P62-autophagic pathway degrades SLC7A11 to regulate ferroptosis in doxorubicin-induced cardiotoxicity.

Doxorubicin-induced cardiotoxicity (DIC) poses a significant challenge, impeding its widespread application. Emerging evidence suggests the involvement of ferroptosis in the DIC. While the downregulation of SLC7A11 expression has been linked to the promotion of ferroptosis, the precise regulatory mechanism remains unclear. Recent studies, including our own, have highlighted abnormal levels of autophagy adapter protein P62 and autophagy in DIC development. Thus, our study aimed to further investigate the role of autophagy and ferroptosis in DIC, elucidating underlying molecular mechanisms across molecular, cellular, and whole-organ levels utilizing gene knockdown, immunoprecipitation, and mass spectrometry techniques. The results of our findings unveiled cardiomyocyte damage, heightened autophagy levels, and ferroptosis in DOX-treated mouse hearts. Notably, inhibition of autophagy levels attenuated DOX-induced ferroptosis. Mechanistically, we discovered that the autophagy adaptor protein P62 mediates the entry of SLC7A11 into the autophagic pathway for degradation. Furthermore, the addition of autophagy inhibitors (CQ or BAF) could elevate SLC7A11 and GPX4 protein expression, reduce the accumulation of Fe2+ and ROS in cardiomyocytes, and thus mitigate DOX-induced ferroptosis. In summary, our findings underscore the pivotal role of the P62-autophagy pathway in SLC7A11 degradation, modulating ferroptosis to exacerbate DIC. This finding offers significant insights into the underlying molecular mechanisms of DOX-induced ferroptosis and identifies new targets for reversing DIC.

The effects of online game addiction on reduced academic achievement motivation among Chinese college students: the mediating role of learning engagement.

Introduction: The present study aimed to examine the effects of online game addiction on reduced academic achievement motivation, and the mediating role of learning engagement among Chinese college students to investigate the relationships between the three variables. Methods: The study used convenience sampling to recruit Chinese university students to participate voluntarily. A total of 443 valid questionnaires were collected through the Questionnaire Star application. The average age of the participants was 18.77 years old, with 157 males and 286 females. Statistical analysis was conducted using SPSS and AMOS. Results: (1) Chinese college students' online game addiction negatively affected their behavioral, emotional, and cognitive engagement (the three dimensions of learning engagement); (2) behavioral, emotional, and cognitive engagement negatively affected their reduced academic achievement motivation; (3) learning engagement mediated the relationship between online game addiction and reduced academic achievement motivation.

NOP2-mediated m5C methylation of XPD is associated with hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Our previous study has confirmed that XPD acts as an anti-oncogene and is downregulated in HCC. The mechanism of XPD downregulation in HCC is unclear. In this work, we obtained the datasets related to HCC patients from GSE76427, LIRI-JP, and TCGA-LIHC cohorts. Among 15 m5C regulators (NSUN2, NSUN3, NSUN4, NSUN5, NSUN6, NSUN7, DNMT1, TRDMT1, DNMT3A, DNMT3B and NOP2, TET1, TET2, and TET3, ALYREF), 14 m5C regulators were upregulated in tumor tissues of HCC patients, except for TET2. HCC patients were divided into Cluster A and B with different m5C methylation patterns. Cluster B was enriched in metabolism-related signaling pathways, and Cluster A was prominently associated with the cell cycle signaling pathway. Moreover, XPD was positively correlated with NOP2. Cluster B exhibited upregulation of XPD and had an obvious survival advantage with respect to Cluster A. Additionally, NOP2 and XPD were downregulated in HCC tumors and cells. In vitro assays revealed that NOP2 overexpression enhanced XPD expression by elevating the m5C methylation of XPD, which contributed to inhibit proliferation, migration, and invasion of HCC cells. In conclusion, this work demonstrated that XPD mRNA stability was elevated by NOP2-mediated m5C methylation modification and then inhibited the malignant progression of HCC, suggesting that XPD may be a potential target for HCC treatment.

Blocking RIPK2 Function Alleviates Myocardial Ischemia/Reperfusion Injury by Regulating the AKT and NF-κB Pathways.

