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Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.

Small extracellular vesicles (sEVs) are extracellular nanovesicles that contain bioactive proteins, lipids, RNA, and DNA. A variety of biological process is regulated with sEVs. sEVs are an intercellular messenger regulating recipient cell function and play a role in disease initiation and progression. sEVs derived from certain cells, such as mesenchymal stem cells and immune cells, have the potential for clinical therapy as they possess the characteristics of their parental cells. With better understanding of sEVs biogenesis, their transportation properties, extended circulatory capability, and exceptional biocompatibility, sEVs emerge as a potential therapeutic tool in the clinic. Here, we summarize applications of sEVs‐based therapies in different diseases and current knowledge about the strategies in bioengineered sEVs, as well as the challenges for their use in clinical settings., Small extracellular vesicles (sEVs) are extracellular nanovesicles that contain bioactive proteins, lipids, RNA, and DNA. A variety of biological process is regulated with sEVs. sEVs are an intercellular messenger regulating recipient cell function and play a role in disease initiation and progression. sEVs derived from certain cells, such as mesenchymal stem cells and immune cells, have the potential for clinical therapy as they possess the characteristics of their parental cells. With better understanding of sEVs biogenesis, their transportation properties, extended circulatory capability, and exceptional biocompatibility, sEVs emerge as a potential therapeutic tool in the clinic. Here, we summarize applications of sEVs‐based therapy in different diseases and current knowledge about the strategies in bioengineered sEVs, as well as the challenges for their use in clinical settings.

BackgroundGamma-delta (γδ) T lymphocytes are primed to potently respond to pathogens and transformed cells by recognizing a broad range of antigens. However, adoptive immunotherapy with γδT cells has exhibited mixed treatment responses. Better understanding of γδT cell biology and stratifying healthy donors for allogeneic adoptive therapy is clinically needed to fully realize the therapeutic potential of γδT cells.MethodsWe examine 98 blood samples from healthy donors and measure their expansion capacity after zoledronate stimulation, and test the migration and cytotoxic effector function of expanded γδT cells in 2D culture, 3D tumor spheroid and patient-derived melanoma organoid assays.ResultsWe find that γδT cell expansion capacity is independent of expansion methods, gender, age and HLA type. Basal γδT cell levels in Peripheral blood mononuclear cell (PBMC) correlate well with their expansion, migration and cytotoxic effector capacity in vitro. Circulating γδT cells with lower expression of PD-1, CTLA-4, Eomes, T-bet and CD69, or higher IFN-γ production expand better. γδT cells with central memory and effector memory phenotypes are significantly more abundant in good expanders. A cut-off level of 0.82% γδT cells in PBMC stratifies good versus poor γδT cell expansion with a sensitivity of 97.78%, specificity of 90.48% and area under the curve of 0.968 in a healthy individual. Donors with higher Vδ2 Index Score in PBMC have greater anti-tumor functions including migratory function and cytotoxicity.ConclusionsOur results demonstrate that the interindividual γδT cell functions correlate with their circulating levels in healthy donors. Examination of circulating γδT cell level may be used to select healthy donors to participate in γδT-based immunotherapies.

Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme of glycolysis, is a critical regulator in tumor metabolism. PKM2 has been demonstrated to overexpressed in various cancers and promoted proliferation and metastasis of tumor cells. The errant expression of PKM2 has inspired people to investigate the function of PKM2 and the therapeutic potential in cancer. In addition, some studies have shown that the upregulation of PKM2 in tumor tissues is associated with the altered expression of lncRNAs and the poor survival. Therefore, researchers have begun to unravel the specific molecular mechanisms of lncRNA-mediated PKM2 expression in cancer metabolism. As the tumor microenvironment (TME) is essential in tumor development, it is necessary to identify the role of PKM2 in TME. In this review, we will introduce the role of PKM2 in different cancers as well as TME, and summarize the molecular mechanism of PKM2-related lncRNAs in cancer metabolism. We expect that this work will lead to a better understanding of the molecular mechanisms of PKM2 that may help in developing therapeutic strategies in clinic for researchers.

