Functional analysis of the mating type genes in Verticillium dahliae.

BACKGROUND: Populations of the plant pathogenic fungus Verticillium dahliae display a complex and rich genetic diversity, yet the existence of sexual reproduction in the fungus remains contested. As pivotal genes, MAT genes play a crucial role in regulating cell differentiation, morphological development, and mating of compatible cells. However, the functions of the two mating type genes in V. dahliae, VdMAT1-1-1, and VdMAT1-2-1, remain poorly understood. RESULTS: In this study, we confirmed that the MAT loci in V. dahliae are highly conserved, including both VdMAT1-1-1 and VdMAT1-2-1 which share high collinearity. The conserved core transcription factor encoded by the two MAT loci may facilitate the regulation of pheromone precursor and pheromone receptor genes by directly binding to their promoter regions. Additionally, peptide activity assays demonstrated that the signal peptide of the pheromone VdPpg1 possessed secretory activity, while VdPpg2, lacked a predicted signal peptide. Chemotactic growth assays revealed that V. dahliae senses and grows towards the pheromones FO-a and FO-α of Fusarium oxysporum, as well as towards VdPpg2 of V. dahliae, but not in response to VdPpg1. The findings herein also revealed that VdMAT1-1-1 and VdMAT1-2-1 regulate vegetative growth, carbon source utilization, and resistance to stressors in V. dahliae, while negatively regulating virulence. CONCLUSIONS: These findings underscore the potential roles of VdMAT1-1-1 and VdMAT1-2-1 in sexual reproduction and confirm their involvement in various asexual processes of V. dahliae, offering novel insights into the functions of mating type genes in this species.

Expression and diagnostic value of interleukin-22 in rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by a high incidence and mortality rate, highlighting the need for biomarkers to detect ILD early in RA patients. Previous studies have shown the protective effects of Interleukin-22 (IL-22) in pulmonary fibrosis using mouse models. This study aims to assess IL-22 expression in RA-ILD to validate foundational experiments and explore its diagnostic value. The study included 66 newly diagnosed RA patients (33 with ILD, 33 without ILD) and 14 healthy controls (HC). ELISA was utilized to measure IL-22 levels and perform intergroup comparisons. The correlation between IL-22 levels and the severity of RA-ILD was examined. Logistic regression analysis was employed to screen potential predictive factors for RA-ILD risk and establish a predictive nomogram. The diagnostic value of IL-22 in RA-ILD was assessed using ROC. Subsequently, the data were subjected to 30-fold cross-validation. IL-22 levels in the RA-ILD group were lower than in the RA-No-ILD group and were inversely correlated with the severity of RA-ILD. Logistic regression analysis identified IL-22, age, smoking history, anti-mutated citrullinated vimentin antibody (MCV-Ab), and mean corpuscular hemoglobin concentration (MCHC) as independent factors for distinguishing between the groups. The diagnostic value of IL-22 in RA-ILD was moderate (AUC = 0.75) and improved when combined with age, smoking history, MCV-Ab and MCHC (AUC = 0.97). After 30-fold cross-validation, the average AUC was 0.886. IL-22 expression is dysregulated in the pathogenesis of RA-ILD. This study highlights the potential of IL-22, along with other factors, as a valuable biomarker for assessing RA-ILD occurrence and progression.

A randomized, blind, parallel controlled phase I clinical trial to evaluate the safety and preliminary immunogenicity of 23-valent pneumococcal polysaccharide vaccine in healthy people aged 2 years and older.

