Objective: In in vitro systems for differentiating and expanding natural killer (NK) cells, feeder cells provide essential cell-cell contact and paracrine signals that drive precursor proliferation and terminal maturation. However, existing xenogeneic feeder cells or tumor-derived genetically modified feeder cells pose risks of residual immunogenicity and malignant transformation, limiting clinical use. This study aims to develop a humanized mesenchymal-like stromal cell (hematopoietic organoid-derived human mesenchymal stromal cells, HO-hMSCs) derived from iPSC-based hematopoietic organoids, and elucidate its mechanisms of NK-supportive activity to enable a safe, efficient platform for clinical-grade NK cell production. Methods: Human induced pluripotent stem cells (iPSCs) were differentiated into hematopoietic organoids, from which HO-hMSCs were isolated. Flow-cytometric phenotyping and bulk RNA-sequencing were performed to compare HO-hMSCs with umbilical cord-derived MSCs (UC-hMSCs). The effect of HO-hMSCs on NK cell differentiation efficiency (CD3 CD56 ) and effector maturation (CD16 expression) were assessed by co-culture experiments, using UC-hMSCs as control. Results: 1) Hematopoietic organoid induction and NK differentiation: iPSCs were induced to form hematopoietic organoids using cytokine cocktails, which further differentiated into high-purity CD45 CD56 NK cells [(82.8%±12.07)% efficiency on day 21]. 2) HO-hMSC characteristics: HO-hMSCs exhibited upregulated expression of Notch pathway ligands (DLL4, JAG1, 4.06-8.04-fold), homeobox genes (HOXA3, HOXA5, log FC=1.28 and 1.44), and key regulators of NK development (GATA3, BCL11A) and cytokine receptors (IL7R, IL27RA, 6.76 to 13.34-fold increase). 3) Functional validation: Compared to UC-hMSCs, HO-hMSCs co-culture significantly enhanced NK cell proportion by 30.5% (P<0.05) and increased CD16 positivity (+20.5%). Conclusion: This study for the first time reveals that human hematopoietic organoid-derived HO-hMSCs possess potent hematopoietic niche-supportive activity. It provides a humanized, feeder-free platform for robust clinical-grade NK cell production and expands the translational utility of organoid technologies in cell therapy.

Objective To compare the effects of 20 mg qd and 10 mg bidadministration of iprrazole enteric-coated tablets on the control of gastric acid in healthy subjects.Methods A randomized,single-center,parallel controlled trial was designed to include 8 healthy subjects.Randomly divided into 2 groups,20 mg qd administration group:20 mg enteric-coated tablets of iprrazole in the morning;10 mg bid administration group:10 mg enteric-coated tablets of iprrazole in the morning and 10 mg in the evening.The pH values in the stomach of the subjects before and 24 h after administration were monitored by pH meter.The plasma concentration of iprazole after administration was determined by HPLC-MS/MS.The main pharmacokinetic parameters were calculated by Phoenix WinNonlin(V8.0)software.Results The PK parameters of iprrazole enteric-coated tablets and reference preparations in fasting group were as follows:The Cmax of 20 mg qd group and 10 mg bid group were(595.75±131.15)and(283.50±96.98)ng·mL-1;AUC0-t were(5 531.94±784.35)and(4 686.67±898.23)h·ng·mL-1;AUC0-∞ were(6 003.19±538.59)and(7 361.48±1 816.77)h·ng·mL-1,respectively.The mean time percentage of gastric pH＞3 after 20 mg qd and 10 mg bid were 82.64％and 61.92％,and the median gastric pH within 24 h were 6.25±1.49 and 3.53±2.05,respectively.The mean gastric pH values within 24 h were 5.71±1.36 and 4.23±1.45,respectively.The correlation analysis of pharmacokinetic/pharmacodynamics showed that there was no significant correlation between the peak concentration of drug in plasma and the inhibitory effect of acid.Conclusion Compared with the 20 mg qd group and the 10 mg bid group,the acid inhibition effect is better,the administration times are less,and the safety of the two administration regimes is good.

