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 causes of abnormal rising trends of isolation rate and infection of Staph-ylococcus aureus in the breast surgery department of a specialized cancer hospital.METHODS By means of pro-spective survey in combination with retrospective survey,an epidemiological survey was conducted for 5 patients with hospital-associated S.aureus infection who were treated in breast surgery department of Sun Yat-sen Univer-sity Cancer Center from Jan.2023 to Aug.2023,and the homology was observed.RESULTS The incidence rate of hospital-associated S.aureus infection(ward E 0.08％,ward F 0.38％)of the breast surgery department patients was higher during the period from Jan.2023 to Aug.2023,higher than 0.004％of the whole patients during the same period.The environmental sampling result showed that the colonized rate of S.aureus was 17.39％(4/23)and in nasal cavity 7.41％(2/27)in hands of the healthcare workers,and 28.57％in nasal cavity of logistical per-sonnel.Bundle interventions could reduce the incidence of hospital-associated methicillin-resistant S.aureus(MRSA)infection and the colonized rate in hands of the healthcare workers but had less impact on the colonized rate in the nasal cavity.The result of pulse field gel electrophoresis(PFGE)indicated that there was risk of cross transmission of colonized S.aureus between the hands of healthcare workers and the nasal cavities.The hand hy-giene,measures for contact transmission and environmental disinfection were supposed to be taken as the major links for control of the hospital-associated S.aureus infection.CONCLUSIONS The sporadic community-ac-quired infections and hospital-associated infections are the leading causes of the abnormal rise of the isolation rate and the infection rate of S.aureus in the breast surgery department.The bundle prevention and control measures can block the transmission of infections.

OBJECTIVE To investigate the causes of abnormal rising trends of isolation rate and infection of Staph-ylococcus aureus in the breast surgery department of a specialized cancer hospital.METHODS By means of pro-spective survey in combination with retrospective survey,an epidemiological survey was conducted for 5 patients with hospital-associated S.aureus infection who were treated in breast surgery department of Sun Yat-sen Univer-sity Cancer Center from Jan.2023 to Aug.2023,and the homology was observed.RESULTS The incidence rate of hospital-associated S.aureus infection(ward E 0.08％,ward F 0.38％)of the breast surgery department patients was higher during the period from Jan.2023 to Aug.2023,higher than 0.004％of the whole patients during the same period.The environmental sampling result showed that the colonized rate of S.aureus was 17.39％(4/23)and in nasal cavity 7.41％(2/27)in hands of the healthcare workers,and 28.57％in nasal cavity of logistical per-sonnel.Bundle interventions could reduce the incidence of hospital-associated methicillin-resistant S.aureus(MRSA)infection and the colonized rate in hands of the healthcare workers but had less impact on the colonized rate in the nasal cavity.The result of pulse field gel electrophoresis(PFGE)indicated that there was risk of cross transmission of colonized S.aureus between the hands of healthcare workers and the nasal cavities.The hand hy-giene,measures for contact transmission and environmental disinfection were supposed to be taken as the major links for control of the hospital-associated S.aureus infection.CONCLUSIONS The sporadic community-ac-quired infections and hospital-associated infections are the leading causes of the abnormal rise of the isolation rate and the infection rate of S.aureus in the breast surgery department.The bundle prevention and control measures can block the transmission of infections.

