RNA-based gene therapy has been widely used for various diseases, and extensive studies have proved that suitable delivery routes greatly help the development of RNA therapeutics. Identifying a safe and effective delivery system is key to realizing RNA therapeutics' clinical translation. Inhalation is a non-invasive pulmonary delivery modality that can enhance the retention of therapeutic agents in the lungs with negligible toxicity, thereby improving patient compliance. Inhaled RNA therapeutics are increasingly becoming an area of focus for researchers; however, only several clinical trials have explored inhaled delivery of RNA for pulmonary diseases. This review presents an overview of recent advances in inhaled delivery systems for RNA therapeutics, including viral and nonviral systems, highlighting state of the art regarding inhalation in the messenger RNA (mRNA) field. We also summarize the applications of mRNA inhalants in infectious and other lung diseases. Simultaneously, the research progresses on small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and different types of RNA are also discussed to provide new strategies for developing RNA inhalation therapy. Finally, we clarify the challenges inhaled RNA-based therapeutics face before their widespread adoption and provide insights to help advance this exciting field to the bedside.

Objective : To study the effect and mechanism of action of Silibinin on the differentiation of 3T3-F442A preadipocytes in murine． Methods : The effects of 0－400 μmol / L Silibinin on the proliferation of 3T3-F442A adi- pocytes at 24，48 and 72 h were detected by 3-(4，5-dimethylthiazol-2) -2，5-diphenyltetrazolium bromide ( MTT) assay，and the effects of Silibinin on the adipogenesis of 3T3-F442A adipocytes were visualized by Oil Red O stai- ning ; RT-qPCR , Western blot and ELISA assays were used to detect the effects of Silibinin on 3T3-F442A adipo- cyte differentiation-associated transcription factor CCAAT / enhancer binding protein ( C / EBP) α , C / EBP β , per- oxisome proliferator-activated receptor γ cular endothelial growth factor (VEGF) -α and VEGF receptor 2 (VEGFR-2) ，matrix metalloproteinase (MMP) -2 and MMP-9，mitogen-activated protein kinase (MEK) and phosphorylated MEK (p-MEK) ，and extracellular regu- lated protein kinase (ERK) and phosphorylated ERK (p-ERK) expression. (PPARγ) ，adipocyte protein 2 (aP2) ，adipose generation-associated vas Results : MTT assay showed that the cell proliferation rate of 3T3-F442A preadipocytes decreased after 100，200，and 400 μmol /L Silibinin treatment compared with the control group (P＜0. 001) ; Oil Red O staining assay showed that the accumulation of red lipid droplets of the cells in the 160 μmol /L Silibinin assay group significantly decreased ; RT-qPCR assay showed that mRNA expression of C/EBPα , C/EBPβ , PPARγ , aP2，VEGF-α , VEGFR-2，MMP-2，and MMP-9 was down-reg- ulated in 3T3-F442A adipocytes treated with 160 μmol /L Silibinin compared with the control group (P＜0. 001) ; Western blot assay showed that protein expression of C /EBPα , C /EBPβ , PPARγ and aP2 was down-regulated in 3T3-F442A adipocytes treated with 160 μmol /L Silibinin (P＜0. 001) ，and the phosphorylation level of p-MEK/ MEK and p-ERK/ ERK proteins was down-regulated compared with the control group (P ＜0. 001) ; ELISA assay showed that the protein concentrations of MMP-2 and MMP-9 in the cell supernatant were down-regulated (P < 0. 001) in 3T3-F442A adipocytes treated with 160 μmol /L Silibinin． Conclusion Silibinin inhibited 3T3-F442A adipocyte differentiation and adipogenesis through inhibition of the MEK/ ERK pathway and matrix metalloproteinase activity.

