Biochar with enhanced performance prepared based on "graphite-structure regulation" conjecture designed to effectively control water pollution.

In this work, corn straw was used as raw material, Hummers method and activation were used to adjust the graphite structure in biochar, and preparing straw based biochar (H-BCS) with ultra-high specific surface area (3441.80 m2/g), highly total pore volume (1.9859 cm3/g), and further enhanced physicochemical properties. Compared with untreated straw biochar (BCS), the specific surface area and total pore volume of H-BCS were increased by 47.24 % and 55.85 %, respectively. H-BCS showed good removal ability in subsequent experiments by using chloramphenicol (CP), hexavalent chromium (Cr6+), and crystal violet (CV) as adsorption models. In addition, the adsorption capacities of H-BCS (CP: 1396.30 mg/g, Cr6+: 218.40 mg/g, and CV: 1246.24 mg/g) are not only higher than most adsorbents, even after undergoing 5 cycles of regeneration, its adsorption capacity remains above 80 %, indicating significant potential for practical applications. In addition, we also speculated and analyzed the conjecture about the "graphite-structure regulation" during the preparation process, and finally discussed the possible mechanism during the adsorption processes. We hope this work could provide a new strategy to solve the restriction of biochar performance by further exploring the regulation of graphite structure in carbon materials.

B7-H3 and CD47 co-expression in gastric cancer is a predictor of poor prognosis and potential targets for future dual-targeting immunotherapy.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent types of cancer worldwide. B7-H3, an immune checkpoint molecule with promising potential, has been found to be overexpressed in various cancers. CD47 is an anti-phagocytic molecule that interacts with the signal regulatory protein alpha (SIRPα) to affect phagocytes. The relationship between the expression of B7-H3 and CD47, two potential therapeutic targets found in tumor cells, remains unknown. In this study, our objective is to investigate the clinical significance of co-expression of B7-H3 and CD47, as well as the potential therapeutic value of combination therapy in GC. METHODS: We utilized immunohistochemistry (IHC) to assess the expression of B7-H3, CD47, CD68, CD86 and CD163 in tissue microarrays obtained from 268 GC patients who underwent surgeries. Western blotting was employed to assess the protein level of B7-H3 and CD47 in GC tissues. The co-localization of B7-H3/CD47 and CD68 in GC tissues was determined using multiplex immunohistochemistry (m-IHC). We further verified the relationship between B7-H3/CD47 and macrophage infiltration via flow cytometry. To estimate the clinical outcomes of patients from different subgroups, we employed the Kaplan-Meier curve and the Cox model. RESULTS: Among the 268 GC cases, a total of 180 cases exhibited positive expression of B7-H3, while 122 cases showed positive expression of CD47. In fresh GC clinical tissues, B7-H3 and CD47 protein level was also higher in tumor tissue than in adjacent normal tissue. Remarkably, 91 cases demonstrated co-expression of B7-H3 and CD47. We observed a significant correlation between B7-H3 expression and tumor stage (P = 0.001), differentiation (P = 0.045), and depth (P = 0.003). Additionally, there was a significant association between B7-H3 and CD47 expression (P = 0.018). The percentage of B7-H3 and CD47 double positive cells in fresh GC tumor tissues were elevated compared with control adjacent tissues regardless of CD45- or CD45+ cells (P = 0.0029, P = 0.0012). Patients with high B7-H3 or CD47 expression had significantly lower overall survival (OS) rates compared to those with low expression levels (P = 0.0176 or P = 0.0042). Surprisingly, patients with combined high expression of B7-H3 and CD47 exhibited a considerably worse prognosis than others (P = 0.0007). Univariate analysis revealed that cases with high expression of B7-H3, CD47, or both had significantly higher hazard ratios (HR) than cases with low expression of these markers. Furthermore, the results of multivariate analysis indicated that B7-H3/CD47 co-expression and CD47 expression alone are independent prognostic factors for overall survival. Moreover, significant correlations were observed between B7-H3 and CD68 expression, CD47 and CD68 expression, as well as B7-H3/CD47 co-expression and CD68 expression in GC patients (P < 0.001, P = 0.003, and P < 0.001). Flow cytometry test showed that the percentage of CD68-positive cells but not CD86-positive cells among B7-H3-positive or CD47-positive immune cells in GC tumor tissue was elevated significantly compared with adjacent tissue. CONCLUSION: Our findings demonstrated a correlation between B7-H3 expression and CD47 expression in GC patient tissues. Co-expression of B7-H3 and CD47 can serve as an indicator of poor prognosis in GC patients. In GC tumor tissue, but not adjacent tissue, B7-H3 and CD47 expression was accompanied with macrophage infiltration.