BACKGROUND: Despite some progress in pneumococcal immunization, the global burden of pneumococcal infection remains high, and pneumococcal disease remains a public health concern. Studies in China and abroad have found that 23-valent pneumococcal polysaccharide vaccine (PPV23) vaccination can effectively prevent invasive pneumococcal disease. This phase Ⅰ clinical study assessed the safety and immunogenicity of a PPV23 vaccine candidate. METHODS: All subjects were randomly assigned to receive one dose intramuscular injection of experimental vaccine or control vaccine at a ratio of 1:1. The incidence of any adverse events was observed within 30 min, 0-7 days and 8-28 days post vaccination and the incidence of abnormal blood biochemical and blood routine indicators were tested on the 4th day post vaccination, the incidence of serious adverse events (SAEs) at 6 months post vaccination was recorded. Blood samples were collected prior to vaccination and on the 28th day post vaccination, and serum antibodies were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: The most common adverse reaction was pain at the injection site, followed by erythema. There was no significant difference of the incidence of systemic adverse reactions between the two vaccine groups. The adverse reactions observed in the trial were all common vaccination-related reactions, and no serious adverse reactions were observed. Compared to pre-vaccination, the (geometric mean concentrations) GMCs of IgG (immunoglobulin G) specific antibody against each serotype were all increased in the experimental group and the control group, there were statistical differences in seroconversion rates of serotypes 4 and 20 between the two vaccine groups. CONCLUSION: This clinical study showed good safety of the PPV23 vaccine candidate produced by Ab&b Biotechnology Co., Ltd.JS had good safety after vaccination in people aged 2 years and older. At the same time, good immunogenicity was also demonstrated.

GhCOL2 Positively Regulates Flowering by Activating the Transcription of GhHD3A in Upland Cotton (Gossypium hirsutum L.).

Plants have evolved sophisticated signaling networks to adjust flowering time, ensuring successful reproduction. Two crucial flowering regulators, FLOWERING LOCUS T (FT) and CONSTANS (CO), play pivotal roles in regulating flowering across various species. Previous studies have indicated that suppressing Gossypium hirsutum CONSTANS-LIKE 2 (GhCOL2), a homolog of Arabidopsis CO, leads to delayed flowering in cultivated cotton. However, the underlying regulatory mechanisms remain unknown. In this study, a yeast one-hybrid and dual-LUC expression assays were used to elucidate the molecular mechanism through which GhCOL2 regulates the transcription of GhHD3A. RT-qPCR was used to examine the expression of GhCOL2 and GhHD3A. Our findings reveal that GhCOL2 directly binds to CCACA cis-elements and atypical CORE (TGTGTATG) cis-elements in the promoter regions of HEADING DATE 3 A (HD3A), thereby activating GhHD3A transcription. Notably, GhCOL2 and GhHD3A exhibited high expression levels in the adult stage and low levels in the juvenile stage. Interestingly, the expression of GhCOL2 and GhHD3A varied significant between the two cotton varieties (Tx2094 and Maxxa). In summary, our study enhances the understanding of the molecular mechanism by which cotton GhCOL2-GhHD3A regulates flowering at the molecular level. Furthermore, it contributes to a broader comprehension of the GhCOL2-GhHD3A model in G. hirsutum.

Identification of discriminatory factors and construction of nomograms for differentiating AOSD and sepsis.

OBJECTIVE: This study aimed to develop nomogram prediction models to differentiate between adult-onset Still's disease (AOSD) and sepsis. METHODS: We retrospectively collected laboratory test data from 107 hospitalized patients with AOSD and sepsis at the Affiliated Hospital of Xuzhou Medical University. Multivariate binary logistic regression was used to develop nomogram models using arthralgia, WBC, APTT, creatinine, PLT, and ferritin as independent factors. The performance of the model was evaluated by the bootstrap consistency index and calibration curve. RESULTS: Model 1 had an AUC of 0.98 (95% CI, 0.96-1.00), specificity of 0.98, and sensitivity of 0.94. Model 2 had an AUC of 0.96 (95% CI, 0.93-1.00), specificity of 0.92, and sensitivity of 0.94. The fivefold cross-validation yielded an accuracy (ACC) of 0.92 and a kappa coefficient of 0.83 for Model 1, while for Model 2, the ACC was 0.87 and the kappa coefficient was 0.74. CONCLUSION: The nomogram models developed in this study are useful tools for differentiating between AOSD and sepsis. Key Points • The differential diagnosis between AOSD and sepsis has always been a challenge • Delayed treatment of AOSD may lead to serious complications • We developed two nomogram models to distinguish AOSD from sepsis, which were not previously reported • Our models can be used to guide clinical practice with good discrimination.

