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.

OBJECTIVES: To investigate the clinical application of the digital-assisted reconstruction of the mandible and tumors with free fibula transplantation and immediate implantation via the intraoral approach. METHODS: Twelve patients with benign mandibular tumors were collected. Three-dimensional mandibular reconstruction was performed digitally before surgery to simulate mandibular tumor resection, fibula resection and reconstruction, and implant implantation. The intraoperative resection of the mandibular tumor was conducted through the intraoral approach under the guidance of a guide plate, and fibula resection, molding, reconstruction, and oral fixation were immediately performed. Implant implantation was performed during the second phase of implant surgery and denture restoration was performed 1-2 months after surgery. RESULTS: The types of mandibular defects were BrownⅠ (one case), Ⅰc (four cases), Ⅱ (one case), Ⅱc(three cases), and Ⅲ (three cases). The length of the fibular bone was 12-22 cm. The number of fibular molding amputations was as follows: two cases in two segments, six cases in three segments, three cases in four segments, and one case in five segments. All of these cases underwent folding fibular reconstruction of mandibular and alveolar bone defects. A total of 44 implants were implanted, and none failed after operation. CONCLUSIONS The intraoral approach is a reliable method for the resection of mandibular benign tumors, with few postoperative complications and the ability to position and fix accurately the reconstructed folded fibula under digital design. The immediate implantation of the transplanted fibula does not affect the blood supply and has a high success rate. It is an effective and reliable method for the resection and reconstruction of mandibular benign tumors.
Humans ; Fibula/transplantation* ; Mandibular Neoplasms/surgery* ; Mandibular Reconstruction/methods* ; Bone Transplantation/methods* ; Male ; Middle Aged ; Female ; Mandible/surgery* ; Adult ; Free Tissue Flaps ; Surgery, Computer-Assisted

OBJECTIVE: To investigate the effectiveness of posterior lateral perforator flap in lower limb combined with free fibula for maxillary tissue defect repair. METHODS: Between December 2018 and December 2023, 16 patients with the maxillary malignant tumors were admitted. There were 10 males and 6 females, with an average age of 64.3 years (range, 54-75 years). There were 7 cases of maxillary gingival cancer, 5 cases of hard palate cancer, and 4 cases of maxillary sinus cancer. According to the 2017 American Joint Committee on Cancer (AJCC) TNM stage, there were 8 cases of stage Ⅲ, 6 cases of stage Ⅳa, and 2 cases of stage Ⅳb. After resection of the lesion, the remaining maxillary defects were classified into class Ⅱa in 3 cases, class Ⅱb in 5 cases, and class Ⅲb in 8 cases according to Brown's classification. The size of soft tissue defects ranged from 4 cm×3 cm to 8 cm×6 cm. The posterior lateral perforator flap in lower limb in size of 5 cm×4 cm-9 cm×7 cm were harvested to repair soft tissue defects, and free fibula in length of 6-11 cm were used to repair bone defects. The donor sites of the lower limb were sutured directly (6 cases) or repaired with free skin grafting (10 cases). Six patients with positive lymph node pathology were treated with radiotherapy after operation. At 6 and 12 months after operation, the self-assessment was performed by the University of Washington Quality of Survival Questionnaire Form (QUW-4) in five dimensions (facial appearance, swallowing function, chewing function, speech function, and mouth opening), and swallowing function was evaluated by using the Kubota water swallowing test. RESULTS: Postoperative pathological examination showed that all patients were squamous cell carcinoma. One patient who was treated with radiotherapy developed osteomyelitis and 1 patient developed venous crisis of skin flap. The rest of the flaps and all skin grafts survived, and the wounds healed by first intention. All patients were followed up 1-5 years (mean, 2.8 years). Two patients died of local recurrence of the tumor at the 4th and 5th years after operation, respectively. Except for the chewing function score and total score at 6 months after operation, which showed significant differences compared to preoperative scores ( P<0.05), there was no significant difference in other QUW-4 scale scores between different time points ( P>0.05). The patients' swallowing function evaluated by Kubota water swallowing test reached normal in 4 cases, suspicious in 9 cases, and abnormal in 3 cases at 6 months after operation, and 10, 6, and 0 cases at 12 months after operation, respectively. The swallowing function at 12 months was significantly better than that at 6 months ( Z=-2.382, P=0.017). CONCLUSION The posterior lateral perforator flap in the lower limb combined with free fibula to repair maxillary tissue defects can repair soft and hard tissue defects at the same time, so that the patient's facial appearance, swallowing function, chewing function, speech function, and mouth opening are satisfactorily restored and the mid-term effectiveness is good.
Humans ; Middle Aged ; Male ; Female ; Fibula/surgery* ; Aged ; Perforator Flap ; Plastic Surgery Procedures/methods* ; Maxilla/surgery* ; Maxillary Neoplasms/surgery* ; Free Tissue Flaps/transplantation* ; Lower Extremity/surgery* ; Bone Transplantation/methods* ; Treatment Outcome

