Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

Urothelial carcinoma (UC) is one of the most common malignant tumors. The development of omics technologies has provided new perspectives for the diagnosis and treatment of UC. Genomics, transcriptomics, and proteomics have unveiled the molecular mechanisms and biological characteristics of UC, which are conducive to the discovery of new therapeutic targets and biomarkers. Single-cell omics and spatial transcriptomics have further deepened the understanding of cellular heterogeneity and the tumor microenvironment. These technologies show great potential in molecular typing, non-invasive diagnosis, early screening, and personalized treatment of UC. This article, in response to the national key strategy, will delve into how omics technologies can drive new developments in the diagnosis and treatment of UC, as well as the application and translation prospects of these technologies in UC.

Urothelial carcinoma (UC) is one of the most common malignant tumors. The development of omics technologies has provided new perspectives for the diagnosis and treatment of UC. Genomics, transcriptomics, and proteomics have unveiled the molecular mechanisms and biological characteristics of UC, which are conducive to the discovery of new therapeutic targets and biomarkers. Single-cell omics and spatial transcriptomics have further deepened the understanding of cellular heterogeneity and the tumor microenvironment. These technologies show great potential in molecular typing, non-invasive diagnosis, early screening, and personalized treatment of UC. This article, in response to the national key strategy, will delve into how omics technologies can drive new developments in the diagnosis and treatment of UC, as well as the application and translation prospects of these technologies in UC.

Objective:To detect the prevalence of mosaic loss of chromosome Y in adult men in ten study areas in China, describe the epidemiological distribution of mosaic loss of chromosome Y (mLOY) carriers and assess its prospective association with lung cancer.Methods:Based on the data from baseline survey, genetic analysis and follow-up (as of December 31, 2018) from China Kadoorie Biobank, we used Mosaic Chromosomal Alterations pipeline to detect mLOY carriers in 10 areas in China and described the epidemiological characteristics of mLOY carriers in adult men, including age, area distribution, lifestyle and disease history. We used multivariate logistic regression model to identify the potential relevant factor of mLOY. Cox proportional hazard regression model was fitted to assess the prospective association of mLOY with lung cancer. Stratification analysis were conducted to evaluate the potential modification effects of smoking and age. We also conducted mediation analysis to assess the mediating effect of mLOY in the association between smoking and lung cancer.Results:A total of 42 859 adult men were included in our analysis, in whom 2 458 mLOY carriers were detected (5.7%). The detection rate increased with age ( P<0.05). The detection rate was higher in urban area (7.3%±0.2%) than that in rural area (4.7%±0.1%). The results of logistic regression analysis indicated that smoking might be a risk factor for the detection of mLOY ( OR=1.49, 95% CI:1.36-1.64). After follow-up for average 11.1 years, 1 041 lung cancer cases were observed. The prospective analysis showed that mLOY carriers had an increased risk for lung cancer by 24% compared with non-mLOY carriers ( HR=1.24, 95% CI:1.01-1.52) and expanded mLOY carriers (mLOY cell proportion ≥10%) had an increased risk for lung cancer by 50% ( HR=1.50, 95% CI:1.13-2.00). Stratification analysis showed no modification effects of smoking and age in the association between mLOY and lung cancer (interaction P>0.05). Mediation analysis showed that mLOY could be a mediating factor in the association between smoking and lung cancer, the estimated effect was 0.09 (0.01-0.17). Conclusions:There were significant differences in the detection rate of mLOY in adult men with different social-economic characteristics and lifestyles in ten areas in China. Besides, mLOY carriers, especially expanded mLOY carriers, had increased risk for lung cancer and mLOY might be a mediating factor in the association between smoking and lung cancer.

