Metformin synergistically enhances the antitumour activity of Lenvatinib in hepatocellular carcinoma by altering AKT-FOXO3 signalling pathway.

BACKGROUND AND AIMS: Lenvatinib is a first-line drug commonly used in the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is very limited due to drug resistance. Therefore, there is a great need to explore its combination with other agents to achieve better therapeutic effects. Metformin has been demonstrated to show an anti-cancer effect. This study aimed to investigate the combined effect of lenvatinib with metformin in HCC cells both in vitro and in vivo and elucidate the possible molecular mechanisms. METHODS: Flow cytometry, colony formation, CCK-8 and transwell assays were used to study the effect of Lenvatinib-Metformin combination on the malignant behaviour of HCC cells in vitro. Constructing an animal model of tumour-bearing to study the effect of combined drugs on HCC in vivo. Western blot experiments were performed to assess the relationship between AKT and FOXO3 and the cellular translocation of FOXO3. RESULTS: Our results suggested that Lenvatinib and Metformin synergistically inhibited HCC growth and motility. Mechanistically, the combination of Lenvatinib and Metformin synergistically suppressed the activation of the AKT signalling pathway, which in turn reduced the phosphorylation level of downstream effector FOXO3 and induced its nuclear aggregation. In vivo studies further confirmed the synergistic suppression of lenvatinib with metformin in HCC growth. CONCLUSION: The Lenvatinib-Metformin combination may provide a potential therapeutic strategy to improve the prognosis of HCC patients.

Renal functional impairment in the elderly, the importance of fasting plasma glucose: the Northern Shanghai Study.

BACKGROUND: Chronic kidney disease is a global health problem that is closely related to the aging population. Although plasma glucose levels have been shown to be related to renal dysfunction, risk factors for renal functional impairment in the geriatric population are unknown. The authors therefore aimed to investigate the determinants of renal functional impairment in an elderly population. METHODS: From June 2014 to August 2015, 912 participants (aged > 65 years) were recruited. Renal function was assessed at baseline; follow-up was conducted in 2016. Within the framework of comprehensive cardiovascular examinations, all conventional cardiovascular risk factors, fasting plasma glucose (FPG), and renal function were assessed. Renal function was evaluated by the estimated glomerular filtration rate (e-GFR) using a modified Modification of Diet in Renal Disease formula. Rapid decline in e-GFR was defined as an e-GFR slope > 5 mL/min per 1.73 m2 per year. RESULTS: We observed that FPG levels were significantly higher in participants with (6.15 ± 2.76 mmol/L) than in those without (5.56 ± 1.61 mmol/L) a rapid decline in e-GFR (p = 0.02). The average decline in e-GFR was 0.149 mL/min/1.73m2 per year in this elderly population, and the increasing risk of having rapid decline in e-GFR was 0.44-fold each year. In the full adjustment model, decline in e-GFR (p = 0.02) and rapid decline in e-GFR (OR1.33, 95% CI 1.03-1.72) were significantly associated with FPG, independent of other conventional cardiovascular risk factors. Using the same models, decline in e-GFR (p = 0.04) and rapid decline in e-GFR (OR 1.57, 95% CI 1.05-2.35) were also significantly associated with FPG in diabetic population, but they were not in non-diabetic population. CONCLUSIONS: In community-dwelling elderly Chinese, the average decline in e-GFR was 0.149 mL/min/1.73m2 per year. FPG control is important for delaying renal functional impairment in elderly population. Trial registration NSS, NCT02368938.

The association of four-limb blood pressure differences with cardiovascular risk factors and target organ changes in elderly Chinese: The Northern Shanghai Study.

