Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared the differences between HER2-low and HER2-0 breast cancers, but no consensus has been reached.Additionally, a biomarker to predict pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be identified. Methods: We collected data from 777 patients across three centers, stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could reliably predict pCR. Results: The study found that patients with HER2-0 breast cancer had higher pCR rates compared to patients with HER2-low tumors (289 patients [30.1%] vs. 475 patients [18.1%], p < 0.0001). Survival analysis showed no significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts poorer pCR rates in both the overall patient group and the HER2-0 breast cancer group (overall patients: odds ratio [OR], 0.479; 95% confidence interval [CI], 0.250–0.917; p = 0.026 and HER2-0 patients: OR, 0.267; 95% CI, 0.080–0.892; p = 0.032). In contrast, programmed death ligand 1 (PD-L1) expression was associated with more favorable pCR rates in the overall patient group (OR, 3.199; 95% CI, 1.020–10.037; p = 0.046). Conclusion There is currently insufficient evidence to classify HER2-low breast cancer as a distinct subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to lower pCR rates.

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.

ObjectiveThis study explores the methods of lung tissue extraction and fixation required for pathological studies of fetal rats, based on the unique physiological structure of fetal rat lung tissue and existing lung tissue fixation techniques for adult rats. MethodsSix pregnant adult SD rats at 20.5 days of gestation were subjected to cesarean section to obtain fetal rats. Four healthy fetal rats with similar body weight, vital signs, and respiratory status were selected from each pregnant rat, and they were randomly divided into the following groups using a random number table: direct lung infiltration group, lung infiltration group after intratracheal infusion, whole-body infiltration group of fetal rats, and whole-body infiltration group after intratracheal infusion of fetal rats. To systematically compare and analyze the anatomical morphology under different fixation methods, lung tissues from four groups of fetal rats were harvested, perfused, and fixed, and the gross morphology of lung tissues in each group was observed. Paraffin sections were prepared and stained with Hematoxylin-Eosin (H&E). The histological morphology of the whole lung, alveoli, and bronchi was further examined under optical microscopy. ResultsIn the direct lung infiltration group, the hilar structures were unclear, lung lobation was indistinct, the shape was irregular, lung cavities were small, and alveoli and bronchi were shrunken. In the lung infiltration group after intratracheal infusion, the hilar structures were clear, lobation was pronounced, the shape was regular, lung cavities were large, and alveoli and bronchi were full. Both the whole-body infiltration group and whole-body infiltration group after intratracheal infusion of fetal rats exhibited visible lungs, hearts, skins, and other organs. The lung tissues of both groups showed obvious lobulation, irregular shape, and damage at the margins of lung lobes. In the whole-body infiltration group, the thoracic cavities of the fetus were flattened, lung cavities were small, and alveoli and bronchi were shrunken. In the whole-body infiltration group after intratracheal infusion of fetal rats, the fetal thoracic cavities were full, lung cavities were large, and alveoli and bronchi were relatively full. ConclusionThe lung infiltration after intratracheal infusion method for fetal rat lung tissue fixation outperforms direct lung infiltration, whole-body infiltration of fetal rats, and whole-body infiltration after intratracheal infusion of fetal rats in terms of preservation of the lung tissue's original morphology, paraffin sectioning, staining, and pathological observation and analysis. The embedding, sectioning, and staining processes are also simple and save consumables. Therefore, intratracheal infusion followed by lung infiltration method is recommended for fixation in histopathological observation of fetal rat lung tissue.

Objective:To retrospectively analyze the pathogenic factors of retrograde peri-implantitis (RPI) and assess the effectiveness of treatment, and to provide clinicians evidence for the prevention and treatment of RPI.Methods:A total of 2 731 patients with missing teeth (4 016 implants) who underwent implant restoration in the Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University between January 2004 and December 2022 were included in the study. According to the diagnostic criteria of RPI, a total of 20 cases (23 implants) of RPI were collected, including 4 female (5 implants) and 16 male (18 implants), and the treatment medical records, intraoral photos and cone beam CT or oral panoramic radiographs records of each patient were collected. Each patient with RPI was treated accordingly and followed up regularly to evaluate its efficacy.Results:After treatment, the follow-up time for 20 patients with clinical symptoms of RPI was 13 (6, 40) months (1 month to 13 years), and the survival rate of the treated implants was 91% (21/23). There were 7 patients (8 implants) with inactive RPI, no clinical symptoms, no loosening of the implant, with normal occlusal load, and the disease was at the inactive stage and was not treated. The pulp vitality of the natural tooth adjacent to the implant was normal, and the implant could function normally. There were 13 patients (15 implants) with infected RPI, 1 patient (1 implant) had no loosening of the implant, and the periapical radiolucency of the implant disappeared after endodontic treatment of the natural tooth adjacent to the implant; 12 patients (14 implants) had clinical symptoms such as implant loosening, pus discharge, etc. Among them, 10 patients (12 implants) were successfully implanted in situ or in adjacent sites after removing the implants, and were successfully implanted after 3 to 20 months. Two patients(2 implants) were removed and no further implants were placed. Among them, 2 implants with infected RPI had cystic lesions, which was similar to natural root apex cysts.Conclusions:The etiology of RPI is related to inflammation of adjacent tooth root tips or bacterial residues from inflammatory lesions in the alveolar bone and bone augmentation. RPI can be treated by perfect root canal treatment of adjacent teeth, removal of inflammatory tissue, or simultaneous guided bone regeneration techniques.

