Purpose: Dual anti–human epidermal growth factor receptor 2 (HER2) drugs have become the standard regimen for neoadjuvant systemic treatment (NST) to HER2-positive breast cancer patients. However, the efficacy varies greatly among patients with different HER2 protein expression levels. Materials and Methods: A total of 575 HER2-positive breast cancer patients from multiple centers throughout China from 2013 to 2022 were retrospectively analyzed. We compared clinicopathological features in different HER2 immunohistochemistry classes (HER2 2+/in situ hybridization [ISH] + or HER2 3+), and their difference in response to NST and survival with single or dual anti-HER2 drugs. Drug sensitivity assays were used to evaluate different efficacy of anti-HER2 drugs in vitro. Results: Compared to HER2 3+ subgroup, the HER2 2+/ISH+ group had a higher proportion of hormone receptor–positive status (48.7% vs. 76.1%, p < 0.001), more HER2 protein loss after NST, lower pathological complete response (pCR) rate (46.07% vs. 16.24%, p < 0.001), and tended to have worse disease-free survival (DFS). In HER2 2+/ISH+ patients, treated with pertuzumab and trastuzumab in combination had no significant improvement in pCR (19.12% vs. 12.24%, p=0.287) and DFS (p=0.908) than using alone. Drug sensitivity assay showed poor efficacy with dual anti-HER2 drugs in HER2 2+/ISH+ cell lines; however, fam-trastuzumab deruxtecan drugs had a satisfactory effect. Conclusion Owing to the differences in clinicopathological features and treatment efficacy, we considered the HER2 2+/ISH+ group to be a distinct subtype and defined it as the HER2-moderate–positive subgroup. In this subgroup, dual anti-HER2 drugs did not exert significant improvement in pCR and DFS. Therefore, treatment optimization is warranted, with antibody-drug conjugate drugs as potential options.

To introduce the general thinking, guidelines, work objectives and elaboration process of the general technical requirements adopted by volume Ⅳ of the Chinese Pharmacopoeia 2025 Edition, and to summarize and figure out the main characteristics on dosage forms, physico-chemical testing, microbial and biological testing, reference standards and guidelines The newly revised general chapters of pharmacopoeia give full play to the normative and guiding role of the Chinese Pharmacopoeia standard, track the frontier dynamics of international drug regulatory science and the elaboration of monographs, expand the application of state-of-the-art technologies, and steadily promote the harmonization and unification with the ICH guidelines； further enhance the overall capacity of TCM quality control, actively implement the 3 R principles on animal experiments, and practice the concept of environmental-friendly； replace and/or reduce the use of toxic and hazardous reagents, strengthen the requirements of drug safety control This paper aims to provide a full-view perspective for the comprehensive, correct understanding and accurate implementation of general technical requirements included in the Chinese Pharmacopoeia 2025 Edition.

Objective To study the oral health status of officers and soldiers in a certain unit,so as to provide a basis for the formulation and implementation of oral health support plans.Methods A total of 437 officers and soldiers in a certain unit were enrolled to assess their oral health status through questionnaire survey and clinical examination.Results The prevalences of dental caries and periodontal diseases were 87.6%(383/437)and 90.4%(395/437),respectively;the detection rates of impacted third molars,recurrent aphthous stomatitis,other mucosal diseases,and temporomandibular joint disorders were 12.6%(55/437),54.2%(237/437),29.5%(129/437),and 19.2%(84/437),respectively.In terms of oral medical needs,23.3%(102/437)patients did not need treatment,66.1%(289/437)required elective treatment,9.2%(40/437)required early treatment,and 1.4%(6/437)required urgent treatment.Conclusion Officers and soldiers in this study have a variety of oral diseases,with periodontal diseases having the highest prevalence.Supportting plans should be formulated based on the characteristics of the prevalence of oral diseases among them,and regular oral diagnosis and treatment should be carried out to prevent the development and progression of oral diseases.