[Objective]To explore the application of alcohol in unearthed medical literature,so as to provide reference for the clinical application of alcohol in modern Chinese medicine.[Methods]Based on the unearthed literatures such as Wushier Bingfang,Wuwei Medical Bamboo Slips of Han Dynasty,ZHOU Jiatai Medical Bamboo Slips of Qin Dynasty,Tianhui Medical Bamboo Slips and so on,combined with the relevant records in the handed down literature,the application of alcohol in the unearthed literatures was compared and summarized.[Results]Although there is no specific reason for the use of alcohol in the unearthed medical literature,a comprehensive analysis can be made from the related records in the contemporaneous literature.The analysis showed that in the pre-Qin,Qin and Han Dynasties,most of the alcohol was yellow wine,which was used in the way of alcohol mixing,alcohol decoction and impregnation,and was widely used in the treatment of various diseases.It is concluded that the alcohol has the effect of"changing the medicinal properties,direct to the disease""warming the channels and clearing the collaterals,removing blood stasis and relieving pain""correcting the odor,enhancing the drug effect"and so on.The application of alcohol in the later literature showed different characteristics in each period,but all developed on the basis of the application of alcohol in the Qin and Han Dynasties.[Conclusion]Alcohol has great potential in the clinical treatment of modern Chinese medicine,but the soaking and decocting time of alcohol for medicine,the effect of different temperatures is worth further study.

[Objective]To elucidate the meridian manipulations described in the Han bamboo slips of Zhangjiashan from a meridian perspective,providing a theoretical foundation for the application of ancient meridian manipulations in modern clinical practice.[Methods]Based on the records in the unearthed literature and cultural relics of the pre-Qin,Qin and Han Dynasties,this paper summarizes the Daoyin technique in the pre-Qin,Qin and Han Dynasties,explores the in-depth relationship between Daoyin technique and meridian muscles,and selects the common orthopedic diseases in modern clinic,such as neck pain,ankle pain,knee pain and shoulder pain,which are closely related to meridian muscles.The original text and Daoyin movements are analyzed,and the Daoyin movements are discussed from the perspective of meridian muscles.[Results]It is found that the Daoyin described in the pre-Qin,Qin and Han Dynasties is mainly simple body movements.The meridians described in the Book of Pulse are mostly meridiansand tendons,so the theory of meridians and tendons may be more suitable for the thinking of the physicians at that time.Using the theory of meridians and tendons to analyze the Daoyin in Yinshu,it is found that the Daoyin therapy for neck pain in the book should be mainly treated for the neck pain of the sun meridian muscles;the treatment of lateral ankle pain is mainly adjusted by the Shaoyang meridian muscles of the foot,and the treatment of medial ankle pain is mainly adjusted by the Taiyin meridian muscles of the foot;the Daoyin therapy for knee pain is used to adjust the meridian muscles of the six meridians of the foot;the treatment of shoulder pain,the use of"Yuanxing three hundred"to treat the shoulder pain caused by the Shaoyang and Yangming meridian muscles of the hand,the use of"Qianyuan"to treat the shoulder pain caused by the sun meridian muscle disease,the use of"Zhiluo"to treat the shoulder pain caused by the sun meridian muscle disease,and the use of"Houfu"to treat the shoulder pain caused by the Taiyin meridian muscle disease.It is more reasonable to explain the treatment principles of Daoyin using the theory of meridian sinew,which can further elucidate the treatment principles of Daoyin and clarify the corresponding disease indications for different Daoyin.[Conclusion]Looking at the Daoyin manipulations in Yinshu from the perspective of meridians and tendons can further clarify the diseases treated by Daoyin manipulation,make the treatment more accurate and effective,and provide more ideas for the clinical application of Daoyin manipulation in modern traditional Chinese medicine.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome, and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors, including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high-precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening in the fetal gene reprogramming in HCM.
Cardiomyopathy, Hypertrophic/metabolism* ; Humans ; Animals ; DNA Methylation ; Mice ; Transcriptome ; Chromatin/genetics* ; Early Growth Response Protein 1/metabolism* ; Male ; Epigenome ; Nucleosomes/genetics* ; Female ; Middle Aged ; Disease Models, Animal ; Adult

