BACKGROUND: In the interim analysis of MONARCH plus, adding abemaciclib to endocrine therapy (ET) improved progression-free survival (PFS) and objective response rate (ORR) in predominantly Chinese postmenopausal women with HR+/HER2- advanced breast cancer (ABC). This study presents the final pre-planned PFS analysis. METHODS: In the phase III MONARCH plus study, postmenopausal women in China, India, Brazil, and South Africa with HR+/HER2- ABC without prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) were randomized (2:1) to abemaciclib (150 mg twice daily [BID]) or placebo plus: anastrozole (1.0 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle) (cohort B). The primary endpoint was PFS of cohort A. Secondary endpoints included cohort B PFS (key secondary endpoint), ORR, overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: In cohort A (abemaciclib: n  = 207; placebo: n  = 99), abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs . placebo (28.27 months vs . 14.73 months, hazard ratio [HR]: 0.476; 95% confidence interval [95% CI]: 0.348-0.649). In cohort B (abemaciclib: n  = 104; placebo: n  = 53), abemaciclib plus fulvestrant improved median PFS vs . placebo (11.41 months vs . 5.59 months, HR: 0.480; 95% CI: 0.322-0.715). Abemaciclib numerically improved ORR. Although immature, a trend toward OS benefit with abemaciclib was observed (cohort A: HR: 0.893, 95% CI: 0.553-1.443; cohort B: HR: 0.512, 95% CI: 0.281-0.931). The most frequent grade ≥3 adverse events in the abemaciclib arms were neutropenia, leukopenia, anemia (both cohorts), and lymphocytopenia (cohort B). Abemaciclib did not cause clinically meaningful changes in patient-reported global health, functioning, or most symptoms vs . placebo. CONCLUSIONS: Abemaciclib plus ET led to improvements in PFS and ORR, a manageable safety profile, and sustained HRQoL, providing clinical benefit without a high toxicity burden or reduced quality of life. TRIAL REGISTRATION ClinicalTrials.gov (NCT02763566).
Humans ; Female ; Fulvestrant/therapeutic use* ; Breast Neoplasms/metabolism* ; Aminopyridines/therapeutic use* ; Benzimidazoles/therapeutic use* ; Middle Aged ; Aromatase Inhibitors/therapeutic use* ; Aged ; Receptor, ErbB-2/metabolism* ; Adult ; Letrozole/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Anastrozole/therapeutic use*

Testicular histology based on testicular biopsy is an important factor for determining appropriate testicular sperm extraction surgery and predicting sperm retrieval outcomes in patients with azoospermia. Therefore, we developed a deep learning (DL) model to establish the associations between testicular grayscale ultrasound images and testicular histology. We retrospectively included two-dimensional testicular grayscale ultrasound from patients with azoospermia (353 men with 4357 images between July 2017 and December 2021 in The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China) to develop a DL model. We obtained testicular histology during conventional testicular sperm extraction. Our DL model was trained based on ultrasound images or fusion data (ultrasound images fused with the corresponding testicular volume) to distinguish spermatozoa presence in pathology (SPP) and spermatozoa absence in pathology (SAP) and to classify maturation arrest (MA) and Sertoli cell-only syndrome (SCOS) in patients with SAP. Areas under the receiver operating characteristic curve (AUCs), accuracy, sensitivity, and specificity were used to analyze model performance. DL based on images achieved an AUC of 0.922 (95% confidence interval [CI]: 0.908-0.935), a sensitivity of 80.9%, a specificity of 84.6%, and an accuracy of 83.5% in predicting SPP (including normal spermatogenesis and hypospermatogenesis) and SAP (including MA and SCOS). In the identification of SCOS and MA, DL on fusion data yielded better diagnostic performance with an AUC of 0.979 (95% CI: 0.969-0.989), a sensitivity of 89.7%, a specificity of 97.1%, and an accuracy of 92.1%. Our study provides a noninvasive method to predict testicular histology for patients with azoospermia, which would avoid unnecessary testicular biopsy.
Humans ; Male ; Azoospermia/diagnostic imaging* ; Deep Learning ; Testis/pathology* ; Retrospective Studies ; Adult ; Ultrasonography/methods* ; Sperm Retrieval ; Sertoli Cell-Only Syndrome/diagnostic imaging*