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

Objective:To provide clinicians with insights about the patients with breast cancer complicated with thyroid cancer and dermatomyositis,and to improve early detection of the diseases by observing the clinical characteristics of 1 case of breast cancer complicated with thyroid cancer and dermatomyositis and reviewing the literatures about the relationships between these three kinds of diseases.Methods:The medical information of this patient,including gender,age,clinical manifestations,glucocorticoid treatment dose,type of concurrent tumor and the time point it occured and therapeutic regimen were collected and recorded.These clinical data were retrospectively analyzed.Results:The patient with dermatomyositis was diagnosed with breast cancer and thyroid cancer in succession.Oral administration of 50 mg dexamethasone per day was continued in the treatment of dermatomyositis.Then the patient received 4 cycles of pirarubicin/cyclophosphamide (AC) followed by 4 cycles of paclitaxel/Hessaitin (TH) as neoadjuvant chemotherapy for breast cancer.During the 24 weeks of chemotherapy,the breast tumor size was gradually decreased while there was no significant change in thyroid tumor size.The clinical symptoms of dermatomyositis were also improved.The blood lactic acid dehydrogenase and alpha hydroxybutyrate dehydrogenase levels were decreased,but not obviously.After 8 courses of AC-TH neoadjuvant chemotherapy followed by radical resection of thyroid cancer,there was no significant improvement in the symptoms of dermatomyositis 1 week after operation and the myocardial enzyme levels remained unchanged.Then modified radical mastectomy was performed.The myocardial enzymes were examined again 1 week after the second operation all of them were decreased to the normal levels.The clinical symptoms of dermatomyositis were also improved.Conclusion:Although the relationships between the three diseases is still controversial,the clinical data of the patient and relevant literatures collected in this paper support that breast cancer is associated with thyroid cancer and dermatomyositis is associated with breast cancer,but not thyroid cancer.

Objective To investigate the microbiological trends and antibiotic susceptibility of peritoneal dialysis(PD)-related peritonitis (PDAP).Methods All patients who developed PDAP between 2004 and 2015 in Renji Hospital,Shanghai Jiao Tong University School of Medicine were enrolled.Demographic data,results of dialysate pathogen culture and drug susceptibility test were recorded.The trend of peritonitis incidence was measured by Poisson regression and the chi-square test or Fisher exact test method was used to compare the composition of causative organisms and their antimicrobial susceptibilities over time.Results During the study period,a total of 711 episodes of PDAP were occurred in 386 patients.The culture positive rate of pathogens rose from 52.0％ in 2004 to 77.0％ in 2015 (P ＜ 0.001).The distribution of causative organisms of the culture positive peritonitis was gram-positive bacteria (270,59.5％),followed by gram-negative bacteria (129,28.4％),polymicrobial(39,8.6％),fungi (15,3.3％) and mycobacteria (1,0.2％).From 2004 to 2015,the incidence of peritonitis decreased from 0.214 to 0.160 episodes/patient·year (P=0.034).The incidence of coagulase-negative staphylococcus peritonitis decreased from 0.049 to 0.027 episodes/patient · year (P=0.025),while others had no significant change;A significant decline was observed in the sensitivity of Gram-positive strains to the first generation cephalosporin and ampicillin/sulbactam in 2010-2015 group compared with those in 2001-2009 group (61.3％ vs 88.2％,P ＜ 0.001;61.7％ vs 85.5％,P=0,001),whereas the sensitivity to vancomycin remained the same.The sensitivity of Gram-negative strains to ceftazidime and amikacin showed no significant change.As for the gram-positive peritonitis treated with cefradine as empirical treatment,compared with those in 2004-2009 group,in 2010-2015group the proportion of patients requiring to change their treatment regime was significantly higher,and the treatment course was longer.Conclusions A gradual decline is observed in the incidence of PDAP and the culture positive rate of pathogens improves.Peritonitis caused by coagulase-negative staphylococcus decreases overtime.The present empirical treatment protocols may need re-evaluation considering the decreased rate of the first generation cephalosporin sensitivity in recent years.

OBJECTIVEThe term "premature thelarche" refers to isolated breast development before 8 years of age in female, without any other signs of sexual maturation, while "gynecomastia" is the presence of breast tissue in males. This study aimed to investigate the prevalence of premature thelarche and gynecomastia in Chinese infants and toddlers, identify the potential risk factors, and explore the influence of early breast development on physical growth, mental development and psychomotor development.