0.5-5% Supramolecular Salicylic Acid Hydrogel is Safe for Long-Term Topical Application and Improves the Expression of Genes Related to Skin Barrier Homeostasis in Mice Models.

Background: As a keratolytic, salicylic acid (SA) can be topically applied in various formulations and doses in dermatology. Supramolecular SA hydrogel, a new SA formulation with higher bioavailability, is developed and commercially available nowadays. However, there still remain concerns that the long-term and continual application of SA at low concentrations may jeopardize the cutaneous barrier properties. Aim of the Study: To reveal the long-term effects of 0.5-5% supramolecular SA hydrogel on the skin barrier in normal mice models. Materials and Methods: The 0.5%, 1%, 2%, and 5% supramolecular SA hydrogel or hydrogel vehicle without SA was applied to mice's shaved dorsal skin once per day respectively. Tissue samples of the dorsal skin were harvested on day 14 and 28 of the serial application of SA for histopathological observation and transcriptomic analysis. Results: Following topical supramolecular SA hydrogel therapy with various concentrations of SA (0.5%, 1%, 2%, and 5%) for 14 days and 28 days, there were no obvious macroscopic signs of impaired cutaneous health and no inflammatory or degenerative abnormalities were observed in histological results. Additionally, the transcriptomic analysis revealed that on day 14, SA dramatically altered the expression of genes related to the extracellular matrix structural constituent. And on day 28, SA regulated gene expression profiles of keratinization, cornified envelope, and lipid metabolism remarkably. Furthermore, the expression of skin barrier related genes was significantly elevated after the application of SA based on RNA-seq results, and this is likely to be associated with the PPAR signaling pathway according to the enrichment analysis. Conclusion: Our findings demonstrated that the sustained topical administration of the 0.5-5% supramolecular SA hydrogel for up to 28 days did no harm to normal murine skin and upregulated the expression of genes related to the epidermal barrier.

Human umbilical cord mesenchymal stem cell treatment alleviates symptoms in an atopic dermatitis-like mouse model.

BACKGROUND: Atopic dermatitis (AD) is one of the most common immune and inflammatory skin disorders, leading to insufferable itching and skin abnormalities that seriously affect life quality of patients. There are still huge unmet needs for long-term and effective disease control, despite currently available therapies. Evidenced by some preclinical and clinical studies of AD treatment with stem cells, stem cell treatment could significantly and effectively ameliorate AD symptoms. OBJECTIVES: To elucidate underlying mechanisms of how stem cells therapy alleviates AD-like symptoms. METHODS: An AD-like mouse model was constructed and treated with mesenchymal stem cells (MSCs) subcutaneously or subcutaneously combined with intravenously. The differentially expressed genes were sorted out from RNA sequencing results of dorsal skin and blood. RESULTS: Two injection routes of MSCs could alleviate AD-like symptoms and pathologic changes of the skin and immune organs. RNA sequencing of dorsal skin sections and blood provided gene expression signatures for amelioration of skin defects, inflammatory and immune modulation by MSCs, as well as common AD molecular markers for the skin and blood, which may benefit for clinical diagnosis. IL-1ß and its signaling pathway were specifically found to be associated with the development of AD-like dermatitis lesions. MSC treatment effectively inhibited the JAK-STAT pathway and receptors of IL-4, IL-13, IL-17, and IgE. CONCLUSIONS: MSC therapy could regulate abnormal immune and inflammatory status in AD. Mechanistic exploration will contribute to the development of personalized AD treatment based on MSCs.

RNA sequencing and metabolic analysis of imiquimod-induced psoriasis-like mice with chronic restrain stress.

