Abstract Sphingosine-1-phosphate receptor (S1PR1) is involved in vascular development, a key process in tumorigenesis. Our study evaluated its roles in tumor development and prognosis. In particular, S1PR1 expression data were obtained from the TIMER and Oncomine database. We used a bioinformatics approach to evaluate its relationship with prognosis, co-expressed and regulatory genes, correlations with tumor immune cell infiltration and correlations with immune infiltration markers. S1PR1 was significantly lower expression in breast and lung cancer than in corresponding normal tissues. Lower S1PR1 expression was related to poor overall survival and disease-free survival in breast and lung cancer. A functional network analysis suggested that S1PR1 regulates vasculogenesis. In addition, S1PR1 levels were significantly related to infiltrating CD8 + , CD4 + T cells, macrophages, and neutrophils in breast invasive carcinoma; CD8 + T cells, macrophages, neutrophils, and DCs in lung adenocarcinoma; and with B cells, CD8 + , CD4 + T cells, macrophages, neutrophils and DCs in lung squamous cell carcinoma. Furthermore, S1PR1 levels were correlated with multiple immune marker sets in breast and lung cancer. The observed correlations between S1PR1 and both prognosis and immune cell infiltration provide a foundation for further research on its immunomodulatory role in cancer.
Abstract Purpose: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. Experimental Design: We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy. Results: Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden. Conclusions: Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.
Abstract BRAF mutations are found in 1–5% of non-small-cell lung cancer (NSCLC), with V600 and non-V600 accounting for approximately 50% each. It has been confirmed that targeted therapy with dabrafenib + trametinib is effective in patients with metastatic NSCLC carrying BRAF V600E mutations. Preclinical studies have shown that dabrafenib + trametinib may also have inhibitory effects on some types of non-V600E mutations, especially some class II BRAF mutations. However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports. Here, we report a case of NSCLC patient carrying BRAF ex15 p.T599dup, who showed a clinical response to the combined therapy of dabrafenib + trametinib.
ABSTRACT Importance Recurrent respiratory tract infection (RRTI) is common in children. Inappropriate RRTI treatment will lead to asthma and other diseases, thereby seriously affecting the growth and physical health of children. Immune function modulation can prevent and alleviate childhood RRTI. Yupingfeng (YPF), a patented traditional Chinese medicine (TCM), has immunomodulatory effects and is widely used in China to treat children with RRTI. Objective To evaluate the safety and efficacy of YPF monotherapy in treating children with RRTI. Methods This multicenter, randomized, double‐blind, double‐simulation, noninferiority clinical trial was conducted from January 2015 to August 2017, with an 8‐week treatment period and 52‐week follow‐up after the drug withdrawal. Children aged 2–6 years with RRTI meeting the inclusion and exclusion criteria were enrolled in 13 hospitals in China and divided randomly into three groups (2:2:1 ratio) to receive YPF, pidotimod, or placebo. The primary outcome was the proportion of RRTI returning to normal standard level during the follow‐up. The secondary outcomes were reduction in the number of RRTI recurrences, effect on clinical symptoms (in accord with TCM practice), effect per symptom, and safety. The trial was registered at the Chinese Clinical Trials Registry ( www.chictr.org.cn ) under the unique identifier ChiCTR‐IPR‐15006847. Results Three hundred and fifty‐one children were enrolled and randomly assigned to 3 groups; 124, 125, and 61 children in the YPF, pidotimod, and placebo groups, respectively, had completed the trial. During the follow‐up, the proportion of RRTI returning to normal standard level was 73.13%, 67.15%, and 38.81% with YPF, pidotimod, and placebo, respectively ( P < 0.0001). The proportion of cases who returned to normal standard level in the YPF group was 34.32% higher than that in the placebo group. The safety profile did not significantly differ among the groups. Interpretation YPF granules were noninferior to the active control drug pidotimod oral solution for the treatment of RRTI in children, and were superior to placebo, with a high safety profile.
Objective To investigate the expression of Patched-1 and Gli-1 in squamous cell carcinoma.Methods Immunohistochemistry and in situ hybridization were employed to study the expression of Patched-1,Gli-1 in the skin of squamous cell carcinoma and normal skin.Results There was significant stronger expression of Patched-1 and Gli-1 on the squamous cells carcinoma lesions.Conclusion Increased expression of the Hedgehog signaling pathway may play an important role in the pathogenesis and development of quamous cell carcinoma.
