Loss-of-function variants of low-density lipoprotein receptor-related protein 5 (LRP5) can lead to reduced bone formation, culminating in diminished bone mass. Our previous study reported transcription factor osterix (SP7)‍-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration. However, the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown. In this study, we used mice with a conditional knockout (cKO) of LRP5 in mature osteoblasts, which presented decreased osteogenesis. The in vitro experimental results showed that SP7 could promote LRP5 expression, thereby upregulating the osteogenic markers such as alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), and β‍-catenin (P<0.05). For the in vivo experiment, the SP7 overexpression virus was injected into a bone defect model of LRP5 cKO mice, resulting in increased bone mineral density (BMD) (P<0.001) and volumetric density (bone volume (BV)/total volume (TV)) (P<0.001), and decreased trabecular separation (Tb.‍Sp) (P<0.05). These data suggested that SP7 could ameliorate bone defect healing in LRP5 cKO mice. Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.
Animals ; Low Density Lipoprotein Receptor-Related Protein-5/metabolism* ; Osteoporosis/genetics* ; Mice ; Mice, Knockout ; Sp7 Transcription Factor/physiology* ; Osteogenesis ; Bone Density ; Osteoblasts/metabolism* ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Mice, Inbred C57BL ; beta Catenin/metabolism*

OBJECTIVE: To explore the clinical features of patients with necrotizing soft tissue infection (NSTI) and the related factors for sepsis, so as to provide a basis for early intervention and improvement of patients' prognosis. METHODS: A retrospective case series study was conducted to analyze the clinical data of NSTI patients admitted to the department of burns and wound repair surgery of Guangdong Provincial People's Hospital from October 2021 to December 2024. Demographic information, underlying diseases, infection characteristics, laboratory test results and etiological findings at admission, treatment status, occurrence of complications (including sepsis) and prognosis were collected. Univariate and multivariate Logistic regression analyses were used to identify the associated factors for sepsis in NSTI patients. Receiver operator characteristic curves (ROC curves) were plotted to evaluate the predictive value of individual and combined factors for sepsis. RESULTS: A total of 159 NSTI patients were enrolled, mainly middle-aged and elderly males. Most patients had comorbidities, including diabetes mellitus (110 cases, 69.2%) and hypertension (67 cases, 42.1%). The main infection site was the lower extremities (104 cases, 65.4%). Common symptoms included redness (96 cases, 60.4%), swelling (129 cases, 81.1%), local heat (60 cases, 37.7%), pain (100 cases, 62.9%), and skin ulceration or necrosis (9 cases, 5.7%). Imaging findings included soft tissue swelling (66 cases, 57.9%), gas accumulation (41 cases, 36.0%), and abnormal signal/density shadows (50 cases, 43.9%). Staphylococcus aureus was the main pathogenic bacterium [12.0% (31/259)], and drug-resistant Escherichia coli had the highest detection rate among drug-resistant bacteria [35.1% (13/37)]. Regarding debridement and repair, most patients (80 cases, 50.3%) underwent debridement ≥ 72 hours after admission, while only 10.1% (16 cases) received debridement within 6 hours. Most patients underwent multiple debridements, with 2 times of debridements being the most common (68 cases, 42.8%), and the maximum times of debridements reached 6. The largest number of patients received secondary suture (44 cases, 27.7%). In terms of complications, sepsis was the most common (66 cases, 41.51%), followed by acute kidney injury, respiratory failure requiring mechanical ventilation, and multiple organ dysfunction syndrome (MODS), while disseminated intravascular coagulation (DIC) was the least common. During the follow-up period, 9 patients (5.66%) were readmitted within 90 days, and 11 patients died, with a mortality rate of 6.92%. Univariate analysis showed that diabetes, coronary heart disease, gout, body temperature, heart rate, C-reactive protein, platelet count, total bilirubin, albumin, creatinine, out-of-hospital treatment, and out-of-hospital use of antimicrobial agents were significantly associated with sepsis in NSTI patients (all P < 0.05). Multivariate Logistic regression analysis showed that coronary heart disease [odds ratio (OR) = 30.085, 95% confidence interval (95%CI) was 2.105-956.935], C-reactive protein (OR = 1.026, 95%CI was 1.009-1.054), and total bilirubin (OR = 1.436, 95%CI was 1.188-1.948) were independent associated factors for sepsis in NSTI patients (all P < 0.05). ROC curve analysis revealed that the combination of the three predictors yielded the highest AUC for predicting sepsis in NSTI patients compared to any individual predictor [area under the curve (AUC) = 0.799 (95%CI was 0.721-0.878)]. CONCLUSIONS The clinical features of NSTI patients show certain regularity. Coronary heart disease, C-reactive protein, and total bilirubin are independent associated factors for sepsis in NSTI patients.
Humans ; Retrospective Studies ; Male ; Sepsis ; Soft Tissue Infections/microbiology* ; Female ; Middle Aged ; Aged ; Adult ; Prognosis ; Risk Factors ; Necrosis ; Logistic Models ; Fasciitis, Necrotizing

