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*

Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Radiochemotherapy-induced oral mucositis (OM) is a common oral complication in patients with tumors following head and neck radiotherapy or chemotherapy. Erosion and ulcers are the main features of OM that seriously affect the quality of life of patients and even the progress of tumor treatment. To date, differences in clinical prevention and treatment plans for OM have been noted among doctors of various specialties, which has increased the uncertainty of treatment effects. On the basis of current research evidence, this expert consensus outlines risk factors, clinical manifestations, clinical grading, ancillary examinations, diagnostic basis, prevention and treatment strategies and efficacy indicators for OM. In addition to strategies such as basic oral care, anti-inflammatory and analgesic agents, anti-infective agents, pro-healing agents, and photobiotherapy recommended in previous guidelines, we also emphasize the role of traditional Chinese medicine in OM prevention and treatment. This expert consensus aims to provide references and guidance for dental physicians and oncologists in formulating strategies for OM prevention, diagnosis, and treatment, standardizing clinical practice, reducing OM occurrence, promoting healing, and improving the quality of life of patients.
Humans ; Chemoradiotherapy/adverse effects* ; Consensus ; Risk Factors ; Stomatitis/etiology*

Objective:To explore the mechanism of Danxing Zhishuang Prescription in the treatment of Parkinson's disease (PD) by combining network pharmacology with animal models.Methods:TCMSP, BATMAN database, Genecards, and OMIM databases were retrieved to obtain the active components and action targets of Danxing Zhishuang Prescription. Venny 2.1.0 was used to intersect drug targets and PD related genes, and a protein interaction network of the intersection targets was constructed using the STRING 12.0 platform. Topology analysis was performed using Cytoscape 3.10.0 software to identify the key targets of Danxing Zhishuang Prescription on PD; GO functional and KEGG pathway enrichment analysis was performed on key targets using the WeChat platform, and molecular docking was validated through AutoDockTools 1.5.7. Using a random number table method, mice were divided into a blank control group, a model group, and a Danxing Zhishuang Prescription group, with 20 mice in each group; except for the blank group, all other groups of mice were orally administered fisetin to prepare PD models; Danxing Zhishuang Prescription group was orally administered with concentrated Danxing Zhishuang Prescription at a dosage of 10.5 g/kg, while the blank group and model group were orally administered with 0.2 ml of physiological saline for 21 days; Western blot was used to detect the expressions of Akt1, Bcl-2, Bax, and α-Syn proteins.Results:359 intersection targets, 69 core targets, and 185 active components were obtained the treatment of PD with Danxing Zhishuang Prescription. The main active components included quercetin, kaempferol, phenylalanine, etc., and the key targets were AKT1, TP53, TNF, ESR1, etc. KEGG analysis revealed several key signaling pathways, such as AGE-RAGE, PI3K-Akt, fluid shear stress and atherosclerosis signaling pathways. The validation experiment results showed that compared with the model group, the expression of Bcl-2 protein was up-regulated ( P<0.01), and the expressions of Bax, Akt1, and α-Syn proteins were down-regulated in the Danxing Zhishuang Prescription group ( P<0.01). Conclusions:Danxing Zhishuang Prescription has the advantages of multi target and multi pathway treatment for PD. Its mechanism may be related to down-regulating the expressions of Bax, Akt1, and α-Syn proteins, improving brain blood supply, regulating neurotransmitter balance, inhibiting oxidative stress response, and promoting nerve regeneration.