Abstract Background Sphingosine-1-phosphate receptor ( S1PR1 ) is involved in vascular development, a key process in tumorigenesis. This study aimed to evaluate its roles in tumor development and prognosis. Methods S1PR1 expression levels were analyzed using TIMER and Oncomine database, and the prognostic significance of S1PR1 was assessed using PrognoScan and Kaplan-Meier plotter databases. The relationship between S1PR1 and tumor-infiltrated immune cells was analyzed using TIMER. Results S1PR1 expression was remarkably lower in breast and lung cancer tissues than in the corresponding normal tissues. Lower expression was related to poor overall survival and disease-free survival in breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). A functional network analysis confirmed the function of S1PR1 in regulating vasculogenesis. In addition, S1PR1 levels were significantly negative with regard to the tumor purity of BRCA ( r = − 0.508, P = 1.76e-66), LUAD ( r = − 0.353, P = 6.05e-16), and LUSC ( r = − 0.402, P = − 5.20e-20). Furthermore, S1PR1 levels were significantly positive with regard to infiltrating CD8 + ( r = 0.38, P = 5.91e-35) and CD4 + T cells ( r = 0.335, P = 1.03e-26), macrophages ( r = 0.219, P = 3.67e-12), neutrophils ( r = 0.168, P = 2.03e-7), and dendritic cells (DCs) ( r = 0.208, P = 9.14e-11) in BRCA; S1PR1 levels were significantly positive with regard to CD8 + T cells ( r = 0.308, P = 3.61e-12), macrophages ( r = 0.376, P = 1.01e-17), neutrophils ( r = 0.246, P = 4.15e-8), and DCs ( r = 0.207, P = 4.16e-6) in LUAD; and positive with regard to B cells ( r = 0.356, P = 1.57e-15), CD8 + ( r = 0.459, P = 3.83e-26) and CD4 + T cells ( r = 0.338, P = 3.98e-14), macrophages ( r = 0.566, P = 2.61e-45), neutrophils ( r = 0.453, P = 1.79e-25), and DCs ( r = 0.56, P = 2.12e-40) in LUSC. Conclusions S1PR1 levels are positively correlated with multiple immune markers in breast and lung cancer. These observed correlations between S1PR1 and the prognosis and immune cell infiltration provide a foundation for further research on its immunomodulatory role in cancer.
Objective: To study the relationship between the expression of matrix metalloproteinase-2 (MMP-2)、tissue inhibitors of metalloproteinase-2 (TIMP-2) and microvessel density (MVD) in patients with psoriasis vulgaris. Methods: The biopsies were taken from psoriatic lesions in 17 patients with active psoriasis vulgaris and the skin of 10 normal controls. The expression of MMP-2 and TIMP-2 were detected by the SP immunohistochemical method. MVD was detected by immunohistochemical method with monoclonal antibody specific for the endothelial marker CD34. Results: MVD in the lesions of psoriasis vulgaris was higher than that in normal comrol (P＜0.01) MMP-2、 TIMP-2 were expressed moderate to intense staining in the psoriatic lesions, but very weak to absent in the normal skin. The expression level of MMP-2 was positive correlation with MVD(r=0.625, P＜0.01), and TIMP-2 was negative associated with MVD in active psoriasis vulgaris (r=-0.424, P＜0.01). Conclusion: The overexpression of MMP-2 could be responsible for cell-cell and cell-matrix changes noted in psoriatic epidermis. Downregulation of TIMP-2 that may serve as an aetiological factor in the development of psoriasis. The abnormal expression of MMP-2、TIMP-2 protein are closely correlated with the increase of MVD in psoriatic lesions. These findings indicate that there is a close correlation between the state of the superficial vasculature and the clinical status of psoriasis. It was concluded that MMP-2 TIMP-2 might play important roles in the occurrence and progression of angiogenesis in psoriasis. Further mechanistic investigations are required with the potential that MMP-2、TIMP-2 protein may be help to explain the pathogenesis of microvascular abnormalities in psoriatic skin. The expanded superficial microvascular bed in psoriatic skin is a necessary component for maintaining clinical lesions and these blood vessels are thus a legitimate target for treatment.
Abstract Maternal immune system tolerance to the semiallogeneic fetus is essential for a successful pregnancy; however, the mechanisms underlying this immunotolerance have not been fully elucidated. Here, we demonstrate that myeloid-derived suppressor cells play an important role in maintaining feto-maternal tolerance. A significant expansion of granulocytic myeloid-derived suppressor cells was observed in multiple immune organs and decidual tissues from pregnant mice. Pregnancy-derived granulocytic myeloid-derived suppressor cells suppressed T cell responses in a reactive oxygen species-dependent manner and required direct cell–cell contact. Mechanistic studies showed that progesterone facilitated differentiation and activation of granulocytic myeloid-derived suppressor cells, mediated through STAT3 signaling. The STAT3 inhibitor JSI-124 and a specific short hairpin RNA completely abrogated the effects of progesterone on granulocytic myeloid-derived suppressor cells. More importantly, granulocytic myeloid-derived suppressor cell depletion dramatically enhanced the abortion rate in normal pregnant mice, whereas adoptive transfer of granulocytic myeloid-derived suppressor cells clearly reduced the abortion rate in the CBA/J X DBA/2J mouse model of spontaneous abortion. These observations collectively demonstrate that granulocytic myeloid-derived suppressor cells play an essential role in the maintenance of fetal immunotolerance in mice. Furthermore, our study supports the notion that in addition to their well-recognized roles under pathologic conditions, myeloid-derived suppressor cells perform important functions under certain physiologic circumstances.
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