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 evaluate the impact of hemoglobin concentration on 5-year cardiovascular mortality in patients with hypertrophic obstructive cardiomyopathy(HOCM).Methods:This study retrospectively analyzed 325 non-surgically treated HOCM patients hospitalized at Fuwai Hospital from October 2009 to December 2014.Baseline information was compared between patients with or without cardiac death.The impact of hemoglobin concentration on 5-year cardiovascular mortality in HOCM patients was analyzed.Results:The median follow-up time was(43.55±19.70)months.During the follow-up period,a total of 29 patients(8.9%)experienced cardiac death.Univariate Cox regression analysis demonstrated that hemoglobin concentration was significantly associated with 5-year cardiac mortality in HOCM patients(P<0.001).After adjusting for potential cardiovascular risk factors in multivariate Cox regression analysis,hemoglobin concentration(P=0.011)remained negatively associated with 5-year cardiac mortality in HOCM patient.HOCM patients with decreased hemoglobin level faced a 3.118-fold increase in 5-year cardiac mortality(HR=4.118,95%CI:1.114-14.822,P=0.030).Kaplan-Meier survival analysis showed that HOCM patients with decreased hemoglobin levels had a significantly higher risk of 5-year cardiac mortality(log-rank test,χ2=24.38,P<0.001).Conclusions:Lower hemoglobin concentration is an independent risk factor for 5-year cardiac mortality in patients with HOCM.Compared to patients with normal hemoglobin levels,HOCM patients with decreased hemoglobin level face a 3-fold increase in 5-year cardiac mortality.

Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared the differences between HER2-low and HER2-0 breast cancers, but no consensus has been reached.Additionally, a biomarker to predict pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be identified. Methods: We collected data from 777 patients across three centers, stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could reliably predict pCR. Results: The study found that patients with HER2-0 breast cancer had higher pCR rates compared to patients with HER2-low tumors (289 patients [30.1%] vs. 475 patients [18.1%], p < 0.0001). Survival analysis showed no significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts poorer pCR rates in both the overall patient group and the HER2-0 breast cancer group (overall patients: odds ratio [OR], 0.479; 95% confidence interval [CI], 0.250–0.917; p = 0.026 and HER2-0 patients: OR, 0.267; 95% CI, 0.080–0.892; p = 0.032). In contrast, programmed death ligand 1 (PD-L1) expression was associated with more favorable pCR rates in the overall patient group (OR, 3.199; 95% CI, 1.020–10.037; p = 0.046). Conclusion There is currently insufficient evidence to classify HER2-low breast cancer as a distinct subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to lower pCR rates.