AIM: Psoriasis is one of the most common dermatological disorders, characterized by increased epidermal hyperplasia and immune cell infiltration. Psychological stress has been reported to contribute to the severity, aggravation, and relapse of psoriasis. However, the exact mechanism involved in psychological stress's impact on psoriasis is still unclear. We aim to investigate the role of psychological stress in psoriasis from a transcriptomic and metabolomic perspective. MAIN METHOD: We developed a chronic restrain stress (CRS)-imiquimod (IMQ)-induced psoriasis-like mouse model and performed a comprehensive comparative transcriptomic and metabolic analysis with control mice, CRS-treated mice, and IMQ-treated mice to investigate how psychological stress affects psoriasis. KEY FINDING: We found that CRS-IMQ-induced psoriasis-like mice showed significant exacerbation of psoriasis-like skin inflammation compared with mice treated with IMQ only. Mice of the CRS + IMQ group showed increased expression of keratinocyte proliferation and differentiation genes, differential regulation of cytokines, and promotion of linoleic acid metabolism. Correlation analysis of differentially expressed genes in the CRS-IMQ-induced psoriasis-like mice and human psoriasis datasets compared with respective controls revealed 96 overlapping genes of which 30 genes showed consistent induced or repressed expression in all human and mouse datasets. SIGNIFICANCE: Our study provides new insights into the effects of psychological stress on psoriasis pathogenesis and the mechanisms involved, which provides clues for development of therapeutics or biomarkers.

Firefly swarm intelligence based cooperative localization and automatic clustering for indoor FANETs.

At present, the applications of multiple unmanned aerial vehicles (UAVs) are becoming more and more widespread, covering many civil and military fields. When performing tasks, UAVs will form a flying ad hoc network (FANET) to communicate to each other. However, subject to high mobility, dynamic topology, and limited energy of FANETs, maintaining stable communication performance is a challenging task. As a potential solution, the clustering routing algorithm divides the entire network into multiple clusters to achieve strong network performance. Meanwhile, the accurate localization of UAV is also strongly required when FANETs are applied in the indoor scenario. In this paper, we propose a firefly swarm intelligence based cooperative localization (FSICL) and automatic clustering (FSIAC) for FANETs. Firstly, we combine the firefly algorithm (FA) and Chan algorithm to better cooperative locate the UAVs. Secondly, we propose the fitness function consisting of link survival probability, node degree-difference, average distance, and residual energy, and take it as the light intensity of the firefly. Thirdly, the FA is put forward for cluster-head (CH) selection and cluster formation. Simulation results indicate that the proposed FSICL algorithm achieves the higher localization accuracy faster, and the FSIAC algorithm achieves the higher stability of clusters, longer link expiration time (LET), and longer node lifetime, all of which improve the communication performance for indoor FANETs.

A case of complete recovery in a hypereosinophilic dermatitis patient with dupilumab.

BACKGROUND: Hypereosinophilic dermatitis (HED) is a subtype of hypereosinophilic syndrome (HES). Glucocorticoids are preferred for treatment but carry substantial side effect profiles. Symptoms of HED may recur after systemic glucocorticoid tapering. As an interleukin-4 receptor (IL-4Rα) monoclonal antibody targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), dupilumab might be an efficacious adjuvant therapy for HED. METHOD: We report a young male diagnosed with HED who suffered from erythematous papules with pruritus for over five years. Once reducing the dosage of glucocorticoid was, his skin lesions relapsed. RESULTS: After using dupilumab, the patient's condition significantly improved with the glucocorticoid dosing decreased successfully. CONCLUSION: In conclusion, we report a new application of dupilumab in HED patients, especially with difficulties in reducing the glucocorticoid dose.

γ-Aminobutyric acid promotes the inhibition of hair growth induced by chronic restraint stress.