Pancreatic cancer (PC) is a highly fatal disease which originated from pancreatic epithelial and acinar cells, and the survival rate of pancreatic cancer patients is only about 12%. Approximately 95% of pancreatic cancer presents as ductal adenocarcinoma (PDAC). Pancreatic cancer is characterized by high aggressiveness, rapid progression and progression, and high resistance to treatment. Common somatic mutated genes in the early stage of pancreatic cancer include KRAS, CDKN2A, TP53, and SMAD4. Most pancreatic cancer patients are affected by environmental risk factors such as age, sex and diet. Malignant pancreatic cancer is associated with non-invasive, preneoplastic lesions that are thoughted to be precursors, such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystadenoma (MCN). In recent years, people have gradually improved the therapy and diagnosis of pancreatic cancer, and the contribution of imaging technology, which enhancing the usage of minimally invasive pancreatectomy that typically includes pancreaticoduodenectomy and distal pancreatectomy. However, combined administration of the chemotherapeutic gemcitabine and erlotinib is still considered a potential first-line treatment for advanced pancreatic cancer, but the development of chemoresistance often leads to poor therapeutic outcomes. Based on the current research progress for pancreatic cancer, its treatment currently remains one of the most important challenges in the medical field. Although some new treatment options have been provided, there were minor clinical success achieved and therefore new safe and effective therapies of pancreatic cancer are still an urgent need for patients. Among these new therapies for pancreatic cancer, short peptide-based treatment protocols have attracted great attention. Peptide is a compound formed by linking α-amino acids together in peptide chains. It is also an intermediate product of proteolysis. The short peptide-based therapy has many advantages such as precise targeting, easy preparation and low toxicity. Short peptides usually act as tumor suppressors by targeting and recognizing tumor-specific expressed proteins. Currently, there is an increased interest in peptides in pharmaceutical and development research, and approximate 140 peptide therapeutics are currently being evaluated in clinical trials. These peptides provide excellent prospects for targeted drug delivery because of their high selectivity, specificity and simplicity of modification. Peptides have high bioactivity and excellent biodegradability. Clinically, short peptides are increasingly used as combination drugs with chemotherapy for tumor treatment. Peptides can induce cancer cell death by numerous mechanisms and peptides have emerged as a promising drug for the treatment of pancreatic cancer. Here we mainly review the roles of peptides on Wnt/β-catenin, NF-κB, autophagy, and the use of peptides as tracer in pancreatic cancer. We also analyzed the benefits and disadvantages existing in the development process of short peptides, which provide the feasibility of targeted short peptides to become new therapeutic approaches for cancer therapy.

italic>Polygonum capitatum is a characteristic Miao medicine in Guizhou, commonly used in clinical practice to treat gastrointestinal and urinary tract infections. Research has found that it has good antibacterial and anti-inflammatory effects, and its main active ingredient is flavonoids. Lavonoid O-methyltransferase (FOMT) is a key enzyme for oxymethylation modification of flavonoid compounds. In order to understand the function and properties of FOMT protein in Polygonum capitatum, the transcriptome was sequenced by Illumina HiSeq 4000 high throughput sequencing technology. Then, the obtained transcripts were annotated and analyzed, and the whole genome of the FOMT gene family in Polygon capitalis was mined and identified. A total of 99 298 Unigenes were obtained, of which 71 514 were successfully annotated by the public database. In the genome of Polygonum capitatum, a total of 50 FOMT genes were identified. The phylogenetic tree showed that FOMT genes were divided into two subfamilies: caffeoyl CoA O-methyltransferase (CCoAOMT) and caffeic acid O-methyltransferase (COMT). Gene sequence analysis showed that the number of FOMT encoded amino acids ranged from 99 to 1 053 aa, the molecular weight ranged from 11 224.91 to 86 687.42 Da, and the isoelectric point ranged from 4.79 to 9.45. The 50 FOMT family members were hydrophobic proteins. Subcellular localization results showed that 54% of FOMT subfamily CCoAOMT and COMT members were located in cytoplasm and 28% were located in chloroplasts. The FOMT gene was tissue specific and highly expressed in the flowers of Polygonum capitatum, followed by the stems, and the least expressed in the roots. In this study, the FOMT gene family of Polygonum capitatum was identified and analyzed to provide theoretical basis for further study of FOMT function and biosynthesis of methylated flavonoids.