Objective To evaluate the effect of cytochrome P450 3A5(CYP3A5)genetic polymorphism on the blood drug concentration of tacrolimus(TAC)in patients with lupus nephritis(LN),to determine the appropriate initial dose for LN patients of different genotypes and the differences in time to remission,and to analyze factors associated with LN prognosis.Methods Patients with active LN attending the outpatient clinic of the Department of Rheumatology and Immunology,West China Hospital,Sichuan University were enrolled.Their CYP3A5 genotypes were determined.According to the different genotypes,the patients were assigned to two groups,the AA+GA group,or the rapid metabolism group with the genotype CYP3A5*1/*1,i.e.,AA+CYP3A5*1/*3,and the GG group,or the slow metabolism group with the genotype CYP3A5*3/*3.The basic information,clinical manifestations,history of other diseases,and medication history of the enrolled patients were collected.According to the principle of simple random grouping,patients in each group were randomly divided into two subgroups,receiving TAC at initial doses of 0.05 mg/(kg·d)and 0.075 mg/(kg·d),respectively.Data on laboratory test indicators,including TAC blood drug concentration,blood pressure,and other relevant clinical follow-up indicators,were collected each month from each group.Patients were also evaluated each month for their clinical remission status.When patients in the 0.05 mg/(kg·d)initial dose group did not achieve clinical remission after 2 months,the TAC dose was increased to 0.075 mg/(kg·d),and the patients were observed until the end of the 6th month.Patients in the 0.075 mg/(kg·d)initial dose group were observed for 6 months,regardless of their remission status.Results In the LN patient subgroups receiving TAC at the same initial dose,the cumulative remission rate of patients with the GG genotype was higher than that of patients with the AA+GA genotype,but only in the 0.05 mg/(kg·d)initial dose group,the difference in cumulative remission rate between the two genotypes was statistically significant(P<0.05).According to a comparison of patients with the same genotype who received TAC at different initial doses,the remission rate of patients receiving 0.075 mg/(kg·d)initial dose was higher than that of the 0.05 mg/(kg·d)initial dose group,but only in patients with AA+GA genotype,the difference in remission rate between the two initial dose groups was statistically significant(P<0.05).Whether it was different genotypes in the same TAC initial dose group or different TAC initial doses of the same genotype,there was no statistically significant difference in the time to achieve complete remission(P>0.05).Regardless of the different initial TAC doses,patients with the GG genotype maintained higher TAC blood concentrations than those with the AA+GA genotype throughout the course of treatment.TAC blood concentration during treatment(OR=1.941;95%CI,1.47-2.563;P<0.001),CYP3A5*1 genotype carrier status(OR=0.161;95%CI,0.053-0.492;P=0.001),and the initial TAC dose(OR=0.205;95%CI,0.113-0.371;P<0.001)were all significant factors influencing treatment efficacy.When TAC blood concentration was higher,patients with the GG genotype receiving TAC at an initial dose of 0.075 mg/(kg·d)were more likely to achieve clinical remission.There were no statistically significant differences in the incidence of adverse reactions between subgroups with the same genotype but receiving TAC at different initial doses(P>0.05).Conclusion The efficacy of TAC in treating LN patients is correlated with CYP3A5 genotypes,TAC blood drug concentration,and TAC initial dose.The blood drug concentration of TAC is influenced by CYP3A5 genotypes,with the TAC blood drug concentrations of the slow metabolism group being higher than that of the fast metabolism group.When the TAC blood drug concentration reaches 6-10 ng/mL,it is more likely for LN patients to achieve clinical remission.

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
Humans ; Prions ; Neurodegenerative Diseases/pathology* ; Amyloid beta-Peptides ; Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; Parkinson Disease

Objective To investigate the water quality and sanitary conditions of rural self-provided wells water in Haidian District, Beijing, and to provide reference for strengthening water supply management of self-provided wells. Methods The water quality monitoring data of rural self-provided wells in Haidian District from 2018 to 2022 were analyzed. Results A total of 1 568 water samples were tested in 2018-2022 , of which 1 486 were qualified, with a qualified rate of 94.77%. The qualified rate in each year was 86.75% , 92.86% , 97.48% , 98.06% , and 99.34% , respectively , and the difference was statistically significant ( χ²= 75.296 , P＜0.05). The qualified rates of sensory traits and general chemical indexes, toxicological indexes and microbial indexes were 97.70%, 97.58% and 98.28%, respectively. There were statistically significant differences in the qualified rates among the three indexes in 2018, 2019 and 2021 (P < 0.05). The unqualified indicators included total hardness, total number of colonies, total coliform, fluoride, nitrate and turbidity, with a qualified rate of 97.96%, 98.41%, 99.17%, 99.11%, 98.47% and 99.94%, respectively. Conclusion The water quality of self-provided wells in rural Haidian District is good. Relevant departments should continue to strengthen the supervision of self-provided wells, such as the supervision of self-provided wells disinfection devices and water treatment equipment, to ensure the safety of drinking water for residents.

Objective: To explore the influencing factors of role adaptation of college freshmen, so as to provide empirical support for developing adaptive education in college. Methods: A cluster sampling method was used to select 3 126 freshmen from six universities of Hefei City and Wuhu City in Anhui Province in October 2022, who were investigated with Positive Psychological Capital Questionnaire (PPQ), Freshmen s Role Adaptability Scale, Connor Davidson Resilience Scale (CD-RISC) and Life Satisfaction Scale. Independent sample t-test and oneway ANOVA were used to compare the scores (caverage score of items) of various variables of college freshmen with different demographic characteristics. Pearson correlation analysis and multiple linear regression analysis were conducted to analyze the correlation. Results: There were statistically significant differences in scores of psychological capital, resilience, life satisfaction and role adaptation among college freshmen of different origin (large and mediumsized cities: ３.６３± ０.５４，３.７３±０.６４，３.４７±０.８０，３.１４±０.６５；county level city or county seat:３.５７±０.５２，３.６１±０.６３，３.３５±０.７５，３.０９±０.６３；villages and towns:３.５０±０.５０，３.５４±０.５８，３.２３±０.７５，３.０６±０.６０), whether in class committee (yes:３.６３±０.５２，３.６９±０.６０，３.４０± ０.７６ ，３.１８±０.５９； no:３.４３±０.５０，３.４８±０.６４，３.２５±０.７７，２.９３±０.６５), father s education level (junior high school or below:３.５２± ０.５１ ，３.５７±０.６１，３.２７±０.７５，３.０７±０.６１； senior high school or technical secondary school:３.６２±０.５３，３.６８±０.６３，３.４４±０.７８，３.１２±０.６３；junior college or above:３.６８±０.５６，３.７８±０.６４，３.５７±０.８０，３.１９±０.６８)，mother s education level(junior high school or below:３.５３±０.５１，３.５８±０.６１，３.２８±０.７５，３.０６±０.６０；senior high school or technical secondary school:３.６３±０.５５，３.７０±０.６３，３.４８±０.７８，３.１５±０.６６；junior college or above:３.７２±０.５４，３.８６±０.６５，３.６２±０.８３，３.２７±０.７０) ( F / t =11.89,21.89,23.02,3.83；10.08，9.20， 5.20 ，10.63；19.34，20.76，29.52，6.44；22.51，26.79，30.94，13.92， P <0.05). The differences of scores in resilience and role adaptation of different genders (boys:3.66±0.64, 3.12±0.65; girls:3.56±0.59, 3.05±0.58) and in life satisfaction whether being an only child (yes:3.40±0.79; no:3.33±0.76) among college freshmen were statistically significant ( t =4.51, 2.75, 2.35, P <0.05). Pearson correlation analysis showed that psychological capital, resilience and life satisfaction of college freshmen were positively correlated with role adaptation ( r =0.49, 0.49, 0.36), while psychological capital, resilience and role adaptation were positively correlated ( r =0.60, 0.59) and Psychological capital was positively correlated with resistance ( r =0.81)( P <0.01). The results of multiple linear regression analysis showed that gender, whether in class committee, psychological capital, resilience and life satisfaction were positively associated with role adaptation among college freshmen ( R 2=0.28, β =0.04, 0.10, 0.23, 0.26, 0.07， P <0.05). Conclusions Role adaptation of college freshmen is related with psychological capital, resilience and life satisfaction. Schools should strengthen mental health education to promote smooth role transition for college freshmen.

Objective To observe the effects of Huatan Quyu Decoction on cognitive function and the expressions of GABA and VILIP-1 in brain tissue of rats with cerebral small vessel disease;To discuss its mechanism for treatment on cerebral small vessel disease.Methods Totally 48 male SD rats were randomly divided into blank group,model group,Huatan Quyu Decoction low-and high-dosage groups,with 12 rats in each group.Except for the blank group,a rat model of cerebral small vessel disease was prepared by in vitro injection of homologous microemboli.Huatan Quyu Decoction low-and high-dosage groups were given Huatan Quyu Decoction 1.25 and 2.5 g/kg by gavage,the blank group and model group were gavage with equal amounts of distilled water for 28 consecutive days.Morris water maze experiment was conducted on day 1,7,14,and 28 after administration to evaluate the learning and memory abilities of rats,HE staining was used to observe pathological changes in hippocampal tissue,and immunohistochemical staining was used to detect the expressions of GABA and VILIP-1 proteins in brain tissue.Results Compared with the blank group,the escape latency of Morris water maze experiment in model group significantly prolonged(P<0.05),and the number of crossing platforms was significantly reduced(P<0.05);the arrangement of hippocampal tissue cells was disordered,gaps widen,and nuclei atrophy and necrosis,the GABA expression in brain tissue significantly decreased(P<0.05),while the VILIP-1 expression significantly increased(P<0.05).Compared with the model group,the escape latency of Morris water maze experiment in the Huatan Quyu Decoction low-and high-dosage groups significantly shortened(P<0.05)on day 7,14,and 28 of administration,and the number of crossing platforms significantly increased(P<0.05),GABA expression significantly increased(P<0.05),while VILIP-1 expression significantly decreased(P<0.05).Compared with the Huatan Quyu Decoction low-dosage group,the escape latency of Morris water maze experiment in Huatan Quyu Decoction high-dosage group decreased at various time points,and the number of crossing platforms increase,the pathological damage of hippocampal tissue was reduced,the expression of GABA in brain tissue increased,and the expression of VILIP-1 decreased,with statistical significance(P<0.05).Conclusion Huatan Quyu Decoction can increase the expression of GABA in brain tissue and inhibit the expression of VILIP-1,thereby improve the cognitive function of rats with cerebrovascular disease.

Objective To construct a rational and efficient bed resource allocation management model to reduce pre-hos-pital waiting times,ensure patient safety,and improve satisfaction.Methods Based on lean management principles,a bed re-source allocation management model was developed and continuously optimized.The study compared bed turnover rates and effi-ciency indices,as well as preoperative waiting times for surgical patients,average length of stay,patient satisfaction,and anxiety incidence before and after the implementation of the lean model to evaluate its effectiveness.Results After implementing the lean bed resource allocation model,the bed efficiency index increased by 14.29％,and bed turnover rates improved by 3.34％.The average preoperative waiting time for surgical patients decreased by 100％,and the average length of stay reduced by 87.71％.Patient satisfaction increased by 2.4％,while anxiety incidence dropped by 28.1％.Conclusion The implementa-tion of a lean bed resource allocation model can enhance hospital bed efficiency,shorten preoperative waiting times for surgical patients,reduce average length of stay,and improve patient satisfaction.