Aim To evaluate the bioequivalence of two oral preparations of rivaroxaban tablets(test preparation T and refe-rence preparation R)in fasting/postprandibular state in healthy Chinese subjects.Methods A randomized,open,single-dose,four-cycle,completely repeated crossover experiment was used in this study.A total of 70 healthy male and female subjects were enrolled,including 38 subjects in the fasting group and 32 sub-jects in the postprandial group.Rivaroxaban tablets(2.5 mg/tablet)were taken orally once per cycle and their reference preparations were tested.The plasma rivaroxaban concentration was determined by LC-MS/MS method.The pharmacokinetic parameters of rivaroxaban tablets were calculated by WinNonlin software,and the parameters were analyzed and processed.Re-sults The PK parameters of rivaroxaban tablets and reference preparations in fasting group were as follows:Cmax was(72.48±17.08)and(66.36±15.64)μg·L-1,respectively.AUC0-t were(383.49±101.06)and(370.43±102.16)h·ng·mL-1,and AUC0-inr were(389.58±102.28)and(375.84±103.01)h·μg·L-,respectively.Main PK parameters of subjects taking rivaroxaban tablets orally after meals:Cmax were(66.48±15.64 and 60.87±13.44)μg·L-1,AUC0-t were(404.44±72.58)and(381.80±79.93)h·μg·L-1,re-spectively.AUC0_inf was(410.88±73.55)and(393.64±69.71)h·μg·L-1,respectively.Under fasting and postmeal conditions,subjects took rivaroxaban test and reference prepara-tion orally,one tablet(2.5 mg/tablet)each time.The geometric mean of the main pharmacokinetic parameters of rivaroxaban in plasma(Cmax,AUC0-t,AUC0-inf)and their corresponding values had a 90％confidence interval ranging from 80.00％to 125.00％.No serious adverse events or unexpected adverse e-vents occurred in both groups.Conclusion Rivaroxaban tablets are bioequivalent and safe in vivo under fasting and postprandial conditions.

Aim To evaluate the bioequivalence of two oral preparations of rivaroxaban tablets(test preparation T and refe-rence preparation R)in fasting/postprandibular state in healthy Chinese subjects.Methods A randomized,open,single-dose,four-cycle,completely repeated crossover experiment was used in this study.A total of 70 healthy male and female subjects were enrolled,including 38 subjects in the fasting group and 32 sub-jects in the postprandial group.Rivaroxaban tablets(2.5 mg/tablet)were taken orally once per cycle and their reference preparations were tested.The plasma rivaroxaban concentration was determined by LC-MS/MS method.The pharmacokinetic parameters of rivaroxaban tablets were calculated by WinNonlin software,and the parameters were analyzed and processed.Re-sults The PK parameters of rivaroxaban tablets and reference preparations in fasting group were as follows:Cmax was(72.48±17.08)and(66.36±15.64)μg·L-1,respectively.AUC0-t were(383.49±101.06)and(370.43±102.16)h·ng·mL-1,and AUC0-inr were(389.58±102.28)and(375.84±103.01)h·μg·L-,respectively.Main PK parameters of subjects taking rivaroxaban tablets orally after meals:Cmax were(66.48±15.64 and 60.87±13.44)μg·L-1,AUC0-t were(404.44±72.58)and(381.80±79.93)h·μg·L-1,re-spectively.AUC0_inf was(410.88±73.55)and(393.64±69.71)h·μg·L-1,respectively.Under fasting and postmeal conditions,subjects took rivaroxaban test and reference prepara-tion orally,one tablet(2.5 mg/tablet)each time.The geometric mean of the main pharmacokinetic parameters of rivaroxaban in plasma(Cmax,AUC0-t,AUC0-inf)and their corresponding values had a 90％confidence interval ranging from 80.00％to 125.00％.No serious adverse events or unexpected adverse e-vents occurred in both groups.Conclusion Rivaroxaban tablets are bioequivalent and safe in vivo under fasting and postprandial conditions.

