Kirsten rat sarcoma viral oncogene homolog (KRAS) protein inhibitors are a promising class of therapeutics, but research on molecules that effectively penetrate the blood-brain barrier (BBB) remains limited, which is crucial for treating central nervous system (CNS) malignancies. Although molecular generation models have recently advanced drug discovery, they often overlook the complexity of biological and chemical factors, leaving room for improvement. In this study, we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties. Our approach utilizes a variational autoencoder (VAE) generative model integrated with reinforcement learning for multi-objective optimization. This method specifically aims to enhance BBB permeability (BBBp) while maintaining high-affinity substructures of KRAS inhibitors. To support this, we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models. Additionally, we introduce two novel metrics, the knowledge-integrated reproduction score (KIRS) and the composite diversity score (CDS), to assess structural performance and biological relevance. Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets.

Objective To investigate the unmet needs for assistive technology for people with physical disabilities in Chengdu,and analyze the related factors. Methods From November,2023 to March,2024,the persons with physical disabilities in Chengdu were selected from Sichuan Individuation service platform,and investigated using World Health Organization rapid Assistive Tech-nology Assessment. Results A total of 558 questionnaires were set up,and 527 effective questionnaires retured.26.8%of them reported un-met needs for aids,with the highest need for mobility aids(66.0%).Lack of support(54.9%),high price(26.3%)and lack of knowledge about aids(20.3%)were the main reasons for not obtaining the aids they needed.Loss of spouse(OR=3.615),serious mobility impairment(OR＞2.926)and serious self-care impairment(OR＞2.781)were the risks of unmet needs for aids. Conclusion It is important to popularize policies and products of aids,pay attention to personal adaptation for people with different barriers,and strengthen the service system,to meet the needs of people with disabilities.

Objective:To investigate the clinicopathological features and molecular characteristics of β-catenin-deficient colorectal cancer.Methods:The clinical, pathological and molecular features of 11 colorectal cancers with β-catenin protein loss diagnosed at the 960th Hospital of People′s Liberation Army of China, from January 2012 to November 2022 were analyzed.Results:Among the 11 patients, 3 were males and 8 were females. Their age ranged from 43 to 74 years, with the median age of 59 years. Six were in the left colon and 5 were in the right colon. One of the 11 cases had lymph node metastasis, 10 cases were well and moderately differentiated adenocarcinoma, and 1 was mucinous adenocarcinoma. Eight cases were of TNM stage T4, 2 of T1 stage and 1 of Tis stage. β-catenin protein was not detected using immunohistochemistry. Sanger sequencing revealed the presence of fragment-deletion mutation in exon 3 of CTNNB1 gene, resulting in loss of β-catenin protein expression.Conclusion:β-catenin deficiency is present in a small number of colorectal cancers and may be associated with exon 3 mutations of CTNNB1 gene.

Traumatic supraorbital fissure syndrome (TSOFS) is a symptom complex caused by nerve entrapment in the supraorbital fissure after skull base trauma. If the compressed cranial nerve in the supraorbital fissure is not decompressed surgically, ptosis, diplopia and eye movement disorder may exist for a long time and seriously affect the patients′ quality of life. Since its overall incidence is not high, it is not familiarized with the majority of neurosurgeons and some TSOFS may be complicated with skull base vascular injury. If the supraorbital fissure surgery is performed without treatment of vascular injury, it may cause massive hemorrhage, and disability and even life-threatening in severe cases. At present, there is no consensus or guideline on the diagnosis and treatment of TSOFS that can be referred to both domestically and internationally. To improve the understanding of TSOFS among clinical physicians and establish standardized diagnosis and treatment plans, the Skull Base Trauma Group of the Neurorepair Professional Committee of the Chinese Medical Doctor Association, Neurotrauma Group of the Neurosurgery Branch of the Chinese Medical Association, Neurotrauma Group of the Traumatology Branch of the Chinese Medical Association, and Editorial Committee of Chinese Journal of Trauma organized relevant experts to formulate Chinese expert consensus on the diagnosis and treatment of traumatic supraorbital fissure syndrome ( version 2024) based on evidence of evidence-based medicine and clinical experience of diagnosis and treatment. This consensus puts forward 12 recommendations on the diagnosis, classification, treatment, efficacy evaluation and follow-up of TSOFS, aiming to provide references for neurosurgeons from hospitals of all levels to standardize the diagnosis and treatment of TSOFS.

