Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which ranks as the sixth of cancer-related death. Despite the emergence of targeted therapy, advanced-stage HCC remains ...largely incurable due to low response rate and therapeutic resistance. In this review, we mainly focused on the current progression of multi-kinase inhibitors and immunotherapies in the treatment of HCC. We highlight the mechanism underlying the ineffectiveness of these targeted therapies, including oncogenic alterations in driver genes and downstream pathways, high heterogeneity of HCC, and the mutual interaction of tumor microenvironment that promotes therapeutic resistance. We also discussed how these previous studies suggested for future therapeutic strategies. Besides, the complexity of HCC heterogeneity and cancer revolution need to be recognized in personalized therapy. Establishment of a drug screening system and identification of biomarkers of response is also in urgent need to overcome drug resistance. Meanwhile, a combination of targeted therapies could also be explored as a promising strategy in the future.
•Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to therapeutic resistance.•Multiple factors contribute to drug resistance of HCC patients against MKIs.•Further studies are expected to identify biomarkers for response and promote efficacy of immunotherapy.•Insight into heterogeneity of HCC and combined therapy could be the next step forward the future of precision medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Day by day, we are realizing the goal of the great rejuvenation of the Chinese nation, which necessitates the development of sufficient cultural self-confidence. The amalgamation of traditional ...culture and English learning is an essential prerequisite for us to effectively communicate the Chinese story to the world. This paper proposes an optimized ridge regression model with regularization constraints to enhance the preprocessing of cultural data. Subsequently, we propose a statistical model for analyzing the teaching styles of English texts from four perspectives, taking into account the characteristics of English language teaching and the cardinal text statistics algorithm based on word frequency optimization. This model’s analysis revealed that textbook articles reflecting traditional Chinese culture accounted for only 1.8% of all types, resulting in an uneven distribution of grades. Following the implementation of improvements to tackle this issue, 74.86% of the students expressed their belief that enhanced teaching could bolster their cultural confidence. Similarly, 86.6% of the teachers expressed their belief that incorporating Chinese culture into English teaching could enhance students’ cultural awareness, and 90% of the teachers believed it could boost students’ identification with Chinese culture and cultural confidence. It shows that the new teaching method optimized by conducting textual statistical analysis helps to bring into play the role of English education in colleges and universities in enhancing cultural self-confidence.
The high-quality development of the manufacturing industry is an important strategic task for Chinese economic development. The rapid development of the manufacturing industry is also accompanied by ...problems such as overcapacity and environmental pollution. This paper analyzes the impact of capacity utilization on the high-quality development of manufacturing and establishes a nonlinear threshold regression model on this basis, and studies and analyzes environmental regulations as a threshold variable under the influence of capacity utilization rate on the high-quality development of the manufacturing industry. The research results show that: capacity utilization, profitability, foreign direct investment, and government participation all have a significant positive impact on the high-quality development of the manufacturing industry; environmental regulations have a significant negative impact on the high-quality development of the manufacturing industry. And in the model of the effect of capacity utilization on the high-quality development of the manufacturing industry, environmental regulation has a single threshold effect. With the increase in the intensity of environmental regulation, the coefficient and significance of the effect of capacity utilization on the high-quality development of the manufacturing industry have changed. Finally, this article puts forward corresponding policies and suggestions based on the results of data analysis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic ...niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin-NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.
Immune checkpoint inhibitors target the inhibitory receptors on T cells to reinstate their antitumor ability and have shown significant efficacy in treating various cancers. However, because of tumor ...heterogeneity and many other uncover reasons, the objective response rate for programmed death 1 and programmed death-ligand 1 (PD-1/PD-L1) blockade is only 20 to 30%; its response rate in solid tumors is relatively low, and different degrees of side effects have occurred. There are still many unknown factors affecting the therapeutic effectiveness of PD-1/PD-L1 blockade. Additionally, screening the responding tumor patients accurately and improving the response rate and efficacy are huge challenges for tumor precise treatment. Here, we attempt to summarize the recent progress in response prediction and combined application of PD-1/PD-L1 blockade and briefly discuss the methods and evaluations combined with PD-1/PD-L1 blockade to improve the implementation of precision immunotherapy.
