Neurotoxicity of fine and ultrafine particulate matter: A comprehensive review using a toxicity pathway-oriented adverse outcome pathway framework.

Fine particulate matter (PM2.5) can cause brain damage and diseases. Of note, ultrafine particles (UFPs) with an aerodynamic diameter less than or equal to 100 nm are a growing concern. Evidence has suggested toxic effects of PM2.5 and UFPs on the brain and links to neurological diseases. However, the underlying mechanism has not yet been fully illustrated due to the variety of the study models, different endpoints, etc. The adverse outcome pathway (AOP) framework is a pathway-based approach that could systematize mechanistic knowledge to assist health risk assessment of pollutants. Here, we constructed AOPs by collecting molecular mechanisms in PM-induced neurotoxicity assessments. We chose particulate matter (PM) as a stressor in the Comparative Toxicogenomics Database (CTD) and identified the critical toxicity pathways based on Ingenuity Pathway Analysis (IPA). We found 65 studies investigating the potential mechanisms linking PM2.5 and UFPs to neurotoxicity, which contained 2, 675 genes in all. IPA analysis showed that neuroinflammation signaling and glucocorticoid receptor signaling were the common toxicity pathways. The upstream regulator analysis (URA) of PM2.5 and UFPs demonstrated that the neuroinflammation signaling was the most initially triggered upstream event. Therefore, neuroinflammation was recognized as the MIE. Strikingly, there is a clear sequence of activation of downstream signaling pathways with UFPs, but not with PM2.5. Moreover, we found that inflammation response and homeostasis imbalance were key cellular events in PM2.5 and emphasized lipid metabolism and mitochondrial dysfunction, and blood-brain barrier (BBB) impairment in UFPs. Previous AOPs, which only focused on phenotypic changes in neurotoxicity upon PM exposure, we for the first time propose AOP framework in which PM2.5 and UFPs may activate pathway cascade reactions, resulting in adverse outcomes associated with neurotoxicity. Our toxicity pathway-based approach not only advances risk assessment for PM-induced neurotoxicity but shines a spotlight on constructing AOP frameworks for new chemicals.

Cross-sectional study on the health of workers exposed to occupational noise in China.

OBJECTIVE: This study aimed to understand the health of workers exposed to occupational noise and explore the influencing factors related to workers' health, especially the impact of noise on workers' hearing. This work can provide a basis for formulating relevant measures for occupational noise prevention and control in the future. METHODS: On the basis of the key occupational disease monitoring project in Chongqing, China, in 2021, the data of 1125 workers exposed to occupational noise were analyzed. Data included demographic information, occupational history, clinical physical examination information, and noise detection information of the working environment. Chi-square test and multifactorial logistic regression were used for statistical analysis. RESULTS: The prevalence rates of abnormal electrocardiogram (ECG), blood pressure (BP), and pure tone audiometry (PTA) were 21.9% (246/1125), 27.8% (313/1125), and 18.0% (202/1125), respectively. Male workers accounted for 78.8%. Compared with male workers, female workers had a lower prevalence of abnormal PTA (OR = 0.28, 95% CI = 0.16-0.50). Workers working in medium enterprises had a lower prevalence of abnormal BP than workers in micro enterprises (OR = 0.36, 95% CI = 0.19-0.66). The prevalence of abnormal BP and PTA of workers increased with age. After adjusting for age, sex, and body mass index, the prevalence of abnormal ECG of mining workers was higher than that of manufacturing workers (OR = 1.54, 95% CI = 1.07-2.24), and the prevalence of abnormal PTA had a rising trend with the increase in noise exposure value. CONCLUSION: Noise-exposed workers have a high prevalence of abnormal ECG, BP, and PTA, and factors such as age, enterprise size, and workplace noise exposure are correlated with the aberrant health of workers. Governments, enterprises, and individuals need to attach great importance to the possible adverse effects of noise. They must also actively adopt various effective measures to protect the occupational safety and health of workers.