AIM: To explore the improvement effect and mechanism of crocin on cognitive impairmrnt of Alzheimer's disease (AD) rats. METHODS: The hippocampus of SD rats were injected with Aβ 25-35 to establish AD model, then rats were randomly divided into AD group, AD + low, medium, high dose of crocin groups (10, 20, 40 mg/kg) and AD + donepezil group (1 mg/kg), intraperitoneal injection treatment for 4 weeks, set sham group. Dark avoidance test and water maze test were used to evaluate the learning and memory abilities of rats, ELISA was used to detect serum Aβ content, HE staining and Tunel staining were used to determine pathological changes and neuronal apoptosis of hippocampus of rats, immunohistochemistry was used to detect the expression of Brdu, Dcx and NeuN in hippocampus of rats, and Western blot was used to detect the protein expression of Aβ, DKK3, β-catenin, p-GSK-3β/GSK-3β, Caspase-3, Bax, Bcl-2 in hippocampus of rats. RESULTS: Compared to sham group, the learning and memory abilities of AD group rats were decreased, serum Aβ content increased, the pathological change in hippocampus was serious, neuronal apoptosis was increased, the expression of Brdu, Dcx, NeuN were decreased, the protein expression of Aβ, DKK3, p-GSK-3β/GSK-3β, Caspase-3, Bax were increased, protein expression of β-catenin, Bcl-2 were decreased (P<0.01). Compared to AD group, after the treatment of doses of crocin and donepezil, the learning and memory abilities of AD rats were improved, serum Aβ content were increased, and the pathological change in hippocampus were alleviated, neuronal apoptosis were reduced, the expression of Brdu, Dcx, NeuN were decreased, the protein expression of Aβ, DKK3, p-GSK-3β/ GSK-3β, Caspase-3, Bax were decreased, the protein expression of β-catenin, Bcl-2 were increased, notely, dose-dependent effect of crocin was significant. CONCLUSION: Crocin reduced neuronal apoptosis and mediated DKK3 to regulate GSK-3β/ β-catenin pathway to improve the cognitive impairment of AD rats.

Objective:To explore the regulatory effect of exosomes derived from healthy human adipose stem cells (ADSC) on the fibrosis of localized scleroderma fibroblasts (LSFs) in vitro. Methods:From January 2021 to January 2022, fat from 10 healthy donors in Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences was collected by liposuction. Adipose stem cells were isolated and cultured in vitro, and exosomes (ADSC-Exo) were collected. Fibroblasts were isolated from skin tissue of 15 patients with localized scleroderma during the same period and cultured in vitro. Induced differentiation and staining, nanoparticle tracking analysis, transmission electron microscopy, PKH26 staining and Western blotting were used to identify ADSC and their exosomes. The effect of ADSC on the expression of fibrosis markers [collagen Ⅰ, collagen Ⅲ, α-smooth muscle actin (α-SMA)] in LSFs through its exosomes was examined by extracellular vesicle secretion inhibition assay. The proliferation and migration abilities of LSFs treated with ADSC-Exo were tested by CCK-8 method and scratch test. Real-time quantitative PCR, immunofluorescence staining and Western blotting were used to detect the expression levels of collagen Ⅰ, collagen Ⅲ, α-SMA, transforming growth factor β (TGF-β) and p-Smad2/3 in LSFs. Independent sample t-test was used to compare between the two groups. One-way ANOVA was used for multi-group comparison, and SNK- q test was used for pairwise comparison. Results:ADSC and LSFs were successfully isolated and cultured in vitro, and ADSC-Exo was extracted. Extracellular vesicle secretion inhibition assay demonstrated that ADSC decreased fibrotic markers of LSFs by secreting extracellular vesicles. Results of CCK-8 and scratch test showed that the proliferation and migration ability of LSFs was decreased by ADSC-Exo treatment. The results of real-time quantitative PCR, immunofluorescence staining and Western blotting showed that compared with the control group, the expressions of collagen Ⅰ, α-SMA, TGF-β and p-Smad 2/3 in the ADSC-Exo treatment group were significantly decreased. Conclusion:In vitro, ADSC-Exo can affect the biological behavior and reduce the expression of fibrosis markers in LSFs by inhibiting the TGF-β/Smad pathway.

