Summary Background MicroRNAs (miRNAs) can be used as prognostic biomarkers in many types of cancer. We aimed to identify miRNAs that were prognostic in patients with nasopharyngeal carcinoma. Methods ...We retrospectively analysed miRNA expression profiles in 312 paraffin-embedded specimens of nasopharyngeal carcinoma from Sun Yat-sen University Cancer Center (Guangzhou, China) and 18 specimens of non-cancer nasopharyngitis. Using an 873 probe microarray, we assessed associations between miRNA signatures and clinical outcome in a randomly selected 156 samples (training set) and validated findings in the remaining 156 samples (internal validation set). We confirmed the miRNAs signature using quantitative RT-PCR analysis in 156 samples from a second randomisation of the 312 samples, and validated the miRNA signature in 153 samples from the West China Hospital of Sichuan University in Chengdu, China (independent set). We used the Kaplan-Meier method and log-rank tests to estimate correlations of the miRNA signature with disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival. Findings 41 miRNAs were differentially expressed between nasopharyngeal carcinoma and non-cancer nasopharyngitis tissues. A signature of five miRNAs, each significantly associated with DFS, was identified in the training set. We calculated a risk score from the signature and classified patients as high risk or low risk. Compared with patients with low-risk scores, patients with high risk scores in the training set had shorter DFS (hazard ratio HR 2·73, 95% CI 1·46–5·11; p=0·0019), DMFS (3·48, 1·57–7·75; p=0·0020), and overall survival (2·48, 1·24–4·96; p=0·010). We noted equivalent findings in the internal validation set for DFS (2·47, 1·32–4·61; p=0·0052), DMFS (2·28, 1·09–4·80; p=0·030), and overall survival (2·87, 1·38–5·96; p=0·0051) and in the independent set for DFS (3·16, 1·65–6·04; p=0·0011), DMFS (2·39, 1·05–5·42; p=0·037), and overall survival (3·07, 1·34–7·01; p=0·0082). The five-miRNA signature was an independent prognostic factor. A combination of this signature and TNM stage had better prognostic value than did TNM stage alone in the training set (area under receiver operating characteristics 0·68 95% CI 0·60–0·76 vs 0·60 0·52–0·67; p=0·013), the internal validation set (0·70 0·61–0·78 vs 0·61 0·54–0·68; p=0·012), and the independent set (0·70 0·62–0·78 vs 0·63 0·56–0·69; p=0·032). Interpretation Identification of patients with the five-miRNA signature might add prognostic value to the TNM staging system and inform treatment decisions for patients at high risk of progression. Funding Science Foundation of Chinese Ministry of Health, National Natural Science Foundation of China, Pearl River Scholar Funded Scheme, Guangdong Key Scientific and Technological Innovation Program, Guangdong Natural Science Foundation, Fundamental Research Funds for the Central Universities.
Background Locally produced IgE contributes to the initiation and development of eosinophilic inflammation in eosinophilic nasal polyps independent of systemic atopy. However, whether CXCR5+ CD4+ T ...follicular helper (TFH ) cells are involved in local IgE production at mucosal sites remains unexplored. Objective We sought to explore the presence, phenotype, and function of CXCR5+ CD4+ TFH cells in eosinophilic nasal polyp tissues compared with noneosinophilic nasal polyp and control normal nasal tissues. Methods TFH cell-surface phenotypes and subsets and B-cell subsets in nasal tissues and peripheral blood were studied by means of flow cytometry. Immunohistochemistry was used to detect the tissue location of TFH cells. Sorted nasal TFH cells and CXCR5− T cells were cultured with autologous naive B cells purified from blood. Results Nasal TFH cells expressed inducible costimulator, programmed cell death protein 1, and the transcription factor B-cell lymphoma 6 (Bcl-6) at an intermediate level when compared with bona fide TFH cells in tonsils and circulating TFH cells. Although counts of total TFH cells and IL-21+ , IFN-γ+ , and IL-17+ TFH cells were increased in both eosinophilic and noneosinophilic nasal polyp tissues compared with those in normal nasal tissues, IL-4+ TFH cell counts were only increased in eosinophilic polyp tissues. IL-4 and IL-21 were involved in polyp TFH cell–induced IgE production from naive B cells, and nasal IL-4+ TFH cell counts correlated highly with local IgE levels in vivo . IL-4+ Bcl-6+ CD4+ TFH cells were identified in ectopic lymphoid structures in eosinophilic nasal polyps. TFH cells also positively correlated with germinal center B cells and plasma cells in nasal tissues. Conclusion Nasal IL-4+ TFH cells might be involved in local IgE production in eosinophilic nasal polyps.