Owing to their outstanding recentering capability, shape memory alloy (SMA) dampers are emerging as promising passive dampers for seismic applications. However, compared to typical seismic dampers, ...the inherent energy dissipation capability of SMAs is often deemed barely satisfactory. To enhance the damping capacity of SMA dampers, this study suggests combining SMA elements with steel dampers based on bending steel plates. In this new SMA-steel damper, the steel dampers are mainly responsible for absorbing seismic energy, whereas the SMA bars primarily play the role of recovering inelastic deformation. Experimental tests were conducted at room temperature to verify the cyclic behavior of the proposed damper. The hysteretic parameters, such as strength, stiffness, equivalent damping ratio, and residual deformation, are of particular interest and quantified as a function of the loading amplitude. According to test results, the new damper is confirmed to possess desirable recentering capability and high damping. To further understand the damper, numerical simulations were carried out in the finite element (FE) analysis software ABAQUS. The numerical results validated the experimental data. Based on the calibrated FE model, the thickness of the bending steel plate of the steel damper and the diameter of the SMA bars were varied in the parametric analysis to examine its effect on the recentering tendency and damping mechanism.
Emerging research on the use of new technology suggests that internet use is generally associated with high levels of efficiency among older adults in the following areas: quality of life, mood, ...positive psychological well-being, and the individual and societal costs of caring for them. However, there is little empirical evidence specifically concerning the causal effects of older adults' internet use on their depression level. There is a need for more replication studies to help confirm that the emerging evidence on the impact of internet use is accurate and applicable to different populations and in different situations.
Using national data from the China Family Panel Study in 2016, this study helps to fill the above mentioned research gap. This study followed a two-step analytical strategy to empirically examine the association between internet use and reported depression in older adults. In the first step, we estimated a binary logistic regression model with internet use as the dependent variable and 8 demographic and socioeconomic factors as the confounding variables. In the second step, we performed a propensity score analysis to control for potential bias using the confounding variables confirmed in the first step.
The results show that older adults who reported internet use have lower depression levels than did those who did not use the internet, with adjustments made for gender, age, urban or rural residence, pension status, educational background, physical health, life satisfaction, and intelligence level.
These findings suggest that it is critical to advocate for technology-based policies and programs that promote older adults' internet use to improve their social well-being, which can also serve as a policy strategy to help alleviate older adults' depression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Amino acids were decomposed evidently by THP at 120 °C (8.9%) and 160 °C (26.7%).•Amino acids degradation in AD was promoted largely via decomposition during THP.•Varied THP temperature changed ...dominating bacteria utilizing amino acids in AD.•120 °C played little role in promoting amino acids metabolic pathways during AD.•160 °C effectively enhanced amino acids metabolism via Stickland pathway during AD.
Three semi-continuous anaerobic digesters with raw sludge (R1) or thermally hydrolyzed sludge (120 °C (R2) or 160 °C (R3)) were operated to investigate the effects of thermal hydrolysis on the metabolism of amino acids during high solid anaerobic digestion with sewage sludge. Thermal hydrolysis pretreatment (THP) decomposed protein in terms of hydrolytic amino acid in raw sludge by 8.90% and 26.69% under 120 °C and 160 °C, respectively. The decomposition of amino acids during THP was the main contributor to the final enhanced amino acids degradation in sewage sludge with THP after anaerobic digestion. The dominating bacterial genera related to amino acids degradation in R2 and R3 shifted to Fastidiosipila and Proteiniphilum/Tissierella, respectively, from Gelria in R1, influencing the utilization of amino acids, especially glutamic acid, glycine and proline. Different from 120 °C, THP at 160 °C played an important role in promoting amino acid metabolism during AD through the Stickland pathway by the bacteria belonged to order Clostridiales.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatocellular carcinoma has a poor prognosis due to its rapid development and early metastasis. In this report, we characterized the metabolic features of hepatocellular carcinoma using a ...nontargeted metabolic profiling strategy based on liquid chromatography-mass spectrometry. Fifty pairs of liver cancer samples and matched normal tissues were collected from patients having hepatocellular carcinoma, including tumor tissues, adjacent noncancerous tissues, and distal noncancerous tissues, and 105 metabolites were filtered and identified from the tissue metabolome. The principal metabolic alternations in HCC tumors included elevated glycolysis, gluconeogenesis, and β-oxidation with reduced tricarboxylic acid cycle and Δ-12 desaturase. Furthermore, increased levels of glutathione and other antioxidative molecules, together with decreased levels of inflammatory-related polyunsaturated fatty acids and phospholipase A2, were observed. Differential metabolite levels in tissues were tested in 298 serum specimens from patients with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Betaine and propionylcarnitine were confirmed to confer good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum specimens further showed that this combination biomarker is useful for diagnosis of hepatocellular carcinoma with a supplementary role to α-fetoprotein.
