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.

BACKGROUND:Sarcopenia refers to age-related progressive,systemic muscle mass reduction and/or muscle strength decline or muscle physiological function decline,which is related to the occurrence of a variety of adverse outcomes in older adults.Exercise is considered to be one of the main strategies for combating sarcopenia in older adults,but there is a lack of specific intervention methods of different exercise patterns to intervene in sarcopenia. OBJECTIVE:To elaborate the main influencing factors of sarcopenia and the research progress of different exercise methods to improve sarcopenia in older adults,providing reference and basis for combating sarcopenia in older adults. METHODS:Web of Science,PubMed,CNKI,VIP,WanFang databases were retrieved for relevant literature published from January 2000 to October 2023 using the keywords of"sarcopenia,sport,exercise intervention,resistant training,aerobic exercise,whole body vibration training,mixed training,physical performance,muscle strength,muscle mass"in Chinese and English,respectively.A total of 126 articles were included for review. RESULTS AND CONCLUSION:Resistance exercise is still the most effective way to prevent and treat senile sarcopenia,and the effect of high-intensity resistance exercise is more significant.However,in practical application,we should pay attention to the gradual increase of training load intensity.Aerobic exercise combined with resistance exercise is more effective to improve muscle mass and function in the elderly than a single exercise mode.It is suggested that older adults can carry out the transition of low-intensity aerobic exercise in the early stage and increase resistance exercise individually in the late stage.Whole body vibration training is a new treatment method for the prevention and treatment of senile sarcopenia,but particular attention should be paid to the effects of frequency,amplitude,and duration on patients during practical application.Multicomponent exercise combines different exercise modes,which can give full play to their respective advantages,so as to personalize exercise interventions.

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.

Objective:To investigate the level of digital health anxiety in elderly patients with cancer pain outside the hospital, and to analyze the influencing factors, so as to provide valuable reference for intervention in technology anxiety and personalized digital health services.Methods:The convenience sampling method was applied to select a total of 160 elderly patients with cancer pain who were treated in the General Surgery Department of the Second Hospital of Anhui Medical University from March 2018 to October 2022 as the research objects. The general information questionnaire, Technology Anxiety Scale, Family Adaptability and Cohesion Scale and Elderly Social Network Scale were used to conduct a cross-sectional survey. Multiple linear regression method was used to analyze the influencing factors of mobile medical technology anxiety score in elderly patients with cancer pain.Results:Finally, 153 questionnaires were effectively collected. The total score of technical anxiety scale of 153 elderly patients with cancer pain was (45.24 ± 9.67) points. Multiple linear regression results showed that family per capita monthly income ( t=-2.89, P= 0.004), living conditions ( t=-2.04, P=0.043), family support ( t=-2.42, P=0.017) and social network ( t=-7.81, P<0.001) were the main influencing factors of technical anxiety scores in elderly patients with cancer pain. Conclusions:Elderly cancer pain patients with lower family income, living alone, lower family support score and lower social network score have higher scores of digital health anxiety after discharge. Individualized intervention measures should be provided for such patients to reduce their anxiety level of digital health outside the hospital.

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.

