The novel DNA methylation marker FIBIN suppresses non-small cell lung cancer metastasis by negatively regulating ANXA2.

OBJECTIVES: The clinical T1 stage solid lung cancer with metastasis is a serious threat to human life and health. In this study, we performed RNA sequencing on T1 advanced-stage lung cancer and adjacent tissues to identify a novel biomarker and explore its roles in lung cancer. METHODS: Quantitative reversed-transcription PCR, reverse transcription PCR and Western blot, MSP and Methtarget were utilized to evaluate FIBIN expression levels at both the transcriptional and protein levels as well as its methylation status. Differential target protein was evaluated for relative and absolute quantitation by isobaric tags. Co-IP was performed to detect the interactions between target protein. Precise location and expression levels of target proteins were revealed by immunofluorescence staining and component protein extraction using specific kits, respectively. RESULTS: We reported that FIBIN was frequently silenced due to promoter hypermethylation in lung cancer. Additionally, both in vitro and in vivo experiments confirmed the significant anti-proliferation and anti-metastasis capabilities of FIBIN. Mechanistically, FIBIN decreased the nuclear accumulation of ß-catenin by reducing the binding activity of GSK3ß with ANXA2 while promoting interaction between GSK3ß and ß-catenin. CONCLUSION: Our findings firstly identify FIBIN is a tumor suppressor, frequently silenced due to promoter hypermethylation. FIBIN may serve as a predictive biomarker for progression or metastasis among early-stage lung cancer patients.

Diagnostic utility of HFLC% and IG% for acute Pancreatitis-A retrospective Case-Control study.

Objective: To evaluate the occurrence, development and outcome value of hyperfluorescent lymphocyte percentage (HFLC%) and immature granulocyte percentage (IG%) for acute pancreatitis (AP). Methods: The laboratory data collected from 1533 patients diagnosed with AP between August 2018 and August 2022 were retrospectively analyzed. The patients were classified into mild acute pancreatitis (MAP) and non-mild acute pancreatitis (Non-MAP) groups; non-MAP groups were additionally subgrouped based on HFLC% at day 7. White blood cells (WBC), HFLC%, and IG% were examined from day 1 (baseline) to day 14 post-admission using Sysmex XN Series Hematology Analyzers. C-reactive protein (CRP), serum amylase (AMY), and lipase (LPS) were detected by Beckman AU5800. Results: A total of 623 patients were finally included in the study [MAP group (n = 358) and Non-MAP group (n = 265)]. WBC, IG%, and CRP were higher in the Non-MAP group from day 1 to day 12 (all P<0.05). The HFLC% was not statistically significant from day 1 to day 6; yet, it increased on day 6 and 7 in the Non-MAP group. We divided patients in the Non-MAP group with complete data(101 patients) into HFLC% ≥ 2.9 %(31 patients) and HFLC% < 2.9 %(70 patients) according to the threshold of 7th day HFLC%. WBC, HFLC%, IG%, and CRP effectively predicted the progression of MAP to Non-MAP (all P < 0.001). HFLC% was the most obvious value, followed by CRP and IG%. Combined with HFLC%, IG%,CRP and WBC in day7, the ROC analysis showed that the area under ROC curve of the combined indicators was the largest (AUC = 0.912, P < 0.001) and had higher sensitivity and specificity than single-item assessment of AP outcomes(P < 0.05). HFLC% < 2.9 %, IG% > 1.7 %, CRP >28.66 mg/L, and WBC >9.24 × 109/L indicated the possibility of AP disease aggravation. Also, HFLC% <2.9 % was directly associated with infection, SIRS, APPACHII grade, and ICU admission (all P < 0.05). In non-MAP there was a significant negative correlation between HFLC% and APACHE-II score (rs = -0.312, P = 0.023). Conclusion: HFLC% <2.9 % on 7th day was directly indicated more infection, systemic inflammatory response syndrome(SIRS), higher APPACH II grade and ICU admission. HFLC% may be an independent laboratory marker for prognosis in AP. Combining HFLC% with IG%, CRP, and WBC helps evaluate AP patients' disease development and outcome.

CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis.

BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.

Development and application of the physiologically-based toxicokinetic (PBTK) model for ochratoxin A (OTA) in rats and humans.

Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (Fup) of OTA in plasma of rat and human was 0.02-0.04% and 0.13-4.21%, respectively. In vitro experiments, the maximum enzyme velocity (Vmax) and Michaelis-Menten constant (Km) of OTA in rat and human liver microsomes were 3.86 and 78.17 µg/g min-1, 0.46 and 4.108 µg/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.

Systematic characterization of the chemical constituents in vitro and in vivo of Qianghuo by UPLC-Q-TOF-MS/MS.

The Chinese herb Qianghuo is an antiphlogistic herb with many effects and complex components. In this study, the chemical composition of Qianghuo and its components in rat plasma after oral administration were investigated using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). The extracts, blank plasma, and plasma containing the drug were analyzed by mass spectrometry, and data collected in both positive and negative ion modes were analyzed using Masslynx software, and the structures were confirmed by combining the compound fragment ions and mass spectrometry cleavage pathways. A total of 62 in vitro chemical components were identified, including 27 coumarins, 18 organic acids, 5 amino acids, 5 glycosides, 2 flavonoids, 4 nucleotides, and 1 ester, which were summarized from the obtained compounds in terms of their possible cleavage patterns. Among the identified 31 compounds in rat plasma, 21 were prototypes, mostly coumarins, organic acids, and flavonoids, and 10 were metabolites, which were mainly generated via hydroxylation and methylation pathways. Based on these, this study provides a theoretical foundation for quality control and basic research on Qianghuo medicinal substances.

Prevalence of falls, injury from falls and associations with chronic diseases among community-dwelling older adults in Guangzhou, China: a cross-sectional study.

Introduction: As a developing country with the largest older adult population in the world, strengthening the research on falls among the older adults is undoubtedly an urgent item in China. This study aimed to explore the prevalence and risk factors associated with falls and injury from falls among community-dwelling older adults in Guangzhou, China, particularly focusing on their associations with chronic diseases. Methods: A total of 1,629 participants aged 65 years and above were selected from 11 counties in Guangzhou by the multi-stage stratified random sampling method in 2021. Socio-demographic characteristics, health and lifestyle factors, the status of falls, and injury from falls were measured by structured questionnaires through face-to-face interviews. Chi-square tests and logistic regression analysis were used to identify factors associated with falls and injury from falls. Chord diagrams were used to explore their associations with chronic diseases. Results: A total of 251 participants (15.41%, 95% CI: 13.98%-17.25%) reported falls, and 162 participants (9.46%, 95% CI:7.72%-11.55%) indicated an injury from falls. Logistic regression analysis showed the results as follows: female patients (adjusted OR = 1.721, 95% CI: 1.681-1.761) aged ≥80 years (1.910, 1.847-1.975), unemployed (1.226, 1.171-1.284), uninsured (1.555, 1.448-1.671), average monthly household income of 2,001-4,000 CNY (1.878, 1.827-1.930), number of services provided by the community health center ≥13 times per year (1.428, 1.383-1.475), illness within 2 weeks (1.633, 1.595-1.672), high-intensity physical activity (2.254, 2.191-2.32), sedentary (1.094, 1.070-1.117), and number of chronic disease illnesses ≥3 (1.930, 1.870-1.993). Meanwhile, those risk factors were also associated with injury from falls. The older adults with medium-intensity physical activity were at lower risk (0.721, 0.705-0.737) of falls and higher risk (1.086, 1.057-1.117) of being injured from falls. Chord diagrams showed the correlations between chronic diseases and falls and injury from falls among community-dwelling older adults in Guangzhou, China. Conclusion: The high prevalence of falls is found among community-dwelling older adults in Guangzhou, China, which is related to multiple factors such as demographic variables, lifestyle, and health status, especially for chronic diseases. Therefore, targeted interventions should be developed and implemented urgently.

Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia.