OBJECTIVES: This study aimed to explore the expression of lysosomal-associated membrane protein 5 (LAMP5) and microRNA (miR)-302a-3p in oral squamous cell carcinoma (OSCC) and their functional mechanism on the invasion and metastasis of OSCC. METHODS: The expression of LAMP5 in OSCC and its sensitivity as a prognostic indicator were analyzed on the basis of The Cancer Genome Atlas database. Western blot, quantitative reverse transcription polymerase chain reaction, and cell immunocytochemistry were used to detect the expression of LAMP5 in OSCC tissues and cells. The effect of LAMP5 on the proliferation, migration, and invasion of OSCC cells was evaluated through cell counting kit-8, immunocytochemistry, migration, and invasion assays, respectively. The miRNA targeting prediction websites were used to predict the miR that regulates LAMP5 and verify the targeted regulatory effect of miR-302a-3p on LAMP5. The effect of LAMP5 knockdown on OSCC tumor growth was evaluated in a nude mouse tumorigenesis model. RESULTS: LAMP5 was highly expressed in OSCC tissues and cells. It showed high sensitivity in the early diagnosis of OSCC. LAMP5 knockdown significantly inhibited the proliferation, migration, and invasion of OSCC cells, whereas LAMP5 overexpression increased these cell activities. The expression of LAMP5 was regulated by miR-302a-3p. In vivo, LAMP5 knockdown significantly inhibited the growth of OSCC tumor. CONCLUSIONS LAMP5 promotes the malignant progression of OSCC by enhancing the proliferation, migration, and invasion of OSCC cells. The expression of LAMP5 is negatively regulated by miR-302a-3p.
MicroRNAs/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Animals ; Carcinoma, Squamous Cell/genetics* ; Neoplasm Invasiveness ; Cell Proliferation ; Mice, Nude ; Cell Movement ; Lysosomal Membrane Proteins/genetics* ; Mice ; Cell Line, Tumor ; Neoplasm Metastasis

Objective:To investigate the correlation factors of complete clinical response in idiopathic inflammatory myopathies(IIMs)patients receiving conventional treatment.Methods:Patients diagnosed with IIMs hospitalized in Peking University People's Hospital from January 2000 to June 2023 were in-cluded.The correlation factors of complete clinical response to conventional treatment were identified by analyzing the clinical characteristics,laboratory features,peripheral blood lymphocytes,immunological indicators,and therapeutic drugs.Results:Among the 635 patients included,518 patients finished the follow-up,with an average time of 36.8 months.The total complete clinical response rate of IIMs was 50.0％(259/518).The complete clinical response rate of dermatomyositis(DM),anti-synthetase syn-drome(ASS)and immune-mediated necrotizing myopathy(IMNM)were 53.5％,48.9％and 39.0％,respectively.Fever(P=0.002)and rapid progressive interstitial lung disease(RP-ILD)(P=0.014)were observed much more frequently in non-complete clinical response group than in complete clinical re-sponse group.The aspartate transaminase(AST),lactate dehydrogenase(LDH),D-dimer,erythrocyte sedimentation rate(ESR),C-reaction protein(CRP)and serum ferritin were significantly higher in non-complete clinical response group as compared with complete clinical response group.As for the treat-ment,the percentage of glucocorticoid received and intravenous immunoglobin(IVIG)were significantly higher in non-complete clinical response group than in complete clinical response group.Risk factor analysis showed that IMNM subtype(P=0.007),interstitial lung disease(ILD)(P=0.001),eleva-ted AST(P=0.012),elevated serum ferritin(P=0.016)and decreased count of CD4+T cells in peripheral blood(P=0.004)might be the risk factors for IIMs non-complete clinical response.Conclu-sion:The total complete clinical response rate of IIMs is low,especially for IMNM subtype.More effec-tive intervention should be administered to patients with ILD,elevated AST,elevated serum ferritin or decreased count of CD4+T cells at disease onset.