Stress plays a critical role in hair loss, although the underlying mechanisms are largely unknown. γ-aminobutyric acid (GABA) has been reported to be associated with stress; however, whether it affects stress-induced hair growth inhibition is unclear. This study aimed to investigate the potential roles and mechanisms of action of GABA in chronic restraint stress (CRS)-induced hair growth inhibition. We performed RNA-seq analysis and found that differentially expressed genes (DEGs) associated with neuroactive ligand-receptor interaction, including genes related to GABA receptors, significantly changed after mice were treated with CRS. Targeted metabolomics analysis and enzyme-linked immunosorbent assay (ELISA) also showed that GABA levels in back skin tissues and serum significantly elevated in the CRS group. Notably, CRS-induced hair growth inhibition got aggravated by GABA and alleviated through GABAA antagonists, such as picrotoxin and ginkgolide A. RNA sequencing analysis revealed that DEGs related to the cell cycle, DNA replication, purine metabolism, and pyrimidine metabolism pathways were significantly downregulated in dermal papilla (DP) cells after GABA treatment. Moreover, ginkgolide A, a GABAA antagonist extracted from the leaves of Ginkgo biloba, promoted the cell cycle of DP cells. Therefore, the present study demonstrated that the increase in GABA could promote CRS-induced hair growth inhibition by downregulating the cell cycle of DP cells and suggested that ginkgolide A may be a promising therapeutic drug for hair loss.

The complicated use of dupilumab in the treatment of atypical generalized pemphigus Erythematous: A report of two cases.

Pemphigus is a rare autoimmune disease and has the potential to be fatal without treatment. Pemphigus erythematosus (PE) is a benign type of pemphigus foliaceus. Glucocorticoids and immunosuppressive agents are primary therapeutic modalities in pemphigus erythematosus, which may lead to considerable side effects. There is a growing need for new pemphigus therapies with fewer adverse effects. Dupilumab is a humanized monoclonal IgG4 antibody that inhibits the signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13) and has been applied for atopic dermatitis and asthma. Recently, dupilumab was thought to be beneficial in aggressive refractory pemphigus vulgaris. We report two cases: a 39-year-old male and a 59-year-old woman diagnosed with PE with atypical clinical features. With dupilumab, patients' skin lesions significantly improved, and suitable maintenance glucocorticosteroid doses were reached. In conclusion, we reported the short-term effectiveness and safety of dupilumab in two cases of atypical generalized PE. As an adjunct, such a biologic agent is expected to be efficacious in pemphigus erythematosus.

The combined action of biochar and nitrogen-fixing bacteria on microbial and enzymatic activities of soil N cycling.

This study aims to investigate the positive effects of the combined use of Enterobacter cloacae and biochar on improving nitrogen (N) utilization. The greenhouse pots experimental results showed the synergy of biochar and E. cloacae increased soil total N content and plant N uptake by 33.54% and 15.1%, respectively. Soil nitrogenase (NIT) activity increased by 253.02%. Ammonia monooxygenase (AMO) and nitrate reductase (NR) activity associated with nitrification and denitrification decreased by 10.94% and 29.09%, respectively. The relative abundance of N fixing microorganisms like Burkholderia and Bradyrhizobium significantly increased. Sphingomonas and Ottowia, two bacteria involved in the nitrification and denitrification processes, were found to be in lower numbers. The E. cloacae's ability to fix N2 and promote the growth of plants allow the retention of N in soil and make more N available for plant development. Biochar served as a reservoir of N for plants by adsorbing N from the soil and providing a shelter for E. cloacae. Thus, biochar and E. cloacae form a synergy for the management of agricultural N and the mitigation of negative impacts of pollution caused by excessive use of N fertilizer.

Adsorption of chloramphenicol from water using Carex meyeriana Kunth-derived hierarchical porous carbon with open channel arrays.

A carbon material with both open macrochannel arrays and abundant micro/mesopores was prepared, characterized, and applied for removing chloramphenicol (CAP) from water. In the preparation process, Carex meyeriana Kunth (CM) with natural channel arrays was used as the precursor for producing the biochar, and NaOH was used for removing silicon and formatting micro- and mesopores of the porous carbon. The product (PCCM) exhibited the highest specific surface area (2700.24 m2 g-1) among the reported CM-derived porous carbons. The adsorption performances of PCCM were evaluated through batch adsorption experiments. The maximum adsorption capacity of PCCM toward CAP was 1659.43 mg g-1. The adsorption mechanism was investigated with the aid of theoretical calculations. Moreover, PCCM exhibited better performance than other porous carbon adsorbents in fixed-bed experiments, which may be due to its structural advantages.