Tyrosine kinase inhibitors in HER2-positive metastatic breast cancer with trastuzumab emtansine resistance: insights from a multicenter retrospective real-world study.

The use of trastuzumab emtansine (T-DM1) has revealed significant efficacy in HER2-positive metastatic breast cancer (MBC). However, optimal therapeutic strategies following T-DM1 failure remain a subject of debate in clinical practice. In this multicenter, retrospective, real-world study, we sought to examine the effectiveness and safety of tyrosine kinase inhibitors (TKIs) as a therapeutic strategy in HER2-positive MBC who developed T-DM1 resistance. Between September 2018 and December 2022, 66 patients were enrolled. The median progression-free survival of TKIs-based therapy was 10.1 months (95% CI, 4.7-15.6). Objective response rate and clinical benefit rate were 18.2 and 66.7%, respectively. TKIs-based therapy demonstrated better effectiveness in patients who had previously derived benefit from T-DM1 and featured acquired resistance to trastuzumab. The most common adverse events were diarrhea (36, 54.5%), hand-foot syndrome (31, 47.0%), and leucopenia (30, 45.5%). In conclusion, TKIs-based therapy showed promising effectiveness and safety in HER2-positive MBC patients after T-DM1 failure.

Direct shear behaviors of excavated clay reinforced with geocomposite drainage layer encapsulated in thin sand layers.

The objective of this study is to assess the effectiveness of a novel structure comprising a geocomposite drainage layer and a thin sand layer (GDL + sand) in mitigating the rapid dumping of excavated clay and its associated issues, such as landslides. Two sets of direct shear tests were conducted to investigate the influence of sand layer thickness and compaction degree on the interface shear behavior of the GDL + sand structure. As the sand layer thickness increased, both the interface shear strength and friction angle gradually increased, first more sharply and then at a slower rate toward stability, while the interface cohesion decreased gradually. The optimal sand layer thickness for achieving the most effective reinforcement in stabilizing the clay was identified as 10 mm. A higher sand layer compaction degree was found to result in increased interface shear strength, interface friction angle, and interface cohesion. Building on these findings, the reinforcing efficiency of the GDL + sand structure was investigated through mechanism analysis in comparison to that of a geogrid + sand structure and GDL structure as per the interface friction coefficient. The ranking of interface friction coefficients among the three structures emerged as: geogrid + sand > GDL + sand > GDL. These results suggests that the GDL + sand structure exhibits superior reinforcement efficiency compared to the GDL structure and offers better drainage efficiency than the geogrid + sand structure.

Application Effect of Plan-do-check Action Cycle Nursing Protocol on Improving the Accuracy of Urine Specimen Collection in Newborn Female Infants.

Background: The effect of traditional disposable infant urine collectors is not ideal for female newborns. Due to the poor adhesion of the traditional urine collection bag, it does not meet the physiological and anatomical characteristics of female newborns. Therefore, it is necessary to adopt effective nursing in urine specimen collection in newborn female infants. Objective: To explore the effect of plan-do-check action cycle nursing protocol on improving the accuracy of urine specimen collection in newborn female infants. Design: This was a randomized controlled study. Setting: This study was carried out in the Department of Pediatrics, Strategic Support Force Medical Center. Participants: A total of 120 female newborns admitted to our hospital from January 2021 to June 2022 were selected and divided into a control group and a study group, with 60 cases in each group. Interventions: The control group collected urine samples by routine methods, which used the traditional disposable urine bag collection method. The study group collected urine samples using the plan-do-check action cycle nursing mode. Primary Outcome Measures: (1) success rate of urine collection, collection times, and sample contamination rate (2) cleanliness of the vaginal opening (3) satisfaction of urine collection (4) retention time of urine samples and (5) urine pondus hydrogenii values. Results: Compared to the control group, the success rate of urine collection in the study group was higher, the collection times and specimen contamination rate were significantly lower, the time for collecting urine samples in the study group was shorter, the cleanliness of female vaginal opening in the study group was significantly better, the proportion of female urine pondus hydrogenii 6-7 in the study group was significantly higher (all P < .05). Conclusion: The application of the plan-do-check action cycle management mode in the urine samples of newborn female infants can not only effectively improve the success rate of collection but also improve the cleanliness of the vaginal mouth and make the test results more accurate.

