Risk assessment of e-waste - Liquid Crystal Monomers re-suspension caused by coastal dredging operations.

The Pearl River Estuary (PRE), one of the primary e-waste recycling centers in the world, has been suffering from the pollution of Liquid Crystal Monomers (LCMs), critical materials with persistent, bio-accumulative, and toxic substances used in electronic devices. It has been detected in seabed sediment with both high frequency and concentration near PRE - Hong Kong (HK) waters. In the same area, dredging operations with in-situ sediment have been frequently used in the last decades for coastal land reclamation projects. Dredging is known to cause a huge amount of sediment re-suspension into water columns, with potential damage to marine ecosystems and biodiversity. In this study, we proposed a new risk assessment strategy to estimate the secondary pollution due to the re-suspension sediment highly contaminated by LCMs. We formulate a robust and reliable probabilistic approach based on unsupervised machine learning and hydrodynamic and sediment transport numerical simulation. New risk indexes were also proposed to better quantify the impact of contaminated sediments. We applied the methodology to assess the potential impact of dredging operations in the PRE and Hong Kong waters on the local marine ecosystem. The results of the analysis showed how the potentially contaminated areas depended on the dredging locations.

Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for neoadjuvant treatment of resectable hepatocellular carcinoma with high risk of recurrence: A multicenter retrospective study.

Background: Early recurrence is common after surgical resection (SR) for hepatocellular carcinoma (HCC) with high risk of recurrence and is associated with poor prognosis. The combinations of lenvatinib (LEN), anti-PD-1 antibodies (PD-1) and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. It is unknown whether triple therapy for neoadjuvant treatment of resectable HCC with high risk of recurrence is effective. This article aimed to compare the outcomes of surgery alone and neoadjuvant combination treatment with triple therapy before SR in patients with HCC with high risk of recurrence. Methods: A retrospective study was conducted on patients diagnosed with HCC with high risk of recurrence who received treatment with or without triple therapy. The records of 24 patients in the triple therapy group and 76 patients in the surgery-alone group were analyzed. Propensity score matching (PSM) was performed to minimize the influence of potential confounders. Results: One hundred patients were enrolled. In the triple therapy group, 8 (33.3%) and 12 (50.0%) patients had complete and partial responses, respectively, as assessed by an investigator. Before PSM, the overall survival (OS) rates for the triple therapy group at 6, 12, 18, and 24 months were 100.0%, 100.0%, 100.0%, and 85.7%, respectively, compared with corresponding 92.1%, 73.7%, 53.9%, and 48.7% for the surgery-alone group (P<0.001). The disease-free survival (DFS) rates were 82.2%, 66.95%, 48.8%, and 48.8% for the triple therapy and 41.92%, 28.34%, 27.05%, and 22.99% for the surgery-alone group (P=0.003). After PSM, DFS and OS were significantly longer in the triple therapy group than in the surgery-alone group (DFS, p=0.019; OS, p=0.003). Conclusions: Neoadjuvant combination treatment before SR had a high rate of tumor response and provided significantly better postoperative survival outcomes than surgery alone in patients with HCC with high risk of recurrence.

Experimental study on the monotonic mechanical behavior of completely decomposed granite soil reinforced by disposable face-mask chips.

In response to the global outbreak of the coronavirus pandemic (COVID-19), a staggering amount of personal protective equipment, such as disposable face masks, has been used, leading to the urgent environmental issue. This study evaluates the feasibility of mask chips for the soil reinforcement, through triaxial tests on samples mixed with complete decomposed granite (CDG) and mask chips (0%, 0.3%, 0.5%, 1%, 5% by volume). The experimental results show that adding a moderate volumetric amount of mask chips (0.3%-1%) improves the soil strength, especially under high confining pressure. The optimum volumetric content of mask chips obtained by this study is 0.5%, raising the peak shear strength up to 22.3% under the confining stress of 120 kPa. When the volumetric content of mask chips exceeds the optimum value, the peak shear strength decreases accordingly. A limited amount of mask chips also increases the elastic modulus and makes the volumetric response more dilative. By contrast, excessive mask chips create additional voids and shift the strong soil-mask contacts to weak mask-mask contacts. The laser scanning microscope (LSM) and scanning electron microscope (SEM) images on the typical samples demonstrate the microstructure of mask fibers interlocking with soil particles, highly supporting the macro-scale mechanical behavior.

Lifespan dynamics of cluster conformations in stationary regimes in granular materials.