Objective:To understand the electrocardiogram and echocardiography examination results of population in key areas of unexplained sudden death in Yunnan Province (referred to as Yunnan sudden death).Methods:From 2014 to 2022, electrocardiogram examination was performed on population (including same incident cases, relatives of the cases, villagers of the affected villages, and control individuals) in key areas of Yunnan sudden death from May to October each year. Echocardiography examination was performed on relatives of the cases and villagers of the affected villages, and the types of electrocardiogram and echocardiography changes were sorted out and analyzed.Results:Electrocardiogram examination was conducted on 1 same incident case, 241 relatives of the cases, 464 villagers of the affected villages, and 99 control individuals, respectively. The types of electrocardiogram changes in the same incident case were Q-T interval prolongation and sinus tachycardia. A total of 17 types of electrocardiogram changes were detected in the relatives of the cases, mainly including sinus arrhythmia (12.45%, 30/241), sinus bradycardia (11.20%, 27/241), and left axis deviation (8.30%, 20/241). A total of 21 types of electrocardiogram changes were detected in the villagers of the affected villages, mainly including left axis deviation (9.48%, 44/464), sinus bradycardia (8.19%, 38/464), and T-wave abnormalities (7.76%, 36/464). A total of 10 types of electrocardiogram changes were detected in the control individuals, mainly including sinus arrhythmia (12.12%, 12/99), T-wave abnormalities (9.09%, 9/99), and sinus bradycardia (7.07%, 7/99). Echocardiography examination was conducted on 49 relatives of the cases and 365 villagers of the affected villages, respectively. A total of 12 types of echocardiography changes were detected in the relatives of the cases, mainly including tricuspid regurgitation (18.37%, 9/49), decreased right ventricular diastolic function (8.16%, 4/49), aortic regurgitation (6.12%, 3/49), and atrial septal defect (6.12%, 3/49). A total of 15 types of echocardiography changes were detected in the villagers of the affected villages, mainly including tricuspid regurgitation (8.77%, 32/365), aortic regurgitation (6.85%, 25/365), and decreased left ventricular diastolic function (6.58%, 24/365).Conclusion:There are many types of changes in electrocardiogram and echocardiography in the population of key areas of Yunnan sudden death.

ObjectiveTo investigate the trends in diabetes mortality rate and the characteristics of decreased population in Fengxian District, Shanghai from 2012 to 2021. MethodsData from the death registration records of the residents in Fengxian District between 2012 and 2021, sourced from the Shanghai Death Surveillance System, were analyzed. Indicators such as the crude mortality rate due to diabetes, the standardized mortality rate, years of life lost (YLL), and the probability of premature death were estimated. Annual percentage change (APC) was used to analyze the temporal trends of mortality and the probability of premature death due to diabetes. Rate decomposition analysis was used to assess the contributions of demographic and non-demographic factors to diabetes mortality. ResultsFrom 2012 to 2021, there were 1 471 deaths due to diabetes in Fengxian District, with a crude mortality rate of 27.51/100 000 and a standardized mortality rate of 17.58/100 000. The crude mortality rate showed an overall increasing trend (APC=4.58%, Z=3.49, P<0.05). The potential years of life lost (PYLL) due to diabetes over this period amounted to 9 715 person-years, with a PYLL rate of 1.82 ‰, and the average years of life lost (AYLL) was 11.94 years. The probability of premature death was 0.41% (APC=3.36%, t=2.33, P<0.05). Both population aging and non-aging factors contributed to the increase in diabetes mortality, with overall contribution rates of 67.99% and 32.01%, respectively. Among men, the contribution rates were 60.57% and 39.43%, while among women, they were 79.43% and 20.57%, respectively. ConclusionFrom 2012 to 2021, both the crude mortality rate and the probability of premature death due to diabetes showed an upward trend among the residents in Fengxian District, with a higher YLL. Population aging was the main factor causing the increase in mortality rate, while non-demographic factors had a greater impact on the rise in diabetes mortality among men than that in women. Therefore, the management on male diabetes patients should be strengthened.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