Background The outbreak of COVID-19 has profoundly influenced people’s lifestyles; these impacts have varied across subgroups of people. The pandemic-related impacts on the health outcomes of people with dermatological conditions are unknown. Objective The aim of this paper was to study the association of COVID-19 pandemic–related impacts with health-related quality of life in patients with skin diseases. Methods This was a cross-sectional study among Chinese patients with skin diseases. A self-administered web-based questionnaire was distributed through social media. Demographic and clinical data and pandemic-related impacts (isolation status, income changes, and employment status) were collected. The main outcomes included perceived stress (Visual Analog Scale), symptoms of anxiety (Generalized Anxiety Disorder-7) and depression (9-Item Patient Health Questionnaire), quality of life (Dermatology Life Quality Index), and health utility mapping based on the EQ-5D-3L descriptive system. Multivariable logistic regression was used to investigate the associations. Results A total of 506 patients with skin diseases completed the survey. The mean age of the patients was 33.5 years (SD 14.0), and 217/506 patients (42.9%) were male. Among the 506 respondents, 128 (25.3%) were quarantined, 102 (20.2%) reported unemployment, and 317 (62.6%) reported decrease or loss of income since the pandemic. The pandemic-related impacts were significantly associated with impaired mental well-being and quality of life with different effects. Unemployment and complete loss of income were associated with the highest risks of adverse outcomes, with increases of 110% to 162% in the prevalence of anxiety, depression, and impaired quality of life. Conclusions Isolation, income loss, and unemployment are associated with impaired health-related quality of life in patients with skin diseases during the COVID-19 pandemic.

BACKGROUND The outbreak of COVID-19 has profoundly influenced people’s lifestyles; these impacts have varied across subgroups of people. The pandemic-related impacts on the health outcomes of people with dermatological conditions are unknown. OBJECTIVE The aim of this paper was to study the association of COVID-19 pandemic–related impacts with health-related quality of life in patients with skin diseases. METHODS This was a cross-sectional study among Chinese patients with skin diseases. A self-administered web-based questionnaire was distributed through social media. Demographic and clinical data and pandemic-related impacts (isolation status, income changes, and employment status) were collected. The main outcomes included perceived stress (Visual Analog Scale), symptoms of anxiety (Generalized Anxiety Disorder-7) and depression (9-Item Patient Health Questionnaire), quality of life (Dermatology Life Quality Index), and health utility mapping based on the EQ-5D-3L descriptive system. Multivariable logistic regression was used to investigate the associations. RESULTS A total of 506 patients with skin diseases completed the survey. The mean age of the patients was 33.5 years (SD 14.0), and 217/506 patients (42.9%) were male. Among the 506 respondents, 128 (25.3%) were quarantined, 102 (20.2%) reported unemployment, and 317 (62.6%) reported decrease or loss of income since the pandemic. The pandemic-related impacts were significantly associated with impaired mental well-being and quality of life with different effects. Unemployment and complete loss of income were associated with the highest risks of adverse outcomes, with increases of 110% to 162% in the prevalence of anxiety, depression, and impaired quality of life. CONCLUSIONS Isolation, income loss, and unemployment are associated with impaired health-related quality of life in patients with skin diseases during the COVID-19 pandemic.

Background The outbreak of coronavirus disease-2019 (COVID-19) ineluctably caused social distancing and unemployment, which may bring additional health risks for patients with cancer. To investigate the association of the pandemic-related impacts with the health-related quality of life (HRQoL) among patients with melanoma during the COVID-19 pandemic, we conducted a cross-sectional study among Chinese patients with melanoma. Methods A self-administered online questionnaire was distributed to melanoma patients through social media. Demographic and clinical data, and pandemic-related impacts (unemployment and income loss) were collected. HRQoL was determined by the Functional Assessment of Cancer Therapy-General (FACT-G) and its disease-specific module (the melanoma subscale, MS). Results A total of 70 patients with melanoma completed the study. The mean age of the patients was 55.2 ± 14.8 years, 45.7% (32/70) were male, and 21.4% (15/70) were unemployed since the epidemic. Unemployment of the patients and their family members and income loss were significantly associated with a lower FACT-G score, while the MS score was associated with the unemployment of the patients’ family members. Conclusions Our findings suggested that unemployment is associated with impaired HRQoL in melanoma patients during the COVID-19 epidemic.

