Zhenjiang City Fourth People's Hospital

BACKGROUND: MicroRNAs (miRNAs) are involved in gastric cancer development and progression. However, the expression and role of miRNAs in gastric cancer stromal cells are still unclear. METHODS: The miRNAs differentially expressed in gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) relative to adjacent non-cancerous tissue-derived MSCs (GCN-MSCs) and in cancer tissues relative to adjacent non-cancerous tissues were screened using miRNA microarray and validated by quantitative RT-PCR. The impact of GC-MSCs on HGC-27 cells was observed in vitro using colony formation and transwell assays, and these cells were subcutaneously co-injected into mice to assess tumour growth in vivo. Exogenous downregulation of miR-221 expression in cells was achieved using an miRNA inhibitor. RESULTS: miR-214, miR-221 and miR-222 were found to be commonly upregulated in GC-MSCs and cancer tissues. Their levels were tightly associated with lymph node metastasis, venous invasion and the TNM stage. Gastric cancer tissue-derived mesenchymal stem cells significantly promoted HGC-27 growth and migration and increased the expression of miR-221 via paracrine secretion, and the targeted inhibition of miR-221 in GC-MSCs could block its tumour-supporting role. GC-MSC-derived exosomes were found to deliver miR-221 to HGC-27 cells and promoted their proliferation and migration. CONCLUSIONS: Gastric cancer tissue-derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancer.

BACKGROUND: In the past few decades, it has been demonstrated with animal models and clinical studies that a chronic inflammatory process significantly contributes to Alzheimer's disease (AD) pathogenesis. METHODS: We systematically searched on PubMed and Web of Science for studies associated with peripheral inflammatory biomarkers in AD and mild cognitive impairment (MCI) before July 2018. Meta-analysis was conducted to summarise results of studies relative to peripheral cytokines and chemokines in AD and MCI. RESULTS: Mean (± SD) concentrations of peripheral inflammatory biomarkers for AD, MCI and healthy controls were extracted from these studies. Our meta-analysis revealed consistently elevated concentrations of inflammatory biomarkers such as C-reactive protein, interleukin-1β (IL-1β), IL-2, IL-6, IL-12, IL-18, monocyte chemotactic protein-1 (MCP-1), MCP-3, IL-8 and interferon-γ-inducible protein 10 in AD patients, whereas no consistent results were obtained for elevated concentrations of cytokines or chemokines except MCP-1 in MCI patients. CONCLUSIONS: In conclusion, these results provided evidence to support that systematic inflammation might be a biomarker for AD diagnosis, whereas it might be a later event during AD disease progression.

BACKGROUND: Accumulating data indicated that circRNA plays important roles in regulating many biological processes of the tumor, the present study is designated for exploring roles of the circ-ZEB1.33-miR-200a-3p-CDK6 regulating axis in human hepatocellular carcinoma (HCC). METHODS: The regulation axis as predicted by using online tool circNet, the expression and correlation of circ-ZEB1.33-miR-200a-3p-CDK6 was verified in human HCC. The diagnostic value of both tumor and serum circ-ZEB1.33 was estimated by using clinical samples. The roles of circ-ZEB1.33-miR-200a-3p-CDK6 in regulating cell cycle were explored by using in vitro studies. RESULTS: Overexpression of circ-ZEB1.33 and CDK6, downregulation of miR-200a-3p were detected in human HCC tissues, negative correlation between circ-ZEB1.33 and miR-200a-3p, positive correlation between circ-ZEB1.33 and CDK6 were confirmed in human HCC tissues. Tissue and serum circ-ZEB1.33 were related to different TMN stages and prognosis in HCC patients. RNA pull-down assay implied that circ-ZEB1.33 could decrease miR-200a-3p by sponging miR-200a-3p, and the luciferase reporter assay indicated that miR-200a-3p could downregulate CDK6 transcription by targeting its 3'UTR. The in vitro assays indicated that circ-ZEB1.33 could promote the proliferation of HCC cells by increasing the percentage of S phase regulated by CDK6/Rb. CONCLUSION: Proliferation promotion roles of the circ-ZEB1.33-miR-200a-3p-CDK6 regulating axis are existed and verified in human HCC, both tumor and serum circ-ZEB1.33 can serve as an indicator for the prognosis of HCC patients.

