Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals.

A disintegrin and metalloprotease 17 (ADAM17) is a membrane-tethered protease that triggers multiple signaling pathways. It releases active forms of the primary inflammatory cytokine tumor necrosis factor (TNF) and cancer-implicated epidermal growth factor (EGF) family growth factors. iRhom2, a rhomboid-like, membrane-embedded pseudoprotease, is an essential cofactor of ADAM17. Here, we present cryoelectron microscopy (cryo-EM) structures of the human ADAM17/iRhom2 complex in both inactive and active states. These reveal three regulatory mechanisms. First, exploiting the rhomboid-like hallmark of TMD recognition, iRhom2 interacts with the ADAM17 TMD to promote ADAM17 trafficking and enzyme maturation. Second, a unique iRhom2 extracellular domain unexpectedly retains the cleaved ADAM17 inhibitory prodomain, safeguarding against premature activation and dysregulated proteolysis. Finally, loss of the prodomain from the complex mobilizes the ADAM17 protease domain, contributing to its ability to engage substrates. Our results reveal how a rhomboid-like pseudoprotease has been repurposed during evolution to regulate a potent membrane-tethered enzyme, ADAM17, ensuring the fidelity of inflammatory and growth factor signaling.

ATP6V1B1 regulates ovarian cancer progression and cisplatin sensitivity through the mTOR/autophagy pathway.

Early detection and effective chemotherapy for ovarian cancer, a serious gynecological malignancy, require further progress. This study aimed to investigate the molecular mechanism of ATPase H+-Transporting V1 Subunit B1 (ATP6V1B1) in ovarian cancer development and chemoresistance. Our data show that ATP6V1B1 is upregulated in ovarian cancer and correlated with decreased progression-free survival. Gain- and loss-of-function experiments demonstrated that ATP6V1B1 promotes the proliferation, migration, and invasion of ovarian cancer cells in vitro, while ATP6V1B1 knockout inhibits tumor growth in vivo. In addition, knocking down ATP6V1B1 increases the sensitivity of ovarian cancer cells to cisplatin. Mechanistic studies showed that ATP6V1B1 regulates the activation of the mTOR/autophagy pathway. Overall, our study confirmed the oncogenic role of ATP6V1B1 in ovarian cancer and revealed that ATP6V1B1 promotes ovarian cancer progression via the mTOR/autophagy axis.

Emergent trends in organ-on-a-chip applications for investigating metastasis within tumor microenvironment: A comprehensive bibliometric analysis.

Background: With the burgeoning advancements in disease modeling, drug development, and precision medicine, organ-on-a-chip has risen to the forefront of biomedical research. Specifically in tumor research, this technology has exhibited exceptional potential in elucidating the dynamics of metastasis within the tumor microenvironment. Recognizing the significance of this field, our study aims to provide a comprehensive bibliometric analysis of global scientific contributions related to organ-on-a-chip. Methods: Publications pertaining to organ-on-a-chip from 2014 to 2023 were retrieved at the Web of Science Core Collection database. Rigorous analyses of 2305 articles were conducted using tools including VOSviewer, CiteSpace, and R-bibliometrix. Results: Over the 10-year span, global publications exhibited a consistent uptrend, anticipating continued growth. The United States and China were identified as dominant contributors, characterized by strong collaborative networks and substantial research investments. Predominant institutions encompass Harvard University, MIT, and the Chinese Academy of Sciences. Leading figures in the domain, such as Dr. Donald Ingber and Dr. Yu Shrike Zhang, emerge as pivotal collaboration prospects. Lab on a Chip, Micromachines, and Frontiers in Bioengineering and Biotechnology were the principal publishing journals. Pertinent keywords encompassed Microfluidic, Microphysiological System, Tissue Engineering, Organoid, In Vitro, Drug Screening, Hydrogel, Tumor Microenvironment, and Bioprinting. Emerging research avenues were identified as "Tumor Microenvironment and Metastasis," "Application of organ-on-a-chip in drug discovery and testing" and "Advancements in personalized medicine applications". Conclusion: The organ-on-a-chip domain has demonstrated a transformative impact on understanding disease mechanisms and drug interactions, particularly within the tumor microenvironment. This bibliometric analysis underscores the ever-increasing importance of this field, guiding researchers and clinicians towards potential collaborative avenues and research directions.