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia in the elderly. This study aimed to evaluate urban-rural disparities in its prevalence and management in elderly Chinese. METHODS: Consecutive participants aged ≥ 65 years attending outpatient clinics were enrolled for AF screening using handheld single-lead electrocardiogram (ECG) from April 2017 to December 2022. Each ECG rhythm strip was reviewed from the research team. AF or uninterpretable single-lead ECGs were referred for 12-lead ECG. Primary study outcome comparison was between rural and urban areas for the prevalence of AF. The Student's t-test was used to compare mean values of clinical characteristics between rural and urban participants, while the Pearson's chi-square test was used to compare between-group proportions. Multivariate stepwise logistic regression analysis was performed to estimate the association between AF and various patient characteristics. RESULTS: The 29,166 study participants included 13,253 men (45.4%) and had a mean age of 72.2 years. The 7073 rural participants differed significantly (P ≤ 0.02) from the 22,093 urban participants in several major characteristics, such as older age, greater body mass index, and so on. The overall prevalence of AF was 4.6% (n = 1347). AF was more prevalent in 7073 rural participants than 22,093 urban participants (5.6% vs. 4.3%, P < 0.01), before and after adjustment for age, body mass index, blood pressure, pulse rate, cigarette smoking, alcohol consumption and prior medical history. Multivariate logistic regression analysis identified overweight/obesity (OR = 1.35, 95% CI: 1.17-1.54) in urban areas and cigarette smoking (OR = 1.62, 95% CI: 1.20-2.17) and alcohol consumption (OR = 1.42, 95% CI: 1.04-1.93) in rural areas as specific risk factors for prevalent AF. In patients with known AF in urban areas (n = 781) and rural areas (n = 338), 60.6% and 45.9%, respectively, received AF treatment (P < 0.01), and only 22.4% and 17.2%, respectively, received anticoagulation therapy (P = 0.05). CONCLUSIONS In China, there are urban-rural disparities in AF in the elderly, with a higher prevalence and worse management in rural areas than urban areas. Our study findings provide insight for health policymakers to consider urban-rural disparity in the prevention and treatment of AF.

Oligodendrocyte lineage cells, including oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs), are essential in establishing and maintaining brain circuits. Autophagy is a conserved process that keeps the quality of organelles and proteostasis. The role of autophagy in oligodendrocyte lineage cells remains unclear. The present study shows that autophagy is required to maintain the number of OPCs/OLs and myelin integrity during brain aging. Inactivation of autophagy in oligodendrocyte lineage cells increases the number of OPCs/OLs in the developing brain while exaggerating the loss of OPCs/OLs with brain aging. Inactivation of autophagy in oligodendrocyte lineage cells impairs the turnover of myelin basic protein (MBP). It causes MBP to accumulate in the cytoplasm as multimeric aggregates and fails to be incorporated into integral myelin, which is associated with attenuated endocytic recycling. Inactivation of autophagy in oligodendrocyte lineage cells impairs myelin integrity and causes demyelination. Thus, this study shows autophagy is required to maintain myelin quality during aging by controlling the turnover of myelin components.
Animals ; Autophagy/physiology* ; Oligodendroglia/metabolism* ; Myelin Sheath/physiology* ; Aging/pathology* ; Myelin Basic Protein/metabolism* ; Cell Lineage/physiology* ; Mice ; Oligodendrocyte Precursor Cells ; Mice, Inbred C57BL ; Brain/cytology* ; Cells, Cultured ; Cell Count

Objective:To analyze the factors associated with long-term survival after radical resection of hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC),and to construct random forest and Cox regression models,to evaluate the two models.Methods:A total of 368 patients with HBV-infected HCC who underwent radical resection were selected retrospectively.These patients were categorized as having a good prognosis(n=266)or a poor prognosis(n=102)based on their survival and mortality status.Univariate and Cox regression analysis were used to identify fac-tors that predict poor prognosis in HCC patients after surgery,and Cox regression and random forest prediction models were constructed and evaluated.Results:There were significant differences in smoking history,Child-Pugh classifica-tion,cirrhosis,microvascular invasion,TNM staging,tumor capsule integrity,platelet-to-lymphocyte ratio(PLR),regular antiviral therapy,HBV-DNA load,alpha-fetoprotein(AFP),neutrophil-to-lymphocyte ratio(NLR),systemic immune in-flammatory index(SII),and albumin-to-globulin ratio(AGR)between the two groups(P<0.05);Cox regression showed that cirrhosis,microvascular invasion,regular antiviral treatment,HBV-DNA load,NLR,PLR,SII,and AGR were related factors that negatively affected the prognosis of patients with HBV-infected HCC after surgery(P<0.05),with an AUC of 0.870 for predicting prognosis;the importance ranking obtained by the random forest model was HBV-DNA load,cirrho-sis,regular antiviral therapy,microvascular invasion,NLR,PLR,AGR,and SII,with an AUC of 0.926 for predicting prog-nosis;the AUC predicted by the random forest model was greater than that predicted by the Cox regression model(Z=2.411,P=0.016).Conclusion:HBV-DNA load,cirrhosis,regular antiviral therapy,microvascular invasion,NLR,PLR,AGR,and SII are factors that affect the poor prognosis of patients with HBV-related HCC after surgery.The random for-est prediction model constructed based on these factors has high predictive value and is superior to the Cox regression prediction model.