Objective·To construct truncations of CYLD,and to preliminarily analyze their effects on the proliferation of gastric cancer cells.Methods·TCGA,GTEx,and Kaplan-Meier Plotter databases were used to analyze the differences in the expression levels of CYLD between gastric cancer tissues and normal tissues,and their relationship with the prognosis of gastric cancer patients.Immunohistochemistry and Western blotting were used to detect the expression of CYLD in cancer tissues and adjacent noncancerous tissues.Western blotting and qRT-PCR were used to analyze the protein and mRNA expression levels of CYLD in gastric mucosal epithelial cells and gastric cancer cells.According to the sequence and structural characteristics of CYLD gene,primers were designed to construct its truncations.Their expression was detected and identified by agarose gel electrophoresis and Western blotting,and localization was observed by immunofluorescence.In the human gastric adenocarcinoma cells(AGS)with CYLD knockdown,blank NC was added to the control group,and the full-length CYLD,enzyme-inactivated mutant,and three truncated plasmids were added to the experimental group.The proliferation changes of cells in each group were detected by CCK-8 and plate cloning assays.Co-immunoprecipitation,deubiquitination,and Western blotting assays were performed to examine the binding ability of full-length CYLD,the enzyme-inactivated mutant,and the truncated variants to CAMK2A,the level of CAMK2A deubiquitination,and the expression of STAT3 and p-STAT3 proteins.Results·CYLD expression in normal gastric tissues and cells was significantly higher than in gastric cancer tissues and cells,and the prognosis of patients with high expression of CYLD was better.The truncations of human CYLD were successfully constructed,and full length CYLD,enzyme-inactivated mutant,and truncations were mainly localized in the cytoplasm.Knockdown of CYLD in gastric cancer cells significantly enhanced the proliferative ability of gastric cancer cells.Reconstitution of CYLD-knockdown cells with CYLD-WT,or truncated variants containing the CAP3 or USP domains significantly inhibited the proliferation of gastric cancer cells.In addition,CYLD bound to CAMK2A mediated K63 deubiquitination modification,and inhibited CAMK2A-induced phosphorylation of STAT3.Conclusion·The human CYLD truncation plasmids are successfully constructed,and the full length CYLD and its CAP3 and USP segments significantly inhibit the proliferation of gastric cancer cells.

Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has the potential to emerge as a distinct subtype. Several studies have compared the differences between HER2-low and HER2-0 breast cancers, but no consensus has been reached.Additionally, a biomarker to predict pathological complete response (pCR) rates in patients with HER2-low breast cancer remains to be identified. Methods: We collected data from 777 patients across three centers, stratifying them into HER2-low and HER2-0 groups. We compared differences in survival and pCR rates between the two groups and investigated potential biomarkers that could reliably predict pCR. Results: The study found that patients with HER2-0 breast cancer had higher pCR rates compared to patients with HER2-low tumors (289 patients [30.1%] vs. 475 patients [18.1%], p < 0.0001). Survival analysis showed no significant advantage for HER2-low tumors over HER2-0 breast cancers. Binary logistic analysis revealed that androgen receptor (AR) expression predicts poorer pCR rates in both the overall patient group and the HER2-0 breast cancer group (overall patients: odds ratio [OR], 0.479; 95% confidence interval [CI], 0.250–0.917; p = 0.026 and HER2-0 patients: OR, 0.267; 95% CI, 0.080–0.892; p = 0.032). In contrast, programmed death ligand 1 (PD-L1) expression was associated with more favorable pCR rates in the overall patient group (OR, 3.199; 95% CI, 1.020–10.037; p = 0.046). Conclusion There is currently insufficient evidence to classify HER2-low breast cancer as a distinct subtype. Our study revealed that AR expression, along with negative PD-L1 expression, contributes to lower pCR rates.

Objective To investigate differences in postoperative analgesia efficacy,inflammatory response,and recovery between intraplanar(in-plane)and extraplanar(out-of-plane)thoracic paravertebral block(TPVB)techniques under ultrasound guidance in patients undergoing thoracoscopic radical resection for lung cancer,thereby providing evidence for selecting the optimal block technique in clinical practice.Methods Eighty patients undergoing thoracoscopic radical resection for lung cancer between March and September 2022 were randomly assigned to an intraplanar group(n=40)or an extraplanar group(n=40).Before induction of anesthesia,both groups received 10 mL of 0.33％ropivacaine injected into the T4 and T6 paravertebral spaces under ultrasound guidance,using their respective in-plane or out-of-plane techniques.The following parameters were compared between the groups:nerve block procedure duration,onset time of block,visual analogue scale(VAS)pain scores within 48 hours postoperatively,incidence of postoperative nausea and vomiting(PONV),and serum inflammatory and stress markers including C-reactive protein(CRP),interleukin-6(IL-6),cortisol(Cor),and norepinephrine(NE).Results No significant differences were observed between the groups in block procedure duration,onset time,or analgesic duration(P＞0.05).Compared with the extraplanar group,the intraplanar group demonstrated a significantly reduced incidence of PONV(15.0％vs.35.0％,P=0.039)and significantly lower serum levels of CRP,IL-6,and Cor at 24 hours postoperatively(P＜0.05).No pleural punctures occurred in the intraplanar group(0％),whereas the extraplanar group had a 15.0％incidence rate.However,the overall complication rate in both groups showed no statistically significant difference(P=0.060).Conclusion Both ultrasound-guided in-plane and out-of-plane TPVB techniques provide effective postoperative analgesia for thoracoscopic radical lung cancer surgery.However,the in-plane technique significantly reduces the incidence of PONV and postoperative inflammatory responses while demonstrating higher operational safety,making it the preferred clinical choice.