Establishment of a differential diagnosis method and an online prediction platform for AOSD and sepsis based on gradient boosting decision trees algorithm.

OBJECTIVE: The differential diagnosis between adult-onset Still's disease (AOSD) and sepsis has always been a challenge. In this study, a machine learning model for differential diagnosis of AOSD and sepsis was developed and an online platform was developed to facilitate the clinical application of the model. METHODS: All data were collected from 42 AOSD patients and 50 sepsis patients admitted to Affiliated Hospital of Xuzhou Medical University from December 2018 to December 2021. In addition, 5 AOSD patients and 10 sepsis patients diagnosed in our hospital after March 2022 were collected for external validation. All models were built using the scikit-learn library (version 1.0.2) in Python (version 3.9.7), and feature selection was performed using the SHAP (Shapley Additive exPlanation) package developed in Python. RESULTS: The results showed that the gradient boosting decision tree(GBDT) optimization model based on arthralgia, ferritin × lymphocyte count, white blood cell count, ferritin × platelet count, and α1-acid glycoprotein/creatine kinase could well identify AOSD and sepsis. The training set interaction test (AUC: 0.9916, ACC: 0.9457, Sens: 0.9556, Spec: 0.9578) and the external validation also achieved satisfactory results (AUC: 0.9800, ACC: 0.9333, Sens: 0.8000, Spec: 1.000). We named this discrimination method AIADSS (AI-assisted discrimination of Still's disease and Sepsis) and created an online service platform for practical operation, the website is http://cppdd.cn/STILL1/ . CONCLUSION: We created a method for the identification of AOSD and sepsis based on machine learning. This method can provide a reference for clinicians to formulate the next diagnosis and treatment plan.

Diagnostic value and safety of medical thoracoscopy for pleural effusion of different causes.

BACKGROUND: Pleural effusions occur for various reasons, and their diagnosis remains challenging despite the availability of different diagnostic modalities. Medical thoracoscopy (MT) can be used for both diagnostic and therapeutic purposes, especially in patients with undiagnosed pleural effusion. AIM: To assess the diagnostic efficacy and safety of MT in patients with pleural effusion of different causes. METHODS: Between January 1, 2012 and April 30, 2021, patients with pleural effusion underwent MT in the Department of Respiratory Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University (Shaanxi, China). According to the discharge diagnosis, patients were divided into malignant pleural effusion (MPE), tuberculous pleural effusion (TBPE), and inflammatory pleural effusion (IPE) groups. General information, and tuberculosis- and effusion-related indices of the three groups were analyzed. The diagnostic yield, diagnostic accuracy, performance under thoracoscopy, and complications of patients were compared among the three groups. Then, the significant predictive factors for diagnosis between the MPE and TBPE groups were analyzed. RESULTS: Of the 106 patients enrolled in this 10-year study, 67 were male and 39 female, with mean age of 57.1 ± 14.184 years. Among the 74 thoracoscopy-confirmed patients, 41 (38.7%) had MPE, 21 had (19.8%) TBPE, and 32 (30.2%) were undiagnosed. Overall diagnostic yield of MT was 69.8% (MPE: 75.9%, TBPE: 48.8%, and IPE: 75.0%, with diagnostic accuracies of 100%, 87.5%, and 75.0%, respectively). Under thoracoscopy, single or multiple pleural nodules were observed in 81.1% and pleural adhesions in 34.0% with pleural effusions. The most common complication was chest pain (41.5%), followed by chest tightness (11.3%) and fever (10.4%). Multivariate logistic regression analyses showed effusion appearance [odds ratio (OR): 0.001, 95%CI: 0.000-0.204; P = 0.010] and carcinoembryonic antigen (OR: 0.243, 95%CI: 0.081-0.728; P = 0.011) as significant for differentiating MPE and TBPE, with area under the receiver operating characteristic curve of 0.977 (95%CI: 0.953-1.000; P < 0.001). CONCLUSION: MT is an effective, safe, and minimally invasive procedure with high diagnostic yield for pleural effusion of different causes.