Objective:To investigate the variation of reference ranges of hemodynamic parameters in normal pregnancy and their relation to maternal basic characteristics.Methods:A total of 598 healthy pregnant women who underwent regular prenatal examination at the Third Affiliated Hospital of Guangzhou Medical University from January to December 2023 were prospectively enrolled, and noninvasive hemodynamic monitors were used to detect changes in hemodynamic parameters of the pregnant women with the week of gestation, including cardiac output (CO), stroke volume (SV), thoracic fluid content (TFC), systemic vascular resistance (SVR), mean arterial pressure (MAP), and heart rate (HR). Relationships between hemodynamic parameters and maternal basic characteristics, including age, height, and weight, were analyzed using restricted cubic spline.Results:(1) CO ( r=0.155, P<0.001), TFC ( r=0.338, P<0.001), MAP ( r=0.204, P<0.001), and HR ( r=0.352, P<0.001) were positively correlated with the week of gestation, and SV was negatively correlated with the week of gestation ( r=-0.158, P<0.001). There was no significant correlation between SVR and gestational age ( r=-0.051, P=0.258). (2) CO exhibited a positive correlation with maternal height and weight (all P<0.001). The taller and heavier of pregnant women, the higher their CO. A linear relationship was observed between maternal weight and SV, MAP and HR (all P<0.01). As maternal weight increased, SV, MAP and HR showed an upward trend. Furthermore, there was an inverse association between maternal age and SVR ( P<0.001). (3) There was a significant nonlinear association observed between TFC and body mass index during pregnancy ( P<0.05). Additionally, a nonlinear relationship was found between SVR and MAP in relation to maternal age (all P<0.05). Notably, when the age exceeded 31 years old, there was an evident upward trend observed in both SVR and MAP. Conclusions:The hemodynamic parameters of normal pregnant women are influenced by their height, body weight, and age. It is advisable to maintain a reasonable weight during pregnancy and give birth at an appropriate age.

Objective:To understand the current status of pubertal sexual characteristics development of girls aged 6-18 years in Tongzhou District of Beijing and to compare the differences in sexual characteristics development among girls characterized as thin, normal, overweight, and obese.Methods:A cross-sectional survey was conducted among 2 844 girls aged 6-18 years in Tongzhou District of Beijing from September 2022 to July 2023. The developmental stages of breast and pubic hair were assessed on site, and menarche status was inquired. Weight and height were measured. The girls were subsequently characterized into thin, normal, overweight and obese groups. Basic information (including family and personal history) was obtained through questionnaires. Probit probability unit regression was applied to calculate the age of each Tanner stage of sexual characteristics development and the age of menarche. The χ 2 test was applied to compare the counting data between two or multiple groups. Results:A total of 2 844 girls were surveyed and 2 704 girls met the inclusion criteria, resulting in a valid response rate of 95.1%. Among these girls, 1 105 (40.9%) were aged 6-9 years, 1 053 (38.9%) were aged 10-13 years, and 546 (20.2%) were aged 14-18 years. The of height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ), and body mass index-for-age Z-score (BAZ) were 0.46(-0.23,1.16), 0.69(-0.16,1.67), and 0.67(-0.27,1.73) respectively. The prevalences of thin, overweight, and obesity were respectively 1.7% (45/2 704), 17.3% (467/2 704), and 19.9% (538/2 704), respectively. There were 45 girls in the thin group, 1 654 girls in the normal weight group, 1 005 girls in the overweight and obesity group. The age of Tanner stage breast 2 (B2), Tanner stage pubic hair 2 (P2), and menarche was 9.0 (95% CI 8.9-9.1), 10.5 (95% CI 10.4-10.6), and 11.4 (95% CI 11.3-1.5) years, respectively. The current status of breast and pubic hair maturity in girls with pubertal development shows that 64.6% (1 211/1 874) of these girls had breast development preceding pubic hair development, 32.4% (607/1 874) had concurrent breast and pubic hair development, and 3.0% (56/1 874) had pubic hairs development preceding breast development. The interval age between B2 and B5 was 4.7 (95% CI 4.6-4.8) years, between P2 and P5 was 4.5 (95% CI 4.4-4.6) years, and between B2 and menarche was 2.4 (95% CI 2.3-2.5) years. The ages of sexual characteristics development in overweight and obese groups were earlier than that in normal and thin groups. The ages of B2 in thin, normal, overweight, and obese groups were 10.0 (95% CI 9.5-10.6), 9.3 (95% CI 9.2-9.4), and 8.6 (95% CI 8.4-8.7) years, respectively. The age of menarche in thin, normal, overweight, and obese groups were 13.1 (95% CI 12.4-13.7), 11.6 (95% CI 11.4-11.7), and 11.1 (95% CI 11.0-11.2) years, respectively. The interval ages between B2 and B5 and between P2 and P5 was 4.5 and 4.1 years, respectively in the overweight and obese groups, and those in normal group and thin group was 4.7 and 4.5 years, 4.6 and 4.7 years, respectively. Conclusions:The ages of sexual characteristics development and menarche tend in Tongzhou District of Beijing to be earlier than that being reported of Beijing's survey 20 years ago. Girls characterized as overweight and obese not only start puberty at an earlier age than girls of normal weight, but also have a shorter developmental process.