We examine stationary regimes in granular materials from a dynamical systems theory perspective. The aim is to enrich the classical view of the critical state regime in granular materials, and more broadly, to improve the fundamental understanding of the underlying mesoscale mechanisms responsible for macroscopic stationary states in complex systems. This study is based on a series of discrete element method simulations, in which two-dimensional assemblies of nonuniformly sized circular particles are subjected to biaxial compression under constant lateral confining pressure. The lifespan and life expectancy of specific cluster conformations, comprising particles in force chains and grain loops, are tracked and quantified. Results suggest that these conformational clusters reorganize at similar rates in the critical state regime, depending on strain magnitudes and confining pressure levels. We quantified this rate of reorganization and found that the material memory rapidly fades, with an entirely new generation of force chains and grain loops replacing the old within a few percent strain.

Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study.

BACKGROUND: Lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). We assessed the safety and clinical efficacy of triple therapy [LEN+PD-1+transcatheter arterial chemoembolization (TACE)] in uHCC. METHODS: uHCC patients with an ECOG PS score of 0-1 and Child-Pugh class A who underwent triple therapy were included. The primary endpoint was objective response rate (ORR) based on mRECIST. Secondary endpoints were conversion rate to liver resection and treatment-related adverse events. RESULTS: Between November 2018 and December 2020, 62 uHCC patients who underwent triple therapy at four major cancer centers in China were analyzed, including 35 in BCLC-C, 21 in BCLC-B, and 6 in BCLC-A. With a median follow-up of 12.2 months (range, 7.6-33.3 months), the investigator and blinded independent central review-assessed ORR were 80.6% and 77.4%, respectively. A total of 33 patients (53.2%) reached the standard of conversion to resectable HCC and 29 patients underwent resection. The median interval between start of triple therapy and resection was 123 days (range, 55-372 days). Pathological complete response and major pathological response were observed in 16 and 24 patients, respectively. Median overall survival and progression-free survival were not reached. Treatment-related adverse events occurred in 74.2% of the patients (grade ≥3, 14.5%; grade ≥4, 4.8%). CONCLUSION: Combination of LEN, PD-1 and TACE showed a high rate of tumor response and convert resection in uHCC patients, with manageable toxicity.

Association of liver abnormalities with in-hospital mortality in patients with COVID-19.

BACKGROUND & AIMS: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. METHODS: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching. RESULTS: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes. CONCLUSIONS: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19. LAY SUMMARY: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes.

Data in intelligent approach for estimation of disc cutter life using hybrid metaheuristic algorithm.

This data in brief presents the monitoring data measured during shield tunnelling of Guangzhou-Shenzhen intercity railway project. The monitoring data includes shield operational parameters, geological conditions, and geometry at the site. The presented data were arbitrarily split into two subsets including the training and testing datasets. The field observations are compared to the forecasting values of the disc cutter life assessed using a hybrid metaheuristic algorithm proposed for "Prediction of disc cutter life during shield tunnelling with artificial intelligent via incorporation of genetic algorithm into GMDH-type neural network" [1]. The presented data can provide a guidance for cutter exchange in shield tunnelling.

Data on evolutionary hybrid neural network approach to predict shield tunneling-induced ground settlements.

The dataset presented in this article pertains to records of shield tunneling-induced ground settlements in Guangzhou Metro Line No. 9. Field monitoring results obtained from both the two tunnel lines are put on display. In total, 17 principal variables affecting ground settlements are tabulated, which can be divided into two categories: geological condition parameters and shield operation parameters. Shield operation parameters are specifically provided in time series. Another value of the dataset is the consideration of karst encountered in the shield tunnel area including the karst cave height, the distance between karst cave and tunnel invert, and the karst cave treatment scheme. The dataset can be used to enrich the database of settlement caused by shield tunneling as well as to train artificial intelligence-based ground settlement prediction models. The dataset presented herein were used for the article titled "Evolutionary hybrid neural network approach to predict shield tunneling-induced ground settlements" (Zhang et al., 2020).

Long non-coding RNA RP11-284P20.2 promotes cell proliferation and invasion in hepatocellular carcinoma by recruiting EIF3b to induce c-met protein synthesis.

