Association of short-term exposure to ambient fine particulate matter and ozone with outpatient visits for anxiety disorders: A hospital-based case-crossover study in South China.

BACKGROUND: The short-term adverse effects of ambient fine particulate matter (PM2.5) and ozone (O3) on anxiety disorders (ADs) remained inconclusive. METHODS: We applied an individual-level time-stratified case-crossover study, which including 126,112 outpatient visits for ADs during 2019-2021 in Guangdong province, China, to investigate the association of short-term exposure to PM2.5 and O3 with outpatient visits for ADs, and estimate excess outpatient visits in South China. Daily residential air pollutant exposure assessments were performed by extracting grid data (spatial resolution: 1 km × 1 km) from validated datasets. We employed the conditional logistic regression model to quantify the associations and excess outpatient visits. RESULTS: The results of the single-pollutant models showed that each 10 µg/m3 increase of PM2.5 and O3 exposures was significantly associated with a 3.14 % (95 % confidence interval: 2.47 %, 3.81 %) and 0.88 % (0.49 %, 1.26 %) increase in odds of outpatient visits for ADs, respectively. These associations remained robust in 2-pollutant models. The proportion of outpatient visits attributable to PM2.5 and O3 exposures was up to 7.20 % and 8.93 %, respectively. Older adults appeared to be more susceptible to PM2.5 exposure, especially in cool season, and subjects with recurrent outpatient visits were more susceptible to O3 exposure. LIMITATION: As our study subjects were from one single hospital in China, it should be cautious when generalizing our findings to other regions. CONCLUSION: Short-term exposure to ambient PM2.5 and O3 was significantly associated with a higher odds of outpatient visits for ADs, which can contribute to considerable excess outpatient visits.

Systematic proteomics analysis revealed different expression of laminin interaction proteins in breast cancer: lower in luminal subtype and higher in claudin-low subtype.

Background: Breast cancer is a major public health concern. Proteomics enables identification of proteins with aberrant properties. Here, we identified proteins with abnormal expression levels in breast cancer tissues and systematically analyzed and validated the data to locate potential diagnostic and therapeutic targets. Methods: Protein expression level in breast cancer tissues and para-carcinoma tissues were detected by Isobaric Tags for Relative and Absolute Quantification (iTRAQ) technology and further screened through Gene Expression Profiling Interactive Analysis (GEPIA) database. Cellular components, protein domain and Reactome pathway analysis were performed to screen functional targets. Abnormal expression levels of functional targets were validated by Oncomine database, quantitative real time polymerase chain reaction (qRT-PCR) and proteomics detection. Protein correlation analysis was performed to explain the abnormal expression levels of potential targets in breast cancer. Results: Overall, 207 and 207 proteins were up- and down-regulated, respectively, in breast cancer tissues, and approximately 50% were also detected in the GEPIA database. The overlapping proteins were mainly extracellular proteins containing epidermal growth factor-like domain in leukocyte adhesion molecule (EGF-Lam) domain and enriched in laminin interaction pathway. Moreover, the downregulated laminin interaction proteins could be functional targets, which were also validated through Oncomine-Richardson and Oncomine-Curtis database. However, the lower expression level of laminin interaction proteins only fit for luminal breast cancer cells with no or low metastasis ability because the proteins achieved higher expression level in more invasive claudin-low breast cancer cells. In addition, when compared with corresponding in situ carcinoma tissues, above-mentioned proteins also showed higher expression levels in invasive carcinoma tissues. Finally, we have revealed the negative correlation between the laminin interaction proteins and the claudins. Conclusions: The laminin interaction protein, especially for laminins with ß1 and γ1 subunits and their integrin receptors with α1 and α6 subunits, showed lower expression levels in luminal breast cancer with no or lower metastatic ability, but showed higher expression levels in claudin-low breast cancer with higher metastatic ability; and their higher expression could be related to the low claudin expression.

Chinese Medicine Prolongs Overall Survival of Chinese Patients with Advanced Gastric Cancer: Treatment Pattern and Survival Analysis of a 20-Year Real-World Study.

OBJECTIVE: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients. METHODS: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias. RESULTS: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001). CONCLUSIONS: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285).

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy.

Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

Exploring the mechanism of Erteng-Sanjie capsule in treating gastric and colorectal cancers via network pharmacology and in-vivo validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Erteng-Sanjie capsule (ETSJC) has therapeutic effects against gastric cancer (GC) and colorectal cancer (CRC). However, its underlying pharmacological mechanism remains unclear. AIM OF THE STUDY: To explore the pharmacological mechanism of ETSJC against GC and CRC via network pharmacology and in-vivo validation. MATERIALS AND METHODS: Data on the ingredients of ETSJC were obtained from the TCMSP and HERB databases. Further, details on the related targets of the active ingredients were collected from the HERB and SwissTargetPrediction databases. The targets in GC and CRC, which were screened from the OMIM, GeneCards, and TTD databases, were uploaded to STRING for a separate protein-protein interaction network analysis. The common targets shared by ETSJC, GC, and CRC were then screened. Cytoscape and STRING were used to construct the networks of herbs-compounds-targets and PPI. Metascape was utilized to analyze the enrichment of the GO and KEGG pathways. Molecular docking was used to validate the potential binding mode between the core ingredients and targets. Finally, the predicted results were verified with animal experiment. RESULTS: Eight core ingredients (resveratrol, quercetin, luteolin, baicalein, delphinidin, kaempferol, pinocembrin, and naringenin) and six core targets (TP53, SRC, PIK3R1, AKT1, MAPK3, and STAT3) were filtered via network analysis. The molecular mechanism mainly involved the positive regulation of various processes such as cell migration, protein phosphorylation, and the PI3K-Akt signaling pathway. Molecular docking revealed that the core ingredients could be significantly combined with all core targets. The animal experiment revealed that ETSJC could suppress proliferation and promote apoptosis of both GC and CRC tumor cells by regulating the PI3K/Akt signaling pathway. CONCLUSIONS: Multiple targets (TP53, SRC, AKT1, and STAT3) were important in GC and CRC. ETSJC could act on these targets and engage in different pathways against GC and CRC. Simultaneously, inhibiting the PI3K/Akt signaling pathway was a promising therapeutic mechanism for treating GC and CRC.

Analysis of risk factors and interactions for pain in temporomandibular disorder: A cross-sectional study.

BACKGROUND: Risk factors for temporomandibular disorder (TMD) pain remain unclear. OBJECTIVES: This study aimed to identify risk factors for TMD pain using a biopsychosocial model and to investigate interactions between potential risk factors-oral behaviours (OBs), psychological factors and sleep quality-and their direct and indirect effects on TMD pain. METHODS: This was a cross-sectional study of 488 patients with TMDs (422 women; 30.8 ± 9.4 years). Pain was assessed using the Numerical Rating Scale. Demographic, behavioural, psychological and biomedical data were collected through clinical examination, face-to-face interviews and questionnaires. Multiple linear regression analysis was used to identify factors associated with TMD pain. Mediation and moderation analysis were used to evaluate interactions between variables. Significant mediation ('0' not included in the 95% confidence interval (CI)) and moderation (p < .05) effects on TMD pain were identified. RESULTS: Marital status, diagnosis subgroup, previous medication use, depression and sleep quality were significant risk factors for TMD pain (p < .05). Significant mediation effects were observed as follows: depression and sleep quality mediated the association between OBs and pain; sleep quality mediated the association between somatization, depression, anxiety and pain; and depression mediated the association between sleep quality and pain (all 95% CI did not contain '0'). CONCLUSIONS: (1) Marital status, diagnosis subgroup, previous medication use, depression and sleep quality were associated with TMD pain. (2) OBs can exacerbate pain by promoting depression and reducing sleep quality. Psychological factors and sleep quality can interact to exacerbate pain.

The Graphene Quantum Dots Gated Nanoplatform for Photothermal-Enhanced Synergetic Tumor Therapy.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5-10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

Complexation and extraction of trivalent actinides over lanthanides using highly soluble phenanthroline diamide ligands with different side chains.

Although phenanthroline diamide ligands have been widely reported, their limited solubility in organic solvents and poor performance in the separation of trivalent actinides (An(III)) and lanthanides (Ln(III)) at high acidity are still clear demerits. In this study, we designed and synthesized three highly soluble phenanthroline diamide ligands with different side chains. By introducing alkyl chains and ester groups, the ligands solubility in 3-nitrotrifluorotoluene is increased to over 600 mmol/L, significantly higher than the previous reported phenanthroline diamide ligands. Based on anomalous aryl strengthening, benzene ring was incorporated to enhance ligand selectivity toward Am(III). Extraction experiments demonstrated favorable selectivity of all the three ligands towards Am(III). The optimal separation factor (SFAm/Eu) reaches 53 at 4 mol/L HNO3, representing one of the most effective separation of An(III) over Ln(III) under high acidity. Slope analysis, single crystal structure analysis, as well as titration of ultraviolet visible spectroscopy, mass spectrometry, and nuclear magnetic resonanc confirmed the formation of 1:1 and 1:2 complex species between the metal ions and the ligands depending on the molar ratio of metal ions in the reaction mixture. The findings of this study offer valuable insights for developing phenanthroline diamide ligands for An(III)/Ln(III) separation.