Background: The association of four-limb systolic blood pressure differences (SBPDs) including inter-arm (IASBPD), inter-leg (ILSBPD) and ankle-brachial index (ABI) with cardiovascular risk factors and target organ changes (TOCs) remains controversial. This study aims at investigating the association of those parameters with cardiovascular risk factors and TOCs in an elderly Chinese population.Methods: A total of 1528 subjects derived from the Northern Shanghai Study were studied. Four-limb BPs were simultaneously measured by VP-1000 device. Cardiovascular risk factors and TOCs including parameters of left ventricular structure and function, carotid intima-media thickness, carotid-femoral pulse-wave velocity (CF-PWV), estimated glomerular filtration rate (eGFR) and urinary albumin/creatinine ratio, were evaluated with standardized methods.Results: ABI significantly associated age (ß = -0.004, p < .01), female gender (ß = 0.02, p < .01), body mass index (ß = -0.004, p < .01), smoking (ß = -0.04, p < .01), high-density lipoprotein (ß = 0.04, p < .01), low-density lipoprotein (ß = -0.01, p = .01) and diabetes mellitus (ß = -0.02, p < .01), while the fourth root of IASBPD significantly associated with body mass index (ß = 0.03, p < .01), high-density lipoprotein (ß = -0.10, p = .02) and brachial SBP (ß = 0.003, p < .01); the fourth root of ILSBPD significantly associated with high-density lipoprotein (ß = -0.12, p < .01) and diabetes mellitus (ß = 0.09, p = .01). IASBPD, ILSBPD, and ABI all significantly associated with CF-PWV and eGFR (all p < .05) in either unadjusted or adjusted models, but not with other TOCs.Conclusion: Four-limb SBPDs, namely ABI, IASBPD, and ILSBPD, bore various burdens of cardiovascular risk factors and significantly and independently associated with CF-PWV and eGFR.

Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy.

While most mitochondrial proteins are encoded in the nucleus and translated on cytosolic/endoplasmic reticulum ribosomes, proteins encoded by mitochondrial DNA are translated on mitochondrial ribosomes. Mitochondrial GTPases 1 (MTG1) regulates mitochondrial ribosome assembly and translation, but its impact on cardiac adaptation to stress is unknown. Here, we found that MTG1 is dramatically elevated in hearts of dilated cardiomyopathy patients and in mice exposed to left ventricular pressure overload (AB). To examine the role of MTG1 in cardiac hypertrophy and heart failure, MTG1 loss/gain of function studies were performed in cultured cardiomyocytes and mice exposed to hypertrophic stress. MTG1 shRNA and adenoviral overexpression studies indicated that MTG1 expression attenuates angiotensin II-induced hypertrophy in cultured cardiomyocytes, while MTG1 KO mice exhibited no observable cardiac phenotype under basal conditions. MTG1 deficiency significantly exacerbated AB-induced cardiac hypertrophy, expression of hypertrophic stress markers, fibrosis, and LV dysfunction in comparison to WT mice. Conversely, transgenic cardiac MTG1 expression attenuated AB-induced hypertrophy and LV dysfunction. Mechanistically, MTG1 preserved mitochondrial respiratory chain complex activity during pressure overload, which further attenuated ROS generation. Moreover, we demonstrated that TAK1, P38 and JNK1/2 activity is downregulated in the MTG1 overexpression group. Importantly, dampening oxidative stress with N-acetylcysteine (NAC) lowered hypertrophy in MTG1 KO to WT levels. Collectively, our data indicate that MTG1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by preserving mitochondrial function and reducing oxidative stress and downstream TAK1 stress signaling.

Fabrication and analysis of tantalum pentoxide optical waveguide resonator of high thermal stability.

We fabricated waveguide resonators with high thermal stability using tantalum pentoxide thin film covered with PECVD silicon dioxide cladding. Without complex athermal design, low temperature dependence of 7.4 pm/°C and 8.15 pm/°C were measured in waveguide Bragg gratings (WBG) and Fabry-Perot resonator sandwiched by a pair of identical WBG mirrors, respectively. Suggested by semi-analytical perturbation calculations, the athermal properties of tantalum pentoxide waveguide grating are attributed not only to the low thermo-optical coefficient in tantalum pentoxide thin film but also to the strong chromatic dispersion of the guided modes. Guidelines are proposed to design waveguide-based frequency devices of low thermo-optical effect without complex athermal design.

The tumor suppressor DLC1 inhibits cancer progression and oncogenic autophagy in hepatocellular carcinoma.