Blocking exosomal secretion aggravated 1,4-benzoquinone-induced cytotoxicity.

Benzene exposure inhibits the hematopoietic system and leads to the occurrence of various types of leukemia. However, the mechanism underlying the hematotoxicity of benzene is still largely unclear. Emerging evidence has shown that exosomes are involved in toxic mechanisms of benzene. To understand the effect of 1,4-benzoquinone (PBQ; an active metabolite of benzene in bone marrow) on the exosomal release characteristics and role of exosomal secretion in PBQ-induced cytotoxicity. Exosomes were isolated from PBQ-treated HL-60 cells, purified by ultracentrifugation, and verified by transmission electron microscopy, nanoparticle tracking analysis and the presence of specific biomarkers. Our results showed that PBQ increased exosomal secretion in a dose-dependent manner, reaching a peak in 3 h at 10 µM PBQ treatment and then slowly decreasing in HL-60 cells. The exosomes contained miRNAs, which have been reported to be associated with benzene exposure or benzene poisoning. In particular, mir-34a-3p and mir-34A-5p were enriched in exosomes derived from PBQ-treated cells. In addition, the inhibition of exosomal release by GW4869 (an inhibitor of exosomal release) exacerbated PBQ-induced cytotoxicity, including increased intracellular reactive oxygen species levels, decreased mitochondrial membrane potential, and increased the apoptosis rate. Our findings illustrated that exosomes secretion plays an important role in antagonizing PBQ-induced cytotoxicity and maintaining cell homeostasis.

Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer.

MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) orchestrates diverse environmental signals to facilitate cell growth and is frequently activated in cancer. Translocation of MTORC1 from the cytosol to the lysosomal surface by the RRAG GTPases is the key step in MTORC1 activation. Here, we demonstrated that transcription factors MEF2A and MEF2D synergistically regulated MTORC1 activation via modulating its cyto-lysosome shutting. Mechanically, MEF2A and MEF2D controlled the transcription of FNIP1 and FNIP2, the components of the FLCN-FNIP1 or FNIP2 complex that acts as a RRAGC-RRAGD GTPase-activating element to promote the recruitment of MTORC1 to lysosome and its activation. Furthermore, we determined that the pro-oncogenic protein kinase SRC/c-Src directly phosphorylated MEF2D at three conserved tyrosine residues. The tyrosine phosphorylation enhanced MEF2D transcriptional activity and was indispensable for MTORC1 activation. Finally, both the protein and tyrosine phosphorylation levels of MEF2D are elevated in human pancreatic cancers, positively correlating with MTORC1 activity. Depletion of both MEF2A and MEF2D or expressing the unphosphorylatable MEF2D mutant suppressed tumor cell growth. Thus, our study revealed a transcriptional regulatory mechanism of MTORC1 that promoted cell anabolism and proliferation and uncovered its critical role in pancreatic cancer progression.Abbreviation: ACTB: actin beta; ChIP: chromatin immunoprecipitation; EGF: epidermal growth factor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FLCN: folliculin; FNIP1: folliculin interacting protein 1; FNIP2: folliculin interacting protein 2; GAP: GTPase activator protein; GEF: guanine nucleotide exchange factors; GTPase: guanosine triphosphatase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF2: myocyte enhancer factor 2; MEF2A: myocyte enhancer factor 2A; MEF2D: myocyte enhancer factor 2D; MEF2D-3YF: Y131F, Y333F, Y337F mutant; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NR4A1: nuclear receptor subfamily 4 group A member 1; RPTOR: regulatory associated protein of MTOR complex 1; RHEB: Ras homolog, mTORC1 binding; RPS6KB1: ribosomal protein S6 kinase B1; RRAG: Ras related GTP binding; RT-qPCR: real time-quantitative PCR; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; TMEM192: transmembrane protein 192; WT: wild-type.

An investigation on cervical cancer and human papillomavirus vaccine knowledge, and analysis of influencing factors for choosing domestic or imported 2vHPV vaccine among females in Shenzhen, China.