Supporting Expressive and Faithful Pictorial Visualization Design with Visual Style Transfer.

Pictorial visualizations portray data with figurative messages and approximate the audience to the visualization. Previous research on pictorial visualizations has developed authoring tools or generation systems, but their methods are restricted to specific visualization types and templates. Instead, we propose to augment pictorial visualization authoring with visual style transfer, enabling a more extensible approach to visualization design. To explore this, our work presents Vistylist, a design support tool that disentangles the visual style of a source pictorial visualization from its content and transfers the visual style to one or more intended pictorial visualizations. We evaluated Vistylist through a survey of example pictorial visualizations, a controlled user study, and a series of expert interviews. The results of our evaluation indicated that Vistylist is useful for creating expressive and faithful pictorial visualizations.

One-Step Synthesis of Nitrogen-Doped Porous Biochar Based on N-Doping Co-Activation Method and Its Application in Water Pollutants Control.

In this work, birch bark (BB) was used for the first time to prepare porous biochars via different one-step methods including direct activation (BBB) and N-doping co-activation (N-BBB). The specific surface area and total pore volume of BBB and N-BBB were 2502.3 and 2292.7 m2/g, and 1.1389 and 1.0356 cm3/g, respectively. When removing synthetic methyl orange (MO) dye and heavy metal Cr6+, both BBB and N-BBB showed excellent treatment ability. The maximum adsorption capacities of BBB and N-BBB were 836.9 and 858.3 mg/g for MO, and 141.1 and 169.1 mg/g for Cr6+, respectively, which were higher than most previously reported biochar adsorbents. The probable adsorption mechanisms, including pore filling, π-π interaction, H-bond interaction, and electrostatic attraction, supported the biochars' demonstrated high performance. In addition, after five recycles, the removal rates remained above 80%, which showed the high stability of the biochars. This work verified the feasibility of the one-step N-doping co-activation method to prepare high-performance biochars, and two kinds of biochars with excellent performance (BBB and N-BBB) were prepared. More importantly, this method provides new directions and ideas for the development and utilization of other biomasses.

Magnetic Luffa-Leaf-Derived Hierarchical Porous Biochar for Efficient Removal of Rhodamine B and Tetracycline Hydrochloride.

Luffa leaf (LL) is an agricultural waste produced by loofah. In this work, LL was used as biomass carbon source for biochars for the first time. After carbonization, activation, and chemical co-precipitation treatments, a magnetic lignocellulose-derived hierarchical porous biochar was obtained. The specific surface area and total pore volume were 2565.4 m2/g and 1.4643 cm3/g, and the surface was rich in carbon and oxygen functional groups. The synthetic dye rhodamine B (RhB) and the antibiotic tetracycline hydrochloride (TH) were selected as organic pollutant models to explore the ability to remove organic pollutants, and the results showed good adsorption performances. The maximum adsorption capacities were 1701.7 mg/g for RhB and 1755.9 mg/g for TH, which were higher than most carbon-based adsorbents. After 10 cycles of use, the removal efficiencies were still maintained at more than 70%, showing good stability. This work not only verified the feasibility of lignocellulose LL as a carbon source to prepare biochar but also prepared a magnetic hierarchical porous adsorbent with good performances that can better treat RhB and TH, which provided a new idea and direction for the efficient removal of organic pollutants in water.

Therapeutic potential of mesenchymal stem cells for refractory inflammatory and immune skin diseases.

Inflammatory and immunological skin diseases such as psoriasis, systemic sclerosis, dermatomyositis and atopic dermatitis, whose abnormal skin manifestations not only affected life quality but also caused social discrimination, have been wildly concerned. Complex variables such as hereditary predisposition, racial differences, age and gender can influence the prevalence and therapeutic options. The population of patients with unsatisfactory curative effects under current therapies is growing, it's advisable to seek novel and advanced therapies that are less likely to cause systemic damage. Mesenchymal stem cells (MSCs) have been proven with therapeutic benefits in tissue regeneration, self-renewal and differentiation abilities when treating refractory skin disorders in preclinical and clinical studies. Here we highlighted the immune modulation and inflammation suppression of MSCs in skin diseases, summarized current studies, research progress and related clinical trials, hoping to strengthen the confidence of promising MSCs therapy in future clinical application.