METHODA total of 1 510 full term and healthy children at the age of 0-48 months were sampled by stratified cluster random sampling method from 8 provinces from 2011-2012. Weight, height and breast development were assessed by senior primary pediatricians, while Bayley Scale of Infant Development-I (BSID-I) was used to measure the mental developmental index (MDI) and psychomotor developmental index (PDI) for children aged 2-30 months. Social-demographic Questionnaires were completed by the caregivers.

RESULTThe combined prevalence of premature thelarche and gynecomastia was 1.6% (23/1 475), girls 2.2% (15/695), boys 1.0% (8/780), all within 2 years of age. The birth weight, feeding patterns in first 4 months, delivery mode, weaning time and social economic status were not significantly associated with the breast development. However, lower father's education level (OR = 3.632, 95%CI = 1.565-8.432) as well as smoking mother (OR = 18.960, 95%CI = 1.590-226.304) were significantly related to breast development even after adjusting for potential confounders. Lower weight (-0.479 ± 0.648 vs. 0.005 ± 0.987, P < 0.05) and height (-0.602 ± 1.042 vs. 0.008 ± 0.986, P < 0.05) Z score were found in breast development group, even after adjusting for age, gender and father' education level. Neither mental development (t = -0.082, P > 0.05) nor psychomotor development (t = 1.054, P > 0.05) was associated with breast development.

CONCLUSIONWe showed a similar prevalence of premature thelarche with the data reported in similar studies reported from other countries. Among the 0-48 months old infants and toddlers, Father's education level and smoking mother were both related to breast development. Breast development was significantly associated with physical growth, but had no correlation with the mental or psychomotor development.

African Continental Ancestry Group ; Body Height ; Body Weight ; Breast ; growth & development ; Child Development ; Child, Preschool ; Cross-Sectional Studies ; Environmental Exposure ; Female ; Gynecomastia ; epidemiology ; etiology ; Humans ; Infant ; Infant, Newborn ; Male ; Multivariate Analysis ; Prevalence ; Puberty, Precocious ; epidemiology ; etiology

Objective To evaluate the targeted killing of malignant melanoma cells by aclarubicin liposomes conjugated with vascular endothelial growth factor(ADM-VEGF-SSL)in vitro.Metheds To detect the binding abilitv of liposomes to malignant melanoma(MM)cells,the human malignant melanoma cell line A375 was cultured in the presence of ADM-VEGF-3H-SSL or ADM-3H-SSL for 2 days followed by the detection of radioactivity of these cells.Then.A375 cells were cultured with various concentrations(0.01,0.1,1,10,100 mol/L)of ADM-VEGF-SSL,ADM-SSL or free ADM for 48 hours in the 48-hour cytotoxity test,or for 0.5 hour followed by another 48-hour culture in drug-free medium in the 0.5-hour cytotoxity test.After that,MTT assay was used to detect the survival rate of these cells.Results ADM-VEGF-SSL could specifically bind to and kill A375 cells.The binding rate of ADM-VEGF-SSL was 2.15 folds as high as that of ADM-SSL.The survival rate of A375 cells after being treated with ADM-VEGF-SSL for 48 hour was similar to that with flee ADM(P＞0.05).but lower than that with ADM-SSL(P＜0.05),while the survival rate of melanocytes treated with ADM-VEGF-SSL was higher than that with free ADM or ADM-SSL(both P＜0.05).As shown by the 0.5-hour cytotoxity test.shortening the treatment course did not attenuate the effect of ADM-VEGF-SSL on A375 cells.Conclusions ADM-VEGF-SSL can specifically recognize A375 cells.efficiently deliver adriamycin into tumor cells,markedly inhibit the proliferation of A375 cells,and eventually,a targeted kill of these cells is realized.

Feeding adult male rats with gossypol acetic acid at a dose of 15 nig/kg/day for 50 days led to infertility. Spermatogenesis and sperm motility were impaired ( table 1 ) . However, testosterone, K+ and Na+ concentsrations in serum and RTF were found to be unchanged (table 2, 3 ) . It suggests that at low antifertility doses gossypol disrupts spermatogenesis in the seminiferous epithelium without affecting testosterone, K+ and Na+ secretion and translation in testis.