Pressure ulcers are very common in hospital patients. Though many studies have been reported in many countries, the large-scale benchmarking prevalence of pressure ulcers in China is not available. The aim of this study is to quantify the prevalence of pressure ulcers and the incidence of hospital-acquired pressure ulcers and analyze risk factors in hospitalized patients in China. A multi-central cross-sectional survey was conducted in one university hospital and 11 general hospitals in China. The Minimum Data Set (MDS) recommended by European Pressure Ulcer Advisory Panel (EUPAP) was used to collect information of inpatients. All patients stayed in hospital more than 24 hours and older than 18 years signed consent form and were included. Data from 39952 out of 40415 (98.85%) inpatients were analyzed. Of the 39952 patients, 631 patients (including 1024 locations) had pressure ulcers. The prevalence rate of pressure ulcers in 12 hospitals was 1.58% (0.94-2.97%). The incidence of hospital-acquired pressure ulcers (HAPU) was 0.63% (0.20-1.20%). The most common locations developed pressure ulcers were sacrum, heels, and iliac crests. The common stages of pressure ulcers were stage I and II. Patients in Intensive Care Unit, Geriatric and Neurological Department were easier to develop pressure ulcers. The prevalence and incidence of pressure ulcers in China was lower than that reported in European and other countries. The stages of pressure ulcers in China were different than that reported in European countries. Our study provides with a baseline value for intensive research on pressure ulcer in China.

Abstract Objective The long non‐coding RNA zinc finger E‐box‐binding homeobox 1 antisense 1 (ZEB1‐AS1) acts as an oncogenic regulator in many human tumours. In the present study, we identify the role and potential molecular biological mechanisms of ZEB1‐AS1 in colon adenocarcinoma (COAD). Methods QRT‐PCR was used to detect the expression of ZEB1‐AS1, miR‐455‐3p and p21‐activated kinases 2 (PAK2) in COAD tissues. CCK8 assay, EdU assay, transwell assay and scratch wound assay were used to explore the biological function of ZEB1‐AS1 in COAD cells. Bioinformatics, luciferase reporter assays and an RNA pull‐down assay were used to demonstrate the mechanism of ZEB1‐AS1. We further explore the role of ZEB1‐AS1 in vivo though xenograft tumour assay. Results We found that ZEB1‐AS1 expression was significantly up‐regulated in COAD tissues, and high ZEB1‐AS1 level was correlated with the poor prognosis of COAD patients. MiR‐455‐3p plays an anti‐cancer role in COAD by targeting PAK2. We confirmed that ZEB1‐AS1 promotes PAK2 expression by sponging miR‐455‐3p, thus facilitating COAD cell growth and metastasis. Conclusions To sum up, this result illustrates the novel molecular mechanism of ZEB1‐AS1 in COAD and provides a new target for the diagnosis and treatment of COAD patients.

BACKGROUND: Many clinicians do not encourage breastfeeding in hepatitis B virus (HBV) carriers, since HBV DNA can be detected in breast milk and breast lesions may increase exposure of infants to HBV. The aim of this study was to determine whether breastfeeding may add risk for perinatal HBV transmission. METHODOLOGY/PRINCIPAL FINDINGS: Totally 546 children (1-7-year-old) of 544 HBV-infected mothers were investigated, with 397 breastfed and 149 formula-fed; 137 were born to HBeAg-positive mothers. All children had been vaccinated against hepatitis B but only 53.3% received hepatitis B immune globulin (HBIG). The overall prevalence of HBsAg+, HBsAg-/anti-HBc+, and anti-HBs (≥10 mIU/ml) in children was 2.4%, 3.1%, and 71.6% respectively. The HBsAg prevalence in breast- and formula-fed children was 1.5% and 4.7% respectively (P = 0.063); the difference was likely due to the higher mothers' HBeAg-positive rate in formula-fed group (formula-fed 49.0% vs. breastfed 15.9%, P<0.001). Further logistic regression analyses showed that breastfeeding was not associated with the HBV infection in the children, adjusting for the effect of maternal HBeAg status and other factors different between the two groups. CONCLUSIONS/SIGNIFICANCE: Under the recommended prophylaxis, breastfeeding is not a risk factor for mother-to-child transmission of HBV. Therefore, clinicians should encourage HBV-infected mothers to breastfeed their infants.

. These data demonstrate that Asiatic acid both inhibits the activation of the NLRP3 inflammasome by downregulating mitochondrial reactive oxygen species directly to protect dopaminergic neurons from, and improves mitochondrial dysfunction in SH-SY5Y cells, which were established as a model of Parkinson’s disease. Our finding reveals that Asiatic acid protects dopaminergic neurons from neuroinflammation by suppressing NLRP3 inflammasome activation in microglia cells as well as protecting dopaminergic neurons directly. This suggests a promising clinical use of Asiatic acid for PD therapy.