ObjectiveTo investigate the anti-Alzheimer's disease （AD） effect of Dipsacus asper（DA） in the Caenorhabditis elegans model， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor α （PPARα）/transcription factor EB （TFEB） pathway. MethodsFirst， transgenic AD C. elegans individuals were assigned into the blank control， model， positive control （WY14643， 20 µmol·L^-1）， and low-， medium-， and high-dose （100， 200， and 400 mg·L^-1， respectively） DA groups. The amyloid β-42 （Aβ₄₂） formation in the muscle cells， the paralysis time， and the deposition of amyloid β-protein （Aβ） in the head were detected. The lysosomal autophagy in the BV2 cell model was examined by Rluc-LC3wt/G120A. The expression levels of lysosomal autophagy-related proteins LC3Ⅱ， LC3I， LAMP2， and TFEB were detected by Western blot. Real-time quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of autophagy-related genes beclin1 and Atg5 and lysosome-related genes LAMP2 and CLN2 downstream of PPARα/TFEB. A reporter gene assay was used to detect the transcriptional activities of PPARα and TFEB. Immunofluorescence was used to detect the fluorescence intensity of PPARα， and the active components of the ethanol extract of DA were identified by UPLC-MS. RCSB PDB， Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and Autodock were used to analyze the binding between the active components and PPARα-ligand-binding domain （LBD）. ResultsCompared with the model group， the positive control group and 200 and 400 mg·L^-1 DA groups showed prolonged paralysis time （P<0.05）， and all the treatment groups showed decreased Aβ deposition in the head （P<0.01）. DA within the concentration range of 50-500 mg·L^-1 did not affect the viability of BV2 cells. In addition， DA enhanced the autophagy flux （P<0.05）， up-regulated the mRNA levels of beclin1， Atg5， LAMP2， and CLN2 （P<0.05， P<0.01）， promoted the nuclear translocation of TFEB （P<0.05）， increased LAMP2 expression and autophagy flux （P<0.05， P<0.01）， and enhanced the transcriptional activities of PPARα and TFEB （P<0.01）. The positive control group and 200 and 400 mg·L^-1 DA groups showed enhanced fluorescence intensity of PPARα in the BV2 nucleus （P<0.01）. UPLC-MS detected nine known compounds of DA， from which 8 active components of DA were screened out. The docking results suggested that a variety of components in DA could bind to PPARα-LBD and form stable hydrogen bonds. ConclusionDA may reduce the pathological changes in AD by regulating the PPARα-TFEB pathway.

Objective:To evaluate clinical outcomes of occlusion-guided vascularized folded fibula flap reconstruction with delayed implant restoration for mandibular defects after benign tumor resection.Methods:A total of 12 patients with benign mandibular tumors underwent free folded fibula flap reconstruction at the First Affiliated Hospital of Bengbu Medical University between January 2020 and December 2023, including 7 males and 5 females, aged 21-52 years. Six months after mandibular reconstruction, the internal fixation titanium plates were removed, and dental implants were placed using a preoperatively fabricated occlusal guide, followed by second-stage implant surgery and prosthetic restoration. Mandibular CT scans were obtained 6 months after reconstruction to compare the fitting accuracy between the preoperative virtual design and the actual reconstructed mandible. The implant stability quotient (ISQ) was measured 3 months after implant placement. Masticatory efficiency and Enneking lower limb function scores were evaluated at the following time points: before tumor surgery (T1), before implant placement (T2), 6 months (T3) and 9 months (T4) after implant crown restoration. One-way repeated measures ANOVA was used to analyze the masticatory efficiency and lower limb function scores.Results:The free folded fibula grafts were successfully performed via an intraoral approach in all 12 patients, with a 100% of survival rate. Mandibular defects included Brown class I in 6 cases, class II in 2 cases, and class III in 4 cases. A total of 42 implants were placed with successful osseointegration. The ISQ measured at 3 months post-placement was 64.10±4.18. At 6 months postoperatively, morphological analysis comparing the preoperative virtual surgical design with the actual postoperative reconstructed mandible revealed a reconstruction accuracy of 84.27%±4.23%. Significant differences were observed in Enneking scores and masticatory efficiency across all four time points (all P<0.001). Masticatory function showed significant improvement at T4 compared that at T2 [(88.06±3.66)% vs. (65.44±3.82)%, P<0.05]. Conclusion:Occlusal function-guided mandibular reconstruction with vascularized folded fibula flap after removal of benign mandibular tumors is a reliable method, which is associated with minimal donor-site morbidity and enables patients to restore precise occlusion and to achieve favorable masticatory efficiency.

Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of thera-peutics,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 bio-logical 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 effi-cacy 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 in-hibitors.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 explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma. METHODS: A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167). RESULTS: Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein. CONCLUSION The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.
Humans ; Male ; Xeroderma Pigmentosum/genetics* ; Basal Cell Carcinoma/genetics* ; DNA-Binding Proteins/genetics* ; Melanoma/genetics* ; Mutation ; Skin Neoplasms/genetics* ; Middle Aged ; Exome Sequencing ; Pedigree

In the field of rectal cancer treatment, transanal local excision techniques (such as transanal endoscopic microsurgery [TEM] and transanal minimally invasive surgery [TAMIS]) have gradually become an important therapeutic option for patients with rectal cancer at various stages, owing to their minimally invasive characteristics and organ-preserving advantages. For low-risk T1 stage tumors, local excision can achieve radical tumor control while preserving organ function. For some patients with high-risk T1 stage or T2-3 stage rectal cancer, the efficacy of combined chemoradiotherapy and local excision is expected to be comparable to that of radical total mesorectal excision (TME). In patients with advanced rectal cancer who achieve clinical complete response (cCR) after neoadjuvant therapy, local excision can confirm the pathological remission status. However, it is necessary to balance the risk of surgical complications against the potential benefits of organ preservation with the "watch and wait" strategy. Currently, transanal local excision techniques have broad application prospects, and comprehensive assessment of patients' overall condition, implementation of multidisciplinary collaboration, and conduct of long-term follow-up are crucial to ensuring the safety of treatment.

Objective:To investigate the effects of individual versus connected microdroplet culture modes in time-lapse (TL) incubators on embryo development parameters and pregnancy outcomes in patients undergoing whole embryo culture to blastocyst stage.Methods:Using a retrospective cohort study, clinical data from 3 507 fresh blastocyst transfer cycles were analyzed. These cycles involved patients who underwent assisted reproductive technology treatment with whole embryo culture to blastocyst stage at the Reproductive Medical Center of Northwest Women's and Children's Hospital between January 2019 and December 2023. Based on different culture modes, patients were divided into two groups, connected group ( n=2 446, using connected microdroplet culture) and individual group ( n=1 061, using individual microdroplet culture). Baseline characteristics, embryo development parameters, pregnancy outcomes, and neonatal outcomes were compared between the two groups. Generalized linear models (GLM) were used to adjust for confounding factors and analyze the effect of culture mode. Results:Embryo development assessment showed the day 3 (D3) high-quality embryo rate in the connected group [60.12% (12 136/20 187)] was significantly lower than that in the individual group [63.62% (4 705/7 395), P<0.001], whereas the high-quality blastocyst formation rate [34.93% (7 052/20 187)] and the available blastocyst formation rate [56.07% (11 319/20 187)] were both significantly higher than those in the individual group [33.08% (2 446/7 395), P=0.004; 51.45% (3 805/7 395), P<0.001], with statistically significant differences. The implantation rate [67.40% (1 774/2 632)], the clinical pregnancy rate [70.20% (1 717/2 446)], and the live birth rate [60.66% (1 469/2 446)] in the connected group were all significantly higher than those in the individual group [63.40% (724/1 142), P=0.017; 66.73% (708/1 061), P=0.041; 55.89% (593/1 061), P=0.021], with statistically significant differences. Neonatal outcomes showed no statistically significant difference between the two groups (all P>0.05). After adjusting for confounding factors using GLM, connected culture was an independent influencing factor for D3 high-quality embryo rate (a MD=-0.017, 95% CI: -0.034-0.000, P=0.046), high-quality blastocyst formation rate (a MD=-0.020, 95% CI: 0.002-0.037, P=0.026), available blastocyst formation rate (a MD=0.032, 95% CI: 0.015-0.048, P<0.001), live birth rate (a OR=1.182, 95% CI: 1.006-1.388, P=0.042). However, it had no effect on D3 available embryo rate, clinical pregnancy rate, or early miscarriage rate (all P>0.05). Conclusion:In TL incubator systems, individual and connected microdroplet culture modes exert different effects at various stages of embryo development. Individual microdroplet culture can significantly enhance cleavage-stage embryo quality, whereas the connected microdroplet culture was more beneficial for enhancing the blastocyst formation rate and quality, ultimately improving the live birth rate without increasing neonatal risks.