Blueberry anthocyanins improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7 to affect ferroptosis of hepatic stellate cells.

This study aims to investigate the role and molecular mechanism of anthocyanin in improving liver fibrosis through ferroptosis, providing a basis for drug development and targeted therapy. In this study, a mouse model of liver fibrosis was established using CCl4, and the anthocyanin treatment groups were administered 100 mg/kg anthocyanin daily via gavage. Furthermore, real-time fluorescent quantitative PCR (qRT-PCR), Western blotting (WB), and enzyme-linked immunosorbent assay were used to assess liver fibrosis indicators and liver injury markers. Histopathological methods were used to confirm the morphology of liver injury in different treatment groups. The effects of anthocyanins on ferroptosis markers, NCOA4 and FTH1 expression, were examined through qRT-PCR, WB, and Co-IP. Confocal microscopy was used to validate the colocalization of ferritin and lysosomes. A differential expression model of TRIM7 was constructed to verify its impact on the progression of liver fibrosis. The present study demonstrates the hepatoprotective effects of anthocyanins in liver fibrosis, highlighting their ability to enhance hepatic stellate cell (HSC) ferroptosis and regulate ferritin autophagy. Moreover, TRIM7 is identified as a key mediator of anthocyanin-induced regulation of hepatic stellate cells activation for liver fibrosis treatment through modulation of ferroautophagy. Mechanistic investigations further reveal that TRIM7 exerts its influence on the process of ferroautophagy by controlling NCOA4 ubiquitination. Our study discovered that anthocyanins could improve liver fibrosis by regulating NCOA4 ubiquitination through TRIM7, thereby affecting hepatic stellate cells' ferroptosis levels.NEW & NOTEWORTHY This was the first study to demonstrate that anthocyanins can improve the progression of liver fibrosis by promoting hepatic stellate cell (HSC) ferroptosis. Anthocyanins could affect the content of Fe2+ by promoting ferroautophagy in HSCs, thereby promoting the level of ferroptosis. This study demonstrates for the first time that anthocyanins can inhibit the expression of TRIM7 and then affect the ubiquitination of NCOA4 to regulate the level of ferritin autophagy and ferroptosis.

Extreme temperature events and dementia mortality in Chinese adults: a population-based, case-crossover study.

BACKGROUND: The effect of exposure to extreme temperature events (ETEs) on dementia mortality remains largely unknown. We aimed to quantify the association of ETE exposure with dementia mortality. METHODS: We conducted a population-based, case-crossover study among 57 791 dementia deaths in Jiangsu province, China, during 2015-20. Daily mean temperatures were extracted from a validated grid dataset at each subject's residential address, and grid-specific exposures to heat wave and cold spell were assessed with a combination of their intensity and duration. We applied conditional logistic regression models to investigate cumulative and lag effects for ETE exposures. RESULTS: Exposure to ETE with each of all 24 definitions was associated with an increased odds of dementia mortality, which was higher when exposed to heat wave. Exposure to heat wave (daily mean temperature ≥95th percentile, duration ≥3 days (d); P95_3d) and cold spell (≤5th percentile, duration ≥3 d; P5_3d) was associated with a 75% (95% CI: 61%, 90%) and 30% (19%, 43%) increase in odds of dementia mortality, respectively. Definitions with higher intensity were generally associated with a higher odds of dementia mortality. We estimated that 6.14% of dementia deaths were attributable to exposure to heat wave (P90_2d) and cold spell (P10_2d). No effect modifications were observed by sex or age, except that the association for heat wave was stronger among women. CONCLUSIONS: Exposure to both heat wave and cold spell was associated with an increased odds of dementia mortality. Our findings highlight that reducing individual ETE exposures may be helpful in preventing deaths from dementia, especially among women in summer.