A newly identified lncRNA designated as RP11-284P20.2 has been identified to be up-regulated in hepatocellular carcinoma (HCC), but its role in HCC remain poorly understood. Quantitative PCR and immunocytochemical analysis were performed using the HCC tissues to identify the potential interaction partners of RP11-284P20.2. Moreover, RP11-284P20.2 was knocked down in HCC cell lines, HepG2 and SMMC7721, to investigate the influence of this lncRNA on cell growth properties. Additionally, RNA fluorescence in situ hybridization and immunofluorescence, RNA immunoprecipitation, and RNA pull-down assays were performed to determine the interaction of RP11-284P20.2 with c-met mRNA and eukaryotic translation initiation factor 3b (EIF3b). Silencing RP11-284P20.2 inhibited cell viability, migration, invasion, and colony formation, and increased apoptosis. Overexpression of c-met abolished these effects of RP11-284P20.2 in HCC cells. Histopathological examination showed that HCC tissues with high RP11-284P20.2 expression had higher c-met protein level than that in HCC tissues with low RP11-284P20.2 expression. However, there was no positive correlation between the expression levels of RP11-284P20.2 and c-met mRNA. RP11-284P20.2 knockdown led to a decease in c-met protein expression level, but did not affect the c-met mRNA expression level. These data suggest that RP11-284P20.2 regulates c-met protein expression level, which is independent of c-Met mRNA expression level. It was also confirmed that RP11-284P20.2 has high affinity toward both c-met mRNA and EIF3b protein, and hence RP11-284P20.2 probably recruits EIF3b protein to c-met mRNA and further facilitates its translation. RP11-284P20.2 promotes cell proliferation and invasion in hepatocellular carcinoma by recruiting EIF3b to induce c-met protein synthesis.

Durable response to pulsatile icotinib for central nervous system metastases from EGFR-mutated non-small cell lung cancer: A case report.

BACKGROUND: Central nervous system (CNS) metastases are a catastrophic complication of non-small cell lung cancer (NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging. CASE SUMMARY: We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor (EGFR). A standard dosage of icotinib (125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib (1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects. CONCLUSION: This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.

Detection of a novel panel of somatic mutations in plasma cell-free DNA and its diagnostic value in hepatocellular carcinoma.

Background/aims: Circulating cell-free DNA (cfDNA) contains tumor-specific alterations and could potentially serve as "liquid biopsy". The study was to identify a novel panel of hepatocellular carcinoma (HCC)-specific mutations in plasma cfDNA and to assess its value in the diagnosis of HCC. Materials and methods: 33 HCC tissue, 37 blood, and 37 swab specimens were collected from HCC patients and control individuals. Genomic DNA was subjected to next-generation sequencing. The selected mutations in the plasma cfDNA in the HCC versus control groups were compared, and the diagnostic performance of cfDNA mutations was evaluated. Results: A majority of selected mutations in the HCC tissue DNA, ranging from 52% to 84%, was detected in the matched plasma cfDNA. For the selected mutations, receiver operating characteristic (ROC) analysis revealed an area under the ROC curve (AUC) of 0.92, sensitivity of 65%, and specificity of 100% for the diagnosis of HCC regardless of alpha-fetoprotein (AFP) status. Detection of the selected mutations in cfDNA in combination with AFP exhibited better diagnosis performance, with AUC of 0.96, sensitivity of 73%, and specificity of 100% for AFP-negative patients, whereas the AUC was 0.86 with sensitivity of 53% and specificity of 100% for AFP-positive patients. Furthermore, the rates of the selected mutations were significantly greater in recurrent HCC than in non-recurrent HCC (P<0.05). Conclusions: This study has identified a novel panel of somatic mutations, and detection of the mutations in plasma cfDNA shows good diagnostic performance. Therefore, this approach holds promise as a novel tool for diagnosing HCC.

FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.

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.

Long Noncoding RNA HCAL Facilitates the Growth and Metastasis of Hepatocellular Carcinoma by Acting as a ceRNA of LAPTM4B.

Long noncoding RNAs (lncRNAs) are a new class of regulatory noncoding RNAs. Emerging evidences indicate that lncRNAs play a critical role in the development of hepatocellular carcinoma (HCC). Although several lncRNAs have been annotated, the association of most lncRNAs with HCC is unknown. In this study, we investigated lncRNA alterations in HCC by performing lncRNA microarray analysis. We identified a novel lncRNA called HCC-associated lncRNA (HCAL) that was highly expressed in HCC tissues. HCAL upregulation was clinically associated with poor differentiation, intravascular cancer embolus, and decreased survival of patients with HCC. HCAL silencing significantly inhibited the growth and metastasis of HCC cells both in vitro and in vivo. Interestingly, transcriptome-sequencing analysis of HCAL-knockdown cells showed alterations in some cancer-related pathways. Mechanistically, HCAL directly interacted with and functioned as a sponge for microRNAs such as miR-15a, miR-196a, and miR-196b to modulate LAPTM4B expression. Taken together, our findings suggest the presence of a novel lncRNA-miRNA-mRNA regulatory network, i.e., the HCAL-miR-15a/miR-196a/miR-196b-LAPTM4B network, in HCC and indicate that HCAL may be a potential target for treating HCC.

