of observers had a certain impact on the classification results, and the inter-observer consistency of orthopaedic residents was slightly better than that of senior orthopaedic surgeons. The intra-observer consistency of two evaluations of three classification systems by 4 observers showed that the consistency of the novel comprehensive classification was better for the other 3 observers, except that the consistency of observer Ⅳ in the AO/OTA classification of 2018 version was slightly higher than that of the novel comprehensive classification. The results showed that the novel comprehensive classification has higher repeatability, and the intra-observer consistency of senior orthopaedic surgeons was better than that of orthopaedic residents. CONCLUSION The novel comprehensive classification system has good intra- and inter-observer consistency, and has high validity in the classification of CT images of ITF patients; the experience of observers has a certain impact on the results of the three classification systems, and those with more experiences have higher intra-observer consistency.
Male ; Female ; Humans ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Observer Variation ; Reproducibility of Results ; Hip Fractures/surgery* ; Tomography, X-Ray Computed/methods* ; Radiography

The fall armyworm (FAW), Spodoptera frugiperda, is a destructive pest native to America and has recently become an invasive insect pest in China. Because of its rapid spread and great risks in China, understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies. Here, we assembled a chromosome-level genome of a male FAW (SFynMstLFR) and compared re-sequencing results of the populations from America, Africa, and China. Strain identification of 163 individuals collected from America, Africa and China showed that both C and R strains were found in the American populations, while only C strain was found in the Chinese and African populations. Moreover, population genomics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations. Taken together, FAWs invaded into China were most likely originated from Africa. Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW, of which 283 genes are specific to FAW. Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles, and several detoxification genes such as AOX, UGT and GST specially responded to the pesticides. These findings will be useful in developing effective strategies for management of FAW in China and other invaded areas.
Animals ; China ; Genomics ; Humans ; Male ; Pesticides ; Spodoptera/genetics* ; Transcriptome