Summary Background Human babesiosis is an emerging zoonosis. “ Babesia venatorum ” has been identified in only four asplenic men and a child so far. We aimed to describe the epidemiological, ...clinical, and laboratory characteristics of a series of cases with “ B venatorum ” infection identified in a sentinel hospital in China. Methods We recruited participants with a recent tick bite at Mudanjiang Forestry Central Hospital, Heilongjiang province, China. Cases were diagnosed through PCR followed by sequencing, microscopic identification, or isolation by animal inoculation, or both. Findings 48 individuals (30 women or girls; median age 45 years, range 7 months to 75 years) with “ B venatorum ” infection were identified. 32 of these individuals were confirmed cases and 16 were probable cases. None of the 48 cases had received a blood transfusion or had a splenectomy. Geographically, cases were distributed diffusely throughout the hospital catchment area. Of the 32 confirmed cases, 21 (66%) presented with a fever, 13 (41%) with a headache, 12 (38%) with myalgia or arthralgia, and three (9%) with chills. 14 (44%) patients had fatigue, eight (25%) had dizziness, and eight (25%) had hypersomnia. Six (19%) patients had an erythematous non-pruritic rash around the tick-bite site and two (6%) had lymphadenopathy. Seven (22%) and four (13%) patients had anaemia and thrombocytopenia, respectively, and seven (50%) of 14 patients with confirmed infection had increased hepatic transaminase concentrations. In the confirmed cases, concentrations of intercellular adhesion molecule 3 (p<0·001), P-selectin (p<0·05), and platelet endothelial cell adhesion molecule 1 (p<0·001) were significantly reduced, whereas tumour necrosis factor α (p<0·01) and vascular cell adhesion molecule 1 (p<0·001) were significantly increased. Interpretation “ B venatorum ” infection should be included in the differential diagnosis of patients with a tick-exposure history in areas where this pathogen has previously been identified in ticks or people. Funding Natural Science Foundation of China and Mega-Project for Infectious Diseases.
Summary Background Anaplasma phagocytophilum and Anaplasma ovis cause human infections. We investigated the potential for human pathogenicity of a newly discovered Anaplasma species infecting goats ...in China. Methods We collected blood samples from patients with a history of tick bite in the preceding 2 months at Mudanjiang Forestry Central Hospital of Heilongjiang Province from May 1, to June 10, 2014, to detect the novel Anaplasma species by PCR. We inoculated positive samples into cell cultures. We characterised the isolated pathogen by morphological and phylogenetic analyses. We tested serum antibodies by indirect immunofluorescence assay. Findings 28 (6%) of 477 patients assessed were infected with the novel Anaplasma species according to PCR and sequencing. We isolated the pathogen in vitro from three patients. Phylogenetic analyses of rrs, gltA, groEL, msp2 , and msp4 showed that the pathogen was distinct from all known Anaplasma species. We provisionally nominate it “ Anaplasma capra ”. 22 (92%) of 24 patients with data available had seroconversion or a four-fold increase in antibody titres. All 28 patients developed non-specific febrile manifestations, including fever in 23 (82%), headache in 14 (50%), malaise in 13 (46%), dizziness in nine (32%), myalgia in four (14%), and chills in four (14%). Additionally, ten (36%) of 28 patients had rash or eschar, eight (29%) had lymphadenopathy, eight (29%) had gastrointestinal symptoms, and three (11%) had stiff neck. Five patients were admitted to hospital because of severe disease. Six (35%) of 17 patients with data available had high hepatic aminotransferase concentrations. Interpretation The emergence of “ A capra ” as a cause of human disease suggests that individuals living in or travelling to endemic regions in northern China should take precautions to reduce their risk of exposure to this novel tick-borne pathogen. Funding Natural Science Foundation of China and the US National Institutes of Health.
