Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

Objective To investigate the correlation between untreated premenopausal women with sys-temic lupus erythematosus(SLE)and 25 hydroxyvitamin D[25(OH)D]levels.Methods A total of 80 newly diagnosed premenopausal female SLE patients admitted to our hospital from July 2020 to June 2023 were se-lected as the SLE group,and 80 healthy premenopausal women were selected as the control group during the same period.Chemiluminescence method was used to detect the level of 25(OH)D,ELISA to detect autoanti-bodies in SLE patients,and the proportion of SLE patients with 25(OH)D deficiency or insufficiency was ana-lyzed.Pearson correlation analysis was used to investigate the correlation between 25(OH)D and 24-hour uri-nary protein quantification,complement 3(C3),complement 4(C4),systemic lupus erythematosus activity(SLEDAI)score,and specific lupus autoantibody titers in SLE patients.Multiple logistic regression was used to analysis the risk factors for developing SLE in premenopausal women.The receiver operating characteristic(ROC)curve and area under the curve(AUC)were used to analyze the value of various indicators in predic-ting the occurrence of SLE in premenopausal women.Results The serum 25(OH)D level in the SLE patient group was lower than that in the control group(P＜0.05).According to the diagnostic criteria for vitamin D deficiency and insufficiency,the proportion of patients with vitamin D deficiency in the SLE group was 22.50％(18/80),and the proportion of patients with vitamin D deficiency was 63.75％(51/80).The serum levels of C3 and C4 in SLE patients were lower than those in the control group(P＜0.05).The levels of anti-double stranded DNA(dsDNA)antibody and anti-cardiolipin IgG(CL IgG)antibody were higher than those in the control group(P＜0.05).Pearson correlation analysis showed that serum 25(OH)D levels in SLE pa-tients were negatively correlated with anti-CL IgG antibody,anti-dsDNA antibody,24-hour urine protein quan-tification,and SLEDAI scores(r=-0.339,-0.294,-0.328,-0.392,P＜0.05),and positively correlated with complement C3 and C4 levels(r=0.241,0.178,P＜0.05).Multivariate logistic regression analysis showed that 25(OH)D,anti-dsDNA antibody,anti-CL IgG antibody,C3,C4,24-hour urinary protein quantifi-cation level,and SLEDAI score were independent influencing factors for the occurrence of SLE in premenopa-usal women(OR=1.125,0.413,0.203,99.791,33.162,0.045,0.096,P＜0.05).The AUC of each indicator predicting the occurrence of SLE in premenopausal women were 0.911,0.800,0.768,0.978,0.893,and 0.893,re-spectively.Conclusion 25(OH)D plays an important role in the onset and development of SLE and can be used as a predictive indicator of disease activity.It is recommended to screen for 25(OH)D in newly diagnosed SLE patients and treat patients with deficiency or insufficiency.

Objective:By conducting a retrospective analysis of the clinical data of 14 patients diagnosed with invasive fungal rhinosinusitis (IFRS) confirmed by metagenomics next generation sequencing (mNGS) technology, we aim to explore the rapid diagnosis value of mNGS in IFRS.Methods:The clinical data of 14 IFRS patients admitted to TianJin First Central Hospital were retrospectively analyzed from February 2021 to October 2023. The study cohort comprised 8 males and 6 females, with ages ranging from 14 to 77 years. All patients were diagnosed as IFRS by performing mNGS sequencing technology of nasal sinus lesion biopsy specimens. Clinical data such as laboratory examination, imaging examination, histopathological examination results, treatment plan and prognosis were summarized and analyzed.Results:All 14 patients were diagnosed as IFRS, with mNGS detecting pathogens such as Rhizopus (7 cases), Aspergillus (5 cases), Trichoderma (1 case), and Scedosporium apiospermum (1 case). Follow-up evaluations were conducted for a period ranging from 2 months to 2 years post-treatment. At the end of follow-up, 11 out of 14 IFRS patients achieved a complete cure with no signs of recurrence, while the symptoms of the remaining 3 patients significantly improved with comprehensive treatment. Conclusion:mNGS emerges as a highly effective diagnostic tool for IFRS, providing valuable microbiological evidence for clinical diagnosis and demonstrating promising clinical utility.