Summary Infection of hepatitis B virus ( HBV ) occurs in ~10% of infants of HBV ‐infected mothers with positive hepatitis B e antigen ( HB eAg) after immunoprophylaxis. We aimed to evaluate the safety and efficacy of telbivudine used during late pregnancy for preventing mother‐to‐child transmission of HBV . We conducted a multicenter prospective cohort study in 5 hospitals from 2012 to 2014, which enrolled HBV ‐infected singleton pregnant women with positive HB eAg. By their choice, women were divided into therapy (telbivudine 600 mg/day, from gestation 28‐32 weeks to 3‐4 weeks postpartum) and control (no antiviral agent) groups. Infants received passive‐active immunoprophylaxis and follow‐up at the age of 7‐14 months. Totally, 328 pregnant women were included: 149 in the telbivudine group and 179 in the control group. Baseline HBV DNA levels were similar in the 2 groups (7.43 vs 7.37 log 10 IU /mL, P = .711). At delivery, HBV DNA levels in the telbivudine and control groups were 3.80 and 7.26 log 10 IU /mL, respectively ( P &lt; .0001). Of the infants, 128 (85.9%) in the telbivudine group and 156 (87.2%) in the control group were followed up. No infant in the telbivudine group had chronic infection, while 2 (1.28%) infants in the control group did ( P = .503). Three (2.34%) infants in the telbivudine group, but none in the control group, had severe congenital or developmental abnormalities ( P = .090). The data indicate that telbivudine may block perinatal HBV transmission. However, larger studies are required to clarify whether anti‐ HBV therapy in pregnancy is associated with severe adverse effects in the foetuses and infants.

Chemoresistance has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Long noncoding RNAs play important roles in breast cancer tumorigenesis and chemoresistance. However, the involvement and regulation of lncRNAs in breast cancer chemoresistance are not completely understood. Here, we reported that Linc00839 was localized in the nucleus and upregulated in chemoresistant breast cancer cells and tissues, and high level of Linc00839 was associated with a poor prognosis. Knockdown of Linc00839 significantly suppressed proliferation, invasion, and migration, sensitized cells to paclitaxel in vitro and inhibited transplant tumor development in vivo. Mechanistically, we found that Myc could directly bind to the promoter region of Linc00839 and activate its transcription. Furthermore, Linc00839 overexpression increased the expression of Myc and the RNA-binding protein Lin28B and activated the PI3K/AKT signaling pathway. We also discovered that Lin28B positively interacted with Linc00839 and was upregulated in breast cancer tissues. Taken together, for the first time, we showed that Linc00839 was activated by Myc and promoted proliferation and chemoresistance in breast cancer through binding with Lin28B. These findings provide new insight into the regulatory mechanism of Linc00839 and propose a Myc/Linc00839/Lin28B feedback loop that could be used as a novel therapeutic target for breast cancer.

BACKGROUND: Osteosarcoma (OS) is a common primary bone malignancy. Long noncoding RNA HCG18 is known to play an important role in a variety of cancers. However, its role in OS and relevant molecular mechanisms are unclear. METHODS: Real-time quantitative PCR was performed to determine the expression of target genes. Function experiments showed the effects of HCG18 and miR-365a-3p on OS cell growth. RESULTS: HCG18 expression was increased in OS cell lines. Moreover, in vitro and in vivo experiments demonstrated that HCG18 knockdown inhibited OS cell proliferation. Mechanistically, HCG18 was defined as a competing endogenous RNA by sponging miR-365a-3p, thus elevating phosphoglycerate kinase 1 (PGK1) expression by directly targeting its 3'UTR to increase aerobic glycolysis. CONCLUSION: HCG18 promoted OS cell proliferation via enhancing aerobic glycolysis by regulating the miR-365a-3p/PGK1 axis. Therefore, HCG18 may be a potential target for OS treatment.