TRAF6, a well-known adapter molecule, plays pivotal role in TLR/IL-1R associated signaling pathway. Although TRAF6 has been shown to have oncogenic activity in various malignant tumors, the details remain unclear. In this study, we demonstrated that TRAF6 facilitates Ras (G12V) and EGF-induced cellular transformation through EGFR. Silencing of TRAF6 expression significantly downregulated AP-1 activity, as well as MMP-2,9 expression after EGF stimulation. Furthermore, we found that TRAF6 plays an essential role in cutaneous squamous cell carcinoma (cSCC) malignant phenotypes, affecting cell growth and migration. CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is over-expressed in tumors and induces tumorigenesis. Our results showed that CD147 formed complex with EGFR and TRAF6. Knockdown of TRAF6 disrupted the CD147-EGFR complex, thereby inducing EGFR endocytosis. Therefore, TRAF6 might be a novel molecular target for cSCC prevention or therapy.

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment and mediate tumor progression in various cancers. A previous study demonstrated that TRAF6 promotes the malignant phenotype of melanoma cells. However, the role of TRAF6 in melanoma CAFs remains unclear. In this study, we found that TRAF6 was significantly upregulated in CAFs adjacent to melanoma cells. Functional assays showed that TRAF6 promoted fibroblast proliferation and migration as well as MMP and α-SMA expression. Moreover, the expression of TRAF6 in fibroblasts promoted the malignant phenotype of melanoma cells in vitro and in vivo. Meanwhile, the intervention of TRAF6 expression in melanoma cells affected the activation of CAFs. We found that FGF19 was a key cytokine regulated by TRAF6 through NF-κB1 using luciferase assay and chromatin immunoprecipitation in melanoma cells. Because plasma FGF19 levels are elevated in patients with melanoma, it may significantly induce fibroblast activation in vitro and in vivo. Taken together, our results support that TRAF6 is a key molecule that mediates the interaction between melanoma cells and stromal fibroblasts, suggesting that TRAF6 is a potentially promising target in melanoma therapy.

CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein that is highly expressed in tumor cells, particularly melanoma cells, and plays critical roles in tumor cell metastasis through the regulation of matrix metalloprotease (MMP) expression. In this study, we identified Fyn as a novel interacting protein of CD147. Fyn is a member of the Src family of nonreceptor tyrosine kinases that regulates diverse physiological processes, such as T lymphocyte differentiation, through the TCR signaling pathway. Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Two phosphospecific antibodies against Y140 and Y183 were developed to validate the phosphorylation of CD147 by Fyn. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. In addition, CD147-FF significantly blocked MMP-9 expression as well as cell migration. Moreover, we found that Fyn is overexpressed in clinical melanoma tissues as well as in melanoma cell lines. Knockdown of Fyn expression markedly attenuated the malignant phenotype of melanoma cells in vitro and in vivo through downregulation of CD147 phosphorylation, indicating that Fyn/CD147 is a potential target molecule in melanoma treatment. Finally, through virtual screening, we identified amodiaquine as a potential inhibitor targeting the Fyn/CD147 axis. Amodiaquine treatment dramatically inhibited the phosphorylation of CD147 by Fyn, thus attenuating melanoma cell growth and invasion in vitro and in vivo, suggesting that amodiaquine is a promising inhibitor for melanoma treatment.