Objective:To explore the clinical characteristics and outcomes of type 2 autoimmune pancreatitis (AIP) and compare with type 1 AIP.Methods:Clinical data of the patients diagnosed with type 2 AIP by the International Consensus on diagnostic criteria of AIP at Peking Union Medical College Hospital from January 2001 to December 2022 were retrospectively analyzed, and type 1 AIP patients diagnosed in Peking Union Medical College Hospital from January 1985 to December 2016 were collected as controls. The clinical symptoms, treatments and follow-ups were analyzed.Results:A total of 25 patients with type 2 AIP were included, of which 16 cases (64.0%) were pathologically confirmed cases (13 cases by endoscopic ultrasound puncture, 2 cases by surgery, and 1 case by interventional puncture), and 9 cases (36.0%) were suspected. The average age of onset was 40 years old. Most patients ( n=23, 92.0%) had abdominal pain along with emaciation to a various degree. Among them, 3 cases primarily presented as acute pancreatitis. Two cases were diagnosed after surgery for pancreatic masses. Eighteen cases were complicated with inflammatory bowel disease, including 16 cases with ulcerative colitis, one case with Crohn's disease, and one case with indeterminate colitis. All patients had typical imaging manifestations, including 13 cases (52.0%) with diffuse pancreatic enlargement, 12 cases (48.0%) with focal or multifocal pancreatic lesions, and 5 cases (20.0%) with simultaneous focal pancreatic masses and diffuse enlargement. All patients had normal serum IgG4 levels, anti-neutropil cytoplasmic antibodies (ANCA) positivity rate was 35.3% (6/17), and anti-nuclear antibody (ANA) positivity rate was 29.2% (7/24). Two surgical patients recovered well after surgery, and the other patients all achieved clinical and imaging relief after hormone therapy, and no recurrence was seen during follow-up. Compared with type 1 AIP, type 2 AIP had younger onset age, main manifestation as abdominal pain without jaundice, rare involvement with extra-pancreatic organs, the lesions mainly located in the intestine and normal IgG4 level with statistically significant differences. The recurrence rate of type 2 AIP was lower than that of type 1 AIP (0 vs 16%). Conclusions:Type 2 AIP has different clinical characteristics from type 1 AIP. Due to the lack of specific serum markers, the diagnosis is more difficult. It responds well to glucocorticoids and has a low recurrence rate.

Objective Improving the limb management strategy for patients undergoing coronary intervention through radial artery puncture and observe the application effect,and to provide scientific basis for the prevention of limb complications.Methods From March 2023 to February 2024,patients who underwent coronary intervention in the Cardiovascular Department of a Tertiary A hospital in Wenzhou City were selected.They were randomly di-vided into an experimental group of 241 cases and a control group of 236 cases using a random number table method.After surgery,they were all treated with a rotary hemostatic device for compression hemostasis.The experi-mental group implement improvement strategies for surgical limb management,specifically underwent a reverse Bar-beau test upon returning to the ward after surgery to achieve non-occlusive compression,followed by decompression every hour.The compression intensity of the control group was guided by palpating the distal radial artery pulsa-tion,and the first decompression was performed 1 hour after surgery,followed by decompression at intervals of every 2 hours.The main evaluation indicators are the incidence of surgical limb complications and simplified Chinese version of General Comfort Questionnaire(GCQ)scores in 2 groups of patients,while the secondary evaluation indi-cators are the duration of compression and the number of decompression times in both groups.Results The inci-dence of postoperative complications in the experimental group was 14.11%,which was statistically significant com-pared to 44.49%in the control group(χ2=53.308,P<0.001).The GCQ score of the experimental group was(77.71±5.43)points,which was higher than(74.66±5.83)points in the control group,and the difference was statistically signif-icant(t=-3.354,P=0.001).The compression duration of(172±52)minutes and decompression frequency of 2(2,3)in the experimental group were lower than(289±60)minutes and 4(3,4)in the control group,and the differences were statistically significant(P<0.001).Conclusion The non-occlusive compression method of the radial artery based on the reverse Barbeau test can significantly reduce limb complications in patients undergoing coronary inter-vention,shorten the duration of hemostatic compression,reduce the number of depressions,and improve patient com-fort.It provides objective basis for nursing staff to evaluate the intensity of hemostatic compression and the timing of decompression.