Molecular Characteristics of T Cell-Mediated Tumor Killing in Hepatocellular Carcinoma.

Background: Although checkpoint blockade is a promising approach for the treatment of hepatocellular carcinoma (HCC), subsets of patients expected to show a response have not been established. As T cell-mediated tumor killing (TTK) is the fundamental principle of immune checkpoint inhibitor therapy, we established subtypes based on genes related to the sensitivity to TKK and evaluated their prognostic value for HCC immunotherapies. Methods: Genes regulating the sensitivity of tumor cells to T cell-mediated killing (referred to as GSTTKs) showing differential expression in HCC and correlations with prognosis were identified by high-throughput screening assays. Unsupervised clustering was applied to classify patients with HCC into subtypes based on the GSTTKs. The tumor microenvironment, metabolic properties, and genetic variation were compared among the subgroups. A scoring algorithm based on the prognostic GSTTKs, referred to as the TCscore, was developed, and its clinical and predictive value for the response to immunotherapy were evaluated. Results: In total, 18 out of 641 GSTTKs simultaneously showed differential expression in HCC and were correlated with prognosis. Based on the 18 GSTTKs, patients were clustered into two subgroups, which reflected distinct TTK patterns in HCC. Tumor-infiltrating immune cells, immune-related gene expression, glycolipid metabolism, somatic mutations, and signaling pathways differed between the two subgroups. The TCscore effectively distinguished between populations with different responses to chemotherapeutics or immunotherapy and overall survival. Conclusions: TTK patterns played a nonnegligible role in formation of TME diversity and metabolic complexity. Evaluating the TTK patterns of individual tumor will contribute to enhancing our cognition of TME characterization, reflects differences in the functionality of T cells in HCC and guiding more effective therapy strategies.

Rapid biosynthesis of fluorescent CdSe QDs in Bacillus licheniformis and correlative bacterial antibiotic change assess during the process.

Cadmium selenide (CdSe) quantum dots (QDs) were biosynthesized rapidly in 18 h in Bacillus licheniformis ATCC 11946 (B. licheniformis); this process benefited from the cellular machinery of bacteria metal metabolism, in which inorganic Na2 SeO3 and CdCl2 were chosen as raw materials to produce high quality CdSe QDs by a designed two-step protocol. Research outcomes demonstrated that the purified CdSe QDs possessed maximum fluorescence intensities at weak alkalinity solutions and had good fluorescence stabilities at 4°C as well as at room temperature after standing for 1 week. Glutathione (GSH) concentration and superoxide dismutase (SOD) content, both of which were reported to be greatly related to biosynthetic activities in some bacterial matrices, were monitored during the biosynthetic process in B. licheniformis. Bacterial resistance research further showed that the change in rates in bacterial inhibition zone diameter to seven different antibiotics was less than 9% after B. licheniformis was used to manufacture CdSe QDs, showing a relative lower environmental risk in short-term heavy metal exposure.

CdSe quantum dots labeled Staphylococcus aureus for research studies of THP-1 derived macrophage phagocytic behavior.