Long-term exposure to ambient fine particulate matter constituents and mortality from total and site-specific gastrointestinal cancer.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure has been associated with an increased risk of gastrointestinal cancer mortality, but the attributable constituents remain unclear. OBJECTIVES: To investigate the association of long-term exposure to PM2.5 constituents with total and site-specific gastrointestinal cancer mortality using a difference-in-differences approach in Jiangsu province, China during 2015-2020. METHODS: We split Jiangsu into 53 spatial units and computed their yearly death number of total gastrointestinal, esophagus, stomach, colorectum, liver, and pancreas cancer. Utilizing a high-quality grid dataset on PM2.5 constituents, we estimated 10-year population-weighted exposure to black carbon (BC), organic carbon (OC), sulfate, nitrate, ammonium, and chloride in each spatial unit. The effect of constituents on gastrointestinal cancer mortality was assessed by controlling time trends, spatial differences, gross domestic product (GDP), and seasonal temperatures. RESULTS: Overall, 524,019 gastrointestinal cancer deaths were ascertained in 84.77 million population. Each interquartile range increment of BC (0.46 µg/m3), OC (4.56 µg/m3), and nitrate (1.41 µg/m3) was significantly associated with a 27%, 26%, and 34% increased risk of total gastrointestinal cancer mortality, respectively, and these associations remained significant in PM2.5-adjusted models and constituent-residual models. We also identified robust associations of BC, OC, and nitrate exposures with site-specific gastrointestinal cancer mortality. The mortality risk generally displayed increased trends across the total exposure range and rose steeper at higher levels. We did not identify robust associations for sulfate, ammonium, or chlorine exposure. Higher mortality risk ascribed to constituent exposures was identified in total gastrointestinal and liver cancer among women, stomach cancer among men, and total gastrointestinal and stomach cancer among low-GDP regions. CONCLUSIONS: This study offers consistent evidence that long-term exposure to PM2.5-bound BC, OC, and nitrate is associated with total and site-specific gastrointestinal cancer mortality, indicating that these constituents need to be controlled to mitigate the adverse effect of PM2.5 on gastrointestinal cancer mortality.

Ozone, Heat Wave, and Cardiovascular Disease Mortality: A Population-Based Case-Crossover Study.

A case-crossover study among 511,767 cardiovascular disease (CVD) deaths in Jiangsu province, China, during 2015-2021 was conducted to assess the association of exposure to ambient ozone (O3) and heat wave with CVD mortality and explore their possible interactions. Heat wave was defined as extreme high temperature for at least two consecutive days. Grid-level heat waves were defined by multiple combinations of apparent temperature thresholds and durations. Residential O3 and heat wave exposures were assessed using grid data sets (spatial resolution: 1 km × 1 km for O3; 0.0625° × 0.0625° for heat wave). Conditional logistic regression models were applied for exposure-response analyses and evaluation of additive interactions. Under different heat wave definitions, the odds ratios (ORs) of CVD mortality associated with medium-level and high-level O3 exposures ranged from 1.029 to 1.107 compared with low-level O3, while the ORs for heat wave exposure ranged from 1.14 to 1.65. Significant synergistic effects on CVD mortality were observed for the O3 and heat wave exposures, which were generally greater with higher levels of the O3 exposure, higher temperature thresholds, and longer durations of heat wave exposure. Up to 5.8% of the CVD deaths were attributable to O3 and heat wave. Women and older adults were more vulnerable to the exposure to O3 and heat wave exposure. Exposure to both O3 and heat wave was significantly associated with an increased odds of CVD mortality, and O3 and heat wave can interact synergistically to trigger CVD deaths.

Platelet-rich plasma therapy for temporomandibular joint osteoarthritis: A randomized controlled trial.

The study aimed to compare the efficacy of platelet-rich plasma (PRP) injections for the treatment of temporomandibular joint osteoarthritis (TMJ-OA) with hyaluronic acid (HA) therapy. This randomized controlled trial included 70 patients with TMJ-OA, randomly divided into either a PRP or HA group. The pain intensity, maximum mouth opening (MMO), TMJ sound score, and proportion of crepitus were recorded and compared at baseline and at 1, 3, and 6 months. Both groups showed statistically significant improvements in pain intensity, MMO, TMJ sound, and scale scores during the 6-month follow-up period. The improvements in pain intensity during mouth opening at 1 month, MMO at 1, 3, and 6 months, TMJ sound score at 1 and 3 months, and GAD-7 score at 6 months in the PRP group were greater than in the HA group (p < 0.05). Compared with the HA group, imaging improvement in the PRP group was also higher (p < 0.05). Within the limitations of the study it seems that the application of PRP therapy in TMJ-OA is should be considered whenever possible.