Objective To explore the effects of curcumin on pro-inflammatory factors in the lung microvascular endothelial cells (LMVEC) model stimulated by thrombus. Methods The LMVECs were divided into six groups according to the random number table method. No treatment was given to the blank control group ; the model group was cultured for 7 hours in normal medium; the curcumin group was treated with 40 μmol/L curcumin for 72 hours ; the shRNA group was infected with shRNA adenovirus for 72 hours; the irregular chemokines (CX3CL1) overexpression group was infected with CX3CL1 overexpressing adenovirus for 72 hours; the shRNA+curcumin group infected with shRNA adenovirus and treated with 40 μmol/L curcumin together for 72 hours; CX3CL1 overexpression +curcumin group infected with CX3CL1 overexpressing adenovirus and treated with 40 μmol/L curcumin together for 72 hours. After each group was given the corresponding pretreatment, the thrombus natural precipitation was added each group for 12 hours. The contents of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the mRNA expression levels of CX3CL1, CX3CL1 receptor (CX3CR1), IL-6, TNF-α and the protein expression levels of CX3CL1/CX3CR1, CX3CR1/NF-κB in various groups were observed, repeat 3 times in each group. Results The contents and mRNA expression of IL-6, TNF-αand protein expression of CX3CR1, NF-κB in the LMVEC group were significantly higher than those in blank control group [IL-6 (ng/L): 207.90±16.69 vs. 85.93±20.32, TNF-α (ng/L): 239.60±15.27 vs. 101.23±11.92; IL-6 mRNA: 0.66±0.05 vs. 0.11±0.02, TNF-α mRNA: 1.06±0.04 vs. 0.02±0.01; CX3CR1 protein:3.94±0.58 vs. 1.00±0.31, NF-κB protein: 1.20±0.07 vs. 1.00±0.10; all P < 0.05]; the contents of IL-6 in shRNA group, CX3CL1 overexpression group, shRNA + curcumin group, CX3CL1 overexpression + curcumin group were all obviously lower than those in LMVEC group (ng/L: 183.60±11.52, 159.27±15.02, 117.03±7.91, 119.97±11.43 vs. 207.90±16.69, all P < 0.01); the content of TNF-α was markedly increased in shRNA group compared with that of LMVEC group (ng/L: 282.00±5.63 vs. 239.6±15.27), while the contents of TNF-α in CX3CL1 overexpression group, shRNA+ curcumin group, CX3CL1 overexpression + curcumin group were all lower than those in LMVEC group (ng/L: 216.97±9.20, 203.97±19.03, 191.97±17.50 vs. 239.6±15.27, all P < 0.05). The mRNA expression levels in CX3CL1 overexpression group and CX3CL1 overexpression + curcumin group were significantly higher than those in the blank control group and the LMVEC group (CX3CL1 mRNA: 55 210.3±1 209.2, 165 296.3±8 082.4 vs. 3.3±0.6, 2.0±0.0, all P < 0.01). The mRNA expression level of IL-6 in shRNA group was higher than that in LMVEC group (0.82±0.17 vs. 0.66±0.05), the mRNA expression level of IL-6 in CX3CL1 overexpression was lower than that in LMVEC group (0.29±0.03 vs. 0.66±0.05), the changes after pretreatment with curcumin were more significant (1.06±0.03 vs. 0.66±0.05 and 0.15±0.01 vs. 0.66±0.05); the mRNA expressions of TNF-α in shRNA group, CX3CL1 overexpression group, shRNA+ curcumin group were significantly lower than those in LMVEC group (0.41±0.04, 0.88±0.07, 1.01±0.02 vs. 1.06±0.04), the mRNA expression level of TNF-α in CX3CL1 overexpression + curcumin group was significantly higher than that in LMVEC group (1.36±0.01 vs. 1.06±0.04). The protein expression of CX3CL1, CX3CR1, NF-κB in shRNA group, CX3CL1 overexpression group, shRNA + curcumin group, CX3CL1 overexpressing + curcumin group were significantly higher than those in the LMVEC group (CX3CL1 protein: 0.41±0.07, 0.59±0.09, 0.69±0.61, 1.02±0.23 vs. 1.33±0.33, CX3CR1 protein: 0.85±0.18, 1.10±0.16, 1.32±0.18, 1.54±0.08 vs. 3.94±0.58, NF-κB protein: 0.33±0.07, 0.41±0.08, 0.41±0.07, 0.63±0.08 vs. 1.20±0.07). Conclusion Curcumin can inhibit the secretion of IL-6, TNF-α, CX3CR1 and NF-κB in thrombus-stimulated LMVEC model.

Purpose To investigate the clinicopathological characteristics and treatment of combined hepatocellular carcinoma-cholangio carcinoma (cHCC-CC).Methods 24 cases of cHCC-CC were collected.The clinical pathological characteristics,imaging,immunophenotyping and clinical features were retrospectively analyzed and reviewed the literature.Results There were 18 males and 6 females in 24 cases of cHCC-CC.The age ranged from 36 to 68 years (mean age was 54.38).Tumour location:right hepatic lobe in 15 cases,left hepatic lobe in 6 cases,both left lobe and right hepatic lobe in 1 case,hepatic caudate and left lateral lobe in 1 case,diffuse nodular liver tumors in 1 case.Grossly,the texture and color of tumor was related to the composition of tumor.Microscopically,classic cHCC-CC had two areas composed of hepatocellular carcinoma area and cholangiocar cinoma area of mixed distribution or migration distribution.3 cases were cHCC-CC with stem cell properties (cholangiolocellular carcinoma type,CLC type).Immunohistochemical staining revealed that HCC like area mainly expressed CD10,CK8,Hepatocyte and CD10,cHCC-CC area expressed CK7 and EMA.CLC type expressed the immunophenotypic features of intermediate type of HCC.Conclusion The clinical manifestations of cHCC-CC are not specific,the preoperative diagnosis is difficult,and it should be combined with pathological characteristics,imaging features and immunophenotype diagnosis.