A simple biological strategy to couple intracellular irrelated biochemical reactions of staphylococcus aureus CMCC 26003 (S. aureus) with inorganic metal ions to synthesize cadmium selenide quantum dots (CdSe QDs) was demonstrated. Correspondingly, S. aureus as living matrices are internally generated and labeled with fluorescent QDs by the smart strategy. Several key factors in the process of biosynthesis were systematically evaluated. At the same time, ultraviolet-visible (UV-Vis), photo-luminescence (PL), inverted fluorescence microscopy and transmission electron microscopy (TEM) were utilized to study the characters of the as produced CdSe QDs. In addition, cytotoxicity and photostability of the QDs containing bacteria were also tested and evaluated as a whole. The results showed that intracellular CdSe nanocrystals had successfully formed in S. aureus living cells, which were less toxic, highly fluorescent and photostable. These fluorescent S. aureus bacteria were next applied as invading pathogens as well as fluorescent bioprobes for exploring the phagocytic behavior of THP-1-derived macrophage. Results proved that internal CdSe QDs labeling had no significantly adverse effects compared with the kind of infection reference, fluorescein isothiocyanate (FITC) stained S. aureus pathogen. Assuredly, the methods presented here provide researchers with a useful option to analyze the behavior of S. aureus as a type of infectious pathogen, which would also help understand the complex interplay between host cells and the invading bacteria on molecular level.

Characterization of Highly Pathogenic Avian Influenza H5N1 Viruses Isolated from Domestic Poultry in China.

The highly pathogenic avian influenza (HPAI) H5N1 virus has caused several outbreaks in domestic poultry. Despite great efforts to control the spread of this virus, it continues to evolve and poses a substantial threat to public health because of a high mortality rate. In this study, we sequenced whole genomes of eight H5N1 avian influenza viruses isolated from domestic poultry in eastern China and compared them with those of typical influenza virus strains. Phylogenetic analyses showed that all eight genomes belonged to clade 2.3.2.1 and clade 7.2, the two main circulating clades in China. Viruses that clustered in clade 2.3.2.1 shared a high degree of homology with H5N1 isolates located in eastern Asian. Isolates that clustered in clade 7.2 were found to circulate throughout China, with an east-to-west density gradient. Pathogenicity studies in mice showed that these isolates replicate in the lungs, and clade 2.3.2.1 viruses exhibit a notably higher degree of virulence compared to clade 7.2 viruses. Our results contribute to the elucidation of the biological characterization and pathogenicity of HPAI H5N1 viruses.

Characterization of Highly Pathogenic Avian Influenza H5N1 Viruses Isolated from Domestic Poultry in China / 生物医学与环境科学（英文）

The highly pathogenic avian influenza (HPAI) H5N1 virus has caused several outbreaks in domestic poultry. Despite great efforts to control the spread of this virus, it continues to evolve and poses a substantial threat to public health because of a high mortality rate. In this study, we sequenced whole genomes of eight H5N1 avian influenza viruses isolated from domestic poultry in eastern China and compared them with those of typical influenza virus strains. Phylogenetic analyses showed that all eight genomes belonged to clade 2.3.2.1 and clade 7.2, the two main circulating clades in China. Viruses that clustered in clade 2.3.2.1 shared a high degree of homology with H5N1 isolates located in eastern Asian. Isolates that clustered in clade 7.2 were found to circulate throughout China, with an east-to-west density gradient. Pathogenicity studies in mice showed that these isolates replicate in the lungs, and clade 2.3.2.1 viruses exhibit a notably higher degree of virulence compared to clade 7.2 viruses. Our results contribute to the elucidation of the biological characterization and pathogenicity of HPAI H5N1 viruses.

Sex-determining region of Y chromosome-related high-mobility-group box 2 in malignant tumors: current opinions and anticancer therapy.

OBJECTIVE: To gain insight into the mechanism by which sex-determining region of Y chromosome (SRY)-related high-mobility-group box 2 (SOX2) involved in carcinogenesis and cancer stem cells (CSCs). DATA SOURCES: The data used in this review were mainly published in English from 2000 to present obtained from PubMed. The search terms were "SOX2," "cancer," "tumor" or "CSCs." STUDY SELECTION: Articles studying the mitochondria-related pathologic mechanism and treatment of glaucoma were selected and reviewed. RESULTS: SOX2, a transcription factor that is the key in maintaining pluripotent properties of stem cells, is a member of SRY-related high-mobility group domain proteins. SOX2 participates in many biological processes, such as modulation of cell proliferation, regulation of cell death signaling, cell apoptosis, and most importantly, tumor formation and development. Although SOX2 has been implicated in the biology of various tumors and CSCs, the findings are highly controversial, and information regarding the underlying mechanism remains limited. Moreover, the mechanism by which SOX2 involved in carcinogenesis and tumor progression is rather unclear yet. CONCLUSIONS: Here, we review the important biological functions of SOX2 in different tumors and CSCs, and the function of SOX2 signaling in the pathobiology of neoplasia, such as Wnt/ß-catenin signaling pathway, Hippo signaling pathway, Survivin signaling pathway, PI3K/Akt signaling pathway, and so on. Targeting towards SOX2 may be an effective therapeutic strategy for cancer therapy.