Skin cancer can be classified as cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma. Due to the high level of morbidity and mortality, skin cancer has become a global public health issue worldwide while the pathogenesis of skin cancer is still unclear. It is necessary to further identify the pathogenesis of skin cancer and find candidate targets to diagnose and treat skin cancer. A variety of factors are known to be associated with skin cancer including N-glycosylation, which partly explained the malignant behaviors of skin cancer. In this review, we retrieved databases such as PubMed and Web of Science to elucidate its relationship between glycosylation and skin cancer. We summarized some key glycosyltransferases and proteins during the process of N-glycosylation related to skin cancer, which was helpful to unmask the additional mechanism of skin cancer and find some novel targets of skin cancer.

Pattern formation and synchronization stability in the network are dependent on the local kinetics, connection type, and property of coupling channel. The coupling channels is often controlled to reach synchronization and pattern selection. From dynamical viewpoint, all the bifurcation parameters and coupling channels can be adjusted to get desired patterns and behaviors. However, the physical parameters for most of the electronic components are fixed even some of them can be adjusted in slight range. Thermistor is a kind of nonlinear electronic components, and its resistance is dependent on the temperature completely. It can be used to detect the fluctuation of environment temperature by building nonlinear circuits composed of thermistors. The coupling channel can be adjusted by the temperature when the thermistors are used to couple two or more nonlinear circuits. In this paper, the thermistors are used to couple Chua circuits in a square array with regular connection between adjacent nodes in the network. Gradient distribution of temperature on the network can induce diversity in the coupling intensity in the network because the channel resistances of the coupling thermistors are influenced by the heterogeneous distribution of temperature. In fact, the nodes close to the heat source have higher temperature and they are coupled with stronger intensity because of lower resistances for the coupling thermistors. Perfect target waves can be induced and propagated in the network by taming the temperature for coupling channels. Furthermore, statistical synchronization factor is calculated to estimate the synchronization stability and wave propagation in the network. These results suggested that physical components with adjustable parameters can be used in practical control of nonlinear systems.

Temperature has distinct impact on the activation of neural activities by adjusting the excitability and channel conductance. Some biological neurons can percept slight changes of temperature and then appropriate firing modes are induced under different temperatures. Indeed, the temperature-dependent property can be described by using thermistors, which can be included to build functional neural circuits. Therefore, any changes in the resistance of the thermistor can regulate the branch current and also the output voltage completely. In the paper, thermistors are connected to the FitzHugh-Nagumo neural circuit driven by a voltage source, and a thermosensitive neuron oscillator is obtained by applying scale transformation for the physical variables and parameters in the neural circuit. The thermistor is connected to different branch circuits to enhance the sensitivity to changes of temperature. It is confirmed that the neural activities can present distinct mode transition from spiking to bursting and chaotic states. In particular, the external stimulus becomes dependent on temperature when the thermistor is connected to the external voltage source. Stochastic resonance and multiple modes are detected when additive Gaussian white noise is applied on an isolated neuron controlled by temperature. Therefore, a sensitive sensor of temperature is obtained, and this feasible neuron model can be effective to investigate the collective behaviors of neural networks in the presence of time-varying temperature. Also, the Hamilton energy is estimated to predict the mode selection and effect of noise.

Phototube can capture and transmit external illumination with high frequency into photocurrent in the nonlinear circuit, which can be tamed to produce the main dynamical properties of biological neurons. In fact, the involvement of functional electronic components can enhance the biophysical function of artificial neural circuits. In this paper, a photocell is connected to FitzHugh-Nagumo neural circuits, which can be excited by the photocurrent generated from the photocell. Furthermore, a memristor is proposed to couple two light-dependent neural circuits and the synchronization stability is investigated on the coupled dynamical systems by using standard scale transformation on the physical variables and parameters. It is found that phase synchronization and complete synchronization can be obtained by regulating the coupling channel connected by the memristor. The propagation and pumping of field energy are also calculated to predict the occurrence of synchronization.