Exposures to particulate matters and childhood sleep disorders-A large study in three provinces in China.

OBJECTIVES: Evidence on the link between long-term ambient particulate matter (PM) exposures and childhood sleep disorders were scarce. We examined the associations between long-term exposures to PM2.5 and PM1 (PM with an aerodynamic equivalent diameter <2.5 µm and <1 µm, respectively) with sleep disorders in children. METHODS: We performed a population-based cross-sectional survey in 177,263 children aged 6 to 18 years in 14 Chinese cities during 2012-2018. A satellite-based spatiotemporal model was employed to estimate four-year annual average PM2.5 and PM1 exposures at residential and school addresses. Parents or guardians completed a checklist using the Sleep Disturbance Scale for Children. We estimated the associations using generalized linear mixed models with adjustment for characteristics of children, parents, and indoor environments. RESULTS: Long-term PM2.5 and PM1 exposures were positively associated with odds of sleep disorders for almost all domains. For example, increments in PM2.5 and PM1 per 10 µg/m3 were associated with odds ratios of global sleep disorder of 1.24 (95 % confidence interval [CI]: 1.14, 1.35) and 1.31 (95 %CI: 1.18, 1.46), respectively. Similar results were observed for subtypes of sleep disorder. These associations were heterogeneous regionally, with stronger associations among children residing in southeast region than in northeast and northwest regions. Moreover, larger estimates of PM1 were found than that of PM2.5 in southeast region. CONCLUSION: Long-term PM2.5 and PM1 exposures are independently associated with higher risks of childhood sleep disorders, and these associations vary by geographical region.

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

Effects of clonal fragmentation on Pyrrosia nuda depend on growth stages in a rubber plantation.

Introduction: Clonal fragmentation helps to assess clonal plants' growth resilience to human and environmental disturbance. Although clonal integration in epiphytes in tropical rubber plantations is important to understand their role in enhancing biodiversity and ecosystem services, research on this subject is limited. These plantations are typically monospecific economic forests that face increased anthropogenic disturbances. Methods: In this study, we selected the clonal fern Pyrrosia nuda to study its survival status, biomass, maximum quantum yield of photosystem II (Fv/Fm), and frond length in response to the level of clonal fragmentation in a tropical rubber plantation. Results and discussion: The results showed that (1) clonal fragmentation significantly negatively affected the survival rate, biomass, and frond length of clonal plants, but with minimal effects on Fv/Fm at different growth stages; (2) the performance of a ramet (e.g., biomass or frond length) increased with ramet developmental ages and decreased with the number of ramets in a clonal fragment. The age-dependent impacts of clonal fragmentation provide insights into the biodiversity conservation of epiphytes and forest management in man-made plantations. Therefore, to better conserve the biodiversity in tropical forests, especially in environment-friendly rubber plantations, there is a need to reduce anthropogenic disturbances and alleviate the level of fragmentation.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Trichostatin A relieves anxiety-and depression-like symptoms in APP/PS1 mice.

Background: Cognitive deficits and behavioral disorders such as anxiety and depression are common manifestations of Alzheimer's disease (AD). Our previous work demonstrated that Trichostatin A (TSA) could alleviate neuroinflammatory plaques and improve cognitive disorders. AD, anxiety, and depression are all associated with microglial inflammation. However, whether TSA could attenuate anxiety- and depression-like behaviors in APP/PS1 mice through anti-inflammatory signaling is still unclearly. Methods: In the present study, all mice were subjected to the open field, elevated plus maze, and forced swim tests to assess anxiety- and depression-related behaviors after TSA administration. To understand the possible mechanisms underlying the behavioral effects observed, CST7 was measured in the hippocampus of mice and LPS-treated BV2 microglia. Results: The results of this study indicated that TSA administration relieved the behaviors of depression and anxiety in APP/PS1 mice, and decreased CST7 levels in the hippocampus of APP/PS1 mice and LPS-induced BV2 cells. Conclusion: Overall, these findings support the idea that TSA might be beneficial for reducing neurobehavioral disorders in AD and this could be due to suppression of CST7-related microglial inflammation.