AIM: To investigate the role and mechanism of N6-methyladenosine(m6A)methyltransferase 3(METTL3)in the pathogenesis of diabetic cataract.METHODS: We cultured SRA01/04 cells in low and high sugar media for 24h and measured changes in epithelial-mesenchymal transition(EMT)indicators(E-Cadherin, N-Cadherin, ZO-1 and α-SMA)using RT-qPCR and Western blot assays. Cell migration was also assessed using transwell and scratch assays. To investigate the expression level and localization of METTL3 in human lens anterior capsules tissues. Additionally, we used m6A dot blot assay to detect the m6A methylation level of cells cultured in low and high glucose media for 24h, and employed RT-qPCR and Western blot experiments to detect RNA and protein expression of METTL3 in cells. We then treated the cells with METTL3 inhibitor and measured changes in EMT markers by RT-qPCR and Western blot; m6A methylation level was detected by m6A dot blot test; cell migration was detected by Transwell. Finally, the expression of transforming growth factor-β(TGFβ1)in cultured cells was assessed by immunofluorescence staining and the expression levels of TGFβ1 and SNAIL in cells were determined using RT-qPCR and Western blot.RESULTS: Under high glucose conditions, the expression of EMT markers, METTL3, and m6A methylation levels were significantly increased in cells(P<0.05). Furthermore, the migratory ability of cells was higher in high-sugar medium than in low-sugar medium. In human lens anterior capsules, METTL3 expression was higher in patients with diabetic cataract compared to those with age-related cataract. Importantly, treatment with the METTL3 inhibitor STM2457 inhibited EMT in cells, the expression of TGFβ1 and SNAIL, as well as m6A methylation levels in cells(all P<0.05)compared to high-sugar + dimethyl sulfoxide(DMSO)group. Moreover, the migratory capacity of cells was reduced after the addition of STM2457 compared to the high-sugar + DMSO group.CONCLUSION:METTL3 promotes the EMT in human lens epithelial cells under high glucose conditions by activating the TGFβ1/SNAIL pathway, thus contributing to the development of diabetic cataracts.

Objective To investigate the association between platelet count (PLT) and the prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), to establish a new PLT-related scoring model, and to assess its value in predicting the short-term prognosis of HBV-ACLF. Methods A retrospective cohort study was conducted among the patients with HBV-ACLF who were hospitalized and treated in Department of Gastroenterology, The General Hospital of Western Theater Command, from January 2018 to January 2022. Clinical data within 24 hours after admission were collected from all patients, and according to the survival after 180 days of follow-up, the patients were divided into survival group and death group. The independent-samples t test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The Pearson correlation coefficient was used to investigate the correlation between different indicators, and the logistic regression model was used to analyze the influencing factors for prognosis. The receiver operating characteristic (ROC) curve was used to assess the predictive value of the prognostic model, and the Kaplan-Meier curve analysis was used to investigate the survival condition of the high AIP group and the low AIP group. Results A total of 236 patients were enrolled, with a 180-day survival rate of 75.85% (179/236). Compared with the survival group, the death group had significantly higher age (53.98±10.45 vs 47.44±12.46, P =0.001), international normalized ratio (INR) [1.78 (1.46-2.04) vs 1.47 (1.23-1.68), P < 0.001], total bilirubin [275.60 (165.00-451.45) vs 