Dual control of energy consumption is an effective method proposed in China to launch and deepen the transition in energy use. It has obtained favorable results; however, the resource consumption and ...pollution emissions per unit of Gross Domestic Product (GDP) remain high. This article quantitatively studies the current policies’ effects to promote the advancement of dual control of energy consumption and develop future policies. Green production and consumption policies promote the development of dual control of energy consumption; therefore, this paper examines these policies through text mining and a quantitative evaluation system. The results suggest strong state demand for developing green production and consumption and the necessity for scientific evaluation; however, the state’s focus on the relevant policy tools is imbalanced. Constraint policy tools have the highest proportion of restricting pollutant emissions but lack comprehensiveness. Incentive and guidance policy tools have the problems of poor targets and low volume. Additionally, by constructing policy modeling consistency (PMC) index models for evaluating green production and consumption policies, six selected policies indicate solid performance, but some still have problems regarding policy timeframe, policy function, and green process. Based on the conclusions, this paper provides some targeted recommendations.
•Predictive performance of nonlinear model was superior to linear models.•Nonlinear kinetics of tacrolimus may be attributed to the properties of the drug itself.•Published models performed ...inadequately in prediction- and simulation-based diagnostics.•Bayesian forecasting could improve the predictive performance of the models.
Diverse tacrolimus population pharmacokinetic (popPK) models in adult liver transplant recipients have been established to describe the PK characteristics of tacrolimus in the last two decades. However, their extrapolated predictive performance remains unclear. Therefore, in this study, we aimed to evaluate their external predictability and identify their potential influencing factors.
The external predictability of each selected popPK model was evaluated using an independent dataset of 84 patients with 572 trough concentrations prospectively collected from Huashan Hospital. Prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. Furthermore, the effect of model structure on the predictive performance was investigated.
Sixteen published popPK models were assessed. In prediction-based diagnostics, the prediction error within ± 30% was below 50% in all the published models. The simulation-based normalised prediction distribution error test and prediction- and variability-corrected visual predictive check indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting showed improvement in model predictability with two to three prior observations. Additionally, the predictive performance of the nonlinear Michaelis–Menten model was superior to that of linear one- and two-compartment models with first-order elimination, indicating the underlying nonlinear kinetics of tacrolimus in liver transplant recipients, which was consistent with the findings in adult kidney transplant recipients.
The published models performed inadequately in prediction- and simulation-based diagnostics. Bayesian forecasting may improve the predictive performance of the models. Furthermore, nonlinear kinetics of tacrolimus may be mainly caused by the properties of the drug itself, and incorporating nonlinear kinetics may be considered to improve model predictability.
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Background
N
6
-methyladenosine (m
6
A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m
6
A modification plays a critical ...role in cancer development, including hepatocellular carcinoma (HCC). Despite several m
6
A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive.
Methods
Differentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m
6
A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation.
Results
The m
6
A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration.
Conclusion
The m
6
A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies.
Introduction
Proprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. ...Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer.
Methods
Using a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of
PCSK9
and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma.
Results
Overall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients.
Conclusion
PCSK9
could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers.
In this paper, we put forward a time-delay ecological competition system with food restriction and diffusion terms under Neumann boundary conditions. For the case without delay, the conditions for ...local asymptotic stability and Turing instability are constructed. For the case with delay, the existence of Hopf bifurcation is demonstrated by analyzing the root distribution of the corresponding characteristic equations. Furthermore, by using the normal form theory and the center manifold reduction of partial functional differential equations, explicit formulas are obtained to determine the direction of bifurcations and the stability of bifurcating periodic solutions. Finally, some simulation examples are provided to substantiate our analysis.
Background. Congenital hepatic fibrosis is a hereditary fibropolycystic disease caused by ductal plate malformation. It is characterized by portal hypertension, but the manifestations, management, ...and outcome vary in children and adults. To raise awareness of medical staff, we have comprehensively compared the clinical features of congenital hepatic fibrosis between children and adults. Methods. We retrospectively enrolled all patients diagnosed with congenital hepatic fibrosis at the Huashan Hospital from August 2015 to August 2017 and analyzed their familial, clinical, laboratory, imaging, treatment, and follow-up data in detail. In addition, we reviewed cases with congenital hepatic fibrosis reported in the past 20 years in China and analyzed them according to the patients’ age. Results. A total of eight patients were diagnosed with congenital hepatic fibrosis in the study, including four children and four adults. The onset age of the children, who suffered from severe complications of portal hypertension and needed liver transplantation, ranged from 1 to 15 years old. The disorder developed in adults aged 26 to 60 years old. Three adults complained of recurrent abnormal liver function at the onset of illness, and they mainly received conservative treatments. The literature review included 30 children and 33 adults. In comparison, hepatomegaly was more common in children than in adults (57% vs. 21%, p=0.004). Malformation of kidneys and bile duct abnormalities were common, and multisystem involvement included eyes, other digestive organs, and genital and central nervous systems. Conclusions. Serious complications of portal hypertension developed in children requiring liver transplantation, while adults often had mild-to-moderate liver injuries upon onset. Adults with CHF varied a lot in clinical manifestations. Multiorgan involvement and unusual course are helpful to make a diagnosis. Timely histological assessment by liver biopsy and multidisciplinary cooperation are crucial for definitive diagnosis and early intervention.
Liver transplantation (LT) is a highly curative therapy for patients with hepatocellular carcinoma (HCC). However, due to the shortage of donor livers and rapid progression of HCC, a majority of ...patients are dropped out from the waitlist. Recently, immunotherapy has shown great promise in the treatment of advanced HCC. However, the use of immunotherapy is limited in LT mainly due to the potentially increasing risk of graft rejection. One of the main challenges for researchers is the protection of donor graft from an immunotherapy-boosted immune response mounted by the host. Besides, the safety, availability, and costs of immunotherapy are other challenges that need to be addressed. Here, we reviewed the literature involving patients who received immunotherapy prior to transplant to avoid waitlist dropouts and following transplantation to prevent the progression of tumor recurrence and metastasis. Statistically, the incidence of rejection was 25.0% pre-transplant and 18.5% post-transplant. Based on the review of these clinical studies, we can conclude that conducting clinical trials on the safety and efficacy of currently available immunotherapy drugs and identifying novel immunotherapy targets through extensive research may be promising for patients who do not meet the selection criteria for LT and who experience post-transplant recurrence. To date, the clinical experience on the use of immunotherapy before or after LT comes from individual case studies. Although some of the reported results are promising, they are not sufficient to support the standardized use of immunotherapy in clinical practice.
Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified ...eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.
In this paper, synchronization of a network of the coupled Duffing-type oscillators is considered. By using different methods, two kinds of synchronization are investigated over two graph topologies, ...one is the global synchronization in the sense of Lyapunov over the directed graph, the other is the exponential synchronization over the undirected graph. Firstly, the global synchronization condition of nonlinear network is obtained by the Lyapunov method. Then the global exponential synchronization condition and its synchronized region of linear network are obtained. Finally, some simulations are given to verify the theoretical results.
Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two ...SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)-mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression.
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