The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

The bioactivity-guided isolation of potentially active natural products has been widely utilized in pharmaceutical discovery. In this study, by screening fungal extracts against coxsackievirus B3 (CVB3), three new aspochalasins, templichalasins A‒C (1‒3), along with six known aspochalasins (4‒9) were isolated from an active extract derived from the endophytic fungus Aspergillus templicola LHWf045. Compound 1 features a unique 5/6/5/7/5 pentacyclic ring system, while compounds 2 and 3 possess unusual 5/6/6/7 tetracyclic skeletons. Their structures were characterized through extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Additionally, we demonstrated that compound 4 can be readily converted into compounds 1‒3 under mild acidic conditions and proposed a plausible mechanism for this conversion. Bioactivity evaluation of compounds 1‒9 against CVB3 revealed the inhibitory effects of all compounds against the virus. Notably, compound 9 exhibited superior antiviral activity, surpassing the commercial drug ribavirin in selectivity index (SI) value.
Antiviral Agents/isolation & purification* ; Aspergillus/chemistry* ; Molecular Structure ; Enterovirus B, Human/drug effects* ; Endophytes/chemistry* ; Cytochalasins/isolation & purification* ; Drug Discovery ; Humans

Objective:To investigate the prognosis and the factors that influence it in patients with non-gastric gastrointestinal stromal tumors (GISTs) who are at low risk of recurrence.Methods:This was a retrospective cohort study. Clinicopathologic and prognostic data from patients with non-gastric GISTs and at low risk of recurrence (i.e., very low-risk or low-risk according to the 2008 version of the Modified NIH Risk Classification), who attended 18 medical centers in China between January 2000 and June 2023, were collected. We excluded patients with a history of prior malignancy, concurrent primary malignancy, multiple GISTs, and those who had received preoperative imatinib. The study cohort comprised 1,571 patients with GISTs, 370 (23.6%) of whom were at very low-risk and 1,201 (76.4%) at low-risk of recurrence. The cohort included 799 (50.9%) men and 772 (49.1%) women of median age 57 (16–93) years. Patients were followed up to July 2024. The prognosis and its influencing factors were analyzed. Receiver operating characteristic curves for tumor diameter and Ki67 were established, and the sensitivity, specificity, area under the curve (AUC) and optimal cut-off value with 95% confidence intervals were calculated. Propensity score matching was implemented using the 1:1 nearest neighbor matching method with a matching tolerance of 0.02.Results:With a median follow-up of 63 (12–267) months, the 5- and 10-year overall survival (OS) rates of the 1,571 patients were 99.5% and 98.0%, respectively, and the 5- and 10-year disease-free survival (DFS) rates were 96.3% and 94.4%, respectively. During postoperative follow-up, 3.8% (60/1,571) patients had disease recurrence or metastasis, comprising 0.8% (3/370) in the very low-risk group and 4.7% (57/1,201) in the low-risk group. In the low-risk group, recurrence or metastasis occurred in 5.5% (25/457) of patients with duodenal GISTs, 3.9% (25/645) of those with small intestinal GISTs, 9.2% (6/65) of those with rectal GISTs, and 10.0% (1/10) of those with colonic GISTs. Among the 60 patients with metastases, 56.7% (34/60) of the metastases were located in the abdominal cavity, 53.3% (32/60) in the liver, and 3.3% (2/60) in bone. During the follow-up period, 13 patients (0.8%) died of disease. Receiver operating characteristic curves were plotted for tumor diameter and Ki67 and assessed using the Jordon index. This showed that the difference in DFS between the two groups was statistically significant when the cutoff value for tumor diameter was 3.5 cm (AUC 0.731, 95% CI: 0.670–0.793, sensitivity 77.7%, specificity 64.1%). Furthermore, the difference in DFS between the two groups was statistically significant when the cutoff value for Ki67 was 5% (AUC 0.693, 95% CI: 0.624–0.762, sensitivity 60.7%, specificity 65.3%). Multifactorial analysis revealed that tumor diameter ≥3.5 cm, Ki67 ≥5%, and R1 resection were independent risk factors for DFS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). Furthermore, age >57 years, Ki67 ≥5%, and R1 resection were also independent risk factors for OS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). We also grouped the patients according to whether they had received postoperative adjuvant treatment with imatinib for 1 or 3 years. This yielded 137 patients in the less than 1-year group, 139 in the 1-year plus group; and 44 in both the less than 3 years and 3-years plus group. After propensity score matching for age, tumor diameter, Ki67, and resection status, the differences in survival between the two groups were not statistically significant (all P>0.05). The 10-year DFS and OS were 87.5% and 95.5%, respectively, in the group treated with imatinib for less than 1 year and 88.5% and 97.8%, respectively, in the group treated for more than 1 year. The 10-year DFS and OS were 89.6% and 92.6%, respectively, in the group treated with imatinib for less than 3 years and 88.0% and 100.0%, respectively, in the group treated with imatinib for more than 3 years. Conclusion:The overall prognosis of primary, non-gastric, low recurrence risk GISTs is relatively favorable; however, recurrences and metastases do occur. Age, tumor diameter, Ki67, and R1 resection may affect the prognosis. For some patients with low risk GISTs, administration of adjuvant therapy with imatinib for an appropriate duration may help prevent recurrence and improve survival.