In 2020, the domestic (Chinese native) 2v human papillomavirus (HPV) vaccine was approved for use in females. At present, there are obvious differences in demand for different HPV vaccines. We aimed to investigate knowledge level of cervical cancer and HPV vaccine and its influencing factors among the eligible female recipients in Shenzhen, China, and to analyze the factors influencing choice of 2vHPV vaccine (domestic or imported) would be selected. A self-administered questionnaire was carried out on this investigation, and respondents were selected by random sampling method conducted by vaccination doctors. A total of 1197 valid questionnaires were collected, of which 729 (60.9%) were vaccinated with domestic vaccines and 468 (39.1%) were vaccinated with imported. Four hundred and fifty (61.7%) and 306 (65.4%) got a passing grade, respectively (χ2 = 1.637, P = .201). Logistic regression analysis showed that age (P = .002), ethnicity (P < .001), duration of residence in Shenzhen (P < .001), educational level (P < .001) and occupation (P < .001) were significant. It also showed that the manufacturers (P < .001), efficacy (P < .001), safety (P < .001), cognitive approach (P < .001), public opinion (P < .001), convenient acquisition (P < .001) and knowledge reserve (P = .035) were statistically significant. While price (P = .371) and doctor's suggestion (P = .114) were not. In conclusion, eligible female recipients had a high degree of knowledge regarding cervical cancer and HPV vaccine, education level and occupation were the most important factors for scores. Domestic 2vHPV vaccine was more widely utilized than imported, manufacturer, efficacy, safety, cognitive approach, public opinion, convenient acquisition, and knowledge reserve had an impact on selection for recipients, while price and doctor's suggestion did not.

Berberine promotes IGF2BP3 ubiquitination by TRIM21 to induce G1/S phase arrest in colorectal cancer cells.

The increasing incidence of colorectal cancer (CRC) has become a major global public health burden. The natural drug Berberine (BBR) has shown potential in preventing CRC, and IGF2 mRNA binding protein 3 (IGF2BP3) may be a target of BBR. This study aims to investigate the mechanisms of BBR acting on IGF2BP3 to improve CRC. The results showed that IGF2BP3 played an important role in the development of CRC. BBR down-regulated IGF2BP3 expression and inhibited CRC growth in mice. Cell thermodynamic stability analysis (CETSA) and drug affinity responsive target stability (DARTS) analysis showed BBR may bind to IGF2BP3. BBR may induce structural changes in IGF2BP3 and decrease its protein stability in cytoplasm. The results from Co-Immunoprecipitation (Co-IP) suggested that BBR promoted the ubiquitination of IGF2BP3 by tripartite motif-containing protein 21 (TRIM21). Through RNA binding protein Immunoprecipitation (RIP) assay, it was found BBR inhibited the stabilization of CDK4/CCND1 mRNA by IGF2BP3 and promoted G1/S phase arrest in CRC cells. Overexpression of IGF2BP3 in vitro and in vivo attenuated the inhibition of CRC growth by BBR. This work demonstrated the potential of BBR targeting to IGF2BP3 in improving CRC and provided a new strategy for clinical treatment on CRC as well as novel anticancer drug design based on IGF2BP3 and TRIM21.

iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells.

Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer. Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhom proteins, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17. Here, we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 (also known as RHBDF2) to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing the cytoplasmic domain of iRhom2 as a central component of a positive feedback loop in lung cancer cells. This article has an associated First Person interview with the first authors of the paper.

Economic Burden of Malignant Tumors - Yichang City, Hubei Province, China, 2019.

What is already known about this topic?: Malignant tumors are common chronic non-communicable disease and have caused serious health hazards to residents and heavy economic burden of disease to the society. What is added by this report?: This is the first report on the economic burden of multiple types of malignant tumors in Yichang City. In 2019, the direct medical burden of lung cancer in Yichang was the highest, reaching 561.67 million CNY, and the indirect economic burden of lung cancer in Yichang was higher than that of other malignant tumors, costing 326.49 million CNY. What are the implications for public health practice?: The results can provide evidence for the formulation of local cancer prevention and control strategies and public health decision-making.