Blood deficiency syndrome (BDS) refers to a pathological state with blood dysfunction and organ dystrophy in traditional Chinese medicine. Danggui Wuji granules (DWG) was developed from a formula containing Angelicae Sinensis Radix and Musculus et Os Galli Domestici. Herein, we investigated the mechanism of DWG in treating BDS by modulating gut microbiota. We found that DWG protected mice from BDS by elevating the levels of red blood cell count, hemoglobin, and hematocrit in peripheral blood and increasing the erythrocyte membrane Na⁺-K⁺-ATPase activity. Danggui Wuji granules changed the composition and metabolites of colonic flora. Notably, Lactobacillus, Muribaculaceae, and Alistipes were the main genera showing changes after DWG treatment. Our findings revealed that DWG presented a positive therapeutic effect on BDS in mice by regulating the gut microbiota and metabolites. The protective mechanism of DWG was associated with pathways such as metabolic pathways, biosynthesis of secondary metabolites, ABC transporters, ribosome, thyroid hormone synthesis, lysine degradation, galactose metabolism, tyrosine metabolism, etc.

BackgroundHome-based intervention occupies a prominent place in the treatment of autism spectrum disorder （ASD） in children， whereas previous studies on the effect of home-based early intensive behavioral intervention on verbal ability of children with ASD are somewhat inadequate. ObjectiveTo study the effects of intensive family behavioral of intervention based on Verbal Behavior Milestones Assessment and Placement Program （VB-MAPP） on the language ability of children with ASD， so as to provide references for the development of family intervention strategies for children with ASD. MethodsChildren aged 2 to 3 years old who attended the Children's Rehabilitation Department of the Second Affiliated Hospital of Shantou University Medical College from September 2020 to December 2021 and met the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） diagnostic criteria for ASD were selected as the study objects. A non-randomized concurrent control trial was conducted to compare a study group （n=24） receiving home-based early intensive behavioral intervention using VB-MAPP with a control group （n=14） receiving training from other special institutions or early childhood education institutions. The intervention lasted for 6 months in both groups. Before and after the intervention， the VB-MAPP milestone assessment was performed in the two groups， and the VB-MAPP milestone score， mand， trac and listener responds were selected as the study indicators. Then the intervention effect was compared between two groups， and the multiple linear regression was performed to screen the related influencing factors. ResultsAfter intervention， the total milestone assessment score， mand， tact and listener responds scores of study group were higher than those of control group， with statistical difference （Z=-4.339~-2.195， P<0.05 or 0.01）. Multiple linear regression analysis denoted that the average weekly hours of home-based intervention in the first three months had certain effect on listener responds （β=1.029， P<0.05）. ConclusionApplication of home-based early intensive behavior intervention using VB-MAPP may contribute to the improvement of verbal abilities such as mand， tact and listener responds in children with ASD. ［Funded by 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund （number， 20200601）］