[Heavy Metals Pollution in Topsoil from Dagang Industry Area and Its Ecological Risk Assessment].

Based on previous studies and field investigation of Dagang industry area in Tianjin, a total of 128 topsoil samples were collected, and contents of 10 heavy metals (As, Cd, Cr, Co, Cu, Pb, Ni, V, Zn and Hg) were determined. The geoaccumulation index and geostatistics were applied to examine the degree of contamination and spatial distribution of heavy metals in topsoil. The assessment on ecological risk of heavy metals was carried out using Hakanson's method, and the main resources of the heavy metals were analyzed as well. It was found that As, Cd and Co had the highest proportions exceeding Tianjin background value, which were 100%, 97.66% and 96.88%, respectively; the heavy-metal content increased to some extent comparing with that in 2004, and the pollutions of As and Cd were the worst, and other metals were at moderate pollution level or below. The ecological risks of heavy metals were different in topsoil with different land use types, the farmland soil in the southwest as well as soils adjacent to the industrial land were at relatively high potential ecological risk level, and the integrated ecological risk index reached up to 1 437.37. Analysis of correlation and principal component showed that traffic and transportation as well as agricultural activities might be the main resources of heavy metals in the area, besides, the industrial activities in the region might also affect the accumulation of heavy metals.

Sex-determining region of Y chromosome-related high-mobility-group box 2 in malignant tumors: current opinions and anticancer therapy / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To gain insight into the mechanism by which sex-determining region of Y chromosome (SRY)-related high-mobility-group box 2 (SOX2) involved in carcinogenesis and cancer stem cells (CSCs).</p><p><b>DATA SOURCES</b>The data used in this review were mainly published in English from 2000 to present obtained from PubMed. The search terms were "SOX2," "cancer," "tumor" or "CSCs."</p><p><b>STUDY SELECTION</b>Articles studying the mitochondria-related pathologic mechanism and treatment of glaucoma were selected and reviewed.</p><p><b>RESULTS</b>SOX2, a transcription factor that is the key in maintaining pluripotent properties of stem cells, is a member of SRY-related high-mobility group domain proteins. SOX2 participates in many biological processes, such as modulation of cell proliferation, regulation of cell death signaling, cell apoptosis, and most importantly, tumor formation and development. Although SOX2 has been implicated in the biology of various tumors and CSCs, the findings are highly controversial, and information regarding the underlying mechanism remains limited. Moreover, the mechanism by which SOX2 involved in carcinogenesis and tumor progression is rather unclear yet.</p><p><b>CONCLUSIONS</b>Here, we review the important biological functions of SOX2 in different tumors and CSCs, and the function of SOX2 signaling in the pathobiology of neoplasia, such as Wnt/β-catenin signaling pathway, Hippo signaling pathway, Survivin signaling pathway, PI3K/Akt signaling pathway, and so on. Targeting towards SOX2 may be an effective therapeutic strategy for cancer therapy.</p>

Adult Henoch-Schönlein purpura associated with small cell lung cancer: A case report and review of the literature.

