Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways.

Our previous studies have found that Growth factor receptor-bound protein 2-associated binding protein 2 (Gab2)-a docking protein-governs the development of fatty liver disease. Here, we further demonstrate that Gab2 mediates hepatocarcinogenesis. Compared with a faint expression in para-carcinoma tissue, Gab2 was highly expressed in ∼60-70% of human hepatocellular carcinoma (HCC) specimens. Deletion of Gab2 dramatically suppressed diethylnitrosamine-induced HCC in mice. The oncogenic effects of Gab2 in HepG2 cells were promoted by Gab2 overexpression but were rescued by Gab2 knockdown. Furthermore, Gab2 knockout in HepG2 cells restrained cell proliferation, migration and tumor growth in nude mice. Signaling pathway analysis with protein kinase inhibitors demonstrated that oncogenic regulation by Gab2 in hepatic cells involved multiple signaling molecules, including ERK, Akt, and Janus kinases (Jaks), especially those that mediate inflammatory signaling. IL-6 signaling was increased by Gab2 overexpression and impaired by Gab2 deletion via regulation of Jak2 and signal transducer and activator of transcription 3 phosphorylation and the expression of downstream genes, such as Bcl-2 (B-cell lymphoma 2), c-Myc, MMP7 (matrix metalloproteinase-7), and cyclin D1in vitro and in vivo These data indicate that Gab2 mediates the pathologic progression of HCC by integrating multiple signaling pathways and suggest that Gab2 might be a powerful therapeutic target for HCC.-Cheng, J., Zhong, Y., Chen, S., Sun, Y., Huang, L., Kang, Y., Chen, B., Chen, G., Wang, F., Tian, Y., Liu, W., Feng, G.-S., Lu, Z. Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways.

Synthesis and performance of guanidinium-based cationic organic polymer for the efficient removal of TcO4-/ReO4.

Cationic organic polymers have found relatively extensive utility for TcO4-/ReO4- removal, but the harsh preparation conditions constrain their practical application. The bifunctional guanidinium-based cationic organic polymer (GBCOP) was successfully and facilely synthesized in benign conditions within 1 h. Batch experiments showed that GBCOP exhibited rapid removal kinetics (1 min, >98.0%) and a substantial removal capacity of 536.8 mg/g for ReO4-. Even in 1000-fold co-existing NO3- anions, the removal efficiency of GBCOP for ReO4- was 74.0%, indicating its good selectivity. Moreover, GBCOP had high removal efficiencies for ReO4- across a wide pH (3.0-10.0) range and presented remarkable stability under the conditions of strong acid and base. GBCOP could be reused four times while removing 80.8% ReO4- from simulated Hanford wastewater. SEM and XPS results revealed that the mechanism of ReO4- removal involved Cl- ion exchange within the channels of GBCOP. Theoretical calculation results supported that existing the strong electrostatic interaction between guanidinium and ReO4-. This dual-function GBCOP material is cost-effective and holds significant potential for large-scale preparation, making it a promising solution for TcO4- removal from nuclear wastewater.

Separation of lead-212 from natural thorium solution utilizing novel sulfonamide dibenzo-18-crown-6.

The extraction of lead-212 (212Pb) from radioactive thorium (Th) waste is immensely important, as it serves to mitigate environmental risks associated with radioactive waste and provides a vital source for medical isotopes. To economically extract 212Pb from thorium, we synthesized a novel extractant known as 2,13-disulfonyldiethylamine dibenzo-18-crown-6 (DSADB18C6). We assessed its performance in isolating Pb(II) by employing stable lead and optimizing the parameters of the extraction system. The results showcased an exceptional ability to extract Pb(II) efficiently. Within 10 minutes, using 20 mmol of DSADB18C6 and under conditions of 10 mg L-1 lead concentration (HNO3 = 0.5 mol L-1), the extraction efficiency reached up to 96.1%. Even after four rounds of stripping with 0.4 mol L-1 ammonium citrate, the efficiency remained at 90.2%. Moreover, the extraction stoichiometry and thermodynamics revealed that DSADB18C6 exhibited superior extraction performance compared to the commercial extractant 4',4'',(5'')-di-(tert-butyldicyclohexano)-18-crown-6 (DtBuDC18C6), in line with the density functional theory (DFT) calculation result. Furthermore, we successfully separated 212Pb from the thorium nitrate solution, maintaining radioactive equilibrium with its progeny. Gamma-spectroscopy confirmed a recovery yield of extraction exceeding 85.7%. This study presents a viable approach, underscoring the potential of DSADB18C6 as a promising extractant for the effective separation of 212Pb from radioactive thorium sources.

Application of Refrigerant Cooling in a Battery Thermal Management System under High Temperature Conditions: A Review.