In this study, we investig1ated whether microRNA let-7i regulates dendric cell maturation targeting interleukin-10 (IL-10) via the Janus kinase 1-signal transducer and activator of transcription 3 ...(JAK1-STAT3) signal pathway subsequently prolongs rat cardiac allograft survival.
Quantitative real-time reverse transcriptase polymerase chain reaction, enzyme linked immunosorbent assay, and dual-luciferase assay were performed to verify whether IL-10 was the target of let-7i, and regulatory T cells were assessed by flow cytometry and immunohistochemical study. Western blot was performed to detect JAK1, STAT3, and phosphorylated STAT3 expression. Lewis recipients of Dark Agouti hearts were transfused with phosphate-buffered saline, lipopolysaccharide (LPS)-mature dendritic cells (mDCs), or let-7i-inhibitor-mDCs. Allograft survival times were recorded, and histologic studies were performed.
Expression of IL-10 messenger RNA level and production of IL-10 were increased in let-7i-inhibitor-mDCs compared with LPS-mDCs. Luciferase activity showed that the translational level of the IL-10 luciferase reporter was decreased by let-7i mimic but increased by let-7i-inhibitor. MicroRNA let-7i inhibitor suppressed DC maturation; however, pretreatment of IL-10 small interfering RNA attenuated the suppression. Expression of JAK1, STAT3, and phosphorylated STAT3 in mDCs were suppressed by let-7i mimic, and pre-treatment of IL-10 small interfering RNA, however, were upregulated by let-7i inhibitor. Lewis recipients transfused with let-7i-inhibitor-mDCs significantly prolonged Dark Agouti cardiac allograft survival. The allografts transfused with let-7i-inhibitor-mDCs showed slight cell infiltration and significantly preserved graft structure. Inhibition of let-7i increased CD4(+)CD25(+)forkhead box P3(+) regulatory T cells and modulated cytokine profiles in vivo and in vitro.
MicroRNA let-7i regulated DC maturation and function targeting IL-10 through the JAK1-STAT3 pathway. Moreover, transfusion of LPS-induced mDCs transfected with let-7i inhibitor induced prolonged cardiac allograft survival and generated regulatory T cells.
Summary The B7 family of immune costimulatory ligands is a group of cell surface proteins that bind to the surface receptors of lymphocytes to fine-tune immune responses. The aberrant expression of ...these proteins plays a key role in tumor immune evasion. Immunotherapy targeting certain B7 family members, including programmed death ligand 1, has proven quite effective in suppressing tumor growth. However, why such therapy works in only a subgroup of tumors is unclear. We hypothesized that other B7 family members, either alone or in concert with programmed death ligand 1, play a crucial role in tumor pathogenesis and progression. We therefore examined the expression of a newly discovered B7 family member, B7-H4, in 306 cases of ovarian serous carcinoma by immunohistochemistry. We found that 91% (267/293) of the high-grade ovarian serous carcinomas and 69% (9/13) of the low-grade ovarian serous carcinomas expressed B7-H4. The difference between B7-H4 expression in high-grade and low-grade ovarian serous carcinoma was statistically significant (P = .002). Moreover, B7-H4 protein expression in high-grade serous carcinoma was associated with tumor stage (P < .01) but not overall survival or disease-free survival. In conclusion, B7-H4 is frequently expressed in ovarian serous carcinomas, especially high-grade serous carcinomas, and may represent a novel immunotherapeutic target in this cancer.