Objective:To investigate the clinical and pathological characteristics and prognosis of upper tract urothelial carcinoma (UTUC) with concurrent other histological variants.Methods:The clinical data of 566 UTUC patients admitted to Peking University People's Hospital from January 2007 to April 2021 were retrospectively analyzed. Among them, 289 were males and 277 were females, with an average age of (67.3±10.0)years old. Among the patients, 97 had a history of smoking, 29 had undergone kidney transplantation, 120 had diabetes, 76 had coronary heart disease, 146 had hyperlipidemia, 271 had hypertension, and 50 had a history of chronic kidney disease. Among the UTUC cases, 366 had concurrent hydronephrosis, 55 had concurrent bladder cancer, and 43 had a history of previous bladder cancer. The distribution included 210 cases of renal pelvis carcinoma, 5 cases of carcinoma at the renal pelvis-ureter junction, 226 cases of ureteral carcinoma, and 125 cases of multifocal tumors. Patients were classified into the pure UTUC group and the UTUC with concurrent other histological variants group based on postoperative pathology, and their clinical and pathological features were compared. Logistic regression analysis was used to explore risk factors for the occurrence of histological variations in UTUC. The log-rank test was employed to compare the overall survival (OS) and cancer-specific survival (CSS) between the two groups, while Cox regression analysis was performed to investigate prognostic factors.Results:Among the 566 cases, 511 were pure UTUC and 55 were UTUC with concurrent other histological variants. Among the latter, 30 cases had squamous differentiation, 6 had glandular differentiation, 5 had mucinous differentiation, 5 had sarcomatoid carcinoma, 2 had micropapillary carcinoma, 2 had neuroendocrine carcinoma, 1 had giant cell carcinoma, and 4 had other mixed histological variations. The proportion of patients with a history of kidney transplantation was higher in the UTUC with concurrent histological variants group than that in the pure UTUC group [14.5% (8/55) vs. 4.1% (21/511)], with statistically significant difference ( P=0.003). In the UTUC with concurrent histological variants group, the proportion of postoperative high-grade tumors [98.2% (54/55) vs. 80.2% (410/511)], muscle-invasive tumors [89.1% (49/55) vs. 68.1% (348/511)], lymph node metastasis tumors [10.9% (6/55) vs. 2.3% (12/511)], and maximum tumor diameter [(3.60±2.64) cm vs. (2.96±1.98) cm] were higher than those in the pure UTUC group ( P<0.05). Multivariate logistic regression analysis showed that a history of kidney transplantation ( OR=4.991, 95% CI 1.749-13.615, P=0.002) was an independent predictive factor for the occurrence of histological variants. Follow-up was conducted for 1 to 174 months, with a median follow-up time of 32.8 months. UTUC with concurrent histological variants was significantly associated with worse OS and CSS ( P<0.05). Multivariate Cox regression analysis indicated that histological variants were an independent risk factor for OS ( HR=1.860, 95% CI 1.228-2.816, P=0.003) and CSS ( HR=2.146, 95% CI 1.349-3.412, P=0.001). Conclusions:UTUC with concurrent other histological variants exhibited higher postoperative tumor grade and stage compared to pure UTUC, and UTUC with concurrent other histological variants was an independent risk factor for worse prognosis.