Influence of Microbial Treatment on the Preparation of Porous Biochar with Stepped-Up Performance and Its Application in Organic Pollutants Control.

In this study, Irisensata Thunb grass (ITG) was used as a biomass carbon resource to prepare biochars for the first time. After microbial treatment, the obtained microbial-treated ITG (MITG) was activated by using a mixed base as an activator for preparation of biochar (MITGB). The specific surface area and total pore volume of MITGB were 3036.4 m2/g and 1.5252 cm3/g, which were higher than those of biochar prepared without microbial treatment (ITGB, 2930.0 m2/g and 1.5062 cm3/g). Besides, the physicochemical properties of MITGB and ITGB were also quite different including micro morphology, surface chemistry, functional groups, etc. In the experiment of removing organic pollutants with synthetic dye RhB and antibiotic TH as the models, MITGB showed excellent treatment ability. The maximum adsorption capacities of MITGB for RhB and TH were 1354.2 and 1462.6 mg/g, which were higher than most of the biochars. In addition, after five cycles of recycling, the adsorption capacities of the organic pollutant models can still be maintained at more than 80%, which showed high stability. This work verified the feasibility of microbial treatment to further improve the performance of biochar and provided a new idea and direction for exploring other biochars.

Enhancing N uptake and reducing N pollution via green, sustainable N fixation-release model.

The overuse of N fertilizers has caused serious environmental problems (e.g., soil acidification, excessive N2O in the air, and groundwater contamination) and poses a serious threat to human health. Improving N fertilizer utilization efficiency and plant uptake is an alternative for N fertilizers overuses. Enterobacter cloacae is an opportunistic pathogen, also used as plant growth-promoting rhizobacteria (PGPR), has been widely presented in the fields of bioremediation and bioprotection. Here we developed a new N fixation-release model by combining biochar with E. cloacae. The efficiency of the model was evaluated using a greenhouse pot experiment with maize (Zea mays L.) as the test crop. The results showed that biochar combined with E. cloacae significantly increased the N content. The application of biochar combined with E. cloacae increased total N in soil by 33% compared with that of N fertilizers application. The N-uptake and utilization efficiency (NUE) in plant was increased 17.03% and 14.18%, respectively. The activities of urease, dehydrogenase and fluorescein diacetate hydrolase (FDA) was improved, the catalase (CAT) activity decreased. Analysis of the microbial community diversity revealed the abundance of Proteobacteria, Actinobacteria, Firmicutes, and Gemmatimonadetes were significantly improved. The mechanism under the model is that E. cloacae acted as N-fixation by capturing N2 from air. Biochar served as carrier, supporting better living environment for E. cloacae, also as adsorbent adsorbing N from fertilizer and from fixed N by E. cloacae, the adsorption in turn slower the N release. Altogether, the model promotes N utilization by plants, improves the soil environment, and reduces N pollution.

Clinical significance of B7-H3 and HER2 co-expression and therapeutic value of combination treatment in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a digestive system malignancy. Trastuzumab (a HER2-targeted monoclonal antibody) is an important targeted drug for GC. However, the drug resistance limits its clinical efficacy. B7-H3 was suggested to be a promising target for cancer immunotherapy. This study aimed to investigate the clinical significance of B7-H3 and HER2 co-expression and the therapeutic value of combination treatment in GC. METHODS: We examined the expression of B7-H3 and HER2 in 268 GC patients by immunohistochemistry. Pearson test was used to analyze the correlation between categorical variables. Overall survival was assessed by Kaplan-Meier analysis. All in vitro experiments using HER2-positive GC cells were treated with small interfering RNA targeting B7-H3/HER2 or B7-H3 blocking antibody 3E8/trastuzumab to verify the antitumor efficacy of the combination therapy. GC xenograft mouse models were established to evaluate the in vivo anti-tumor effect of combined therapy. RESULTS: There was a significant correlation between B7-H3 and HER2 expression in GC tissues. High co-expression of B7-H3 and HER2 was associated with poor prognosis (P = 0.007) and could be an independent risk factor for survival. In addition, knockdown or targeted therapies of B7-H3/HER2 significantly suppressed cell proliferation, migration, invasion and adhesion in vitro. Trastuzumab combined with 3E8 was significantly effective at reducing mice tumor growth than monotherapy. CONCLUSION: High co-expression of B7-H3 and HER2 indicates a poor prognosis, and combination therapy targeting B7-H3 and HER2 could be an immunotherapeutic strategy for GC.

Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5.

Consistent high-risk human papillomavirus (HPV) infection leads to various malignant cancers. Autophagy can promote cancer progression by helping cancer cells survive under stress or induce oncogenic effects when mutations or abnormalities occur. Mitogen activated protein kinases (MAPKs) can transduce various external or intrinsic stimuli into cellular responses, including autophagy, and dual-specificity phosphates (DUSPs) contribute to the direct regulation of MAPK activities. Previously, we showed that expression of DUSP5 was repressed in HPV16 E7-expressing normal human epidermal keratinocytes (NHEKs). Here we show that clinical HPV16 E7-positive precancerous and cancerous tissues also demonstrate low DUSP5 levels compared with control tissues, indicating that the inverse correlation between HPV16 E7 and DUSP5 is clinically relevant. We furthermore investigated the autophagy response in both DUSP5-deficient and HPV16 E7-expressing NHEKs. Confocal microscopy and Western analysis showed induction of LC3-II levels, autophagosome formation and autophagy fluxes in DUSP5-deficient NHEKs. Furthermore, Western analysis demonstrated specific induction of phosphorylated ERK in DUSP5-deficient and HPV16 E7-expressing NHEKs, indicating that HPV16 E7-mediated repression of DUSP5 results in induced MAPK/ERK signaling. Finally, phosphorylated mTOR and ULK (S757) were reduced in DUSP5-deficient NHEKs, while phosphorylated ULK (S555) and AMPK were increased, thereby inducing canonical autophagy through the mTOR and AMPK pathways. In conclusion, our results demonstrate that HPV16 E7 expression reduces DUSP5 levels, which in turn results in active MAPK/ERK signaling and induction of canonical autophagy through mTOR and MAPK regulation. Given its demonstrated inverse correlation with clinical cancerous tissues, DUSP5 may serve as a potential therapeutic target for cervical cancer.

A Novel Combined Use of Dupilumab for Treatment of Aggressive Refractory Pemphigus Vulgaris Complicated With Pulmonary Tuberculosis: A Case Report and the RNA-seq Analysis.

Background: Pemphigus vulgaris (PV) is a kind of IgG-mediated autoimmune blistering disease (AIBD) that is characterized by loss of keratinocyte adhesion in the epithelium of mucous membranes or skin. Recently, pemphigus vulgaris was thought to be associated with classical T helper 2 (TH2)-type cytokines such as interleukin-4 (IL-4) and interleukin-17 (IL-17) signaling pathway. A humanized monoclonal IgG4 antibody called dupilumab binds to the alpha subunit of the interleukin-4 receptor (IL-4Rα) and inhibits the signaling of IL-4 and interleukin-13 (IL-13), which has been successfully applied for atopic dermatitis and asthma. Currently, the clinical trial evaluating dupilumab in bullous pemphigoid is ongoing. Objective: To determine whether dupilumab may be of benefit in the aggressive refractory pemphigus vulgaris. Methods: We report a 35-year old male with refractory pemphigus vulgaris and pulmonary tuberculosis who received treatment with dupilumab for 10 weeks. The mRNA expression of peripheral blood mononuclear cells (PBMCs) was analyzed by RNA sequencing (RNA-seq) which showed the gene expression changes after treatment. Results: The skin lesions of the patient improved in response to the combined use of dupilumab, moderate dose of glucocorticosteroids, and intravenous immune globulin (IVIG). Downregulations of inflammatory response-related genes and IL-17 signaling pathway-related genes were observed in PBMCs. Conclusion: We describe a patient with refractory pemphigus vulgaris and pulmonary tuberculosis who had the disease under control with combined use of dupilumab as an add-on treatment. Dupilumab may provide a beneficial effect in aggressive refractory pemphigus vulgaris.