Blocking exosomal secretion aggravates 1,4-benzoquinone-induced mitochondrial fission activated by the AMPK/MFF/Drp1 pathway in HL-60 cells.

There is in vivo and in vitro evidence that exposure to benzene or its metabolites could affect the mitochondrial function. However, the underlying molecular mechanism of mitochondrial damage remains to be elucidated. In this study, exposure of human promyelocytic leukemia cells (HL-60) to 1,4-benzoquinone (1,4-BQ; an active metabolite of benzene) increased the intracellular reactive oxygen species levels, decreased the mitochondrial membrane potential, adenosine triphosphate production and mitochondrial DNA (mtDNA) copy number, up-regulated the expression of mitochondrial fission proteins Drp1 and Fis1, and down-regulated the expression of mitochondrial fusion proteins Mfn2 and Opa1. Further study showed that 1,4-BQ mediated mitochondrial fission through activation of the AMP-activated protein kinase/mitochondrial fission factor/dynamin-related protein 1 pathway. Additionally, we also examined the role of exosomal secretion in mitochondrial damage under 1,4-BQ treatment. Results showed that 1,4-BQ increased the total protein level and mtDNA content in exosomes. Upon pre-treatment with the mitochondria-targeted antioxidant SS-31, there was attenuation of the mitochondrial damage induced by 1,4-BQ, accompanied by a change in the exosome release characteristics, while inhibition of exosomal secretion using GW4869 aggravated the 1,4-BQ-mediated mitochondrial fission. We concluded that exosomal secretion may serve as a self-protective mechanism of cells against 1,4-BQ-induced mitochondria damage and mitochondrial dynamics interference.

iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2.

The folding capacity of membrane and secretory proteins in the endoplasmic reticulum (ER) can be challenged by physiological and pathological perturbations, causing ER stress. If unresolved, this leads to cell death. We report a role for iRhom pseudoproteases in controlling apoptosis due to persistent ER stress. Loss of iRhoms causes cells to be resistant to ER stress-induced apoptosis. iRhom1 and iRhom2 interact with IP3 receptors, critical mediators of intracellular Ca2+ signalling, and regulate ER stress-induced transport of Ca2+ into mitochondria, a primary trigger of mitochondrial membrane depolarisation and cell death. iRhoms also bind to the anti-apoptotic regulator BCL-2, attenuating the inhibitory interaction between BCL-2 and IP3 receptors, which promotes ER Ca2+ release. The discovery of the participation of iRhoms in the control of ER stress-induced cell death further extends their potential pathological significance to include diseases dependent on protein misfolding and aggregation.

BoPEP4, a C-Terminally Encoded Plant Elicitor Peptide from Broccoli, Plays a Role in Salinity Stress Tolerance.

Plant peptide hormones play various roles in plant development, pathogen defense and abiotic stress tolerance. Plant elicitor peptides (Peps) are a type of damage-associated molecular pattern (DAMP) derived from precursor protein PROPEPs. In this study, we identified nine PROPEP genes in the broccoli genome. qRT-PCR analysis indicated that the expression levels of BoPROPEPs were induced by NaCl, ABA, heat, SA and P. syringae DC3000 treatments. In order to study the functions of Peps in salinity stress response, we synthesized BoPep4 peptide, the precursor gene of which, BoPROPEP4, was significantly responsive to NaCl treatment, and carried out a salinity stress assay by exogenous application of BoPep4 in broccoli sprouts. The results showed that the application of 100 nM BoPep4 enhanced tolerance to 200 mM NaCl in broccoli by reducing the Na+/K+ ratio and promoting accumulation of wax and cutin in leaves. Further RNA-seq analysis identified 663 differentially expressed genes (DGEs) under combined treatment with BoPep4 and NaCl compared with NaCl treatment, as well as 1776 genes differentially expressed specifically upon BoPep4 and NaCl treatment. GO and KEGG analyses of these DEGs indicated that most genes were enriched in auxin and ABA signal transduction, as well as wax and cutin biosynthesis. Collectively, this study shows that there was crosstalk between peptide hormone BoPep4 signaling and some well-established signaling pathways under salinity stress in broccoli sprouts, which implies an essential function of BoPep4 in salinity stress defense.