Objective:To compare the clinical efficacy and safety of intra-articular platelet rich plasma combined with hyaluronic acid and platelet rich plasma alone in the treatment of knee osteoarthritis.Methods:The relevant literatures published between January 2010 and December 2021 on the randomized control study of intra-articular injection of platelet rich plasma and hyaluronic acid and injection of platelet rich plasma only in the treatment of knee osteoarthritis were searched. The bias risk of all the literatures included in the study was evaluated by Revman 5.3 software, and the data were processed and analyzed by Stata 16.0 software. The standardized mean difference ( SMD) was calculated for the difference of efficacy indexes, and the difference was compared by t- test. The odds ratio ( OR) was calculated for the difference of safety in-dex, and the difference was compared by t- test. Results:①A total of 7 relevant research literatures were in-cluded, all of which were in English. ②A total of 675 patients were included in the study, of which 330 patients were treated with intra-articular injection of platelet rich plasma and hyaluronic acid, and 345 patients were treated with intra-articular injection of platelet rich plasma only. ③The VAS scores of patients with platelet rich plasma and hyaluronic acid injection combined with injection and platelet rich plasma injection alone were compared. After 1 and 3 months of injection, the VAS scores of patients with platelet rich plasma combined with hyaluronic acid injection were compared with those of patients with platelet rich plasma injection only. There was no significant difference[ SMD(95% CI)=-0.02(-0.30, 0.27), t=-0.12, P=0.902; SMD(95% CI)=-0.40(-0.80, 0.00), t=-1.97, P=0.051]. After 6 months of injection, the VAS scores of patients with combined injection of platelet rich plasma and hyaluronic acid were significantly lower than those of patients with injection of platelet rich plasma only, and the difference was statistically significant [ SMD(95% CI)=-0.33 (-0.55, -0.11), t=-2.98, P=0.012]. ④The WOMAC scores of patients with combined injection of platelet rich plasma, hyaluronic acid and platelet rich plasma only were compared. After 12 months of treatment, the WOMAC scores of patients with combined injection of platelet rich plasma and hyaluronic acid were significantly higher than those of patients with PRP only, and the difference was statistically significant [ SMD(95% CI)=-0.30(-0.58, -0.03), t=-2.14, P=0.033]. ⑤The incidence of adverse events of platelet rich plasma combined with hyaluronic acid was lower than that of platelet rich plasma only [ OR(95% CI)=0.55(0.33, 0.93), P=0.021]. Conclusion:Compared with intra-articular injection of platelet rich plasma only, the short-term clinical efficacy of combined injection of platelet rich plasma and hyaluronic acid is equivalent to that of injection of platelet rich plasma only, but the long-term clinical efficacy is significantly better, and the safety of combined injection of platelet rich plasma and hyaluronic acid is significantly better.

Objective:To assess the association between warm ischemia time (WIT) and renal function in patients undergoing laparoscopic partial nephrectomy.Methods:A total of 344 patients treated with laparoscopic partial nephrectomy in Peking University People’s Hospital were included. There were 240 males (69.8%) and 104 females (30.2%) with a median age of 57 (23-89) years.The median BMI was 25.6 (16.7-36.0) kg/m 2.213 cases (61.9%) were associated with hypertension.There were 66 (19.2%) patients with diabetes mellitus. There were 92 cases (26.7%) with smoking history. The median preoperative creatinine was 73 (32-170) μmol/L. The median preoperative estimated glomerular filtration rate (eGFR) was 95 (33-142) ml/(min·1.73m 2). The maximum diameter of the tumor was 2.5 (7-9) cm.314 (91.3%) patients with renal cancer stage T 1. All patients underwent warm ischemia during the operation. The patients were divided into three groups for analysis. Restricted cubic spline regression analysis was used to assess the association between WIT as a continuous variable and percentage change of eGFR. Analysis of covariance was used to compare postoperative eGFR among the three groups, and to adjust for preoperative eGFR and tumor diameter. Results:There were statistically significant differences in the percentage change of postoperative eGFR ( P=0.009) and tumor diameter ( P<0.001) among the three groups. Restricted cubic spline regression analysis showed that with the prolongation of WIT, the percentage change of postoperative eGFR gradually decreased, and the curve began to stabilize after 30 minutes (R 2=0.044, P=0.015). The results of covariance analysis showed that after adjusting for baseline preoperative eGFR and tumor size, the effect of WIT on postoperative eGFR was significantly different among the three groups ( F=3.864, P=0.022). The postoperative eGFR in the WIT<20 min group was significantly higher than that in 20 min≤WIT<30 min group( P=0.009) and WIT≥30 min group( P=0.017). There was no significant difference in postoperative eGFR between the two groups with longer WIT( P=0.806). Conclusions:In partial nephrectomy, patients with WIT less than 20 minutes had higher postoperative eGFR levels than those with WIT greater than 20 minutes. However, when WIT exceeded 20 minutes, prolonged ischemia time did not lead to further decline in renal function.