Objective:To improve the quality standards for Portulaca oleracea medicinal materials and decoction pieces.Methods:Fourteen batches of P.oleracea medicinal materials and 20 batches of its decoction pieces from different producing areas across the country were collected.In accordance with the relevant methods in the general chapters of the Chinese Pharmacopoeia(2020 Edition,Volume Ⅰ),the thin-layer chromatography(TLC)identi-fication method was optimized.The contents of impurities,moisture,total ash,acid-insoluble ash,heavy metals and harmful elements,and extracts were determined.Meanwhile,the HPLC feature chromatograms and content determination methods for P.oleracea medicinal materials and decoction pieces were established.Results:The optimized TLC method showed clear spots,good separation effect and reproducibility.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 14 batches of P.oleracea medicinal materi-als were 0.01％,8.48％,21.68％,5.33％,and 28.44％respectively.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 20 batches of P.oleracea decoction pieces were 0.01％,7.00％,21.09％,3.60％,and 29.63％respectively.The results of the tests for heavy metals and harmful elements showed that the contents of lead,cadmium,arsenic,mercury and copper in 34 batches of samples varied greatly.Moreover,the contents of cadmium,arsenic and copper in some samples exceeded the limit guid-ance values specified in the Pharmacopoeia.Nine common peaks were calibrated in the established HPLC feature chromatogram of P.oleracea,and an HPLC method for simultaneously determining the contents of norepinephrine and dopamine was established.Conclusion:It is recommended to modify the developing solvent for the thin-layer identification of P.oleracea and its proportion to water-saturated n-butanol-acetone-glacial acetic acid-water=4∶1∶1∶1,and change the extraction method of the test sample to ultrasonic extraction for 30 minutes.It is proposed to add the stipulations that the total ash of P.oleracea medicinal materials and decoction pieces should not exceed 25.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.For P.oleracea decoction pieces,the total ash should not exceed 28.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.This study provides an experi-mental basis for the improvement of the quality standards of P.oleracea.

Objective:To analyze the factors associated with long-term survival after radical resection of hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC),and to construct random forest and Cox regression models,to evaluate the two models.Methods:A total of 368 patients with HBV-infected HCC who underwent radical resection were selected retrospectively.These patients were categorized as having a good prognosis(n=266)or a poor prognosis(n=102)based on their survival and mortality status.Univariate and Cox regression analysis were used to identify fac-tors that predict poor prognosis in HCC patients after surgery,and Cox regression and random forest prediction models were constructed and evaluated.Results:There were significant differences in smoking history,Child-Pugh classifica-tion,cirrhosis,microvascular invasion,TNM staging,tumor capsule integrity,platelet-to-lymphocyte ratio(PLR),regular antiviral therapy,HBV-DNA load,alpha-fetoprotein(AFP),neutrophil-to-lymphocyte ratio(NLR),systemic immune in-flammatory index(SII),and albumin-to-globulin ratio(AGR)between the two groups(P<0.05);Cox regression showed that cirrhosis,microvascular invasion,regular antiviral treatment,HBV-DNA load,NLR,PLR,SII,and AGR were related factors that negatively affected the prognosis of patients with HBV-infected HCC after surgery(P<0.05),with an AUC of 0.870 for predicting prognosis;the importance ranking obtained by the random forest model was HBV-DNA load,cirrho-sis,regular antiviral therapy,microvascular invasion,NLR,PLR,AGR,and SII,with an AUC of 0.926 for predicting prog-nosis;the AUC predicted by the random forest model was greater than that predicted by the Cox regression model(Z=2.411,P=0.016).Conclusion:HBV-DNA load,cirrhosis,regular antiviral therapy,microvascular invasion,NLR,PLR,AGR,and SII are factors that affect the poor prognosis of patients with HBV-related HCC after surgery.The random for-est prediction model constructed based on these factors has high predictive value and is superior to the Cox regression prediction model.