Neonatal respiratory system disease is closely associated with embryonic lung development. Our group found that integrin ß4 (ITGB4) is downregulated in the airway epithelium of asthma patients. Asthma is the most common chronic respiratory illness in childhood. Therefore, we suspect whether the deletion of ITGB4 would affect fetal lung development. In this study, we characterized the role of ITGB4 deficiency in bronchopulmonary dysplasia (BPD). ITGB4 was conditionally knocked out in CCSP-rtTA, Tet-O-Cre and ITGB4f/f triple transgenic mice. Lung tissues at different developmental stages were collected for experimental detection and transcriptome sequencing. The effects of ITGB4 deficiency on lung branching morphogenesis were observed by fetal mouse lung explant culture. Deleting ITGB4 from the airway epithelial cells results in enlargement of alveolar airspaces, inhibition of branching, the abnormal structure of epithelium cells and the impairment of cilia growth during lung development. Scanning electron microscopy showed that the airway epithelial cilia of the ß4ccsp.cre group appear to be sparse, shortened and lodging. Lung-development-relevant factors such as SftpC and SOX2 significantly decreased both mRNA and protein levels. KEGG pathway analysis indicated that multiple ontogenesis-regulating-relevant pathways converge to FAK. Accordingly, ITGB4 deletion decreased phospho-FAK, phospho-GSK3ß and SOX2 levels, and the correspondingly contrary consequence was detected after treatment with GSK3ß agonist (wortmannin). Airway branching defect of ß4ccsp.cre mice lung explants was also partly recovered after wortmannin treatment. Airway epithelial-specific deletion of ITGB4 contributes to lung developmental defect, which could be achieved through the FAK/GSK3ß/SOX2 signal pathway.

Neuroglobin plays as tumor suppressor by disrupting the stability of GPR35 in colorectal cancer.

BACKGROUND: The incidence of colorectal cancer (CRC) has increased in recent years. Identification of accurate tumor markers has become the focus of CRC research. Early and frequent DNA methylation tends to occur in cancer. Thus, identifying accurate methylation biomarkers would improve the efficacy of CRC treatment. Neuroglobin (NGB) is involved in neurological and oncological diseases. However, there are currently no reports on epigenetic regulation involvement of NGB in CRC. RESULTS: NGB was downregulated or silenced in majority CRC tissues and cell lines. The hypermethylation of NGB was detected in tumor tissue, but no or a very low methylation frequency in normal tissues. Overexpression of NGB induced G2/M phase arrest and apoptosis, suppressed proliferation, migration, invasion in vitro, and inhibited CRC tumor growth and angiogenesis in vivo. Isobaric tag for relative and absolute quantitation (Itraq)-based proteomics identified approximately 40% proteins related to cell-cell adhesion, invasion, and tumor vessel formation in the tumor microenvironment, among which GPR35 was proved critical for NGB-regulated tumor angiogenesis suppression in CRC. CONCLUSIONS: NGB, an epigenetically silenced factor, inhibits metastasis through the GPR35 in CRC. It is expected to grow into a potential cancer risk assessment factor and a valuable biomarker for early diagnosis and prognosis assessment of CRC.

Expression of fatty acid related gene promotes astaxanthin heterologous production in Chlamydomonas reinhardtii.

Natural astaxanthin is a high-value ketone carotenoid mainly derived from Haematococcus pluvialis, which is an excellent antioxidant for human consumption. To study the role of lipids in accumulation of astaxanthin, the H. pluvialis-derived astaxanthin synthesis pathway genes (ß-carotene ketolase gene, BKT and ß-carotene hydroxylase gene, BCH) and fatty acid elongation gene (mitochondrial trans-2-enoyl-coa reductase gene, MECR) were heterologously co-expressed in C. reinhardtii. Zeaxanthin, the precursor of astaxanthin synthesis, was significantly increased after BKT and BCH were expressed. In contrast, the α-carotene that competes with astaxanthin synthesis for lycopene decreased significantly. This redistribution of carbon flow was conducive to the synthesis of astaxanthin. In addition, the transformant only expressed astaxanthin metabolism related genes (BKT, BCH) would lead to an increase in total lipid, a decrease in monounsaturated fatty acids and an increase in polyunsaturated fatty acids. On this basis, the expression of MECR gene further increased the total lipid, and the relative content of different fatty acids also changed. The astaxanthin content of algal strains transformed with BKT and BCH genes was nearly 50% higher than that of the wild type. On this basis, the astaxanthin content of transformants expressing MECR gene related to long-chain fatty acid synthesis was increased by 227.5%. In this study, an astaxanthin production model similar to H. pluvialis by combining carotenoid metabolism and fatty acid metabolism was constructed in C. reinhardtii. The results suggest that the increase in astaxanthin is indeed linked to the regulation of fatty acid metabolism, and this link may involve the type of fatty acids and the dynamics of astaxanthin ester in cells. The strategy of promoting the synthesis of fatty acids has potential to achieve efficient production of astaxanthin in C. reinhardtii.