Downregulation of deleted in liver cancer 1 (DLC1) is associated with poor prognosis of various cancers, but its functional mechanisms in hepatocellular carcinoma (HCC) remains unclear. In the present study, we investigated the roles of DLC1 in tumor progression and autophagy of HCC. We found that DLC1 was frequently downregulated in HCC tissues. Underexpression of DLC1 correlated with AFP level, vascular invasion, poor differentiation, and poor prognosis. In vitro assays revealed that DLC1 not only suppressed the proliferation, migration, and invasion of HCC cells, but also inhibited autophagy of HCC cells. Mechanistic investigation revealed that DLC1 decreased TCF4 expression and the interaction between ß-catenin and TCF4, then inactivated Wnt/ß-catenin signaling. Additionally, DLC1 suppressed the ROCK1 activity and the dissociation of the Beclin1-Bcl2 complex, thereby inhibiting autophagy of HCC cells. In conclusion, our findings imply that loss of DLC1 contributes to the progression and oncogenic autophagy of HCC.

Predictive value of left atrial appendage lobes on left atrial thrombus or spontaneous echo contrast in patients with non-valvular atrial fibrillation.

BACKGROUND: Left atrial appendage morphology has been proved to be an important predictor of left atrial thrombus (LAT) and left atrial spontaneous echo contrast (LASEC) and stroke in patients with non-valvular atrial fibrillation (NVAF). However, the relation between left atrial appendage (LAA) lobes and LAT or LASEC is still unknown. The aim of this study is to investigate the correlation between the number of left atrial appendage lobes and LAT/LASEC in patients with NVAF. METHODS: This monocentric cross-sectional study enrolled 472 consecutive patients with non-valvular atrial fibrillation, who had transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) prior to cardioversion or left atrial appendage closure (LAAC) from July 2009 to August 2015 in department of cardiology of Shanghai Tenth People's Hospital. Patients who had significant mitral or aortic valve disease, previous cardiac valvular surgery and other complicated cardiac diseases were excluded. Individuals were divided into two groups:the LAT/LASEC group (16.95%), which comprised patients with LAT or LASEC, as confirmed by TEE; and a negative control group (83.05%).Baseline overall group characterization with demographic, clinical, laboratory data and echocardiographic parameters, alongside with information on medication was obtained for all patients. Subgroup analysis with line chart was applied for exploring the association between LAA lobes and LAT/LAESC. Receptor-operating curves (ROC) were used to test the value of LA anteroposterior diameter detected by different echocardiography methods predicting LAT or LASEC. Multivariable logistic regression analysis was used to investigate independent predictors of LAT/LASEC. RESULTS: Among 472 patients, 23 (4.87%) had LA/LAA thrombus and 57 (12.1%) had LA spontaneous echo contrast. Compared to the negative group, patients in LAT/LASEC group had higher CHA2DS2-VASc score (3.79 ± 1.75 vs 2.65 ± 1.76, p < 0.001), larger LAD (measured by TTE, 48.1 ± 7.7 vs 44.6 ± 6.5, P < 0.001; measured by TEE, 52.2 ± 6.2 vs 46.7 ± 7.1, P < 0.001), lower left upper pulmonary venous flow velocity (LUPVFV) (0.54 ± 0.17 m/s vs 0.67 ± 0.26 m/s, CI 95% 0.05-0.22, P = 0.003), more left atrial appendage lobes (1.67 ± 0.77 vs 1.25 ± 0.50, p < 0.001). There was a good discriminative capacity for LAD detected by TTE (area under the curve (AUC), 0.67, CI 95% 0.61-0.73, p < 0.001) and LAD detected by TEE (AUC, 0.73, CI 95% 0.67-0.79, p < 0.001). The subgroup analysis based on gender and different LAA lobes yielded similar results (male group: p < 0.001;female group: p = 0.004) that the number of LAA lobes were significantly associated with LA thrombus or SEC. In multivariable logistic regression analysis, both the number of LAA lobes (odds ratio: 2.37; CI 95% 1.37-4.09; p = 0.002) and the persistent AF (odds ratio: 3.57; CI 95% 1.68-7.57; p = 0.001) provided independent and incremental predictive value beyond CHA2DS2-VASc score. CONCLUSION: The number of LAA lobes is an independent risk factor and has a moderate predictive value for LAT/LASEC among NVAF patients in China.

Comparison of various lipid parameters in association of target organ damage: a cohort study.