Battery thermal management (BTM) is crucial for the lifespan and safety of batteries. Refrigerant cooling is a novel cooling technique that is being used gradually. As the core fluid of refrigerant cooling, refrigerants need to possess excellent properties while meeting environmental requirements. This paper elucidates the current state of refrigerants (single refrigerants and mixed refrigerants), synchronously summarizing them from the perspectives of refrigerant properties and refrigerant cooling (immersion and cold plate indirect). It outlines the advantages and disadvantages of single and mixed refrigerants as well as the research and development in the vehicle thermal management system (TMS). The choice of refrigerant directly affects cooling performance, and research on vehicle air conditioning (AC) systems can indirectly guide the BTM. R1234yf and R152a can directly replace R134a, while although R744 has a strong heating capacity, it cannot directly replace R134a. Specific mixed refrigerants reduce the global warming potential (GWP) and flammability issues, thereby improving system efficiency. Additionally, immersion cooling controls the temperature through container pressure. Coordinated control strategies are crucial for indirect cold plate cooling, offering broad prospects for optimizing the cold plate design and intelligent control. The selection of refrigerant and the optimal design of the cooling method greatly improve the thermal performance of the battery. This may promote the good development of BTM.

High-Temperature Pyrolysis of N-Tetracosane Based on ReaxFF Molecular Dynamics Simulation.

In order to further understand the high-temperature reaction process and pyrolysis mechanism of hydrocarbon fuels, the high-temperature pyrolysis behavior of n-tetracosane (C24H50) was investigated in this paper via the reaction force field (ReaxFF) method-based molecular dynamics approach. There are two main types of initial reaction channels for n-heptane pyrolysis, C-C and C-H bond fission. At low temperatures, there is little difference in the percentage of the two reaction channels. With the temperature increase, C-C bond fission dominates, and a small amount of n-tetracosane is decomposed by reaction with intermediates. It is found that H radicals and CH3 radicals are widely present throughout the pyrolysis process, but the amount is little at the end of the pyrolysis. In addition, the distribution of the main products H2, CH4, and C2H4, and related reactions are investigated. The pyrolysis mechanism was constructed based on the generation of major products. The activation energy of C24H50 pyrolysis is 277.19 kJ/mol, obtained by kinetic analysis in the temperature range of 2400-3600 K.

Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.

Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease.

Tyrosine phosphatase Shp2 mediates the estrogen biological action in breast cancer via interaction with the estrogen extranuclear receptor.

The extranuclear estrogen receptor pathway opens up novel perspectives in many physiological and pathological processes, especially in breast carcinogenesis. However, its function and mechanisms are not fully understood. Herein we present data identifying Shp2, a SH2-containing tyrosine phosphatase, as a critical component of extranuclear ER pathway in breast cancer. The research checked that the effect of Shp2 on the tumor formation and growth in animal model and investigated the regulation of Shp2 on the bio-effect and signaling transduction of estrogen in breast cancer cell lines. The results showed that Shp2 was highly expressed in more than 60% of total 151 breast cancer cases. The inhibition of Shp2 activity by PHPS1 (a Shp2 inhibitor) delayed the development of dimethylbenz(a)anthracene (DMBA)-induced tumors in the rat mammary gland and also blocked tumor formation in MMTV-pyvt transgenic mice. Estradiol (E2) stimulated protein expression and phosphorylation of Shp2, and induced Shp2 binding to ERα and IGF-1R around the membrane to facilitate the phosphorylation of Erk and Akt in breast cancer cells MCF7. Shp2 was also involved in several biological effects of the extranuclear ER-initiated pathway in breast cancer cells. Specific inhibitors (phps1, phps4 and NSC87877) or small interference RNAs (siRNA) of Shp2 remarkably suppressed E2-induced gene transcription (Cyclin D1 and trefoil factor 1 (TFF1)), rapid DNA synthesis and late effects on cell growth. These results introduced a new mechanism for Shp2 oncogenic action and shed new light on extranuclear ER-initiated action in breast tumorigenesis by identifying a novel associated protein, Shp2, for extranuclear ER pathway, which might benefit the therapy of breast cancer.

A prognosis classifier for breast cancer based on conserved gene regulation between mammary gland development and tumorigenesis: a multiscale statistical model.

Identification of novel cancer genes for molecular therapy and diagnosis is a current focus of breast cancer research. Although a few small gene sets were identified as prognosis classifiers, more powerful models are still needed for the definition of effective gene sets for the diagnosis and treatment guidance in breast cancer. In the present study, we have developed a novel statistical approach for systematic analysis of intrinsic correlations of gene expression between development and tumorigenesis in mammary gland. Based on this analysis, we constructed a predictive model for prognosis in breast cancer that may be useful for therapy decisions. We first defined developmentally associated genes from a mouse mammary gland epithelial gene expression database. Then, we found that the cancer modulated genes were enriched in this developmentally associated genes list. Furthermore, the developmentally associated genes had a specific expression profile, which associated with the molecular characteristics and histological grade of the tumor. These result suggested that the processes of mammary gland development and tumorigenesis share gene regulatory mechanisms. Then, the list of regulatory genes both on the developmental and tumorigenesis process was defined an 835-member prognosis classifier, which showed an exciting ability to predict clinical outcome of three groups of breast cancer patients (the predictive accuracy 64∼72%) with a robust prognosis prediction (hazard ratio 3.3∼3.8, higher than that of other clinical risk factors (around 2.0-2.8)). In conclusion, our results identified the conserved molecular mechanisms between mammary gland development and neoplasia, and provided a unique potential model for mining unknown cancer genes and predicting the clinical status of breast tumors. These findings also suggested that developmental roles of genes may be important criteria for selecting genes for prognosis prediction in breast cancer.