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.

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.

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.

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.

Geo-Location Information Aided Spectrum Sensing in Cellular Cognitive Radio Networks.

Apart from the received signal energy, auxiliary information plays an important role in remarkably ameliorating conventional spectrum sensing. In this paper, a novel spectrum sensing scheme aided by geolocation information is proposed. In the cellular cognitive radio network (CCRN), secondary user equipments (SUEs) first acquire their wireless fingerprints via either received signal strength (RSS) or time of arrival (TOA) estimation over the reference signals received from their surrounding base-stations (BSs) and then pinpoint their geographical locations through a wireless fingerprint (WFP) matching process in the wireless fingerprint database (WFPD). Driven by the WFPD, the SUEs can easily ascertain for themselves the white licensed frequency band (LFB) for opportunistic access. In view of the fact that the locations of the primary user (PU) transmitters in the CCRN are either readily known or practically unavailable, the SUEs can either search the WFPD directly or rely on the support vector machine (SVM) algorithm to determine the availability of the LFB. Additionally, in order to alleviate the deficiency of single SUE-based sensing, a joint prediction mechanism is proposed on the basis of cooperation of multiple SUEs that are geographically nearby. Simulations verify that the proposed scheme achieves higher detection probability and demands less energy consumption than the conventional spectrum sensing algorithms.