BACKGROUND: Recommendations of non-HDL amplification varied from different guidelines. We aim to test the relationships between various lipid parameters and target organ damage (TOD) including aortic stiffness, peripheral arterial disease and chronic kidney disease in a community-based elderly cohort. METHODS: 1599 (aged 71.4 ± 6.1 years) participants were recruited. Eight lipid parameters, including total cholesterol (TC), triglycerides (TG), LDL-C, HDL-C, non-HDL-C, TC/HDL ratio, TG/HDL ratio and LDL/HDL ratio, together with other plasma biomarkers like creatinine were measured. Pulse wave velocity (PWV) was measured by the SphygmoCor device, and ankle-brachial index (ABI) was assessed by Omron VP-1000 device. RESULTS: Four individual lipid parameters (TC, TG, LDL-C and HDL-C) significantly correlated with most, but not all, TOD indices. Meanwhile, 4 combined lipid parameters, namely non-HDL-C, TC/HDL, TG/HDL and LCL/HDL, significantly correlated with all TOD (P ≤ 0.033). In multiple linear regression analyses, 4 combined lipid parameters also significantly associated with TOD (P ≤ 0.027), while none of individual lipid parameters significantly associated with all TOD indices. In multiple logistic regression analyses, only non-HDLC and TC/HDL significantly associated with TOD (P ≤ 0.039), and other lipid parameters did not significantly associate with TOD. CONCLUSION: In an elderly community sample, non-HDLC and TC/HDLC were better associated with TOD than other lipid parameters. This finding should be considered in future clinical lipid-lowing therapy. TRIAL REGISTRATION: This trial was retrospectively registered in ClinicalTrials.gov (No. NCT02368938 , registered on 15 Feb 2015).

Blood pressure goal for the elderly Chinese: the findings from the Northern Shanghai Study.

BACKGROUND: The Eighth Joint National Committee Panel (JNC8) recommended a novel blood pressure (BP) goal for individuals with hypertension, which was less stringent than the Seventh Joint National Committee (JNC7) guideline and is still under debate. In our study, we aimed at finding a better BP goal for the elderly Chinese. METHODS: About 1599 community-based elderly participants were recruited in the northern Shanghai and were classified by chronic kidney disease or diabetes mellitus to investigate their BP control conditions based on both the JNC7 and JNC8. Then, participants were categorized into four groups: normotensive individuals (Group 1), individuals at BP goal by JNC7 (Group 2), individuals at BP goal by JNC8 but not by JNC7 (Group 3), and individuals not at-goal by both guidelines (Group 4). Patients' hypertensive target organ damages as left ventricular mass index (LVMI), peak transmitral pulsed Doppler velocity/early diastolic tissue Doppler velocity (E/Ea), pulse wave velocity (PWV), etc. were evaluated. RESULTS: According to the JNC8, 19.0% of the population were reclassified as at-goal. Group 4 had significantly greater LVMI than Group 2 (96.5 vs 91.5 g/m2, p < 0.05) and also had significantly greater E/Ea (10.3 vs 9.7 and 10.3 vs 9.7, p < 0.05) and PWV (10.3 vs 9.3 m/s and 10.3 vs 9.7 m/s, p < 0.05) than both Group 2 and Group 3; however, there were no significant differences of these variables between Group 2 and Group 3. CONCLUSION: In the community-based elderly Chinese, the JNC8 hypertension guideline may set a better BP goal than the JNC7 in identifying patients' left ventricular diastolic dysfunction and arterial stiffening.

Role of CD61+ low-density neutrophils in promoting hepatocellular carcinoma metastasis through CCDC25 upregulation.