Context The reduction in M2 macrophage polarisation plays a major role during diabetic wound healing. Resveratrol (RSV) can promote the polarisation of M2 macrophages and accelerate diabetic wound healing. However, the specific mechanism by which RSV regulates M2 macrophage polarisation to promote diabetic wound healing is unclear.Objective This study evaluated the effectiveness of RSV on diabetic wound healing and analysed the underlying mechanisms.Materials and methods STZ-induced C57/B6 mice were used as a diabetic mice model for a period of 15 days. RSV (10 μmol/L) was injected around the wound to evaluate the effect of RSV on the healing process of diabetic wounds. The human monocyte line THP-1 was used to evaluate the effects of RSV (10 μmol/L) on polarisation of M2 macrophages and the secretion of pro-inflammatory factors.Results In vivo, RSV significantly increased diabetic wound healing (p < 0.05) and make the regenerated skin structure more complete. And it promoted the expression of α-SMA and Collagen I (p < 0.05). Moreover, RSV reduced the secretion of inflammatory factors (TNF-α, iNOS and IL-1β) (p < 0.05) and promoted M2 macrophage polarisation by increasing Arg-1 and CD206 expression (p < 0.01). In vitro, RSV promoted the polarisation of M2 macrophages (p < 0.001) and reduced the secretion of pro-inflammatory factors (TNF-α, IL-6 and IL-1β) (p < 0.05). The therapeutic effects of RSV were all significantly reversed with LY294002 (p < 0.01).Discussion and conclusions RSV has the positive effects on promoting the acceleration and quality of skin wound healing, which provides a scientific basis for clinical treatment in diabetic wound.

This article reviews the effects of chronic fluorosis on the brain and possible mechanisms. We used PubMed, Medline and Cochraine databases to collect data on fluorosis, brain injury, and pathogenesis. A large number of in vivo and in vitro studies and epidemiological investigations have found that chronic fluorosis can cause brain damage, resulting in abnormal brain structure and brain function.Chronic fluorosis not only causes a decline in concentration, learning, and memory, but also has mental symptoms such as anxiety, tension, and depression. Several possible mechanisms that have been proposed: the oxidative stress and inflammation theory, neural cell apoptosis theory, neurotransmitter imbalance theory, as well as the doctrine of the interaction of fluorine with other elements. However, the specific mechanism of chronic fluorosis on brain damage is still unclear. Thus, a better understanding of the mechanisms via which chronic fluorosis causes brain damage is of great significance to protect the physical and mental health of people in developing countries, especially those living in the endemic areas of fluorosis. In brief, further investigation concerning the influence of fluoride on the brain should be conducted as the neural damage induced by it may bring about a huge problem in public health, especially considering growing environmental pollution.

During the process of wound healing, fibroblasts migrate to the wound site and perform essential functions in promoting cell proliferation, as well as synthesizing and secreting the extracellular matrix (ECM). However, in diabetic wounds, senescent fibroblasts exhibit impaired proliferative capacity and fail to synthesize essential ECM components. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating cellular senescence and fibroblast function. However, its specific role in diabetic wounds remains poorly understood. In this study, we conducted a series of in vivo and in vitro experiments using STZ-induced diabetic mice and human dermal fibroblasts. We evaluated cellular senescence markers, including SA-β-gal, P53, P16, P21, and PAI-1, as well as senescence-associated secretory phenotype (SASP) factors. Finally, we observed that PDK4 increased in normal wound healing, but its expression was insufficient in diabetic wounds. Significantly, the overexpression of PDK4 demonstrated the potential to accelerate diabetic wound healing and improve the senescence phenotype both in vivo and in vitro. Furthermore, our study elucidated the underlying mechanism by which PDK4 improved the senescent phenotype through the enhancement of glycolysis and regulation of YAP and JNK pathway. The effect was dependent on metabolic reprogramming and subsequent reduction of reactive oxygen species (ROS), which was mediated by PDK4. Overall, our findings highlight the potential of PDK4 as a promising therapeutic target for addressing diabetic wounds.

A novel anticancer drug delivery system with contrast‐enhanced ultrasound‐imaging performance was synthesized by a typical hard‐templating method using monodispersed silica nanoparticles as the templates, which was based on unique molecularly organic/inorganic hybrid hollow periodic mesoporous organosilicas (HPMOs). The highly dispersed HPMOs show the uniform spherical morphology, large hollow interior, and well‐defined mesoporous structures, which are very beneficial for ultrasound‐based theranostics. The obtained HPMOs exhibit excellent performances in contrast‐enhanced ultrasonography both in vitro and in vivo and can be used for the real‐time determination of the progress of lesion tissues during the chemotherapeutic process. Importantly, hydrophobic paclitaxel‐ (PTX‐) loaded HPMOs combined with ultrasound irradiation show fast ultrasound responsiveness for controlled drug release and higher in vitro and in vivo tumor inhibition rates compared with free PTX and PTX‐loaded HPMOs, which is due to the enhanced ultrasound‐triggered drug release and ultrasound‐induced cavitation effect. Therefore, the achieved novel HPMOs‐based nanoparticle systems will find broad application potentials in clinically ultrasound‐based imaging and auxiliary tumor chemotherapy.