Progress in the Medicinal Value, Bioactive Compounds, and Pharmacological Activities of Gynostemma pentaphyllum.

Gynostemma pentaphyllum (Thunb.) Makino (GP), also named Jiaogulan in Chinese, was known to people for its function in both health care and disease treatment. Initially and traditionally, GP was a kind of tea consumed by people for its pleasant taste and weight loss efficacy. With the passing of the centuries, GP became well known as more than just a tea. Until now, numbers of bioactive compounds, including saponins (also named gypenosides, GPS), polysaccharides (GPP), flavonoids, and phytosterols were isolated and identified in GP, which implied the great medicinal worth of this unusual tea. Both in vivo and in vitro tests, ranging from different cell lines to animals, indicated that GP possessed various biological activities including anti-cancer, anti-atherogenic, anti-dementia, and anti-Parkinson's diseases, and it also had lipid-regulating effects as well as neuroprotection, hepatoprotective, and hypoglycemic properties. With the further development and utilization of GP, the research on the chemical constituents and pharmacological properties of GP were deepening day by day and had made great progress. In this review, the recent research progress in the bioactive compounds, especially gypenosides, and the pharmacological activities of GP were summarized, which will be quite useful for practical applications of GP in the treatment of human diseases.

Plant-derived antioxidants incorporated into active packaging intended for vegetables and fatty animal products: a review.

Nowadays, the food industry is focused on improving the shelf life of products by controlling lipid oxidation using natural antioxidants. The study of natural antioxidants is a field that attracts great interest because of their greater safety compared to synthetic ones. Plant-derived antioxidants being eco-friendly and effective are increasingly playing an important role in food preservation. When incorporated into active packaging, plant-derived antioxidants have no direct contact with foods, and will not change the colour or taste of the foods. They will, however, inhibit the development of rancidity, retard formation of toxic oxidation products, maintain nutritional quality, and prolong the shelf life of products. This review summarises research on the development of plant-derived antioxidants in food packaging. Antioxidants are found in plants such as green tea, olive leaves, ginkgo leaves, rosemary, Indian gooseberry, cinnamon, savoury, bay leaves, mango leaves, sage and clove etc. Antioxidants can scavenge free radicals and inhibit the activity of polyphenol oxidase. Therefore, they can inhibit lipid oxidation and browning of fruit and vegetables. These active substances can be obtained through extracting the plants using solvents with different polarities. The oxidation resistance of active substances can be determined by DPPH radical scavenging capacity, oxygen radical absorbance capacity, PPO enzyme inhibition capacity and other methods. In recent years, research on the preparation of food packaging with plant-derived antioxidants has also made significant progress. One development is to encapsulate plant-derived antioxidants such as tea polyphenols with capsules containing inorganic components. Thus, they can be blended with polyethylene granules and processed into active packaging film by industrial production methods such as melting, extrusion and blowing film. This research promotes the commercial application of active packaging incorporated with plant-derived antioxidants.

Inhibition of microRNA let-7b expression by KDM2B promotes cancer progression by targeting EZH2 in ovarian cancer.

MicroRNA let-7b is a potent tumor suppressor and targets crucial oncogenes. Previous studies have shown that let-7b expression is suppressed in ovarian cancer; however, the regulatory mechanisms of let-7b in ovarian cancer are still not well defined. The cellular role and targets of let-7b in ovarian cancer remain elusive. In the present study, we showed that histone demethylase, KDM2B, directly suppressed let-7b expression by H3K36me2 demethylation. Moreover, let-7b inhibited EZH2 expression in ovarian cancer cells. Based on these results we know that let-7b antagonizes the enhancement of EZH2 expression caused by KDM2B overexpression, and its expression is negatively correlated with KDM2B and EZH2 expression. More importantly, proliferation, migration, and wound healing assays showed that let-7b inhibited ovarian cancer cell proliferation and migration in vitro. Additionally, let-7b overexpression neutralized KDM2B-promoted cell proliferation and migration. Furthermore, downregulation of let-7b increased the xenografted tumor volumes in nude mice that were transplanted with KDM2B-silenced cells. EZH2 silencing reversed the tumor growth enhancement mediated by inhibition of let-7b. Last, we show that let-7b expression is suppressed in ovarian carcinomas and its expression is negatively associated with the clinicopathological features of ovarian cancer, including histological type, histological grade, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastatic status. In conclusion, in ovarian cancer, let-7b expression is epigenetically suppressed by high expression of KDM2B. The loss of let-7b upregulates the expression of EZH2, which promotes ovarian cancer growth in vitro and in vivo.