Objective:To improve the quality standards for Portulaca oleracea medicinal materials and decoction pieces.Methods:Fourteen batches of P.oleracea medicinal materials and 20 batches of its decoction pieces from different producing areas across the country were collected.In accordance with the relevant methods in the general chapters of the Chinese Pharmacopoeia(2020 Edition,Volume Ⅰ),the thin-layer chromatography(TLC)identi-fication method was optimized.The contents of impurities,moisture,total ash,acid-insoluble ash,heavy metals and harmful elements,and extracts were determined.Meanwhile,the HPLC feature chromatograms and content determination methods for P.oleracea medicinal materials and decoction pieces were established.Results:The optimized TLC method showed clear spots,good separation effect and reproducibility.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 14 batches of P.oleracea medicinal materi-als were 0.01％,8.48％,21.68％,5.33％,and 28.44％respectively.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 20 batches of P.oleracea decoction pieces were 0.01％,7.00％,21.09％,3.60％,and 29.63％respectively.The results of the tests for heavy metals and harmful elements showed that the contents of lead,cadmium,arsenic,mercury and copper in 34 batches of samples varied greatly.Moreover,the contents of cadmium,arsenic and copper in some samples exceeded the limit guid-ance values specified in the Pharmacopoeia.Nine common peaks were calibrated in the established HPLC feature chromatogram of P.oleracea,and an HPLC method for simultaneously determining the contents of norepinephrine and dopamine was established.Conclusion:It is recommended to modify the developing solvent for the thin-layer identification of P.oleracea and its proportion to water-saturated n-butanol-acetone-glacial acetic acid-water=4∶1∶1∶1,and change the extraction method of the test sample to ultrasonic extraction for 30 minutes.It is proposed to add the stipulations that the total ash of P.oleracea medicinal materials and decoction pieces should not exceed 25.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.For P.oleracea decoction pieces,the total ash should not exceed 28.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.This study provides an experi-mental basis for the improvement of the quality standards of P.oleracea.

OBJECTIVE: Myocardial ischemia/reperfusion injury (MIRI) is an obstacle to the success of cardiac reperfusion therapy. This study explores whether luteolin can mitigate MIRI by regulating the p53 signaling pathway. METHODS: Model mice were subjected to a temporary surgical ligation of the left anterior descending coronary artery, and administered luteolin. The myocardial infarct size, myocardial enzyme levels, and cardiac function were measured. Latent targets and signaling pathways were screened using network pharmacology and molecular docking. Then, proteins related to the p53 signaling pathway, apoptosis and oxidative stress were measured. Hypoxia/reoxygenation (HR)-incubated HL1 cells were used to validate the effects of luteolin in vitro. In addition, a p53 agonist and an inhibitor were used to investigate the mechanism. RESULTS: Luteolin reduced the myocardial infarcted size and myocardial enzymes, and restored cardiac function in MIRI mice. Network pharmacology identified p53 as a hub target. The bioinformatic analyses showed that luteolin had anti-apoptotic and anti-oxidative properties. Additionally, luteolin halted the activation of p53, and prevented both apoptosis and oxidative stress in myocardial tissue in vivo. Furthermore, luteolin inhibited cell apoptosis, JC-1 monomer formation, and reactive oxygen species elevation in HR-incubated HL1 cells in vitro. Finally, the p53 agonist NSC319726 downregulated the protective attributes of luteolin in the MIRI mouse model, and both luteolin and the p53 inhibitor pifithrin-α demonstrated a similar therapeutic effect in the MIRI mice. CONCLUSION Luteolin effectively treats MIRI and may ameliorate myocardial damage by regulating apoptosis and oxidative stress through its targeting of the p53 signaling pathway. Please cite this article as: Zhai P, Ouyang XH, Yang ML, Lin L, Li JY, Li YM, Cheng X, Zhu R, Hu DS. Luteolin protects against myocardial ischemia/reperfusion injury by reducing oxidative stress and apoptosis through the p53 pathway. J Integr Med. 2024; 22(6): 652-664.
Luteolin/pharmacology* ; Animals ; Myocardial Reperfusion Injury/metabolism* ; Oxidative Stress/drug effects* ; Tumor Suppressor Protein p53/genetics* ; Apoptosis/drug effects* ; Mice ; Signal Transduction/drug effects* ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Myocardial Infarction/prevention & control* ; Reactive Oxygen Species/metabolism*