BACKGROUND: A subset of neutrophils isolated from the peripheral blood mononuclear cells (PBMC) layer has recently been described in cancer patients. METHODS: Double-gradient centrifugation was used to separate the neutrophil subsets. Western blotting and immunohistochemical assays were performed to assess CCDC25 expression levels. RESULTS: In this study, we found that low-density neutrophils (LDNs) were more highly enriched in metastatic hepatocellular carcinoma (HCC) patients than in non-metastatic HCC patients. We then showed a CD61+ LDNs subset, which displayed distinct functions and gene expression, when compared with high-density neutrophils (HDNs) and CD61- LDNs. Transcriptomic analysis revealed that the CD61+ LDNs were predominantly enhanced in the transcription of glycolysis and angiogenesis associated gene, HMGB1 associated gene and granulation protein gene. These CD61+ LDNs displayed a prominent ability to trigger metastasis, compared with HDNs and CD61- LDNs. Specifically, CD61+ LDN-derived HMGB1 protein increased the invasion of HCC cells by upregulating CCDC25. Mechanistically, the CD61+ LDN-derived HMGB1 protein enhanced the invasiveness of HCC cells and triggered their metastatic potential, which was mediated by TLR9-NF-κB-CCDC25 signaling. Blocking this signaling pathway reversed the invasion of the CD61+ LDN-induced HCC cells. In vivo, we consistently showed that CD61+ LDN-derived HMGB1 enhances HCC metastasis to the lungs. CONCLUSIONS: Overall, our findings showed that a subset of CD61+ LDNs has pro-metastatic effects on HCC, and may be used to target HCC in the clinical setting.

Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1.

Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers.

Small GTPase and regulation of inflammation response in atherogenesis.

Small GTPases are key signal transducers from extracellular stimuli to the nucleus that regulate a variety of cellular responses, including changes in gene expression and cell adhesion and migration. Accumulating data have demonstrated that abnormal activation of these small GTPases plays a critical role in the atherosclerosis characterized by vascular abnormalities, especially endothelial dysfunction and inflammation. Here, we discuss the linkage between small GTPases, inflammation, and atherogenesis. First, small GTPases affect gene expression of inflammatory cytokines through proinflammatory signaling pathways, such as nuclear factor-κB, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interlukin-8, and monocyte chemoattractant protein-1. Then, these molecules regulate the vascular inflammation through cell adhesion and migration. In turn, small GTPases are also regulated by extracellular stimuli, such as L-selectin, thrombin, oxidized phospholipids, and interleukins. Thus, these inflammatory cytokines generate a vicious cycle for small GTPases and inflammatory responses in the atherogenesis.

Tumor-associated NK cells facilitate tumor growth via NKp46 in immunocompetent murine hepatocellular carcinoma.

Natural killer(NK) cells comprise one subset of the innate lymphoid cells family. Despite reported anti-tumor activity of NK cells, their tangible contribution to tumor control remains controversial. This is due to the incomplete understanding of NK alterations within tumor microenvironment(TME). Here we showed, using murine hepatocellular carcinoma(HCC) model, that early NK cells deletion markedly attenuated tumor growth in a CD8+T cells dependent manner. This effect was accompanied by an enhanced CD8+T cells effector function in tumor rather than circulating blood. Then, we demonstrated that abundant NKp46+ NK subset, but not NKp46- NK, were recruited towards tumor microenvironment during tumor progression. Frequency of intratumor NKP46+ NK cells were inversely related to CD8+T cells activation, and positively correlated with tumor growth. Intratumor NKp46+ NK cells exhibited dysfunction and increased expression of inhibitory receptors, when compared with NKp46- NK cells. Blockade of NK cells-associated NKp46 effectively attenuated HCC growth. Infusion of tumor-derived NKp46+ NK cells markedly enhanced HCC growth in vivo, in contrast to tumor cells inoculation alone. The further mechanistic investigations unveiled that NK cells boosted tumor growth by NKp46-mediated impairment of CD8+T cells effector function. Overall, this work supported a previously unappreciated regulatory property of tumor-associated NK cells in HCC, and NKp46 as a potential target against HCC in clinical setting.

Upregulation of helicase-like transcription factor predicts poor prognosis and facilitates hepatocellular carcinoma progression.

Helicase-like transcription factor (HLTF) belongs to the family of SWI/SNF proteins, which has been reported to exert oncogenic function in several human cancers. However, to date, its functional role in hepatocellular carcinoma (HCC) has not been revealed. Here, we found that HLTF was highly expressed in HCC tissues compared to nontumor tissues. Additionally, upregulation of HLTF was significantly associated with poor prognosis of patients with HCC. Functional experiments demonstrated that knockdown of HLTF expression significantly inhibited the proliferation, migration, and invasion of HCC cells in vitro, and suppressed tumor growth in vivo. In conclusion, our results suggest that upregulation of HLTF is associated with the development of HCC, and HLTF may be a potential therapeutic target for HCC treatment.