COLEC10 Induces Endoplasmic Reticulum Stress by Occupying GRP78 and Inhibits Hepatocellular Carcinoma.

Collectin subfamily member 10 (COLEC10), a C-type lectin mainly expressed in the liver, is involved in the development of hepatocellular carcinoma (HCC). However, its underlying molecular mechanism in HCC progression remains unknown. In this study, reduced COLEC10 expression in tumor tissues was validated using various HCC cohorts and was associated with poor patient prognosis. COLEC10 overexpression attenuated HCC cell growth and migration abilities in vitro and in vivo. We identified that COLEC10 was a novel interactor of 78-kDa glucose-regulated protein (GRP78), a master modulator of the unfolded protein response in the endoplasmic reticulum (ER). COLEC10 overexpression potentiated ER stress in HCC cells, as demonstrated by elevated expression levels of phosphorylated protein kinase RNA-like ER kinase, phosphorylated inositol-requiring protein 1α, activating transcription factor 4, DNA damage-inducible transcript 3, and X-box-binding protein 1s. The ER in COLEC10-overexpressing cells also showed a dilated and fragmented pattern. Mechanistically, COLEC10 overexpression increases GRP78 occupancy through direct binding by the C-terminal carbohydrate recognition domain in the ER, which released and activated the ER stress transducers protein kinase RNA-like ER kinase and phosphorylated inositol-requiring protein 1α, triggering the unfolded protein response activity. COLEC10-overexpressing HCC cells generated a relatively high reactive oxygen species level and switched to apoptotic cell death under sorafenib-treated conditions. Our study provides the first novel view that COLEC10 inhibits HCC progression by regulating GRP78-mediated ER stress signaling and may serve as a promising therapeutic and prognostic biomarker.

NTF4 plays a dual role in breast cancer in mammary tumorigenesis and metastatic progression.

Breast cancer metastasis can happen even when the primary tumor is relatively small. But the mechanism for such early metastasis is poorly understood. Herein, we report that neurotrophin 4 (NTF4) plays a dual role in breast cancer proliferation and metastasis. Clinical data showed high levels of NTF4, especially in the early stage, to be associated with poor clinical outcomes, supporting the notion that metastasis, rather than primary cancer, was the major determinant of breast cancer mortality for patients. NTF4 promoted epithelial-mesenchymal transition (EMT), cell motility, and invasiveness of breast cancer cells in vitro and in vivo. Interestingly, NTF4 inhibited cell proliferation while promoting cellular apoptosis in vitro and inhibited xenograft tumorigenicity in vivo. Mechanistically, NTF4 elicited its pro-metastatic effects by activating PRKDC/AKT and ANXA1/NF-κB pathways to stabilize SNAIL protein, therefore decreasing the level of E-cadherin. Conversely, NTF4 increased ANXA1 phosphorylation and sumoylation and the interaction with importin ß, leading to nuclear import and retention of ANXA1, which in turn activates the caspase-3 apoptosis cascade. Our findings identified an unexpected dual role for NTF4 in breast cancer which contributes to early metastasis of the disease. Therefore, NTF4 may serve as a prognostic marker and a potential therapeutic target for breast cancer.

ADAM17 regulates the proliferation and extracellular matrix of keloid fibroblasts by mediating the EGFR/ERK signaling pathway.

To investigate the role of a disintegrin and metalloprotease protein 17 (ADAM17) in regulating the proliferation and extracellular matrix (ECM) expression of keloid fibroblasts (KFs) via the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway. ADAM17 expression in keloid tissues was detected by western blotting. KFs were isolated, cultured and divided into the control, shNC (negative control), shADAM17, transforming growth factor-ß1 (TGF-ß1), TGF-ß1 + shNC and TGF-ß1 + shADAM17 groups. The expression of ECM was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Western blotting was performed to detect the expression of proteins. Cell proliferation was detected by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, while cell invasion and migration were examined by Transwell and wound healing assays. The expression of ADAM17 was increased in keloid tissues and KFs. Compared with the control group, the expression of p-EGFR and p-ERK/1/2/ERK1/2, as well as the expression of collagen I, collagen III, connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA), were decreased in KFs from the shADAM17 group, with decreased cell proliferation, invasion and migration. In contrast, the TGF-ß1 group presented the opposite trend in these aspects. In addition, compared with the TGF-ß1 group, KFs from the TGF-ß1 + shADAM17 group had decreased ECM expression, proliferation, invasion and migration. ADAM17 expression was upregulated in keloid tissues. Silencing ADAM17 may inhibit the activity of the EGFR/ERK pathway to limit the deposition of ECM in KFs with reduced proliferation, invasion and migration.