Identification of immune-related hub genes and construction of an immune-related gene prognostic index for low-grade glioma.

Low-grade glioma (LGG) poses significant management challenges and has a dismal prognosis. While immunotherapy has shown significant promise in cancer treatment, its progress in glioma has confronted with challenges. In our study, we aimed to develop an immune-related gene prognostic index (IRGPI) which could be used to evaluate the response and efficacy of LGG patients with immunotherapy. We included a total of 529 LGG samples from TCGA database and 1152 normal brain tissue samples from the GTEx database. Immune-related differentially expressed genes (DEGs) were screened. Then, we used weighted gene co-expression network analysis (WGCNA) to identify immune-related hub genes in LGG patients and performed Cox regression analysis to construct an IRGPI. The median IRGPI was used as the cut-off value to categorize LGG patients into IRGPI-high and low subgroups, and the molecular and immune mechanism in IRGPI-defined subgroups were analysed. Finally, we explored the relationship between IRGPI-defined subgroups and immunotherapy related indicators in patients after immunotherapy. Three genes (RHOA, NFKBIA and CCL3) were selected to construct the IRGPI. In a survival analysis using TCGA cohort as a training set, patients in the IRGPI-low subgroup had a better OS than those in IRGPI-high subgroup, consistent with the results in CGGA cohort. The comprehensive results showed that IRGPI-low subgroup had a more abundant activated immune cell population and lower TIDE score, higher MSI, higher TMB score, lower T cell dysfunction score, more likely benefit from ICIs therapy. IRGPI is a promising biomarker in the field of LGG ICIs therapy to distinguish the prognosis, the molecular and immunological characteristics of patients.

Long-term exposure to ambient fine particulate matter-bound polycyclic aromatic hydrocarbons and cancer mortality: A difference-in-differences approach.

The association of ambient fine particulate matter (PM2.5) exposure with cancer mortality was controversial, which may ascribe to the difference in PM2.5 constituents. Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic constituents in PM2.5, which are suspected to account for PM2.5-induced cancer mortality but are yet to be investigated. We aimed to assess the association between long-term exposure to PM2.5-bound PAHs and cancer mortality and estimate the attributable mortality. A difference-in-differences approach was used to investigate the causal effect of long-term exposure to PM2.5-bound PAHs on cancer mortality. We divided Jiangsu province, China into 53 spatial units and summarized the annual number of cancer deaths in each spatial unit during 2016-2020. Annual population-weighted exposure to PM2.5-bound PAHs of each spatial unit was assessed by an inverse distance weighting method. The association between PM2.5-bound PAHs exposures and cancer mortality was evaluated by controlling spatial differences, temporal trends, PM2.5 mass exposures, temperatures, and socioeconomic status. Records of 793,269 cancer deaths were identified among 84.7 million population. Each ln-unit increase of exposure to total benzo[a]pyrene equivalents (∑BaPeq), total carcinogenic PAHs (∑PAH7c), and total PAHs (∑PAHs) was significantly associated with a 3.21%, 3.48%, and 2.64% increased risk of cancer mortality, respectively; the risk increased monotonically at low-level exposures but attenuated or flattened afterward (all p for nonlinearity <0.05). Similar exposure-response associations were identified for specific PAHs except that the associations for both fluoranthene and benzo[a]anthracene were linear. We estimated that exposure to ∑BaPeq, ∑PAH7c, and ∑PAHs contributed to 5.73%, 8.73%, and 7.33% of cancer deaths, respectively. In conclusion, long-term exposure to PM2.5-bound PAHs was associated with an increased risk of cancer mortality and contributed to substantial cancer deaths. Our findings highlight the importance to prevent deaths from cancer by reducing PM2.5-bound PAHs exposures and the necessity to take into consideration specific constituents in particulate pollution management in future.

HClO imaging in vivo and drug-damaged liver tissues by a large Stokes shift fluorescent probe.