Heat shock protein HSPA13 promotes hepatocellular carcinoma progression by stabilizing TANK.

HSPA13, an important member of the heat shock protein family, plays an essential role in the oncogenesis of many organs, but the mechanism and function in hepatocellular carcinoma (HCC) is still unclear. In the present study, we found that HSPA13 was highly expressed in HCC and predicted poor clinical prognosis. Upregulation of HSPA13 was significantly associated with vascular invasion in HCC patients. Functionally, knockdown experiments demonstrated that HSPA13 promoted HCC proliferation, migration, and invasion. Mechanistic investigation showed that HSPA13 could interact with TANK to inhibit its ubiquitination and degradation. In addition, the expression of HSPA13 and TANK were positively correlated in HCC tissues. To conclude, the present study uncovers the oncogenic function of HSPA13 in the progression of HCC by regulating the stability of TANK. These findings suggest that HSPA13 and TANK may serve as promising targets for the diagnosis and treatment of HCC.

A new species of Oligodon H. Boie in Fitzinger, 1826 (Squamata: Colubridae) from Hainan Island, China.

A new species of the kukri snake genus Oligodon H. Boie in Fitzinger, 1826 is described based on two specimens collected from Shangxi Nature Reserve, Hainan Island, China. Oligodon bivirgatus sp. nov. can be distinguished from its congeners by a unique combination of having 15/15/15 dorsal scale rows, eight maxillary teeth, divided nasal, 3 temporals (1+2), 7 supralabials and 7 infralabials; divided anal plate; reddish-brown dorsum with two distinct dark stripes, and reddish ventral surface (in life) with irregular dark blotches on edge cream. This is the first new Oligodon species described from a type-locality in Hainan Island of China.

The Crosstalk Between Cancer Cells and Neutrophils Enhances Hepatocellular Carcinoma Metastasis via Neutrophil Extracellular Traps-Associated Cathepsin G Component: A Potential Therapeutic Target.

BACKGROUND: Emerging evidences have highlighted the roles of neutrophils, as the major host microenvironment component, in the development of hepatocellular carcinoma (HCC). Neutrophils extracellular traps (NETs) produced in the infection can strengthen the behavior of cancer metastasis. Here, we investigated the roles of NETs in HCC metastasis and further explore the underlying mechanism of how NETs interact with cancer. METHODS: The neutrophils were isolated from whole blood of HCC patients and used to evaluate the formation of NETs. NET markers were detected in tissue samples, plasma and cell climbing slice. Mouse models were used to evaluate the roles of NETs in HCC metastasis in vivo, and the corresponding mechanisms were explored using in vivo and in vitro assays. RESULTS: An increase in the release of NETs in patients with HCC, particularly those with portal vein tumor thrombosis (PVTT). The presence of NETs in HCC tumor tissues closely correlated with a poor prognosis. Functionally, the invasion ability of HCC cells was enhanced by co-culture with HCC neutrophils, through NETs formation, while the neutrophils from a healthy donor (HD) exhibited the inhibition of the invasion ability. Furthermore, we observed an enhanced ability of forming NETs in neutrophils from HCC patients in vitro, especially patients with PVTT or extra-hepatic metastasis. An in-vivo animal study demonstrated that neutrophils of HCC facilitated the metastatic behavior towards the lung. The further mechanistic investigation unveiled that HCC cells-derived cytokine IL-8 triggered NETs formation in an NADPH oxidase-dependent manner, and NETs-associated cathepsin G (cG) promoted HCC metastasis in vitro as well as vivo. Clinically, the expression of the cG protein in tumor tissues displayed a close correlation with the disease prognosis of HCC patients. CONCLUSION: Our findings implicated that the induction of NETs by HCC cells is a critical metastasis-supporting cancer-host interaction and that NETs may serve as an immune-based potential therapeutic target against HCC progression.

Somatotype and Its Impact on Asymptomatic Target Organ Damage in the Elderly Chinese: The Northern Shanghai Study.