AIM:To establish a mouse model of chronic obstructive pulmonary disease(COPD)induced by cigarette smoke(CS)exposure combined with polyinosinic-polycytidylic acid(Poly I:C)nasal drip,and to investigate the mechanism of airway epithelial barrier injury in COPD.METHODS:(1)Ninety-six male BALB/c mice were randomly divided into control group,CS group,Poly I:C group,and CS+Poly I:C group(n=24).The model was established from week 1 to week 8,with pulmonary function tested every 4 weeks.Six mice from each group were sacrificed at the end of weeks 4,8,16,and 24.Changes in minute volume(MV),enhanced pause(Penh),mean linear intercept(MLI)and bronchial wall thickness(BWT)were observed.The protein levels of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),zonula occludens-1(ZO-1)and E-cadherin(E-Cad)in the lung were detected.(2)Human bronchial epithe-lial BEAS-2B cells were stimulated with CS extract(CSE)combined with Poly I:C for 24 h,and then the protein levels of occludin(Occ),ZO-1,and phosphorylated epidermal growth factor receptor(EGFR),P38 and extracellular signal-regu-lated kinase(ERK)1/2 were analyzed.RESULTS:(1)Compared with control group,at the 8th week,the mice in CS and CS+Poly I:C groups showed typical pathological changes in lung tissues,including significant inflammatory cell infil-tration,alveolar cavity expansion,alveolar wall rupture and fusion,and airway wall thickening.The Penh,BWT,MLI,and lung IL-1β and TNF-α levels were significantly increased(P<0.05 or P<0.01),while MV and lung ZO-1 and E-Cad levels were remarkably decreased(P<0.05 or P<0.01).By the 24th week,these pathological changes remained relative-ly stable in CS+Poly I:C group.(2)Compared with control group,CSE and its combination with Poly I:C dramatically in-duced a reduction in ZO-1 and Occ protein expression in BEAS-2B cells(P<0.05 or P<0.01),and increased the levels of phosphorylated EGFR,P38 and ERK1/2(P<0.01).The effects in CSE combined with Poly I:C group were considerably superior to those in CSE or Poly I:C group alone.CONCLUSION:Poly I:C can enhance the pathological changes and airway epithelial barrier damage induced by CS in a mouse model of COPD,which may be related to the activation of EGFR/ERK/P38 signaling pathway.

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).

The utilization of optimal orthodontic force is crucial to prevent undesirable side effects and ensure efficient tooth movement during orthodontic treatment.However,the sensitivity of existing detection techniques is not sufficient,and the criteria for evaluating optimal force have not been yet established.Here,by employing 3D finite element analysis methodology,we found that the apical distal region(A-D region)of mesial roots is particularly sensitive to orthodontic force in rats.Tartrate-resistant acidic phosphatase(TRAP)-positive osteoclasts began accumulating in the A-D region under the force of 40 grams(g),leading to alveolar bone resorption and tooth movement.When the force reached 80 g,TRAP-positive osteoclasts started appearing on the root surface in the A-D region.Additionally,micro-computed tomography revealed a significant root resorption at 80 g.Notably,the A-D region was identified as a major contributor to whole root resorption.It was determined that 40 g is the minimum effective force for tooth movement with minimal side effects according to the analysis of tooth movement,inclination,and hyalinization.These findings suggest that the A-D region with its changes on the root surface is an important consideration and sensitive indicator when evaluating orthodontic forces for a rat model.Collectively,our investigations into this region would aid in offering valuable implications for preventing and minimizing root resorption during patients'orthodontic treatment.