Drug-induced liver injury (DILI), as a classic acute inflammation, has attracted widespread concern due to its unpredictability and severity. Among the various reactive oxygen species, HClO has been used as a marker for the detection of DILI process. Thus, we designed and synthesized a "turn-on" fluorescent probe FBC-DS by modifying 3'-formyl-4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (FBC-OH) with N, N-dimethylthiocarbamate group for sensitively sensing HClO. Probe FBC-DS showed a low detection limit (65 nM), fast response time (30 s), an enormous Stokes shift (183 nm) and 85-fold fluorescence enhancement at 508 nm in the detection of HClO. Probe FBC-DS could monitor exogenous and endogenous HClO in living HeLa cells, HepG2 cells and zebrafish. In addition, probe FBC-DS has been successfully utilized in biological vectors for imaging acetaminophen (APAP)-induced endogenous HClO. Moreover, DILI caused by APAP is evaluated by probe FBC-DS through imaging over-expression of endogenous HClO in the mice liver injury models. All in all, we have every reason to believe that probe FBC-DS can be a potential tool to study the complex biological relationship between HClO and drug-induced liver injury.

Anthocyanins improve liver fibrosis in mice by regulating the autophagic flux level of hepatic stellate cells by mmu_circ_0000623.

Liver fibrosis is a key step in the progression of various chronic liver diseases to liver cirrhosis and even liver cancer, it is also an important link affecting prognosis. Therefore, this study aimed to investigate the therapeutic effect of anthocyanins on liver fibrosis and the molecular mechanism of mmu_circ_0000623 in anthocyanin therapy. In this study, CCL4 was used to build a mouse liver fibrosis model, and the treatment groups were treated with 100 and 200 mg/kg of anthocyanins daily by gavage. Liver fibrosis indicators, macrophage polarization markers, and liver injury markers were further detected by real-time quantitative PCR (qRT-PCR), western blotting (WB), and enzyme-linked immunosorbent assay. Morphological verification of liver injury in different treatment groups was performed by histopathological method. A mouse hepatic stellate cell (HSC) model and a mouse liver fibrosis model were constructed to verify the expression of circ_0000623, miR-351-5p, and TFEB. Transfected with mRFP-GFP-LC3 to detect the autophagic flux of HSCs. We found that 100 mg/kg or 200 mg/kg of anthocyanins could significantly reduce the degree of liver fibrosis in mice. In addition, anthocyanins can inhibit the proliferation, activation, and migration ability of HSCs. circ_0000623 was lowly expressed in mice with liver fibrosis, and anthocyanin treatment could promote its increased expression. Further testing found that anthocyanins could reverse the blocked autophagic flux induced by PDGF or CCL4. This effect is achieved by regulating the expression of TFEB by competitive adsorption of miR-351-5p. Anthocyanins could treat liver fibrosis by modulating circ_0000623/miR-351-5p/TFEB-mediated changes in HSC autophagic flux.

Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study.

BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

An Investigation into the Potential Therapeutic Effects of the Qigu Zhushui Decoction on Mouse Models of Malignant Ascites.

AIM: To determine whether or not a decoction made from Qigu Zhushui has a suppressive impact on malignant ascites in mice. BACKGROUND: Malignant ascites are one of the common complications of advanced malignant tumors. Patients with malignant ascites typically have a poor prognosis, with only 12 to 20 weeks of survival. Currently, the standard treatments for malignant ascites are systemic chemotherapy, which is ineffective in eradicating the disease and is associated with issues such as safety, short duration of sustained high-level drug concentration in localised regions, and drug resistance. OBJECTIVE: To clarify the effect of Qigu Zhushui decoction on inhibiting malignant ascites in mice and provide the experimental basis for further research. METHODS: The ascites model of liver cancer in mice was established by intraperitoneal injection of the H22-H8D8 cell line of liver cancer. ELISA detected the content of CEA, VEGF and TNF-α in ascites. RESULTS: Qigu Zhushui decoction combined with cisplatin group and Qigu Zhushui decoction highdose group could significantly reduce the weight, abdominal circumference and ascites volume of mice, and their survival days and survival rate were also greatly improved; The levels of CEA and VEGF in the combination group decreased significantly, while the level of TNF-α increased; The level of TNF-a in the high dose group of Qigu Zhushui decoction was significantly increased, while the level of CEA and VEGF in the moderate dose group was decreased. CONCLUSION: Qigu Zhushui decoction can reduce the malignant ascites in mice, and the combination of Qigu Zhushui decoction and cisplatin has a significant anti-malignant ascites effect, which can significantly prolong the survival time and improve the survival rate.