Positive association between chlorinated paraffins and the risk of allergic diseases in children and adolescents.

Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.

Arene-Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis.

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.

MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

Subspace Identification of Bridge Frequencies Based on the Dimensionless Response of a Two-Axle Vehicle.

As an essential reference to bridge dynamic characteristics, the identification of bridge frequencies has far-reaching consequences for the health monitoring and damage evaluation of bridges. This study proposes a uniform scheme to identify bridge frequencies with two different subspace-based methodologies, i.e., an improved Short-Time Stochastic Subspace Identification (ST-SSI) method and an improved Multivariable Output Error State Space (MOESP) method, by simply adjusting the signal inputs. One of the key features of the proposed scheme is the dimensionless description of the vehicle-bridge interaction system and the employment of the dimensionless response of a two-axle vehicle as the state input, which enhances the robustness of the vehicle properties and speed. Additionally, it establishes the equation of the vehicle biaxial response difference considering the time shift between the front and the rear wheels, theoretically eliminating the road roughness information in the state equation and output signal effectively. The numerical examples discuss the effects of vehicle speeds, road roughness conditions, and ongoing traffic on the bridge identification. According to the dimensionless speed parameter Sv1 of the vehicle, the ST-SSI (Sv1 < 0.1) or MOESP (Sv1 ≥ 0.1) algorithm is applied to extract the frequencies of a simply supported bridge from the dimensionless response of a two-axle vehicle on a single passage. In addition, the proposed methodology is applied to two types of long-span complex bridges. The results show that the proposed approaches exhibit good performance in identifying multi-order frequencies of the bridges, even considering high vehicle speeds, high levels of road surface roughness, and random traffic flows.

Vertical variation in leaf functional traits of Parashorea chinensis with different canopy layers.

Introduction: Canopy species need to shift their ecological adaptation to improve light and water resources utilization, and the study of intraspecific variations in plant leaf functional traits based at individual scale is of great significance for evaluating plant adaptability to climate change. Methods: In this study, we evaluate how leaf functional traits of giant trees relate to spatial niche specialization along a vertical gradient. We sampled the tropical flagship species of Parashorea chinensis around 60 meters tall and divided their crowns into three vertical layers. Fourteen key leaf functional traits including leaf morphology, photosynthetic, hydraulic and chemical physiology were measured at each canopy layer to investigate the intraspecific variation of leaf traits and the interrelationships between different functional traits. Additionally, due to the potential impact of different measurement methods (in-situ and ex-situ branch) on photosynthetic physiological parameters, we also compared the effects of these two gas exchange measurements. Results and discussion: In-situ measurements revealed that most leaf functional traits of individual-to-individual P. chinensis varied significantly at different canopy heights. Leaf hydraulic traits such as midday leaf water potential (MWP) and leaf osmotic potential (OP) were insignificantly correlated with leaf photosynthetic physiological traits such as maximal net assimilation rate per mass (A mass). In addition, great discrepancies were found between in-situ and ex-situ measurements of photosynthetic parameters. The ex-situ measurements caused a decrease by 53.63%, 27.86%, and 38.05% in A mass, and a decrease of 50.00%, 19.21%, and 27.90% in light saturation point compared to the in-situ measurements. These findings provided insights into our understanding of the response mechanisms of P. chinensis to micro-habitat in Xishuangbanna tropical seasonal rainforests and the fine scale adaption of different resultant of decoupled traits, which have implications for understanding ecological adaption strategies of P. chinensis under environmental changes.

Toxicological evaluation and concentration of airborne PM0.1 in high air pollution period in Guangzhou, China.