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

Objective:To evaluate the association between polycystic ovary syndrome (PCOS)-related symptom combinations and ovarian stimulation high response in infertile patients with PCOS symptoms and controlled ovarian stimulation treatment by recombinant Human Follitropin Alfa (r-hFSHα) solution for injection, and to evaluate the efficacy and safety outcomes of using the r-hFSHα prefilled injection pen in high-risk patients with ovarian hyperstimulation syndrome (OHSS).Methods:This prospective, observational, phase Ⅳ study enrolled 1055 patients with at least one symptom/sign of PCOS using the r-hFSHα prefilled pen for over 4 months follow-up observation from December 2015 to September 2017 in the Second Hospital of Hebei Medical University, Center for Reproductive Medicine, Shandong University, Tangdu Hospital of the Air Force Military Medical University, Dalian Maternity and Child Health Care Hospital, Nanjing Maternity and Child Health Care Hospital, Jiangxi Maternity and Child Health Care Hospital, the First Affiliated Hospital of Xinjiang Medical University, the First Affiliated Hospital of Anhui Medical University, the Affiliated Hospital of Inner Mongolia Medical University. The primary endpoints assessed included the development of polycystic ovaries, elevated serum testosterone levels, menstrual cycle disturbances, development of hirsutism, and completion of egg retrieval. The efficacy endpoints of the study included the number of ocoytes retrieved, the number of M Ⅱ oocyte, the biochemical pregnancy rate, the clinical pregnancy rate, and the implantation rate. Results:In the full analysis set ( n=997), polycystic ovary rate was 54.5% (543/997), serum testosterone level was (0.4±0.2) μg/L, menstrual cycle disorder rate was 45.0% (449/997), hirsutism rate was 10.5% (105/997). The average number of oocytes retrieved after ovarian stimulation was 14.4. The clinical pregnancy rate per transfer cycle was 53.6% (251/468), the live birth rate was 45.3% (212/468), the biochemical pregnancy rate was 60.9% (285/468), the implantation rate was 39.1% (349/893), and the fresh embryo transfer cancellation rate was 24.0% (239/997). OHSS incidence was diagnosed in 1.8% (19/1054) of patients (safety set, n=1054), including 8 (0.8%) mild cases, 10 (0.9%) moderate cases and 1 (0.1%) severe case. According to the results of exploratory analysis, a decrease in body mass index (BMI) was associated with an increased risk of high response. For every 1 kg/m 2 decrease in BMI, the risk of high response (number of retrieved oocytes >15) increased by approximately 9%, the risk of high response (number of retrieved oocytes >20) increased by approximately 9%. For every 1 increase in antral follicle count (AFC), the risk of high response(number of retrieved oocytes >15) increased by approximately 6% and the risk of high response (number of retrieved oocytes >20) by approximately 4%. Conclusion:Patients with at least one symptom/sign of ovarian hyperstimulation achieved good clinical outcomes with the use of the r-hFSHα prefilled pen, and high response was associated with lower BMI and AFC.

p-coumaric acid is one of the aromatic compounds that are widely used in food, cosmetics and medicine due to its properties of antibacterium, antioxidation and cardiovascular disease prevention. Tyrosine ammonia-lyase (TAL) catalyzes the deamination of tyrosine to p-coumaric acid. However, the lack of highly active and specific tyrosine ammonia lyase limits cost-effective microbial production of p-coumaric acid. In order to improve biosynthesis efficiency of p-coumaric acid, two tyrosine ammonia-lyases, namely Fc-TAL2 derived from Flavobacterium columnare and Fs-TAL derived from Flavobacterium suncheonense, were selected and characterized. The optimum temperature (55 ℃) and pH (9.5) for Fs-TAL and Fc-TAL2 are the same. Under optimal conditions, the specific enzyme activity of Fs-TAL and Fc-TAL2 were 82.47 U/mg and 13.27 U/mg, respectively. Structural simulation and alignment analysis showed that the orientation of the phenolic hydroxyl group of the conserved Y50 residue on the inner lid loop and its distance to the substrate were the main reasons accounting for the higher activity of Fs-TAL than that of Fc-TAL2. The higher activity and specificity of Fs-TAL were further confirmed via whole-cell catalysis using recombinant Escherichia coli, which could convert 10 g/L tyrosine into 6.2 g/L p-coumaric acid with a yield of 67.9%. This study provides alternative tyrosine ammonia-lyases and may facilitate the microbial production of p-coumaric acid and its derivatives.
Ammonia-Lyases/chemistry* ; Coumaric Acids ; Escherichia coli/genetics* ; Tyrosine