Autophagy, or self-eating, is an evolutionarily conserved process in which cytosol and organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/vacuole for the degradation and recycling of cytoplasmic components in eukaryotes. It is well recognized that autophagy plays an important role in maintaining cellular homeostasis under physiological and pathophysiological con­ditions and the upregulation of autophagy may serve as an adaptive process to provide nutrients and energy when under stresses. Recently, studies have illustrated that autophagy is intricately related to skin diseases. This review provides a brief synopsis of the process of autophagy and aims to elucidate the roles of autophagy in different skin diseases and to highlight the need for increased research in the field.

CD147 is a membrane protein belonging to immunoglobulin superfamily and expressed in the cell membrane, which is also named with an extracellular matrix metalloproteinase inducer (EMMPRIN) because this molecule induces adjacent fibroblasts or tumor cells to produce MMPs, facilitating tumor cells migration and invasion. Accumulating evidences have shown that CD147 is over-expressed in various tumors, including melanoma, liver cancer, and lung cancer, and orchestrates tumor cell proliferation, apoptosis, invasion and metastasis, multidrug resistance and glycolysis through critical molecules such as MMPs, MCTs, Caveolin-1, and VEGF. In this review, we focus on understanding the characteristics of CD147 in various biological functions, including physiological and pathological processes. Recent novel studies have shown that CD147 is not only a potential diagnostic marker but also a therapeutic target for chemotherapy or the diagnosis of cancer.

The effect of pre-ageing temperature and retrogression heating rate variations on the mechanical properties and electrical conductivity of the RRA treated AA7055 has been investigated. The microstructures under various RRA treated samples are discussed in detail. The results reveal that, near peak aged state plus slow retrogression heating is more applicable for industrial processing. Under the pre-ageing at 105 °C/24 h and a slow retrogression heating rate of 3 °C/min condition, RRA-treated samples possess a better combination of both strength and electrical conductivity than the T6 or T73 states.

The stress tolerance of wetland plants is crucial for their appropriate application in constructed wetland (CW). Ammonia, one of the major pollutants in wastewater, is nutrition for plants at low concentrations but could be toxic at excess concentrations. This study aimed to investigate the effect of external ammonia at different concentrations (0, 1, 2, 4, 8, 10 mg L−1) to a specific submerged plant Potamogeton crispus (P. crispus), which has been used widely in CW. Results showed that the threshold value of ammonia for P. crispus was 4 mg L−1, under which no obvious variations from the control group were detected in all associated observations. When ammonia concentration exceeded 4 mg L−1, plants displayed significant increase in lipid peroxidation product contents (MDA, O2 − and H2O2), antioxidant enzyme activities (T-SOD, POD, and CAT), and a corresponding increase in the percentages of electrolyte leakage. However, external ammonia only had slight effect on the chlorophyll synthesis of P. crispus under the studied concentration range. Excess ammonia exposure (≥4 mg L−1) could affect the physiological responses of P. crispus, by inducing oxidative stress and by limitedly altering permeability of cell membrane and plant photosynthesis. The results of this study supplied useful information for the aquatic vegetation collocation in CW design, and it is suggested to take proper application of P. crispus in CW when treating eutrophication or other relatively heavily polluted water.

The performance response of eight vertical flow constructed wetlands (VFCWs) to different influent COD/N ratios and intermittent aeration in domestic wastewater treatment was investigated. Almost complete nitrification was obtained by intermittent aeration, which well developed alternate anaerobic and aerobic conditions for nitrification and denitrification. Sufficient carbon source supply resulted from influent COD/N ratio of 10 simultaneously obtained high removals of COD (96%), ammonia nitrogen (99%) and total nitrogen (90%) in intermittently aerated VFCWs. In all non-aerated VFCWs, poor nitrification was observed due to oxygen deficiency whilst high COD/N ratios further led to lower COD and nitrogen removal efficiency. The results suggest that intermittent aeration combined with high influent COD/N ratios could achieve high nitrogen removal in VFCWs. © 2013 Elsevier Ltd.