Objective:To explore the clinical efficacy of percutaneous balloon compression (PBC) in the treatment of trigeminal neuralgia (TN) based on the double difference (DID) model.Methods:A retrospective case - control study method was adopted to analyze the general data of 130 patients with trigeminal neuralgia (TN) who were treated in the Department of Neurosurgery of Hebei General Hospital from January 2022 to October 2023. Among them, 49 were males and 81 were females. The age was (53.28±11.67) years, ranging from 25 to 80 years old. According to different treatment methods, the patients were divided into an experimental group ( n=63) and a control group ( n=67). Patients in the experimental group were given percutaneous balloon compression (PBC) treatment, while those in the control group were treated with conservative drug therapy. Propensity score matching method was used for 1∶1 matching. After matching, there were 52 cases in each group. The general data of the two groups were compared. The visual analogue scale (VAS), 36-item short form health survey (SF-36) score, Hamilton depression rating scale (HAMD) score, Hamilton anxiety rating scale (HAMA) score, 5-hydroxytryptamine, neuropeptide P, inflammatory factor interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) before and after treatment, as well as the clinical efficacy of the two groups of patients were comparatively analyzed. Meanwhile, the incidence of postoperative complications in the two groups was compared. The generalized estimating equation (GEE) model was used to analyze the influencing factors of clinical efficacy, and the difference-in-differences (DID) model was used to evaluate the efficacy before and after treatment. Measurement data conforming to the normal distribution were expressed as mean±standard deviation ( ± s), and the t-test was used for comparison between groups; the chi- square test was used for comparison between count data. Results:After treatment, the VAS, SF-36 score, HAMD score, HAMA score, 5-hydroxytryptamine level, neuropeptide P level, IL-1 level, and TNF-α level in the experimental group were (2.98±0.83) points, (75.56±1.18) points, (7.2±0.83) points, (7.15±0.85) points, (76.34±5.47) ng/mL, (50.95±11.01) pg/mL, (29.45±7.08) ng/L, and (21.18±3.55) ng/L respectively. In the control group, there were (3.63±0.95) points, (73.23±1.13) points, (7.98±0.80) points, (8.04±0.84) points, (186.31±11.61) ng/mL, (86.52±13.32) pg/mL, (34.47±6.58) ng/L, and (26.36±5.80) ng/L, respectively. The differences between the two groups were statistically significant ( P<0.05).The cure rate and the total incidence of postoperative complications in the experimental group were 55.77% and 13.46% respectively, while in the control group, they were 40.38% and 30.77% respectively. The differences between the two groups were statistically significant ( P<0.05).The results of the GEE model analysis showed that age, course of disease, VAS, SF-36 score, HAMA score, HAMD score, 5-hydroxytryptamine level, neuropeptide P level, IL-1 level, TNF-α level, treatment method, and the long - diameter ratio of FO significantly affected the clinical efficacy of patients ( P<0.05).The results of the DID model showed that the experimental group was superior to the control group in improving the VAS, SF-36 score, HAMD score, HAMA score, 5-hydroxytryptamine level, neuropeptide P level, IL-1 level, and TNF-α level( P<0.05). Conclusion:PBC can significantly improve the VAS, SF-36 score, HAMD score, HAMA score, 5-hydroxytryptamine, neuropeptide P, IL-1, TNF-α, and incidence of complications in patients with TN. It can also improve the psychological status and quality of life of patients.