Application of Abdominal Imaging Based on Nano Drug Delivery System for Diagnosis and Treatment of Liver Cancer.

Liver cancer has a high incidence and a poor prognosis, which seriously affects human health. Doxorubicin is one of the chemotherapeutics used in the treatment of tumours, but its severe adverse reactions, especially cardiac toxicity, have limited its clinical application. The nanometre drug delivery system enables drug-loaded nanoparticles to be specifically concentrated in tumour tissues, increasing cell uptake and improving curative effect. Therefore, in this paper, folic acid-modified mesoporous silica nanoparticles (MSN-NH2-PEG-FA) were synthesized by modifying the folic acid on the surface of a drug carrier by using the characteristics of the expression of folic acid receptors, and using it as a drug. The carrier was loaded with antitumor drug doxorubicin hydrochloride (DOX), and a nanometre drug delivery system (MSN-NH2-PEG-FA/DOX) was constructed. At the same time, the near-infrared dye Cy5 was used to mark the mother nucleus to construct fluorescent nanoparticles (MSN-NH2-PEG-FA/DOX-Cy5) for cell and tumour imaging, so as to obtain the abdominal image of liver cancer patients, thereby realizing diagnosis and treatment. The research results show that the carrier can specifically gather in the liver area, reduce the distribution in the heart, reduce the toxic and side effects of drugs, and prolong the survival time of patients. The results of this study provide new ideas for the treatment of liver cancer, and provide a new theoretical basis and experimental basis for the study of inorganic nanomaterials as targeted drug delivery systems.

Label-free and "signal-on" homogeneous photoelectrochemical cytosensing strategy for ultrasensitive cancer cell detection.

We report a label-free and "signal-on" homogeneous photoelectrochemical cytosensing system for ultrasensitive detection of cancer cells, which is a truly homogeneous PEC cytosensing system without the photoactive material immobilization and target recognition probe modification, providing a new avenue in early and accurate cancer diagnosis and clinical analysis.

Disparities in end-of-life care, expenditures, and place of death by health insurance among cancer patients in China: a population-based, retrospective study.

BACKGROUND: Disparities in the utilization, expenditures, and quality of care by insurance types have been well documented. Such comparisons have yet to be investigated in end-of-life (EOL) settings in China, where public insurance covers over 95% of the Chinese population. This study examined the associations between health insurance and EOL care in the last six months of life: outpatient visits, emergency department (ED) visits, inpatient services, intensive care unit (ICU) admissions, expenditures, and place of death among the cancer patients. METHODS: A total of 398 patients diagnosed with cancer who survived more than 6 months after diagnosis and died from July 2015 to June 2017 in urban Yichang, China, were included. Descriptive analysis and multivariate regression models were used to investigate the bivariate and independent associations, respectively, between health insurance with EOL healthcare utilization, expenditures and place of death. RESULTS: Urban Employee Basic Medical Insurance (UEBMI) beneficiaries visited EDs more frequently than Urban Resident-based Basic Medical Insurance (URBMI) and New Rural Cooperative Medical Scheme (NRCMS) beneficiaries (marginal effects [95% Confidence Interval]: 2.15 [1.81-2.48] and 1.92 [1.59-2.26], respectively). NRCMS and UEBMI beneficiaries had more hospitalizations than URBMI beneficiaries (1.01 [0.38-1.64] and 0.71 [0.20-1.22], respectively). Compared to URBMI beneficiaries, NRCMS beneficiaries and UEBMI beneficiaries had ¥15,722 and ¥43,241 higher expenditures. Similarly, UEBMI beneficiaries were most likely to die in hospitals, followed by NRCMS (UEBMI vs. NRCMS: 0.23 [0.11-0.36]) and URBMI (UEBMI vs. URBMI: 0.67 [0.57-0.78]) beneficiaries. CONCLUSIONS: The disproportionately lower utilization of EOL care among NRCMS and URBMI beneficiaries, compared to UEBMI beneficiaries, raised concerns regarding quality of EOL care and financial burdens of NRCMS and URBMI beneficiaries. Purposive hospice care intervention might be warranted to address EOL care for these beneficiaries in China.