BACKGROUND: Many clinicians and hepatitis B virus (HBV)-infected pregnant women prefer elective caesarean section (ECS) to prevent mother-to-child transmission of HBV, since some studies found higher transmission of HBV in infants born by vaginal delivery (VD) than by cesarean section. However, other studies showed that ECS does not reduce the risk of being infected with HBV in infants. In this study, we aimed to clarify whether ECS may reduce the risk of mother-to-child transmission of HBV. METHODS: Totally 546 children (1-7-year-old) born to 544 HBsAg-positive mothers from 15 cities and rural areas across Jiangsu Province, China, were enrolled. Of these children, 137 (2 pairs of twins) were born to HBeAg-positive mothers; 285 were delivered by ECS and 261 others by VD (one pair of twin in each group). HBV serologic markers were tested by enzyme or microparticle immunoassay. RESULTS: The maternal and gestational ages, maternal HBeAg-positive rates, and children's ages, gender ratios, hepatitis B vaccine coverage and administrations of HBIG were comparable between ECS and VD groups (all p >0.05). The overall prevalence of HBsAg in the 546 children was 2.4%, with 2.5% (7/285) and 2.3% (6/261) in those born by ECS and VD respectively (p = 0.904). Further comparison of chronic HBV infection in the 137 children of HBeAg-positive mothers showed that the HBsAg-positive rates in ECS and VD groups were 10.3% (7/68) and 8.7% (6/69) respectively (p = 0.750), while the mothers had similar HBV DNA levels (2.38 × 106 vs. 2.35 × 106 IU/ml, p = 0.586). Additionally, the overall rate of anti-HBs ≥10 mIU/ml in the children was 71.6%, with 72.3% and 70.9% in those born by ECS and VD respectively (p = 0.717). CONCLUSIONS: With the recommended immunoprophylaxis against hepatitis B, ECS does not reduce the risk of mother-to-child transmission of HBV. Therefore, ECS should not be used in HBsAg-positive pregnant women to prevent mother-to-child transmission of HBV.

Invasive micropapillary carcinoma (IMPC) is a rare histopathological variant of breast carcinoma that is usually associated with poor clinical characteristics. Whether IMPC has worse prognosis than invasive ductal carcinoma (IDC) is controversial. This retrospective study examined the prognostic difference between IMPC and IDC. We analysed 327 cases of IMPC patients and 4979 IDC cases who underwent primary resection in our institution between 2008 and 2012. Using propensity score matching, the two groups were matched at 1:1 by age, tumour size, nodal status, hormone status, and HER2 status. Differences in prognosis were assessed by Kaplan-Meier estimates and Cox regression analysis. We established the IMPC group and identified 324 IDC patients by propensity score matching. The survival analysis indicated that IMPC patients had no significant reduced overall survival (p = 0.752) or disease-free survival (p = 0.578) compared with IDC patients. Multivariate Cox regression analysis revealed that IMPC was not an independent prognostic factor for disease-free survival (hazard ratio [HR] = 0.944; 95% confidential interval [CI], 0.601-1.481) or overall survival (HR = 0.727; 95% CI, 0.358-1.478). Survival analysis demonstrated no statistically significant difference between IMPC and IDC, indicating that proactive or radical clinical therapy is unnecessary.

BACKGROUND: Anhedonia is a prominent symptom of major depressive disorder (MDD) and schizophrenia. At present, it is believed that hedonic processing rather consists of the anticipatory and consummatory phase. The aim of this research is to explore the different anhedonia components in MDD and schizophrenia in Chinese populations. METHODS: A Chinese version of the Temporal Experience of Pleasure Scale (TEPS) was used to evaluate 176 MDD patients, 346 schizophrenia patients, and 268 healthy controls. Additionally, the 17-item Hamilton Depression Rating Scale (HAMD-17) was used for MDD patients, while the Positive and Negative Syndrome Scale (PANSS) was applied for schizophrenia. RESULTS: The scores of consummatory (TEPS-CON) and anticipatory pleasure (TEPS-ANT) in MDD and schizophrenia were both significantly lower than healthy controls (both P < 0.001). TEPS-CON and TEPS-ANT were negatively correlated with the score of HAMD-17, the duration of illness and admission times in MDD (P < 0.05 or 0.01). TEPS-CON was negatively related to PANSS total scores and negative symptoms (P < 0.05 or 0.01), but no significant correlation was found with duration of illness and admission times in schizophrenia (P > 0.05). There was no significant correlation between TEPS-ANT and any clinical variables (P > 0.05). CONCLUSIONS: The consummatory and anticipatory pleasures were both impaired in MDD and schizophrenia. Consummatory and anticipatory anhedonia can be considered as a "state" in MDD, but as a "trait" in schizophrenia.

