Chemotherapy is one of the major treatments for cancer patients. Although chemotherapeutic drugs can sometimes effectively suppress tumor growth in cancer patients, a significant proportion of ...patients are either intrinsically resistant or later develop resistance to primary chemotherapy, leading to disease relapse and patient mortality. The best way to conquer the resistance is the better understanding of the molecular network in cancer cells in response to drugs. Therefore, identification of signaling pathways and molecules involved in drug resistance is essential for successful treatment of cancers. The Hippo pathway is an emerging signaling pathway that plays important roles in tumorigenesis, stem cell self‐renewal and differentiation, organ size control as well as many other biological processes. Therefore, exploring novel roles of the Hippo pathway in various biological functions has become one of the cutting‐edge research areas in cancer and other biomedical research. Recently, we and others have provided new evidence that the Hippo pathway is involved in the resistance of different types of cancer cells to various chemotherapeutic drugs. In this review, we will discuss the specific roles of the Hippo pathway in chemotherapy, potential applications for studying this network in response to drugs as well as the future direction in identification of therapeutic targets.
KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma
. KRAS(G12C) inhibitors
are in phase-I clinical trials and ...early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation
, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.
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•A type of photopolymer composed polyurethane acrylate is synthesized.•The photopolymer is applied in SLA technique to print shape memory polymers.•The printed samples show excellent ...shape memory performance.•The printed samples have high mechanical strength and good toughness.
In our research, a type of polyurethane acrylate is successfully synthesized and then compounded with epoxy acrylate and isobornyl acrylate as well as radical photoinitiator to get photopolymer. Afterwards, the photopolymer is applied through stereolithography 3D printing to fabricate shape memory polymers. The photopolymer is proved to have high UV-curing activity and the printing accuracy is high. Fold-deploy test and shape memory cycles measurements prove the excellent shape memory performance of the printed objects, including high shape recovery rate, shape fixity and recovery and excellent endurance. The shape fixity and recovery ratios are 96.77 ± 0.06% and 100.00 ± 0.08%, respectively. Tensile test at 70 °C shows that the recovery stress of printed objects can reach as high as 6.4 MPa. Mechanical test shows the printed objects have high strength and good toughness. With excellent shape memory performance, good mechanical properties and high printing accuracy, such material has great potential applications in many fields.
Herein, a selective tandem C–C bond-forming reaction with CO2 was developed to realize the bridging of enaminones and synthesis of 1,4-dihydropyridines, respectively. n-Butylamine significantly ...promoted this CO2 deoxymethylenation procedure catalyzed by 1,5,7-triazabicyclo4.4.0dec-5-ene (TBD) and ZnCl2. The mechanism involving the formation of bis(silyl)acetal, nucleophilic addition, and amine elimination was also interpreted to clarify the bridging of two molecules of enaminones with CO2 and the generation of dihydropyridine derivatives.
Based on the research characteristics of the C-shaped steel structure of the photovoltaic agricultural greenhouse, the stress and strain under the design load of the solar cell module support are ...tested. Compared with the ANSYS simulation and test data, the test results are in good agreement with the simulation analysis results. The maximum stress measured by the main steel frame structure under the required load is far less than the steel stress value, the structural safety strength is high, there is a big reduction Heavy margin. The research results can provide a reference for the engineering design of the photovoltaic agricultural greenhouse steel frame structure.
With the ever-increasing demands for local area services of popular content sharing, device-to-device (D2D) communication is conceived to be a key component of the next-generation cellular networks. ...D2D communications consume low energy and provide high capacity via proximity range transmissions, where multihop transmissions are needed for real-time content sharing. Aiming to solve the challenging problem for multihop D2D communication networks, existing studies only consider communication domain information to create long-range links (LLs) to reduce multihop transmission delay. In contrast, in this paper, we propose a novel social-community-aware LLs establishment strategy, which exploits the interplay between social network features and communication domain constraints. We first formulate the LLs establishment strategy as a cost-minimization problem and then propose an efficient greedy algorithm to solve the formulated problem, which is suitable for scenarios of both single-sink and distributed content sharing. To decrease the computational complexity, we model the optimization problem as a coalition graph game and propose a dynamic algorithm based on local best response and a near-optimal algorithm based on switching operation, which both run in the distributed approach. Numerical results demonstrate that our proposed solution decreases the average path length significantly with low computational complexity compared with other state-of-the-art schemes.
Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence ...argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients.
With the ever-increasing energy consumption in transmissions of explosive growing mobile data, energy-efficient solutions are needed to be integrated into the future mobile networks. The upcoming 5G ...networks support device-to-device (D2D) communication underlaying the cellular networks, which enables proximity cellular users to communicate directly with high data rate and low transmit power. In this paper, targeting the energy-aware D2D communications underlaying cellular system, we investigate the fundamental problems of what is the potential gains of D2D communications for energy saving, which are the fundamental reasons to decrease the energy consumption, and how about the tradeoffs between energy consumption and other network factors of available bandwidth, buffer size and service delay in large scale D2D communication networks. To answer the above challenging problems, we utilize a dynamic graph approach to model the system with human mobility for a realistic D2D communication scenario. Specifically, by formulating a mixed integer linear programming problem that minimizes the energy consumption for data transmission from the cellular base stations to the receivers through any possible ways of transmissions, we obtain the theoretical performance lower bound of system energy consumption, which shows that cellular D2D communications decrease the energy consumption about 65% averagely under the realistic scenario. Furthermore, the obtained fundamental tradeoffs reveal that energy consumption for large bandwidth can be kept at a low level with increase of the buffer size and service delay.
I-BET151 is an inhibitor of bromodomain and extra-terminal domain (BET) proteins that selectively inhibits BET family members (BRD2, BRD3, BRD4, and BRDT). Over the past ten years, many studies have ...demonstrated the potential of I-BET151 in cancer treatment. Specifically, I-BET151 causes cell cycle arrest and inhibits tumor cell proliferation in some hematological malignancies and solid tumors, such as breast cancer, glioma, melanoma, neuroblastoma, and ovarian cancer. The anticancer activity of I-BET151 is related to its effects on NF-κB, Notch, and Hedgehog signal transduction pathway, tumor microenvironment (TME) and telomere elongation. Remarkably, the combination of I-BET151 with select anticancer drugs can partially alleviate the occurrence of drug resistance in chemotherapy. Especially, the combination of forskolin, ISX9, CHIR99021, I-BET151 and DAPT allows GBM cells to be reprogrammed into neurons, and this process does not experience an intermediate pluripotent state. The research on the anticancer mechanism of I-BET151 will lead to new treatment strategies for clinical cancer.
Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number ...of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death
PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice
Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis
Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation.
This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future.
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