Human genetic resources include specimen samples and related information. The application and regulation of human genetic resources in China started at the end of the 20th century and have progressed rapidly. However， many challenges remain. In this paper， we reviewed the current status of sample conservation and management and provided recommendations for further development of human genetic resources in China. The aim is to effectively protect and rationally utilize China's human genetic resources， safeguard national security and people's health， and promote the building of a community of common health for mankind.

Objective:To compare the safety and efficacy of terbutaline and nifedipine for acute intrapartum fetal resuscitation (IUFR).Methods:This was a prospective randomized controlled study involving 110 pregnant women with non-reassuring fetal heart rate tracings (NRFHT) during delivery at Guangzhou Women and Children's Medical Center between January and April 2021. These women were randomly allocated to receive subcutaneous terbutaline sulphate (0.25 mg, terbutaline group) or oral nifedipine (10 mg, nifedipine group), with 55 subjects in each group. Hemodynamic parameters including blood pressure, heart rate, and oxygen saturation before and 5, 15 and 30 min after treatment as well as the success rate of intrapartum resuscitation, the onset time of medication, and the incidence of postpartum hemorrhage were analyzed using t test, Chi-square test or Fisher's exact test. Results:Two groups both showed no significant difference in the mean arterial pressure or oxygen saturation before or after treatment (all P>0.05). The heart rate was not affected in nifedipine group at any time points ( P>0.05). While the patients treated with terbutaline showed accelerated maternal heart rate 5, 15 and 30 min after administration as compared with the baseline[(97.0±20.2), (99.2±13.8), (91.8±12.6) vs (81.7±11.3) bpm, all P<0.001], but it began to decrease at 30 min, with a drop of 6.4 bpm compared with that at 15 min (95% CI: 1.5-11.2, P<0.05). None of the pregnant women had adverse reactions requiring medical intervention. The rates of successful acute resuscitation were similar in the two groups [terbutaline: 78.2% (43/55) vs nifedipine: 70.9% (39/55), χ 2= 0.77, P=0.381]. Terbutaline had a shorter onset time than nifedipine in slowing the frequency of contractions and returning fetal heart rate to class Ⅰ category [2(1-6) vs 6(1-10) min, U=2 348.50, P<0.001]. No significant difference was found between the two groups in terms of NRFHT-indicated cesarean section, assisted vaginal delivery, or second dose of tocolysis within 1 h (all P>0.05) nor in blood loss volume, postpartum hemorrhage rate, low Apgar score, low umbilical artery pH value (pH<7.2), neonatal asphyxia rate, or neonatal intensive care admission rate (all P>0.05). Conclusion:Terbutaline spends less time than nifedipine to take effect and may be an alternative for acute IUFR without significant adverse outcomes.

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

【Objective】 To investigate the clinical and genetic characteristics of hemolytic disease of the newborn(HDN) induced by anti-M complicated with pyruvate kinase deficiency (PKD) disease. 【Methods】 The clinical data of a pregnant woman with unexplained adverse pregnancy outcome in the third trimester were retrospectively analyzed, and neonate anemia status and blood transfusion were followed up. With informed consent, peripheral blood of the neonate and her parents were collected for serological tests and disease-related gene target sequence capture and sequencing. The clinical and genetic characteristics of HDN induced by anti-M or PKD were reviewed. 【Results】 The neonate presented severe anemia, hepatosplenomegalism, hyperbilirubinemia at birth, and was confirmed MN combined with ABO neonatal hemolysis by serological tests. The neonate recovered by receiving blood exchange and phototherapy treatments, but he needed to receive blood transfusion each month because of hemolytic anemia. Genetic analysis showed that the neonate had compound heterozygous mutations (c. 1096C>T; c. 941T>C) of PKLR gene inherited from her parents. 【Conclusion】 The clinical manifestations of PKD are similar to that of HDN caused by anti-M in the early stage of the disease. Clinicians should exclude the metabolic diseases of red blood cells when diagnosing severe HDN caused by anti-M.