Increased adult neurogenesis associated with reactive astrocytosis occurs prior to neuron loss in a mouse model of neurodegenerative disease.

AIMS: This study was to investigate whether cell proliferation and adult neurogenesis are affected at early neurodegenerative stage when neuron loss has not begun to display. METHODS AND RESULTS: Forebrain-specific nicastrin (NCT) conditional knockout (cKO) mice were generated by crossing NCTf/f with CaMKIIα-Cre Tg mice. BrdU was used as a lineage tracer to label proliferating neural progenitor cells (NPCs). Immunohistochemistry (IHC) on BrdU indicated that the total number of BrdU positive (+) cells was increased in NCT cKO mice. IHC on doublecortin (DCX) showed that the total number of DCX+ cells was also increased in NCT cKO mice. NCT cKO mice displayed significant astrogliosis as well. However, NCT cKO mice at 3 months did not show significant neuronal death or synaptic loss. CONCLUSIONS: NCT-dependent γ-secretase activity plays an important role in cell proliferation and immature neuron generation. Enhanced neurogenesis and astrogliosis may be early cellular events prior to the occurrence of neuronal death in neurodegenerative disease.

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2.

Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.

Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells.

Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells. We showed that AT406 induced degradation of IAPs (cIAP-1 and XIAP), but didn't affect another anti-apoptosis protein Mcl-1. Co-treatment of OSI-027 caused simultaneous Mcl-1 downregulation to overcome AT406's resistance. Significantly, shRNA knockdown of Mcl-1 remarkably facilitated AT406-induced apoptosis in HCC cells. In vivo, AT406 oral administration suppressed HepG2 tumor growth in nude mice. Its activity was potentiated with co-administration of OSI-027. We conclude that mTOR could be a key resistance factor of AT406 in HCC cells.

Natural killer cells inhibit pulmonary metastasis of hepatocellular carcinoma in nude mice.

Natural killer (NK) cells have been demonstrated to inhibit tumor growth. However, the role of NK cells in the inhibition of hepatocellular carcinoma metastasis is not well understood. The present study aimed to investigate the roles that NK cells may serve in inhibiting hepatocellular carcinoma metastasis. The role of isolated NK cells in the inhibition, proliferation, migration and invasion of the hepatoma cell line, MHCC97-H, was examined in vitro. Additionally, the survival rate of NK cells labeled with carboxyfluorescein diacetate-succinimidyl ester was assessed in vivo. An orthotopic implantation model was used to evaluate the role of NK cells in suppressing MHCC97-H cells in vivo. The effect of interleukin (IL)-2 stimulation on the tumor-inhibitory role of the NK cells was measured indirectly by analyzing the expression of various NK cell receptors and activated NK cell markers. It was observed that the NK cells inhibited the proliferation, migration and invasion of the MHCC97-H cells in vitro. Furthermore, the NK cells demonstrated long-term survival in the livers of the nude mice, and inhibited lung metastasis of hepatocellular carcinoma in vivo. However, liver tumor growth was not inhibited by the NK cells. IL-2 was identified to enhance the tumor-inhibitory effect of NK cells. The present study concludes that IL-2 may enhance the antitumor activity of the NK cells, and thereby inhibit the metastases of hepatocellular carcinoma in mice.

Mutual regulation between CHD5 and EZH2 in hepatocellular carcinoma.

Chromodomain helicase DNA binding protein 5 (CHD5) acts as a tumor suppressor in many cancers. In the present study, we demonstrated that reduced levels of CHD5 in hepatocellular carcinoma (HCC) tissues were significantly associated with metastasis and poor prognosis. Gain-of-function assays revealed that CHD5 suppressed motility and invasion of HCC cells. Subsequent investigations showed that CHD5 was epigenetically silenced by polycomb repressive complex 2 (PRC2)-mediated the trimethylation of histone H3 at lysine 27 (H3K27me3) in HCC cells. Furthermore, overexpression of CHD5 repressed enhancer of zeste homolog 2 (EZH2) and activated PRC2 target genes, such as p16 and p21. Chromatin immunoprecipitation and luciferase reporter assays also showed that CHD5 and EZH2 bind to each other's promoters and inhibit transcription. These findings uncovered, for the first time, a mutual suppression regulation between CHD5 and EZH2, which may provide new insights into their potential therapeutic significance for HCC.