Objective:To explore expression changes of different vascular endothelial growth factor A (VEGFA) isoforms in human retinal pigment epithelial cell line ARPE-19 cells under high glucose conditions.Methods:ARPE-19 cells were divided into blank control group, control group 1, control group 2, HG1 group, and HG2 group treated with 5.5 mmol/L glucose, 5.5 mmol/L glucose+ 19.5 mmol/L mannitol, 5.5 mmol/L glucose+ 44.5 mmol/L mannitol, 25.0 mmol/L glucose, and 50.0 mmol/L glucose, respectively.The blank control group, control group 1, and control group 2 were treated for 72 hours, while HG1 and HG2 groups were treated for 24, 48, and 72 hours.The relative expression of VEGFA isoforms was detected by fluorescent quantitative PCR.Total VEGFA, SERPINF1 (pigment epithelium-derived factor, PEDF), a negative regulator of VEGF signaling, and VEGF165 (V4, 5, 10) protein expression was measured by Western blot.Results:Total VEGFA mRNA and protein expression in ARPE-19 cells showed statistically significant differences at both 25 mmol/L and 50 mmol/L glucose concentrations across different culture periods (mRNA: F=114.60, 143.60; both P<0.05.protein: F=10.00, 8.04; both P<0.05). Compared to the respective controls, the relative expression of total VEGFA mRNA and protein increased significantly at 24, 48, and 72 hours after treatment (all P<0.05). There was no significant difference in SERPINF1 (PEDF) mRNA or protein expression in ARPE-19 cells across different time points at 25 mmol/L or 50 mmol/L glucose concentrations (mRNA: F=0.86, 0.32; both P>0.05.protein: F=1.25, 0.08; both P>0.05). The mRNA expression levels of VEGFA isoforms in ARPE-19 cells from highest to lowest were VEGF165(V4, 5, 10), VEGF121(V6), VEGF189(V2), VEGF111(V8) and VEGF165b(V7). The relative VEGF111(V8) mRNA expression level was significantly lower in HG1-24 hour group than in control group 1, the relative VEGF189(V2) and VEGF121(V6) mRNA expression levels were significantly higher in HG1-48 hour group than in control group 1, the relative VEGF121(V6) and VEGF165b(V7) mRNA expression levels were significantly higher in HG1-72 hour group than in control group 1, with statistically significant differences (all P<0.05). The relative VEGF111(V8) and VEGF165(V4, 5, 10) mRNA expression levels were significantly higher in the HG2-24 hour group than in control group 2, the relative VEGF165(V4, 5, 10) and VEGF165b(V7) mRNA expression levels were significantly higher in HG2-48 hour group than control group 2, and the relative VEGF189(V2), VEGF111(V8), VEGF165(V4, 5, 10), and VEGF165b(V7) mRNA expression levels were significantly higher in HG2-72 hour group than in control group 2, with statistically significant differences (all P<0.05). The relative VEGF165(V4, 5, 10) protein expression levels in blank control group, control group 1, HG1-24 hour group, HG1-48 hour group, and HG1-72 hour group were 1.01±0.07, 1.05±0.07, 1.16±0.06, 1.37±0.08, and 1.28±0.05, respectively, with a statistically significant overall difference ( F=10.36, P<0.05). The relative VEGF165(V4, 5, 10) protein expression level was significantly higher in HG1-48 hour group than in control group 1 ( P<0.05). The relative protein expression levels of VEGF165(V4, 5, 10) in blank control group, control group 2, HG2-24 hour group, HG2-48 hour group, and HG2-72 hour group were 1.02±0.05, 1.12±0.00, 1.22±0.05, 1.53±0.21, and 1.77±0.04, respectively, with a statistically significant overall difference ( F=16.55, P<0.001). The relative VEGF165(V4, 5, 10) protein levels were significantly higher in HG2-48 hour group and HG2-72 hour group than in control group 2 (both P<0.05). Conclusions:In ARPE-19 cells, mRNA abundance of VEGFA isoforms from highest to lowest were VEGF165(V4, 5, 10), VEGF121(V6), VEGF189(V2), VEGF111(V8), VEGF165b(V7). VEGF121(V6) mRNA expression level is significantly increased at 25 mmol/L high glucose concentration, whereas VEGF165(V4, 5, 10) mRNA expression level shows significant elevation only at 50 mmol/L high glucose.Under both high glucose conditions, isoforms with significantly elevated mRNA expression levels are VEGF189(V2) and VEGF165b(V7), while SERPINF1 (PEDF) expression level does not change significantly.