The present study reports the case of a 53-year-old male who had been suffering from coughing and the presence of a blood-streaked sputum for >1 month. Chest computed tomography (CT) and a bronchoscopic brush smear were performed. The patient was subsequently diagnosed with small cell lung cancer (limited stage). The patient developed polyarthritis, abdominal pain, diarrhea and a purpuric rash at 14 days post thoracotomy surgery for lung cancer. Henoch-Schönlein purpura (HSP) was diagnosed based on the clinical symptoms. The patient received chemotherapy with steroid therapy, which resulted in complete remission of the HSP.

MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing.

Recent studies suggest that microRNAs play important roles in dermal wound healing and microRNA deregulation has been linked with impaired wound repair. Here, using a mouse experimental wound healing model, we identified a panel of 63 differentially expressed microRNAs during dermal wound healing, including members of miR-99 family (miR-99a, miR-99b, miR-100). We further demonstrated that miR-99 family members regulate cell proliferation, cell migration, and AKT/mTOR signaling. Combined experimental and bioinformatics analyses revealed that miR-99 family members regulate AKT/mTOR signaling by targeting multiple genes, including known target genes (e.g., IGF1R, mTOR) and a new target (AKT1). The effects of miR-99 family members on the expression of IGF1R, mTOR and AKT1 were validated at both the mRNA and protein levels. Two adjacent miR-99 family targeting sites were identified in the 3'-UTR of the AKT1 mRNA. The direct interaction of miR-100 with these targeting sites was confirmed using luciferase reporter assays. The microRNA-100-directed recruitment of AKT1 mRNA to the RNAi-induced silencing complex (RISC) was confirmed by a ribonucleoprotein-IP assay. In summary, we identified a panel of differentially expressed microRNAs which may play important roles in wound healing. We provide evidence that miR-99 family members contribute to wound healing by regulating the AKT/mTOR signaling.

Restraint stress alters neutrophil and macrophage phenotypes during wound healing.

Previous studies reported that stress delays wound healing, impairs bacterial clearance, and elevates the risk for opportunistic infection. Neutrophils and macrophages are responsible for the removal of bacteria present at the wound site. The appropriate recruitment and functions of these cells are necessary for efficient bacterial clearance. In our current study we found that restraint stress induced an excessive recruitment of neutrophils extending the inflammatory phase of healing, and the gene expression of neutrophil attracting chemokines MIP-2 and KC. However, restraint stress did not affect macrophage infiltration. Stress decreased the phagocytic abilities of phagocytic cells ex vivo, yet it did not affect superoxide production. The cell surface expression of adhesion molecules CD11b and TLR4 were decreased in peripheral blood monocytes in stressed mice. The phenotype of macrophages present at the wound site was also altered. Gene expression of markers of pro-inflammatory classically activated macrophages, CXCL10 and CCL5, were down-regulated; as were markers associated with wound healing macrophages, CCL22, IGF-1, RELMα; and the regulatory macrophage marker, chemokine CCL1. Restraint stress also induced up-regulation of IL10 gene expression. In summary, our study has shown that restraint stress suppresses the phenotype shift of the macrophage population, as compared to the changes observed during normal wound healing, while the number of macrophages remains constant. We also observed a general suppression of chemokine gene expression. Modulation of the macrophage phenotype could provide a new therapeutic approach in the treatment of wounds under stress conditions in the clinical setting.

EphA2-dependent molecular targeting therapy for malignant tumors.

Clarification of the molecular mechanisms of oncogenesis and drug resistance is a prerequisite for the development of new treatment strategies like molecularly targeted therapies. Recent studies demonstrate that EphA2 is overexpressed in human cancers and that EphA2 increases tumor invasion and survival. Thus, an EphA2 receptor antagonist, such as a specific tyrosine kinase inhibitor (in the form of an antibody, small molecule, peptide, or siRNA) or an antibody-drug conjugate that targets the EphA2 receptor could be the basis for a novel targeted antineoplastic therapy. This review summarizes the role of EphA2 in tumorigenesis and the development of EphA2 receptor antagonists as candidate anti-cancer agents. We suggests that continued research into the function of EphA2 signaling in the pathobiology of neoplasia could lead to more rationally designed therapeutics targeting EphA2 in solid tumors.