The emissions and exposure limits for airborne PM0.1 are lacking, with limited scientific data for toxicity. Therefore, we continuously monitored and calculated the number and mass concentrations of airborne PM0.1 in December 2017, January 2018 and March 2018 during the high pollution period in Guangzhou. We collected PM0.1 from the same period and analyzed their chemical components. A549, THP-1 and A549/THP-1 co-cultured cells were selected for exposure to PM0.1, and evaluated for toxicological responses. Our aims are to 1) measure and analyze the number and mass concentrations, and chemical components of PM0.1; 2) evaluate and compare PM0.1 toxicity to different airway cells models at different time points. Guangzhou had the highest mass concentration of PM0.1 in December 2017, while the number concentration was the lowest. Chemical components in PM0.1 vary significantly at different time periods, and the correlation between the chemical composition or source of PM0.1 and the mass and number concentration of PM0.1 was dissimilar. Exposure to PM0.1 disrupted cell membranes, impaired mitochondrial function, promoted the expression of inflammatory mediators, and interfered with DNA replication in the cell cycle. The damage caused by exposure to PM0.1 at different times exhibited variations across different types of cells. PM0.1 in March 2018 stimulated co-cultured cells to secrete more inflammatory mediators, and CMA was significantly related to the expression of them. Our study indicates that it is essential to monitor both the mass and number concentrations of PM0.1 throughout all seasons annually, as conventional toxicological experiments and the internal components of PM0.1 may not effectively reveal the health damages caused by elevated number levels of PM0.1.

Inetetamab combined with pyrotinib and oral vinorelbine for patients with human epidermal growth factor receptor 2 positive advanced breast cancer: A single-arm phase 2 clinical trial.

Background: Human epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large proportion of patients still develop resistance to trastuzumab. In this study, we investigated the efficacy and safety of inetetamab, another anti-HER2 antibody, combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment. Methods: In this prospective, single-arm, phase 2 trial, patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited. Patients received a combination of inetetamab (loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks), pyrotinib (400 mg orally once daily), and vinorelbine (60 mg/m2 orally once weekly) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and safety. Results: Between February 13, 2022 and December 25, 2022, 30 patients were screened and enrolled in this study. The median age of the patients at enrollment was 54 years, 12 patients (40.0 %) had hormone-receptor-positive disease and 23 patients (76.7 %) had visceral metastasis. The median PFS was 8.63 months (95 % confidence interval [CI] 4.15-13.12 months). The median OS was not reached. The ORR was 53.3 % (16/30) and the DCR was 96.7 % (29/30). The most common Grade III/IV adverse events were leukopenia (n = 5, 16.7 %), neutropenia (n = 4, 13.3 %), and diarrhea (n = 3, 10 %). No treatment-related serious adverse events or deaths occurred. Conclusions: The combination regimen of inetetamab, pyrotinib, and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients. Trial registration: No.NCT05823623; https://www.clinicaltrials.gov/.

[Study on the Effect and Mechanism of Tetrandrine on Bone Marrow Mesenchymal Stem Cell-Mediated Drug Resistance in Leukemia].

OBJECTIVE: To explore the role of bone marrow mesenchymal stem cells (BMSC)，an essential element of the bone marrow microenvironment, in multidrug resistance(MDR) of K562 cells, as well as the reversal effect of tetrandrine (TET) on BMSC-mediated MDR and its potential mechanism. METHODS: A mixed co-culture system and a transwell co-culture system for BMSC and K562 cells were established, and the cells were divided into different groups and treated with daunorubicin (DNR) alone or combined with TET and DNR. The CCK-8 assay was used to detect the proliferation of K562 cells in each group, and the cell inhibition rate was calculated. Cytometric bead array (CBA) was used to detect the expression levels of IFN, IL-2, IL-6 and IL-10 in the supernatant of different groups. RT-qPCR and Western blot were used to detected the expression of STAT3 at mRNA and protein levels, respectively. RESULTS: Compared with K562+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR group was significantly decreased (P < 0.05), while the levels of IL-6 in the culture supernatant and phosphorylated STAT3 in K562 cells were significantly increased (P < 0.05). Compared with K562+BMSC+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR+TET group was significantly increased (P < 0.05), while the level of IL-6 and phosphorylated STAT3 was significantly decreased (P < 0.05). CONCLUSION: BMSC can promote the drug resistance of leukemia cells, and TET may reverse the BMSC-mediated drug resistance via inhibiting IL-6/STAT3 signaling pathway.