Objective To investigate the effects of two driving pressure-based methods to set positive end-expiratory pressure on pulmonary mechanics and oxygenation in patients undergoing laparoscopic and thoracoscopic esophagectomy.Methods Sixty patients undergoing laparoscopic and thoracoscopic esophagectomy were divided into two groups(n=30 each):incremental group(group Ⅰ)and decremental group(group D).PEEP titration was performed in both groups during thoracoscopy and laparoscopy.Respiratory mechanics parameters,hemodynamic parameters,and blood gas analysis were collected for analysis before preoxygenation(T0),10 minutes after intuba-tion(T1),20 minutes after PEEP application for one-lung ventilation(T2),20 minutes after PEEP application for two-lung ventilation(T3),before extubation(T4),and 30 minutes after extubation(Ts).The postoperative pulmonary complications within 3 days and 7 days after operation,hospitalization duration,and costs were recorded.Results Compared with group Ⅰ,patients in group D showed higher oxygenation index and pulmonary compliance during surgery(P＜0.05).In both groups,driving pressure decreased and compliance increased after PEEP titration(P＜0.05).Conclusion Both driving pressure-guided incremental and decremental titration of individualized PEEP improved intraoperative respiratory mechanics in patients undergoing laparoscopic and thoracoscopic esopha-gectomy,and decremental titration was more effective in improving intraoperative respiratory mechanics and oxygenation in patients during operation.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Objective To analyze the correlation between right atrial strain at various stages and various influencing factors in patients with pulmonary hypertension,and to explore the role of right atrial strain in the assessment of pulmonary hypertension.Methods A total of 239 cases diagnosed with pulmonary hypertension who underwent echocardiography and complete right heart catheterization at hospital from October 2021 to December 2023 were included.Conventional ultrasound parameters such as right heart strain,right atrial area(RA area),inferior vena cava diameter(IVC diameter),and collapse rate of the inferior vena cava(IVC diameter changes)were measured.The heart rate(HR)corresponding to the ultrasound images were recorded.General information such as age and gender,as well as catheter data including mean right atrial pressure(mRAP),mean pulmonary artery pressure(mPAP),and pulmonary vascular resistance(PVR),were collected.The relationship between right atrial strain and its influencing factors was analyzed,and further analysis was conducted by dividing into shunt group and non-shunt group based on the presence or absence of left-to-right shunt disease.Results The correlation with RA reservoir strain(RASr)from high to low is RV global strain(RV4CSL),RV free wall strain(RVFWSL),RA area,IVC diameter,mRAP,age,HR,and PVR;the correlation with RAconduit strain(RAScd)from high to low is RV4CSL,RVFWSL,RA area,IVC diameter,mRAP,age,PVR,and HR;the correlation with RA contraction strain(RASct)from high to low is RA area,RV4CSL,RVFWSL,mRAP,IVC diameter,and HR.The collapse rate of the inferior vena cava is correlated with strain at various stages of the right atrium;gender is correlated with RASr and RASct.Conclusions Right atrial strain can reflect changes in right atrial function,with the highest correlation to right ventricular strain and right atrial area.Right atrial strain can indicate the severity of right ventricular function and right atrial remodeling,serving as an evaluative index for the condition and treatment outcomes of pulmonary arterial hypertension.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic