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.

To investigate the protective effects and underlying mechanisms of Qin-Zhu-Liang-Xue decoction (QZLX) in atopic dermatitis (AD) and glucocorticoid resistance, we conducted a single-blinded, randomized controlled clinical trial to evaluate the efficacy and safety of this concoction. Network pharmacology analysis was performed and validated through clinical studies. The efficacy, safety, and mechanism of action of QZLX and glucocorticoid receptor (GR) α recombinant protein were assessed in AD mice induced by 2,4-dinitrofluorobenzene (DNFB). Correlation analysis was performed to determine the clinical relevance of GRα. The trial demonstrated that patients who received QZLX showed considerable improvements in their Scoring Atopic Dermatitis (SCORAD) and Dermatology Life Quality Index (DLQI) scores compared with those who received mizolastine at week 4. Network pharmacological analysis identified GRα as a key target for QZLX in AD treatment. QZLX administration increased the serum GRα expression in AD patients, alleviated AD symptoms in mice, decreased inflammatory cytokine expression, and increased GRα expression without affecting liver or kidney function. In addition, GRα recombinant protein improved AD-like skin lesions in DNFB-induced mice. A negative correlation was observed between GRα expression and clinical parameters, including SCORAD, DLQI, and serum IgE levels. QZLX alleviates AD symptoms through the upregulation of GRα and thus presents a novel therapeutic strategy for the prevention of glucocorticoid resistance in AD management.
Dermatitis, Atopic/drug therapy* ; Animals ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Mice ; Network Pharmacology ; Male ; Female ; Adult ; Receptors, Glucocorticoid/metabolism* ; Disease Models, Animal ; Single-Blind Method ; Middle Aged ; Young Adult

The guidelines advocate for preoperative neoadjuvant radiotherapy and chemotherapy in cases of middle and low locally advanced rectal cancer. While some patients achieved pathological complete response (pCR), which is favorable and allows for potential organ preservation, treatment sensitivity varies and not all patients reach pCR. Identifying the factors influencing pCR is important for enhancing the effectiveness of neoadjuvant therapy and improving patient outcomes. Previous research has identified various factors associated with response to neoadjuvant therapy, which can serve as predictors of pCR. This study reviews recent literature on imaging, pathological, genetic, and molecular characteristics, laboratory indices, and therapeutic factors related to tumor response, both domestically and internationally. The aim is to summarize the latest advancements in understanding the factors associated with pCR in patients with locally advanced middle and low rectal cancer undergoing neoadjuvant therapy, thereby providing a theoretical foundation for standardized clinical treatment approaches.

Background::Influenza and pneumococcal vaccination are a priority in patients with chronic obstructive pulmonary disease (COPD). However, limited information is available on vaccination coverage among patients with acute exacerbations of COPD (AECOPD) in China. This study aimed to determine the rates and associated factors of influenza and pneumococcal vaccination in patients hospitalized with AECOPD.Methods::Baseline data from a national, multicenter, hospital-based study that included adult inpatients with AECOPD between 2017 and 2021 were analyzed. The outcomes of interest were the influenza vaccination in the past year and the pneumococcal vaccination in the past 5 years. To ensure national representativeness, rates were weighted according to the distribution of hospital levels and types enrolled in this study. Multivariable Poisson regression based on mixed-effects models were used to determine the associated factors. The independent variables included the region and hospital features where the participants were located, sociodemographic characteristics (age, sex, rural/urban residence, education, etc.), and clinical indicators (COPD disease history, lung function parameters, comorbidities, etc.). The treatment profiles of the vaccinated and unvaccinated participants were compared.Results::Of 6949 eligible participants, the weighted rates of influenza/pneumococcal, influenza, and pneumococcal vaccination were 2.72% (95% confidence interval [CI]: 2.34%-3.10%), 2.09% (95% CI: 1.76%-2.43%), and 1.25% (95% CI: 0.99%-1.51%), respectively. In multivariable models, age ≥60 years (60-69 years, odds ratio [OR]: 1.90, 95% CI: 1.11-3.25; ≥80 years, OR: 2.00, 95% CI: 1.06-3.78), geographical regions (Northern China relative to Eastern China, OR: 5.09, 95% CI: 1.96-13.21), urban residence (OR: 1.69, 95% CI: 1.07-2.66), a higher education level (junior high school, OR: 1.77, 95% CI: 1.21-2.58; senior high school or above, OR: 2.61, 95% CI: 1.69-4.03), former smoking (OR: 1.79, 95% CI: 1.15-2.79), and regular inhaled medication treatment (OR: 3.28, 95% CI: 2.29-4.70) were positively associated with vaccination. Patients who had experienced severe exacerbations in the past year were less likely to be vaccinated (OR: 0.65, 95% CI: 0.45-0.96). Compared with unvaccinated participants, vaccinated participants adhered better to pharmacological and non-pharmacological treatment.Conclusions::Influenza and pneumococcal vaccination coverage are extremely low. Urgent measures are necessary to increase vaccination coverage among inpatients with AECOPD in China.

Waardenburg syndrome is a rare genetic disease of auditory pigmentation. The main symptom is sensorineural hearing loss. Pigment disorders and other developmental defects in skin, hair, iris, fundus and other parts are specifically divided into four different subtypes, each of which corresponds to different pathogenic genes, which encode transcription factors and signaling molecules that play a key role in the development process of neural crest cells into melanocytes. Because there are multiple subtypes of Waardenburg syndrome, different subtypes exhibit different symptoms, signs and ocular manifestations. Patients with Waardenburg syndrome are often first treated in ENT head and neck surgery due to hearing loss. Lack of theoretical knowledge related to Waardenburg syndrome by ophthalmologists may lead to misdiagnosis or missed diagnosis. Although there are currently limited treatments for the disease, with the continuous development of gene therapy and hearing management methods, the future treatment prospects will be broader.

Objective To investigate the effect of very-long-chain saturated fatty acids on Tau protein phosphorylation and membrane fluidity in human neuroblastoma SH-SY5Y cells,and to explore its role in the pathogenesis of Alzheimer's disease(AD).Methods Human neuroblastoma SH-SY5Y cells in logarithmic growth phase were randomly divided into control group,C22∶0 group,and C24:0 group.Cells in the control group were routinely cultured,while cells in the C22:0 and C24:0 groups were treated with culture medium containing 10 μmol·L-1very-long-chain saturated fatty acids C22:0 and C24:0,respectively.After 24 hours of incubation,cells were collected.The expression levels of total Tau protein,phosphorylated Tau protein at serine 396 site(p-Tau-ser396),glycogen synthase kinase 3β(GSK-3β),and phosphorylated GSK-3 β protein at serine 9 site(p-GSK-3β-Ser9)in cells of each group were detected by using Western blot.The malondialdehyde(MDA)level in cells of each group was determined by using the thiobarbituric acid method.The fluorescence recovery rate and diffusion coefficient of cell membranes were measured by using fluorescence recovery after photobleaching technique,and the fluidity of cell membranes was evaluated.Results The total Tau protein level in SH-SY5Y cells showed no statistically significant difference among the three groups(F=1.807,P＞0.05).However,there was a statistically significant difference in the level of p-Tau-ser396 in SH-SY5Y cells among the three groups(F=18.397,P＜0.05).Specifically,the level of p-Tau-ser396 in SH-SY5Y cells in the C22:0 and C24:0 groups was significantly higher than that in the control group(P＜0.05),and the level of p-Tau-ser396 in SH-SY5Y cells in the C24:0 group was significantly higher than that in the C22:0 group(P＜0.05).There was no statistically significant difference in the GSK-3 β protein level in SH-SY5Y cells among the three groups(F=0.351,P＞0.05).However,there was a statistically significant difference in the level of p-GSK-3β-Ser9 in SH-SY5Y cells among the three groups(F=13.330,P＜0.05).Specifically,the level of p-GSK-3β-ser9 in SH-SY5Y cells in the C22:0 and C24:0 groups was significantly lower than that in the control group(P＜0.05),and there was no statistically significant difference in the level of p-GSK-3β-ser9 in SH-SY5Y cells between the C22:0 group and C24:0 group(P＞0.05).The MDA level in SH-SY5Y cells in the C24:0 group was significantly higher than that in the control group and C22:0 group(P＜0.05);there was no statistically significant difference in the MDA level in SH-SY5Y cells between the control group and C22:0 group(P＞0.05).The fluorescence recovery rate and diffusion coefficient of SH-SY5Y cells in the C22:0 and C24:0 groups showed a decreasing trend compared to the control group,but there was no statistically significant difference in the fluorescence recovery rate and diffusion coefficient of SH-SY5Y cells among the three groups(F=3.891,3.649,P＞0.05).Conclusion Very-long-chain saturated fatty acids C22:0 and C24:0 can promote hyperphosphorylation of Tau protein,induce cellular oxidative damage,and tend to reduce the fluidity cell membranes.Very-long-chain saturated fatty acids may be one of the factors that cause the onset of AD.

Based on the introduction of gut-brain-skin axis, this article discussed the relationship between psychological behavior, intestinal flora, and atopic dermatitis. By combing the literature on the treatment of atopic dermatitis with TCM, it is found that TCM therapy can regulate the relative abundance of intestinal flora, participate in immune metabolism and restore skin barrier function by intervening in the gut-brain-skin axis, so as to achieve the purpose of treating atopic dermatitis.

Objective:To investigate the prognostic value of myocardial flow reserve (MFR) measured by SPECT myocardial blood flow (MBF) quantitative technique in patients with intermediate stenoses of coronary arteries.Methods:From September 2019 to May 2021, patients with intermediate stenoses (50% to 80%) identified by invasive coronary angiography in Fuwai Hospital, Chinese Academy of Medical Sciences, Fuwai Center China Cardiovascular Hospital, and TEDA International Cardiovascular Hospital were prospectively included. All patients underwent a one-day rest/stress SPECT myocardial perfusion imaging (MPI) and SPECT MBF quantification. The radioactivity distribution of each segment of the MPI bullseye polar maps were obtained according to the standard 5-point method to obtain the summed stress score (SSS) and the summed difference score (SDS) to determine the existence of abnormality. ROC curve analysis was used to obtain the optimal prognostic cut-off value for MFR. The primary endpoint was defined as cardiovascular endpoint events. Survival and prognostic analyses were conducted by Kaplan-Meier method and Cox proportional hazard models. The difference of AUCs was analyzed by Delong test.Results:A total of 314 patients (194 males, 120 females; age (59.4±8.6) years) were enrolled. Over a median follow-up duration of 754 (range: 628-914) d, 54 patients had endpoint events. ROC curve showed that the prediction ability of MFR was significantly better than that of conventional MPI (AUCs: 0.713 and 0.512; z=3.76, P<0.001). The optimal prognostic cut-off value for MFR to predict endpoint events in patients with intermediate stenoses was 2.04. Cox multivariate analysis showed that MFR (hazard ratio ( HR)=0.434, 95% CI: 0.282-0.669, P<0.001) was an independent predictor of endpoint events in patients with intermediate stenoses. Kaplan-Meier survival analysis showed that the prevalence of endpoint events in patients with MFR≤2.04 was significantly higher than that in patients with MFR>2.04 (25.4%(43/169) vs 7.6%(11/145); χ2=21.27, P<0.001). Conclusion:The MFR measured by SPECT MBF quantitative technique has an independent predictive value for cardiovascular endpoint events in patients with intermediate stenoses.

The guidelines advocate for preoperative neoadjuvant radiotherapy and chemotherapy in cases of middle and low locally advanced rectal cancer. While some patients achieved pathological complete response (pCR), which is favorable and allows for potential organ preservation, treatment sensitivity varies and not all patients reach pCR. Identifying the factors influencing pCR is important for enhancing the effectiveness of neoadjuvant therapy and improving patient outcomes. Previous research has identified various factors associated with response to neoadjuvant therapy, which can serve as predictors of pCR. This study reviews recent literature on imaging, pathological, genetic, and molecular characteristics, laboratory indices, and therapeutic factors related to tumor response, both domestically and internationally. The aim is to summarize the latest advancements in understanding the factors associated with pCR in patients with locally advanced middle and low rectal cancer undergoing neoadjuvant therapy, thereby providing a theoretical foundation for standardized clinical treatment approaches.

Purpose: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. Materials and Methods: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. Results: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). Conclusion Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.