Association between occupational stress, occupational burnout, and depressive symptoms among medical staff during COVID-19: A cross-sectional study in Chongqing, China.

BACKGROUND: Studies have extensively examined the factors contributing to the onset of occupational stress, burnout, and depression. However, the relationship between these variables is limited. OBJECTIVE: This study aimed to explore the association between occupational stress, burnout, and depressive symptoms and to investigate the mediating effect of burnout between occupational stress and depressive symptoms in medical staff. METHODS: A cross-sectional survey was conducted among medical staff in Chongqing, China. The Core Occupational Stress Scale (COSS), Maslach Burnout Inventory: General Survey (MBI-GS), and Patient Health Questionnaire-9 (PHQ-9) were used to assess the status of occupational stress, burnout, and depressive symptoms, respectively. The bootstrapping analyses using SPSS PROCESS macros version 3 were conducted to examine mediating effects. RESULTS: The study conducted on medical staff in Chongqing revealed that the detection rates of occupational stress, occupational burnout, and depressive symptoms were 31.8%, 23.3%, and 30.3%, respectively. Hierarchical regression analysis revealed that occupational stress and burnout accounted for 19.3% (p < 0.001) and 18.8% (p < 0.001) of the variance in depressive symptoms, respectively. Mediation analysis showed that occupational stress indirectly affected depressive symptoms through the mediating effect of occupational burnout, with a mediation effect value of 0.13 (bootstrap 95% CI: 0.116-0.144) and the mediation effect accounting for 44.8% of the total effect. CONCLUSION: Our results indicated that occupational stress and burnout were predictors of depressive symptoms. Occupational stress had a significant indirect effect on depressive symptoms via burnout. These results suggest that reducing occupational stress and burnout could be effective strategies for preventing depression among medical staff.

Inhibition of Xanthine Oxidase by 4-nitrocinnamic Acid: In Vitro and In Vivo Investigations and Docking Simulations.

Background: Cinnamic acid and its derivatives have gained significant attention in recent medicinal research due to their broad spectrum of pharmacological properties. However, the effects of these compounds on xanthine oxidase (XO) have not been systematically investigated, and the inhibitory mechanism remains unclear.

Objectives: The objective of this study was to screen 18 compounds and identify the XO inhibitor with the strongest inhibitory effect. Furthermore, we aimed to study the inhibitory mechanism of the identified compound.

Methods: The effects of the inhibitors on XO were evaluated using kinetic analysis, docking simulations, and in vivo study. Among the compounds tested, 4-NA was discovered as the first XO inhibitor and exhibited the most potent inhibitory effects, with an IC50 value of 23.02 ± 0.12 µmol/L. The presence of the nitro group in 4-NA was found to be essential for enhancing XO inhibition. The kinetic study revealed that 4-NA inhibited XO in a reversible and noncompetitive manner. Moreover, fluorescence spectra analysis demonstrated that 4-NA could spontaneously form complexes with XO, referred to as 4-NA-XO complexes, with the negative values of △H and ΔS.

Results: This suggests that hydrogen bonds and van der Waals forces play crucial roles in the binding process. Molecular docking studies further supported the kinetic analysis and provided insight into the optimal binding conformation, indicating that 4-NA is located at the bottom outside the catalytic center through the formation of three hydrogen bonds. Furthermore, animal studies confirmed that the inhibitory effects of 4-NA on XO resulted in a significant reduction of serum uric acid level in hyperuricemia mice.

Conclusion: This work elucidates the mechanism of 4-NA inhibiting XO, paving the way for the development of new XO inhibitors.