More and more people are becoming aware of the impact of shoulder and neck lines on total body shape. Injections of type A botulinum toxin to promote trapezius muscle hypertrophy have been increasingly popular in recent years. A vast amount of literature is reviewed and described to provide reference and guidance to clinicians in this study, which focuses on the mechanism and application of botulinum toxin, the trapezius muscle anatomy and aesthetics foundation, the trapezius muscle injection shaping method, and the postoperative effect of the relevant literature.

Objective:To explore the regulatory effect of exosomes derived from healthy human adipose stem cells (ADSC) on the fibrosis of localized scleroderma fibroblasts (LSFs) in vitro. Methods:From January 2021 to January 2022, fat from 10 healthy donors in Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences was collected by liposuction. Adipose stem cells were isolated and cultured in vitro, and exosomes (ADSC-Exo) were collected. Fibroblasts were isolated from skin tissue of 15 patients with localized scleroderma during the same period and cultured in vitro. Induced differentiation and staining, nanoparticle tracking analysis, transmission electron microscopy, PKH26 staining and Western blotting were used to identify ADSC and their exosomes. The effect of ADSC on the expression of fibrosis markers [collagen Ⅰ, collagen Ⅲ, α-smooth muscle actin (α-SMA)] in LSFs through its exosomes was examined by extracellular vesicle secretion inhibition assay. The proliferation and migration abilities of LSFs treated with ADSC-Exo were tested by CCK-8 method and scratch test. Real-time quantitative PCR, immunofluorescence staining and Western blotting were used to detect the expression levels of collagen Ⅰ, collagen Ⅲ, α-SMA, transforming growth factor β (TGF-β) and p-Smad2/3 in LSFs. Independent sample t-test was used to compare between the two groups. One-way ANOVA was used for multi-group comparison, and SNK- q test was used for pairwise comparison. Results:ADSC and LSFs were successfully isolated and cultured in vitro, and ADSC-Exo was extracted. Extracellular vesicle secretion inhibition assay demonstrated that ADSC decreased fibrotic markers of LSFs by secreting extracellular vesicles. Results of CCK-8 and scratch test showed that the proliferation and migration ability of LSFs was decreased by ADSC-Exo treatment. The results of real-time quantitative PCR, immunofluorescence staining and Western blotting showed that compared with the control group, the expressions of collagen Ⅰ, α-SMA, TGF-β and p-Smad 2/3 in the ADSC-Exo treatment group were significantly decreased. Conclusion:In vitro, ADSC-Exo can affect the biological behavior and reduce the expression of fibrosis markers in LSFs by inhibiting the TGF-β/Smad pathway.

More and more people are becoming aware of the impact of shoulder and neck lines on total body shape. Injections of type A botulinum toxin to promote trapezius muscle hypertrophy have been increasingly popular in recent years. A vast amount of literature is reviewed and described to provide reference and guidance to clinicians in this study, which focuses on the mechanism and application of botulinum toxin, the trapezius muscle anatomy and aesthetics foundation, the trapezius muscle injection shaping method, and the postoperative effect of the relevant literature.

Disulfiram, a drug that has been used for alcohol dependence. As an approved drug in clinical medicine, disulfiram can be used as the anticancer drug in the treatment of breast cancer, prostate cancer, glioblastoma, lung cancer, etc. This paper summarized the mechanism of disulfiram for anticancer treatment and the function for liver cancer therapy, and we also analyzed the potential mechanism of disulfiram for the treatment of liver cancer and its’ value in the clinical application.