Objective:To study the correlation between different body weight metabolic phenotypes and their changes and new-onset hyperuricemia in physical examination population.Methods:This study was a retrospective cohort study. A total of 31 956 people who underwent routine physical examination and met the inclusion and exclusion criteria at the Health Management Center of the Second Affiliated Hospital of Dalian Medical University from January 1, 2014 to August 31, 2022 were selected as the study subjects to establish a dynamic physical examination cohort. The end point of follow-up was new-onset hyperuricemia or the end of follow-up period. Cox regression stepwise fitting model was used to analyze the risk of different body weight metabolic phenotypes and hyperuricemia, and stratified analysis was performed for gender. According to body weight metabolic phenotype, the subjects were divided into normal metabolism and normal weight(NMNW) group, normal metabolism and obesity (NMO) group, abnormal metabolism and normal weight (AMNW) group and abnormal metabolism and obesity (AMO) group. The risk of hyperuricemia was calculated according to the changes of body weight metabolic phenotype during the follow-up period. In the sensitivity analysis, the robustness of the results was verified by changing the diagnostic criteria for hyperuricemia, removing patients with hyperuricemia at the first year of follow-up, and removing subjects aged ≥65 years.Results:Compared with the NMNW group, the risk of hyperuricemia in the NMO group, AMNW group and AMO group increased by 78.9%, 61.3%, 115.4%, respectively ( χ2=272.88, 128.15, 496.12, all P<0.001). Patients who were initially classified as NMNW at baseline, if transitioned to NMO or AMO by the follow-up endpoint, their risk of hyperuricemia increased by 122.5% ( χ2=8.01, P<0.05) and 137.4% ( χ2=15.99, P<0.001), respectively. When the baseline AMNW group changed to AMO, the risk of hyperuricemia was increased by 119.2% ( χ2=6.63, P<0.05). For patients with AMO as baseline, if they turned into NMNW and AMNW at the end of follow-up, their risk of hyperuricemia would decrease by 58.3% ( χ2=43.67, P<0.001) and 27.2% ( χ2=16.07, P<0.001). Patients with a baseline of NMO who transitioned to NMNW and AMNW at the follow-up endpoint had their risk of developing hyperuricemia decreased by 36.7% ( χ2=25.35, P<0.001) and 30.9% ( χ2=9.70, P<0.05), respectively. Conclusions:The transition from metabolic health and non-overweight obesity to metabolic abnormalities and overweight obesity is associated with an increased risk of hyperuricemia, and improvements in metabolic health or weight are associated with a decreased risk of hyperuricemia.

Objective:To explore the relationship between weight change and the development of hyperuricemia (HUA) in adults receiving health checkups.Methods:A retrospective cohort study. A total of 37 722 subjects who underwent two or more health checkups at the Health Management Center of the Second Affiliated Hospital of Dalian Medical University from January 2014 to December 2022 were included, and the general information and laboratory findings at the time of the initial health checkups and follow-up were collected. Weight change was defined as the ratio of difference between the weight at the last follow-up and the baseline weight to baseline weight. The subjects were grouped with weight change: significant weight loss group (weight change ≤-5.0%), mild weight loss group (-5.0%

Objective:To explore the application status and trends of the health examination data.Methods:Relevant literatures on health examination data were retrieved from Web of Science from 1 January 2007 to 30 June 2022 and China Knowledge Network Infrastructure from 1 January 1992 to 30 June 2022; and the literature and research contents were visually analyzed by using CiteSpace 6.1 bibliometrics software.Results:Total of 5 517 Chinese articles and 18 563 English articles were selected. The publication volume of health examination data in China increased year by year since 1992, and the international publication volume also showed an increasing trend. The Chinese literature focused on health management, osteoporosis, overweight, and physical examination subjects such as pilots, while the English literature focused on the study of obesity, care and functional cognition after the formation of a cohort of physical examination data. More co-citation papers related to health examination data were published in the journals from developed countries mainly in the United States and the United Kingdom, and the contents of the co-cited journals highly covered disease research on chronic diseases, such as cardiovascular disease, functional cognition and rehabilitation.Conclusions:The number of articles published on health examination data is increasing year by year, and in the future, more studies will use big data algorithms such as machine learning to measure the association between the risk of chronic diseases and related influencing factors.

Objective:To assess the effects of intervention measures on the quality control of health examination institutions in Dalian City.Methods:This cross-sectional study encompassed a comprehensive evaluation of 40 physical examination institutions in Dalian City. Interrupted time series analysis was employed to examine the changes in level and slope of processing rates for significant abnormal health examination results, chief inspection physician qualification rates, and completion rates of basic health examination items before (January 2020 to July 2021) and after (August 2021 to July 2022) intervention. An interrupted time series analysis diagram was generated.Results:After the implementation of intervention measures, the processing rate of significant abnormal results in public physical examination institutions reached 93.52%, while the qualification rate of chief inspection physicians was as high as 98.86%. And completion rate of basic health examination items was 93.86%. The rates of handling important abnormal results in health check-ups at private healthcare institutions before intervention, 1 month after intervention, and long-term intervention showed an upward trend of 1.374%, 0.229%, and 0.664%, respectively ( t=8.61, 12.21, and 108.61, all P<0.05). The qualification rate of chief inspection physicians in public physical examination institutions exhibited an increase of 0.227% and 0.155% before and after the intervention respectively ( t=6.74 and 617.67, all P<0.05). The completion rates of basic health check-up items in public healthcare institutions showed an upward trend before intervention, 1 month after intervention, and long-term intervention, with a rate of 0.446%, 0.067%, and 0.745%, respectively ( t=24.95, 3.25, 138.80, all P<0.05). Conclusions:The implementation of quality control intervention measures for health check-ups has significantly improved the quality control of health examination institutions in Dalian City.

In this study, we presented the isolation and characterization of eight novel seco-guaianolide sesquiterpenoids (1-8) and two known guaianolide derivatives (9 and 10), from the aerial part of Achillea alpina L.. Compounds 1-3 were identified as guaianolides bearing an oxygen insertion at the 2, 3 position, while compounds 4-8 belonged to a group of special 3-nor guaianolide sesquiterpenoids. The structural elucidation of 1-8, including their absolute configurations, were accomplished by a combination of spectroscopic data analysis and quantum electronic circular dichroism (ECD) calculations. To evaluate the potential antidiabetic activity of compounds 1-10, we investigated their effects on glucose consumption in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells. Among the tested compounds, compound 7 demonstrated the most pronounced ability to reverse IR. Moreover, a mechanistic investigation revealed that compound 7 exerted its antidiabetic effect by reducing the production of the pro-inflammatory cytokine IL-1β, which was achieved through the suppression of the NLRP3 pathway.
Humans ; Hypoglycemic Agents/pharmacology* ; Circular Dichroism ; Cytokines ; Glucose ; Hep G2 Cells ; Insulin Resistance

Pancreatic cancer is a more aggressive and refractory malignancy. Resistance and toxicity limit drug efficacy. Herein, we report a lower toxic and higher effective miriplatin (MPt)-loaded liposome, LMPt, exhibiting totally different anti-cancer mechanism from previously reported platinum agents. Both in gemcitabine (GEM)-resistant/sensitive (GEM-R/S) pancreatic cancer cells, LMPt exhibits prominent anti-cancer activity, led by faster cellular entry-induced larger accumulation of MPt. The level of caveolin-1 (Cav-1) determines entry rate and switch of entry pathways of LMPt, indicating a novel role of Cav-1 in nanoparticle entry. After endosome-lysosome processing, in unchanged metabolite, MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM, to degrade POLG and TFAM. Then, via PINK1-Parkin axis, mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA (mtDNA) replication blocking. Additionally, POLG and TFAM are identified as novel prognostic markers of pancreatic cancer, and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity. Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA (target of most platinum agents), and totally distinct mechanism of MPt and other formulations of MPt. Self-assembly offers LMPt special efficacy and mechanisms. Prominent action and characteristic mechanism make LMPt a promising cancer candidate.

Objective:To evaluate the effect of noninvasive prenatal testing (NIPT) as first-line screening in fetal chromosome aneuploidy screening practice, and to provide evidence for the prevention and control strategy of birth defects.Methods:Since July 2019, Hebei province had carried out the NIPT project providing first-line screening for eligible pregnant women in the area (except for those who were not applicable). Pregnant women with high risk received genetic counseling, prenatal diagnosis and intervention guidance. Low risk and false-positive ones received continuous detection and moved to prenatal diagnosis center for counseling and diagnosis if abnormities were discovered. All pregnant women were followed up to learn about pregnancy outcomes and newborn health status. Detection results and clinical data of pregnant women participating the NIPT project from July 2019 to July 2020 were collected. The detection results and effect of NIPT were analyzed.Results:(1) Basic information of the screened population: A total of 424 330 pregnant women were screened, and 423 596 were successfully detected, with a success rate of 99.83% (423 596/424 330). The age of pregnant women was (28.8±4.5) years old; the gestational age of screening was (16.6±2.3) weeks; the proportion of advanced-age pregnant women (≥35 years old) was 10.18% (43 132/423 596); in vitro fertilization-embryo transfer (IVF-ET) rate was 1.58% (6 713/423 596); the twin rate was 1.38% (5 849/423 596); the proportion of primipara was 34.23% (144 977/423 596). (2) Screening results and detection performance: totally, 325, 73 and 20 pregnant women were diagnosed with trisomy 21, 18 and 13; the sensitivity were 99.39%, 100.00% and 100.00%; the specificity were 99.98%, 99.99% and 99.98%; the positive predictive value were 75.76%, 68.87% and 21.51%, respectively. Besides, 249 190 pregnant women were received supplementary reports as well, and 255, 10 and 9 were confirmed for sex chromosome aneuploidy, other autosomal aneuploidy and deletion/duplication syndrome; the positive predictive value were 37.78%, 6.06% and 32.14%, respectively. The sensitivity of NIPT for target trisomy (trisomy 21, 18 and 13) screening in advanced-age, IVF-ET and twin pregnant women were 99.29%, 100.00% and 90.00%, respectively; the specificity were 99.93% for all; the positive predictive value were 82.25%, 61.54% and 69.23%, respectively.Conclusions:NIPT has a significant effect and good performance in the first-line screening of fetal chromosome aneuploidy in the whole population, which might provide reference for the improvement of birth defect prevention and control strategy.