Determinants of place of death for end-stage cancer patients: evidence from China.

OBJECTIVE: To determine factors influence place of death (POD) for end-stage cancer patients and investigate how the healthcare utilization mediates on the effect of socioeconomic status (SES) on POD. DESIGN: A population-based, retrospective study from July 2015 to June 2017. SETTING: Yichang, China. PARTICIPANTS: 894 end-stage cancer patients. MAIN OUTCOME MEASURE: POD. RESULTS: Patients of hospital death experience more inpatient hospitalization services (IHS) and emergency department visits. Patients enrolled in the New Rural Cooperative Medical Scheme (OR = 7.60, P < 0.001) and Urban Employee Basic Medical Insurance (OR = 28.0, P < 0.001) have higher rates of hospital death than those in the Urban Resident-based Basic Medical Insurance. Living with spouse (OR = 1.72, P = 0.019) and receiving higher education (OR = 1.92, P = 0.004), increase the likelihood of hospital death by 72% and 92%, respectively. The probability of hospital death will increase by 14% and decrease by 4% per IHS and outpatient services occur, respectively. Outpatient services (Z = -2.28, P < 0.001), and IHS (Z = 2.17, P < 0.001) mediate 1.81% and 1.89%, respectively, of the effect of health insurance on POD. The overall effect of the mediators is non-statistically significant (Z = 0.09, P = 0.825). CONCLUSION: POD is mainly driven by SES. The relationship between health insurance and POD is partly mediated by outpatient services and IHS, respectively. The results corroborated that hospital and home services should be coherently bridged. Furthermore, benefit packages for end-stage cancer patients could be redesigned.

The combined use of EphA2/MMP-2 expression and MRI findings contributes to the determination of cerebral glioma grade.

Glioma is the most aggressive brain tumor and is associated with a high mortality rate. The aim of the present study was to explore the association between matrix metalloproteinase 2 (MMP-2) and ephrin type-A receptor 2 (EphA2) expression in glioma cells, and to investigate the contribution of magnetic resonance imaging (MRI) in glioma classification. A total of 43 patients with pathologically confirmed glioma were divided into two groups as follows: Low-grade (grades I and II; n=21) and high-grade (grades IV and IV; n=22). Subsequently, immunohistochemistry staining was performed to detect the expression levels of MMP-2 and EphA2 in the low- and high-grade groups. MRI routine and enhanced scans were used to measure the peritumoral edema index (EI), tumor enhancement percentage (EP) and maximum tumor diameter. The results demonstrated that the proportion of MMP-2-positive patients in the high-grade group was 86.36% (19/22), which was significantly higher than that of the low-grade group (57.14%; 12/21) (P<0.05). Furthermore, the proportion of EphA2-positive patients in the high-grade group was 90.91% (20/22), significantly higher than that in the low-grade group (4.76%; 1/21) (P<0.01). In addition, the MRI results indicated that the EI, EP and maximum tumor diameter were significantly higher in the high-grade group compared with the low-grade group (P<0.01, P<0.01 and P<0.05, respectively). Finally, the expression levels of MMP-2 and EphA2 were significantly associated with the EI, EP and maximum tumor diameter (all P<0.05). In conclusion, the expression levels of MMP-2 and EphA2 were positively correlated with glioma invasion. The correlation between these expression levels and MRI assessment of the EI, EP and maximum tumor diameter indicated that the combination of these two methods may be used for the evaluation of the tumor grade and for further clinical treatment applications.