OBJECTIVE: Inflammation and oxidation brought on by myocardial ischemia-reperfusion (MI/R) injury lead to cardiomyocyte apoptosis and necrosis. The receptor interacting serine/threonine kinase 2 (RIPK2) plays significant roles in oxidative stress and excessive inflammation. The purpose of this research is to examine the roles of RIPK2 in MI/R injury. METHODS: The in vivo animal model was constructed by acute coronary I/R, and the in vitro cell model was established by oxygen and glucose deprivation/reperfusion (OGD/R)-stimulated cardiomyocyte injury. RIPK2 expression was examined using qRT-PCR and Western blot. CCK-8 was proposed as a method for detecting cell proliferation. ELISA was utilized to measure inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and myocardial injury indicators (CK-MB, Mb, cTnI, and LDH). The levels of MDA and ROS were determined by the kit and fluorescent probe. H&E was conducted to assess MI/R injury after silencing of RIPK2. RESULTS: In MI/R rats and OGD/R-treated H9C2 cardiomyocytes, RIPK2 was overexpressed at both the mRNA and protein levels. RIPK2 inhibition promoted cell proliferation while inhibiting apoptosis, as evidenced by decreased TUNEL-positive cells and cleaved caspase-3. RIPK2 inhibition reduced MDA and ROS levels, as well as the contents of inflammatory factors. RIPK2 silencing reduced CK-MB, Mb, cTnI, and LDH levels in rat serum and alleviated MI/R injury. Furthermore, RIPK2 inhibition increased p-AKT while decreasing NF-B p-p65 expression. CONCLUSION: Silencing of RIPK2 reduced apoptosis, proinflammatory factors, and oxidative stress in MI/R by activating AKT and suppressing NF-κB signals, suggesting a potential therapeutic strategy for MI/R injury.

Analysis of the willingness of community residents of Chengdu city to participate in various modes of family dental services and the factors influencing their decision.

OBJECTIVES: To determine the various modes of family dental services available in Chengdu city, China and to analyze the willingness of community residents to sign the contract for these services and the factors influencing their decision to do so. METHODS: From September 2020 to October 2020, nine communities in Chengdu city were sampled via stratified multiple-stage random sampling and surveyed by sending questionnaires. The questionnaire sought to gather information on the residents' sociodemographic characteristics, their intention to participate in family dental services, and determine their knowledge of oral health cognition and behavior. RESULTS: A total of 1 227 valid questionnaires were collected. Among the community residents surveyed, 24.78% stated that they were willing to participate in family dental services. Binary logistic regression analysis revealed that the factors affecting the residents' willingness to participate in various modes of family dental services were age (OR=0.571, P<0.05), type of medical insurance (OR=1.534, P<0.05), level of oral health knowledge (OR=1.363, P<0.05), oral health behavior [including the number of time they brush their teeth (OR=1.464, P<0.05), and the frequency of seeking oral medical treatment(OR=1.780, 2.174, P<0.05)]. CONCLUSIONS: The demand of community residents for the family dental services needs to be improved. Young and middle-aged people showed more enthusiasm than older adults to seek family dental services. The type of medical insurance they have and the level of their health literacy were the primary factors that influence their decision to seek such services. Information and education campaigns on oral health should be strengthened to enhance the public's knowledge of this important aspect of hygiene and overall health and promote the development of various modes of family dental services.

Trastuzumab emtansine (T-DM1) versus trastuzumab in Chinese patients with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy for HER2-positive breast cancer in the phase 3 KATHERINE study.

PURPOSE: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE. METHODS: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event. RESULTS: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25-1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm). CONCLUSIONS: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia.

Effect of Yiqihuoxue Formula for the treatment of ischemic stroke: A retrospective study.

This retrospective study assessed the feasible effect of Yiqihuoxue Formula (YQHXF) for the treatment of patients with ischemic stroke (IS).A total of 66 patients with IS were included in this retrospective study. All patients received routine treatment, and were divided into two groups: a treatment group (n = 33) and a control group (n = 33). In addition to the routine treatment, all patients in the treatment group also underwent YQHXF treatment. All patients in both groups were treated for a total of 8 weeks. The outcomes were assessed by National Institute of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), Barthel index scale (BIS), stroke-specific quality of life (SS-QOL) scale, and adverse events. All outcomes were measured before and after the treatment.After treatment, patients in the treatment group showed better improvements in NIHSS scale (P = .01), mRS (P < .01), BIS (P = .04), and SS-QOL scale (P = .04), than patients in the control group. No treatment-associated adverse events were recorded in this study.The results of this study indicated that YQHXF may benefit for patients with IS.

A phase I study of pharmacokinetics of trastuzumab emtansine in Chinese patients with locally advanced inoperable or metastatic human epidermal growth factor receptor 2-positive breast cancer who have received prior trastuzumab-based therapy.

BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that retains the antitumor effects of trastuzumab while also delivering the cytotoxic antimicrotubule agent, DM1, directly to tumor cells that overexpress human epidermal growth factor receptor 2. The pharmacokinetic (PK) profile of T-DM1 has been well characterized in Western, Asian, and Japanese patients; this single-center, phase I study (NCT03153163) examined the PK of T-DM1 and safety specifically in Chinese patients. METHODS: Patients with locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane, received open-label T-DM1 at 3.6 mg/kg every 3 weeks. Serum T-DM1 and total trastuzumab, and plasma DM1 were evaluated, and PK parameters were calculated using standard noncompartmental approaches. Adverse events (AEs) were assessed, and immunogenicity was evaluated by measuring antidrug antibodies to T-DM1. RESULTS: Among 11 Chinese patients, mean (±standard deviation) PK parameters (maximum serum concentration, 77.6 ±â€Š17.4 µg/mL; clearance 11.0 ±â€Š2.6 mL/d/kg; terminal half-life 3.8 ±â€Š1.0 days) were similar to those previously reported in Western and Japanese patients. One patient transiently developed antidrug antibodies, which did not appear to influence safety or PK. T-DM1 was generally well tolerated. Grade 3-4 AEs occurred in 7 patients (63.6%) and serious AEs occurred in 4 patients (36.4%). Platelet count decrease was the most common all-grade AE (10/11; 90.9%), grade 3-4 AE (5/11; 45.5%), and serious AE (3/11; 27.3%), but did not appear to be associated with any clinically significant bleeding events. CONCLUSIONS: T-DM1 PK in Chinese patients was consistent with those in global and Asian populations, supporting its use in patients with advanced human epidermal growth factor receptor 2-positive breast cancer following progression on trastuzumab and a taxane. The safety profile of T-DM1 was consistent with prior experience.

Deposition of Ag Films on Liquid Substrates via Thermal Evaporation for Surface-Enhanced Raman Scattering.

Surface-enhanced Raman scattering (SERS) substrates were prepared by depositing Ag atoms on liquid surfaces via thermal evaporation at room temperature. These free-sustained substrates result in the formation of uniform Ag films, in which ramified Ag aggregates consist of substantial Ag nanoclusters with narrow gaps of several nanometers in between. SERS spectra of rhodamine 6G were investigated for this substrate to evaluate the SERS performance of this characteristic film morphology, and the results indicated that the SERS intensity from the closely-packed Ag nanostructures and small intervals were significantly enhanced. The dependence of SERS enhancement on the film thickness, nanoparticle size, and gap width was studied. An analytical model was proposed to simulate the electric field distribution during SERS detection, and the results validated the experimental observations.

Bioinspired Brochosomes as Broadband and Omnidirectional Surface-Enhanced Raman Scattering Substrates.

Surface-enhanced Raman scattering (SERS) substrates capable of working under laser excitation in a broad wavelength range are highly desirable in diverse application fields. Here, we demonstrate that the bioinspired Ag brochosomes, hollow microscale particles with submicroscale pits, have broadband and omnidirectional SERS performance. The SERS performance of the Ag brochosomes under near-infrared laser excitation makes them promising for applications in biosensing fields, such as the sensitive detection of Staphylococcus aureus bacteria and bovine hemoglobin protein. Additionally, the SERS intensity was insensitive to the incident angle of the laser beam, resulting from the spherical structure of the Ag brochosomes. The omnidirectional SERS performance makes the Ag brochosomes have application potential for in-the-field analysis using a hand-held Raman spectrometer for which it is difficult to accurately control the laser beam normal to the SERS substrates. Overall, the broadband and omnidirectional brochosome SERS substrates will find applications in diverse fields, particularly in biomedicine and in-the-field analysis.

Silencing of Xeroderma Pigmentosum Group D Gene Promotes Hepatoma Cell Growth by Reducing P53 Expression.

BACKGROUND This study investigated the effect of xeroderma pigmentosum group D (XPD) silencing on the growth of hepatoma cells and assessed the mechanisms. MATERIAL AND METHODS XPD gene was silenced by siRNA in hepatoma cells. The experiments were randomly divided into a control group, a liposome control group, a negative control (NC) group, an XPD siRNA group, and an XPD siRNA + P53 inhibitor group. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) was used to detect cell viability 24 h after gene silencing and treatments. Terminal deoxynucleotidyl transferases (TdT)-mediated dUTP nick-end labeling (TUNEL) and flow cytometry were used to detect apoptosis. Invasive ability was detected by Transwell assay. Additionally, the expression of mouse double-minute 2 homolog (Mdm2), mouse double-minute 4 homolog (Mdm4), CyclinD1, P21, Bax, P53, C-sis, and Bcl-2 was detected by real-time polymerase chain reaction and Western blotting. RESULTS Compared with the NC group, XPD siRNA significantly reduced XPD expression at both mRNA and protein levels. XPD siRNA significantly promoted cell proliferation, reduced apoptosis, and promoted cell invasive ability. Expression of CyclinD1, Bcl-2, and C-sis increased significantly after XPD silencing, while the expression of P21, Mdm2, Mdm4, Bax, and P53 significantly decreased (vs. NC, P<0.05). Importantly, P53 inhibitor (1 µM bpV) further enhanced the effect of XPD silencing (vs. XPD silencing, P<0.05). CONCLUSIONS Our data revealed that XPD silencing promoted growth of hepatoma cells by reducing P53 expression.

Surface enhanced Raman scattering substrates prepared by thermal evaporation on liquid surfaces.

We present an effective surface-enhancement Raman scattering (SERS) substrate enabled by depositing metallic film on a liquid surface at room temperature. Thermal evaporation is used to deposit Au atoms on silicone oil surface and then form quasi-continuous films. Due to the isotropic characteristics of the liquid surface, this film consists of substantial nanoparticles with uniform diameter, which is different from films fabricated on solid substrates and can be served as an applicable substrate for SERS detection. With the assistance of this substrate, SERS signals of rhodamine 6G were significantly enhanced, the dependence between SERS spectra and film thickness was investigated. Analytical simulation results confirm the experimental observations and the superiorities of our proposed method for preparation of SERS substrate. This work provides a potential application of metallic film deposition on free-sustained surface and holds promise as an efficient sensor in rapid trace detection of small molecule analytes.

Fulvestrant 500 mg vs 250 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer: a randomized, double-blind registrational trial in China.

The international CONFIRM study showed that fulvestrant 500 mg improved progression-free survival (PFS) vs fulvestrant 250 mg in postmenopausal women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer (LA/MBC). In this randomized, double-blind study, postmenopausal Chinese women with ER-positive LA/MBC and progression after endocrine therapy received fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or fulvestrant 250 mg (every 28 days). Consistency with the international study was assumed if the hazard ratio (HR) for comparison of PFS (primary endpoint) was < 1 (stratified log-rank test). The study was not powered to assess between-group differences.In total, 221 patients were randomized (fulvestrant 500 mg: n = 111; fulvestrant 250 mg: n = 110). Baseline characteristics were balanced. Median PFS was 8.0 months with fulvestrant 500 mg vs 4.0 months with 250 mg (HR = 0.75; 95% confidence interval [CI] 0.54-1.03; P = 0.078). PFS (HR; 95% CI) favored fulvestrant 500 mg in post-antiestrogen (0.86; 0.54-1.37) and post-aromatase inhibitor (0.65; 0.42-1.03) settings. No new safety considerations were observed. These results are consistent with the international CONFIRM study, supporting the superior clinical benefit of fulvestrant 500 mg in women with ER-positive LA/MBC experiencing progression following prior endocrine therapy.

[Periampullary carcinoma with situs inversus totalis: case report and review of the literature].

OBJECTIVE: To explore the diagnosis and surgical treatment of patients with periampullary carcinoma and situs inversus totalis. METHODS: The data of a patient with periampullary carcinoma and complete situs inversus totalis, a rare disease treated in our hospital on Mar. 2006, was reported, and relative articles were reviewed. RESULTS: This patient was diagnosed with stage I to II of periampullary carcinoma. Bilirubin was recovered one week postoperatively. Incomplete adhesive ileus at gastroenteral anastomosis appeared 2 weeks after the operation and was healed by nutritional support, acupuncture, endoscopic drainage and enteral nutrition. From 1936 to 2006, 15 malignant tumors with situs viscerum inversus totalis were reported, only 5 periampullary carcinomas with situs viscerum inversus totalis were reported. CONCLUSIONS: Surgical operation should be considered for malignant tumor patients with situs inversus totalis without contraindication. Attention should be paid to the opposite anatomical structure in this kind of situation.