BACKGROUND:At present,the treatment methods for necrotizing fasciitis mostly use negative pressure sealing suction after thorough debridement.This method requires repeated debridement to completely remove necrotic infected tissue,causing serious physical and economic burdens to patients. OBJECTIVE:To introduce a rare clinical case of calf compartment syndrome caused by diabetic foot necrotizing fasciitis,and summarize the clinical experience of using antibiotic-loaded bone cement for treatment and comprehensive management. METHODS:A total of 6 patients with calf compartment syndrome caused by diabetic necrotizing fasciitis admitted to Wuxi 9th Affiliated Hospital of Soochow University from August 2017 to August 2020 were selected,including 5 males and 1 female with an average age of 54 years.During the perioperative period,the patients'general condition was evaluated and systemic nutritional support treatment was given.In the first stage,all patients received complete debridement to control infection,antibiotic-loaded bone cement packing,and negative pressure sealed drainage.In the second stage,bone cement was removed and wound repair was performed.The wound healing,as well as the occurrence of redness,swelling,and exudation was observed during the follow-up. RESULTS AND CONCLUSION:(1)The wounds of four patients were fresh after twice antibiotic-loaded bone cement packing,and the membrane formation was good,and one patient was good after three times of antibiotic-loaded bone cement packing,and the wounds of all five patients healed well after the second stage of skin grafting.Due to the difficulty in maintaining intraoperative blood pressure and infection in all four compartments of the lower leg,a patient underwent emergency knee amputation.Meanwhile,the stump wound was placed with antibiotic-loaded bone cement.The wound was closed directly after the secondary bone cement was removed,and the wound healed in the first stage.(2)The six patients were followed up for 6-24 months after discharge.At the last follow-up,all six patients had good wound healing and no symptoms such as redness,swelling,and exudation.The quality of life of the patients was significantly improved,and all of them were satisfied with the curative effect.(3)The occurrence of calf compartment syndrome should be vigilant when diabetic foot necrotizing fasciitis is highly suspected.Early diagnosis and timely incision decompression are of great importance.Besides,the application of antibiotic-loaded bone cement in the treatment of calf compartment syndrome caused by diabetic necrotizing fasciitis has a good short-term effect.

Objective:To examine the burden and trends of acute viral hepatitis in Guangdong Province from 1990 to 2019, and provide reference evidences for hepatitis prevention and control in the province.Methods:Data on acute viral hepatitis (hepatitis A, B, C, and E) in Guangdong from 1990 to 2019 were extracted from the Global Burden of Disease Study 2019 database. The incidence, prevalence, mortality, and disability-adjusted life years (DALY) data were analyzed by age and gender, and the estimated annual percentage change (EAPC) was calculated to describe the changing trends in disease burden.Results:From 1999 to 2019, the standardized incidence, prevalence, mortality, and DALY of acute viral hepatitis in Guangdong were higher than the national averages. In 2019, 51.43% (2 245 087/4 365 221) of acute viral hepatitis cases in Guangdong Province were mainly attributed to hepatitis B, and 77.18% (106/138) of deaths were due to acute hepatitis B. In different age groups, except for acute hepatitis B, which was more common in adults, the incidence rates of other types of viral hepatitis such as hepatitis A, B, and E showed an overall decreasing trend with age. The mortality rates of different types of acute viral hepatitis, except for the <5 age group, increased with age. The overall incidence and mortality rates of acute viral hepatitis were higher in men than in women.Conclusions:The overall burden of acute viral hepatitis in Guangdong declined in 2019, but remained higher than the national level. Further efforts are needed to strengthen hepatitis prevention and screening in different population in Guangdong Province, especially in children and the elderly.

Objective:To analyze the relationship between health belief and the stages of parental decision-making on childhood 13-valent pneumococcal conjugate vaccine (PCV13) immunization in China.Methods:Cross-sectional multistage survey sampling method was used to select study subjects. The study subjects were parents who were aged 20-45 years and had one and more children ≤5 years old in three cities in China. A self-administered questionnaire designed based on health belief model was used to collect the information. Multinomial logistic regression analysis was used to assess the relationships between perceived susceptibility, perceived severity of illness, perceived effect of PCV13 and stages of parental decision-making on childhood PCV13 immunization.Results:A total of 1 716 valid questionnaires were returned (89.33%). The average age of the study subjects was (35.33±4.95) years, and 79.60% of them were women. In the study subjects, 48.31% had in action, 21.79% were in contemplation and 29.90% were in pre-contemplation. The multinominal logistic regression analysis indicated that high perceived susceptibility ( OR=0.14, 95% CI:0.09-0.22; OR=0.54, 95% CI:0.39-0.76), high perceived severity of illness ( OR=0.55, 95% CI:0.42-0.73), and high perceived effect of PCV13 ( OR=0.27, 95% CI:0.18-0.40; OR=0.51, 95% CI:0.32-0.81) were significantly lower in those who were in contemplation or pre-compared with those who had in action. For study subjects with low perceived susceptibility, high perceived effect of PCV13 might decrease the probabilities of contemplation ( OR=0.53, 95% CI:0.32-0.87) and pre-contemplation ( OR=0.27, 95% CI:0.18-0.41). For those with high perceived susceptibility, perceived severity of illness might decrease the probability of contemplation ( OR=0.43, 95% CI:0.23-0.82). Conclusions:Childhood PCV13 vaccination willingness and level is low in China. It is important to pay greater attention to the intervention on health belief in child parents, such as perceived effect of PCV13, perceived severity of illness, and perceived susceptibility, in health policy development and health promotion.