OBJECTIVE: To investigate the relationship between asymptomatic target organ damage (TOD) and different somatotypes in a population of elderly from Chinese community-dwelling. METHODS: A total of 2098 Chinese senior residents from northern Shanghai older than 65 years were recruited in the research. The following somatotype parameters were recorded and analyzed: body mass index, waist circumference, hip circumference, and waist-hip ratio were recorded and calculated. Asymptomatic TOD, including urine albumin/creatinine ratio, estimated glomerular filtration rate (eGFR), intima-media thickness (IMT), left ventricular mass index (LVMI), left ventricular diastolic function, and carotid-femoral pulse wave velocity (PWV) was recorded using the MyLab30 Gold CV system and SphygmoCor. RESULTS: Of all 2098 residents, 817 (38.9%) were overweight and 289 (13.8%) were obese. All somatotype measures were significantly correlated with TOD parameters (p<0.05). After adjustment for age and male gender, in total population, LVMI (p<0.001), cardiac diastolic function (E/Ea, p<0.001), PWV (p<0.001), eGFR (p=0.03), and urine albumin/creatinine ratio (p<0.001) changed gradually and significantly correlated with increasing BMI values. Obesity and overweight were independently related to the incidence of LVH, LVDD, artery stiffness, carotid arterial plaque, and microalbuminuria. CONCLUSION: The incidence of asymptomatic TOD was significantly correlated with overweight and obesity, especially in women, whereas the underweight may favor in the prevention of TOD.

Aberrant USP11 expression regulates NF90 to promote proliferation and metastasis in hepatocellular carcinoma.

Growing evidence indicates that deubiquitinase ubiquitin-specific protease 11 (USP11) plays an important role in cellular function by regulating the stability of its substrates. USP11 is dysregulated in many types of cancer and involved in tumor development and progression. We previously showed that USP11 was upregulated in hepatocellular carcinoma (HCC) and promoted HCC cell invasion and metastasis potency. However, the mechanism underlying the role of USP11 in HCC cell metastasis and its function in cell proliferation remain unknown. Here, CCK-8, soft agar assays and nude mouse models showed that USP11 was essential for HCC cells survival and proliferation in vitro and in vivo. Results form mass spectrometry, co-immunoprecipitation, and ubiquitination assays demonstrated that USP11 interacted with nuclear factor 90 (NF90) and promoted its deubiquitination, thereby stabilizing it in HCC cells. Moreover, the effect of USP11 on promoting HCC cells proliferation and metastasis was dependent on NF90, and USP11 expression was positively correlated with NF90 expression in human HCC tissues, as demonstrated via immunohistochemistry. Collectively, the present findings indicated that USP11 binded to and deubiquitinated NF90, thereby stabilizing the protein expression level and promoting HCC cell proliferation and metastasis. NF90 was identified as an important downstream target of USP11. Dysregulated signaling of this novel USP11/NF90 axis might promote HCC proliferation and metastasis, and the axis could be a potential therapeutic target in HCC.

Early detection of ST-segment elevated myocardial infarction by artificial intelligence with 12-lead electrocardiogram.

Patient delay is a worldwide unsolved problem in ST-segment elevated myocardial infarction (STEMI). An accurate warning system based on electrocardiogram (ECG) may be a solution for this problem, and artificial intelligence (AI) may offer a path to improve its accuracy and efficiency. In the present study, an AI-based STEMI autodiagnosis algorithm was developed using a dataset of 667 STEMI ECGs and 7571 control ECGs. The algorithm for detecting STEMI proposed in the present study achieved an area under the receiver operating curve (AUC) of 0.9954 (95% CI, 0.9885 to 1) with sensitivity (recall), specificity, accuracy, precision and F1 scores of 96.75%, 99.20%, 99.01%, 90.86% and 0.9372 respectively, in the external evaluation. In a comparative test with cardiologists, the algorithm had an AUC of 0.9740 (95% CI, 0.9419 to 1), and its sensitivity (recall), specificity, accuracy, precision, and F1 score were 90%, 98% and 94%, 97.82% and 0.9375 respectively, while the medical doctors had sensitivity (recall), specificity, accuracy, precision and F1 score of 71.73%, 89.33%, 80.53%, 87.05% and 0.8817 respectively. This study developed an AI-based, cardiologist-level algorithm for identifying STEMI.