Wound healing is a major secondary complication in type 2 diabetes, which results in significant disability and mortality, imposing a significant clinical and social burden. Sustained activation of the Nod‐like receptor protein (NLRP) inflammasome in wounds is responsible for excessive inflammatory responses and aggravates wound damage. The activation of the NLRP3 inflammasome is regulated by a two‐step process: the priming/licensing (signal 1) step involved in transcription and posttranslation and the protein complex assembly (signal 2) step triggered by danger molecules. This review focuses on the advances made in understanding the pathophysiological mechanisms underlying wound healing in the diabetic microenvironment. Simultaneously, this review summarizes the molecular mechanisms of the main regulatory pathways associated with signal 1 and signal 2, which trigger the NLRP3 inflammasome complex assembly in the development of diabetic wounds (DW). Activation of the NLRP3 inflammasome‐related pathway, involving the disturbance in Nrf2 and the NF‐ κ B/NLRP3 inflammasome, TLR receptor‐mediated activation of the NF‐ κ B/NLRP3 inflammasome, and various stimuli inducing NLRP3 inflammasome assembly play a pivotal role in DW healing. Furthermore, therapeutics targeting the NLRP3 inflammasome‐related pathways may promote angiogenesis, reprogram immune cells, and improve DW healing.

BACKGROUND: Several recent reports have demonstrated that tyrosine (Y)-methionine (M)-aspartic acid (D)-aspartic acid (D) (YMDD) motif mutations can naturally occur in chronic HBV patients without antiviral treatment such as lamivudine therapy. This paper aims to assess the overall spontaneous incidence and related risk factors of YMDD-motif mutations among lamivudine-naïve chronic HBV carriers, so as to provide some clue for clinical treatment of hepatitis B. METHODOLOGY/PRINCIPAL FINDINGS: Chinese and English literatures were searched for studies reporting natural YMDD mutations among untreated chronic HBV patients from 2001 to 2010. The incidence estimates were summarized and analyzed by meta-analyses. Forty-seven eligible articles from eight countries were selected in this review (13 in English and 34 in Chinese). The pooled incidence of YMDD-motif mutation among untreated chronic HBV patients from eight countries was 12.21% (95% CI: 9.69%-14.95%). China had an incidence of 13.38% (95% CI: 10.90%-16.07%) and seven other countries had an incidence of 9.90% (95% CI: 3.28%-19.55%), respectively. Lamivudine therapy would increase the risk of mutations 5.23 times higher than the untreated patients. A higher HBV DNA copy number was associated with increased incidence of natural YMDD mutation. No significant difference was found in YMDD mutation incidence between groups of different gender, age, HBeAg status, patients' ALT (alanine aminotransferase) level, and between the groups of HBV genotype B and C. CONCLUSIONS: The YMDD-motif mutations can occur spontaneously with a relatively high incidence in CHB patients untreated with lamivudine. These mutations might be the consequence of accumulated base mismatch due to the nature of viral polymerase. More fundamental and clinical studies are needed to clarify the influence of YMDD mutations in hepatitis B progression and antiviral treatment.

To investigate the effect and potential mechanism of 3,3'-diindolylmethane (DIM) on ferroptosis against gastric cancer, cells proliferation, lipid reactive oxygen species (ROS) and GSH level were measured in the BGC-823 gastric cancer cells after DIM treatment. Western blotting was used to detect the expression of SLC7A11, GPX4, IP3R and BAP1. Results showed that DIM could induce ferroptosis in the BGC-823 gastric cancer cells via upregulating lipid-ROS level and decreasing GSH generation. Besides, DIM also significantly reduced the protein level of SLC7A11 and GPX4, which was an important regulator of ferroptosis. In addition, DIM promoted the protein level of BAP1 and IP3R in a concentration-dependent manner in the BGC-823 gastric cancer cells. The knockdown of BAP1 could reduce IP3R level and DIM-induced ferroptosis of gastric cancer cells. Taken together, these results indicated that DIM could induce ferroptosis to exert anti-cancer effects via BAP1-IP3R axis, suggesting its effective therapeutic potential in gastric cancer.