Brain-specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury.

Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP-binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time-course changes of cholesterol metabolism-related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post-TBI, we generated nestin-specific Abcg1 knockout (Abcg1-KO) mice using the Cre/loxP recombination system. These Abcg1-KO mice showed reduced plasma high-density lipoprotein cholesterol levels and increased plasma lower-density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1-KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1-KO exacerbated TBI-induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1-KO mice partly rescued TBI-induced neuronal damages mentioned above and improved functional deficits versus vehicle-treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.

KLF15 suppresses tumor growth and metastasis in Triple-Negative Breast Cancer by downregulating CCL2 and CCL7.

Kruppel like factor 15 (KLF15), a transcriptional factor belonging to the Kruppel-like factor (KLF) family of genes, has recently been reported as a tumor suppressor gene in breast cancer. However, the specific mechanisms by which KLF15 inhibits BrCa have not been elucidated. Here we investigated the role and mechanism of KLF15 in triple-negative breast cancer (TNBC). KLF15 expression and methylation were detected by RT-qPCR, RT-PCR and methylation-specific PCR in breast cancer cell lines and tissues. The effects of KLF15 on TNBC cell functions were examined via various cellular function assays. The specific anti-tumor mechanisms of KLF15 were further investigated by RNA sequence, RT-qPCR, Western blotting, luciferase assay, ChIP, and bioinformatics analysis. As the results showed that KLF15 is significantly downregulated in breast cancer cell lines and tissues, which promoter methylation of KLF15 partially contributes to. Exogenous expression of KLF15 induced apoptosis and G2/M phase cell cycle arrest, suppressed cell proliferation, metastasis and in vivo tumorigenesis of TNBC cells. Mechanism studies revealed that KLF15 targeted and downregulated C-C motif chemokine ligand 2 (CCL2) and CCL7. Moreover, transcriptome and metabolome analysis revealed that KLF15 is involved in key anti-tumor regulatory and metabolic pathways in TNBC. In conclusion, KLF15 suppresses cell growth and metastasis in TNBC by downregulating CCL2 and CCL7. KLF15 may be a prognostic biomarker in TNBC.

Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, and about 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed. METHODS: We performed whole-exome sequencing of matched tumor tissues and blood samples from 53 pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. RESULTS: A total of 6,588 protein-altering events were found and the five most frequent mutated genes in our pGI-DLBCL cohort were IGLL5 (47%), TP53 (42%), BTG2 (28%), P2RY8 (26%) and PCLO (23%). Compared to the common DLBCL, significantly less or absence of MYD88 (0%), EZH2 (0%), BCL2 (2%) or CD79B (8%) mutations were identified in pGI-DLBCL. The recurrent potential driver genes were mainly enriched in pathways related to signal transduction, infectious disease and immune regulation. In addition, HBV infection had an impact on the mutational signature in pGI-DLBCL, as positive HBsAg was significantly associated with the TP53 and LRP1B mutations, two established tumor suppressor genes in many human cancers. Moreover, IGLL5 and LRP1B mutations were significantly correlated with patient overall survival and could serve as two novel prognostic biomarkers in pGI-DLBCL. CONCLUSIONS: Our study provides a comprehensive view of the exonic mutation profile of the largest pGI-DLBCL cohort to date. The results could facilitate the clinical development of novel therapeutic and prognostic biomarkers for pGI-DLBCL.

Association between meteorological factors and elderly falls in injury surveillance from 2014 to 2018 in Guangzhou, China.