230.60 (154.90-323.70), P =0.035], Model for End-Stage Liver Disease (MELD) score [21.47 (18.14-24.76) vs 18.67 (15.70-21.62), P < 0.001], and albumin-bilirubin (ALBI) score [-1.06 (-1.64~-0.86) vs-1.32 (-1.73~-1.01), P =0.034], as well as significantly lower PLT [80.00 (50.00~124.50) vs 115.00 (82.00~143.00), P =0.001] and platelet-to-white blood cell ratio (PWR) [13.40 (9.54~20.70) vs 18.49 (13.95~24.74), P =0.001]. The Pearson correlation analysis showed that PLT was negatively correlated with liver cirrhosis and INR ( r =-0.332 and -0.194, P < 0.001 and P =0.003). The multivariate logistic regression analysis showed that age (odds ratio [ OR ]=1.045, 95% confidence interval [ CI ]: 1.015-1.076), PLT ( OR =0.990, 95% CI : 0.983-0.998), and INR ( OR =2.591, 95% CI : 1.363-4.925) were independent risk factors for the 180-day prognosis of HBV-ACLF patients. The new predictive model was established as follows: AIP=0.006×age+0.187×INR-0.001×PLT. The AIP scoring model had an area under the ROC curve (AUC) of 0.718 in predicting the 180-day prognosis of HBV-ACLF patients, with a sensitivity of 81.1% and a specificity of 54.1%, while PLT, PWR, LPACLF score, MELD score, and ALBI score had an AUC of 0.673, 0.659, 0.588, 0.647, and 0.578, respectively. The AIP scoring model had an optimal cut-off value of 0.48. The Kaplan-Meier survival analysis showed that the high AIP group had a significantly lower survival rate than the low AIP group ( P < 0.001). Conclusion The PLT-related scoring model has a better value than other models in predicting the prognosis of HBV-ACLF, and HBV-ACLF patients with a relatively high PLT level tend to have a high overall survival rate.

Objective To investigate the influencing factors and establish a model predicting the performance of needle visualization in fine-needle aspiration (FNA) of thyroid nodules. Methods This study prospectively included 175 patients who underwent FNA of thyroid nodules in the Department of Ultrasound in China-Japan Friendship Hospital and compared the display of the needle tips in the examination of 199 thyroid nodules before and after the application of needle visualization.We recorded the location,the positional relationship with thyroid capsule,ultrasonic characteristics,and the distribution of the soft tissue strip structure at the puncture site of the nodules with unclear needle tips display before using needle visualization.Furthermore,according to the thyroid imaging reporting and data system proposed by the American College of Radiology,we graded the risk of the nodules.Lasso-Logistic regression was employed to screen out the factors influencing the performance of needle visualization and establish a nomogram for prediction. Results The needle tips were not clearly displayed in the examination of 135 (67.8%) and 53 (26.6%) nodules before and after the application of needle visualization,respectively,which showed a significant difference (P<0.001).Based on the positional relationship between the nodule and capsule,anteroposterior/transverse diameter (A/T) ratio,blood supply,and the distribution of subcutaneous strip structure at the puncture site,a nomogram was established to predict the probability of unclear display of the needle tips after application of needle visualization.The C-index of the prediction model was 0.75 (95%CI=0.67-0.84) and the area under the receiver operating characteristic curve was 0.72.The calibration curve confirmed the appreciable reliability of the prediction model,with the C-index of 0.70 in internal validation. Conclusions Needle visualization can improve the display of the needle tip in ultrasound-guided FNA of thyroid nodules.The nomogram established based on ultrasound features such as the positional relationship between the nodule and capsule,A/T ratio,blood supply,and the distribution of subcutaneous strip structure at the puncture site can predict whether needle visualization is suitable for the examination of nodules.
Humans ; Thyroid Nodule/diagnostic imaging* ; Biopsy, Fine-Needle/methods* ; Reproducibility of Results ; Ultrasonography ; Retrospective Studies ; Thyroid Neoplasms