Summary Background Hepatocellular carcinoma (HCC) is prevalent worldwide and improvements in timely and effective diagnosis are needed. We assessed whether measurement of Dickkopf-1 (DKK1) in serum ...could improve diagnostic accuracy for HCC. Methods We analysed data for patients with HCC, chronic hepatitis B virus (HBV) infection, liver cirrhosis, and healthy controls, recruited from two Chinese centres between December, 2008, and July, 2009. A validation cohort matched for age and sex was recruited from another centre in China between February, 2009, and June, 2011. DKK1 was measured in serum by ELISA by independent researchers who had no access to patients' clinical information. We used receiver operating characteristics (ROC) to calculate diagnostic accuracy. Findings We assessed serum DKK1 in 831 participants: 424 with HCC, 98 with chronic HBV infection, 96 with cirrhosis, and 213 healthy controls. The validation cohort comprised 453 participants: 209 with HCC, 73 with chronic HBV infection, 72 with cirrhosis, and 99 healthy controls. Levels of DKK1 in serum were significantly higher in patients with HCC than in all controls. ROC curves showed the optimum diagnostic cutoff was 2·153 ng/mL (area under curve AUC 0·848 95% CI 0·820–0·875, sensitivity 69·1%, and specificity 90·6% in the test cohort; 0·862 0·825–0·899, 71·3%, and 87·2% in the validation cohort). Similar results were noted for early-stage HCC (0·865 0·835–0·895, 70·9%, and 90·5% in the test cohort; 0·896 0·846–0·947, 73·8%, and 87·2% in the validation cohort). Furthermore, DKK1 maintained diagnostic accuracy for patients with HCC who were α-fetoprotein (AFP) negative (0·841 0·801–0·882, 70·4%, and 90·0% in the test cohort; 0·869 0·815–0·923, 66·7%, and 87·2% in the validation cohort), including for patients with early-stage HCC (0·870 0·829–0·911, 73·1%, and 90·0% in the test cohort; 0·893 0·804–0·983, 72·2%, and 87·2% in the validation cohort), compared with all controls. Raised concentrations of DKK1 in serum could differentiate HCC from chronic HBV infection and cirrhosis (0·834 0·798–0·871, 69·1%, and 84·7% in the test cohort; 0·873 0·832–0·913, 71·3%, and 90·6% in the validation cohort). Moreover, measurement of DKK1 and AFP together improved diagnostic accuracy for HCC versus all controls compared with either test alone (0·889 0·866–0·913, 73·3%, and 93·4% in the test cohort; 0·888 0·856–0·920, 78·5%, and 87·2% in the validation cohort). Interpretation DKK1 could complement measurement of AFP in the diagnosis of HCC and improve identification of patients with AFP-negative HCC and distinguish HCC from non-malignant chronic liver diseases. Funding National Key Basic Research Programme of China, National Key Sci-Tech Special Projects of Infectious Diseases, National Natural Science Foundation of China, Research Fund for the Doctoral Programme of Higher Education of China.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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