Introduction: With rapid increase in the aging population, falls injuries have become an important public health problem. However, limited data have been reported on the associations between meteorological factors and falls injuries in the elderly. This study assessed the epidemiology of falls injuries and explored this association in the elderly in Guangzhou, China. Methods: Data on elderly falls injury cases and meteorological variables from 2014 to 2018 in Guangzhou were collected from the Guangzhou Injury Monitoring System and Guangzhou Meteorological Bureau, respectively. The monthly average data on falls injuries and meteorological factors were applied to the data analysis. These correlations were conducted using Pearson correlation analysis. A multiple linear regression model was used to estimate the effects of meteorological factors on falls injuries in the elderly in Guangzhou, China. Results: Accounting for 49.41% of causes of elderly injury were falls in the Guangzhou Injury Monitoring System from 2014 to 2018, which occupied first place for five consecutive years. The monthly number of elderly falls injury cases was lowest in April and highest in December, and had a positive correlation with monthly mean wind speed (r = 0.187, P < 0.01) and a negative correlation with monthly atmospheric pressure (r = -0.142, P < 0.05). A multiple linear regression model was constructed (F = 10.176, P < 0.01), which explained 23.7% of the variances (R 2 = 0.237). Monthly mean wind speed (ß = 76.85, P < 0.01) and monthly mean atmospheric pressure (ß = -3.162, P < 0.01) were independent factors affecting monthly elderly falls injuries. Conclusions: Falls are the primary cause of injury among elderly people in Guangzhou, China. Meteorological factors are related to falls injuries in the elderly population. Decreasing activity during high wind and low atmospheric pressure weather may help reduce the number of elderly falls injury cases.

A novel dibenzofuran from endophytic fungus Mycosphaerella nawae preferentially inhibits CD4+ T cell activation and proliferation.

AIM: To obtain promising immunosuppressants from endophytic fungus. METHODS AND RESULTS: The endophytic fungus Mycosphaerella nawae (ZJLQ129) was isolated from the plant Smilax china L. and its secondary metabolites extracted and fractionated through column chromatography. The metabolites were further modified by a derivatization reaction with ammonium hydroxide. After isolation and derivatization, a new dibenzofuran named as (+)isomycousnine enamine (iME) was obtained. The structures of the derivatives were determined based on chemical evidences and extensive spectroscopic methods including 2D-NMR, DEPT and HRESI-MS spectra. The immune activities of iME were first evaluated on the proliferation and cytokines (IL-2 and IFN-γ) production of T and B cells by using MTT and ELISA methods respectively. Then, its effects on the proliferation of T-cell subsets (CD4+ and CD8+ T cells), as well as CD25 and CD69 expressions were also determined by flow cytometry. Finally, by using Cytometric Bead Array (CBA), the impacts of iME on the secretion of Th1/Th2/Th17 cytokines from purified CD4+ T cells were assayed. The results showed that iME not only selectively suppressed the immune responses of T cells, but also preferentially inhibited the activation and proliferation of CD4+ T cells. CONCLUSION: A novel dibenzofuran derived from endophytic fungus Mycosphaerella nawae preferentially inhibits CD4+ T-cell activation and proliferation. SIGNIFICANCE AND IMPACT OF THE STUDY: This work obtained iME, a new dibenzofuran derived from endophytic fungus. iME has the capacity to inhibit CD4+ T-cell activation and therefore is a novel potential immunosuppressant for development in the future.

[Identification of the potential distribution area of Cunninghamia lanceolata in China under climate change based on the MaxEnt model]. / 基于MaxEnt模型预测气候变化下杉木在中国的潜在地理分布.

Based on the distribution records of Cunninghamia lanceolata, we used the maximum Entropy (MaxEnt) model and geographic information system (GIS) methods, combined with environmental factors such as climate and terrain, to predict the potential distribution areas suitable for C. lanceolata under current and future climate scenarios. The results showed that annual precipitation was the most important factor driving the distribution of C. lanceolata. Under the current climate scenario, the total area of suitable for C. lanceolata growth was about 3.28 million km2, accounting for about 34.5% of the total land area of China. Among all the suitable areas, the lowly, intermediately, and highly suitable areas accounted for 18.3%, 29.7% and 52.0% of the total, respectively. Under future climate scenarios, the suitable area of C. lanceolata would increase, showing a clear trend of northward expansion in China. A concentrated and contiguous distribution region highly suitable for C. lanceolata would appear in the humid subtropical areas of southern China. The model was tested by the receiver operating characteristic curve (ROC). The average area under the curve of ROC of the training set was 0.91, showing high reliability.