Abstract Context Tumors involving the spine are associated with unique symptoms affecting both patient survival and health-related quality of life. Currently, there is no disease-specific instrument ...in Chinese to assess the symptom burden of these patients. Objectives The objective of this study was to translate and validate a Chinese version of the M.D. Anderson Symptom Inventory—Spine Tumor Module (MDASI-SP-C) to assess the symptom burden of Chinese-speaking patients with spinal tumors. Methods MDASI-SP-C was forward-and-backward translated according to standard protocols and administered to patients fulfilling study criteria at a major referral center of spine tumor between November 2014 and September 2015. The generic instruments of Short Form 36 Quality of Life Questionnaire (SF-36), Functional Assessment of Cancer Therapy-General Version (FACT-G), and Karnofsky Performance Scale were used along with MDASI-SP-C. Prevalence and severity distribution of each item were analyzed. Psychometric assessment and hierarchical cluster analysis were performed for the translated instrument. Results One hundred forty-two patients were enrolled. High interdependency and relatively low intra-cluster distances were identified. Cronbach's alpha of the entire instrument, the symptom severity subscale, and the interference subscale was 0.93, 0.91, and 0.92, respectively. Principal axis factoring resulted in a four-factor solution, which was reduced to a three-factor (general symptoms, spine-specific symptoms, and gastrointestinal symptoms) solution on account of clinical interpretation. Correlation coefficients between MDASI-SP-C items and their corresponding domains in SF-36 and/or FACT-G were all greater than 0.3. MDASI-SP-C was able to distinguish patients with different Karnofsky Performance Scale levels. Conclusion MDASI-SP-C demonstrated satisfactory psychometric properties and could be used to better assess the symptom burden of Chinese-speaking patients with spine tumors for improved management of their medical needs.
Background Confocal endomicroscopy is a newly developed endoscopic imaging technology that produces 1000-fold magnification cross-sectional images of the GI surface and subsurface tissue during ...routine endoscopy. The gastric pit patterns identified by confocal endomicroscopy and correlation with histopathologic examination have not yet been established. Objective Our purpose was to explore the appearance of various kinds of gastric pits and clarify the relationship between gastric pit patterns and the histopathologic findings. Design Descriptive study. Setting Qilu Hospital, Shandong University, Jinan, China. Patients A total of 132 consecutive patients underwent confocal endomicroscopy after 7 healthy volunteers had been examined in vivo and 10 samples resected from 10 patients with gastric cancer had been examined ex vivo by use of confocal endomicroscopy. The confocal images obtained from the 132 patients were compared with the histopathologic findings of the biopsy specimens from the corresponding confocal imaging sites in a prospective and blinded fashion. Main Outcome Measurements The relationship between the pit patterns and the histopathologic findings. Results Gastric pit patterns were classified into 7 types. Normal mucosa with fundic glands mainly showed type A (round pits), and corporal mucosa with histologic gastritis showed type B (noncontinuous short rod-like); normal mucosa with pyloric glands mainly showed type C (continuous short rod-like), and antral mucosa with histologic gastritis showed type D (elongated and tortuous branch-like). Goblet cells were easily distinguished by confocal endomicroscopy in intestinal metaplasia mucosa, which showed type F. The sensitivity and specificity of the type E pattern for predicting gastric atrophy were 83.6% and 99.6%, respectively. Corresponding values of the type G pattern for predicting gastric cancer were 90.0% and 99.4%. Limitations No data on interobserver and intraobserver variability. Conclusions The patterns of gastric pits identified by confocal endomicroscopy correlate well with the histopathologic findings. Confocal endomicroscopy may prove useful in predicting histopathologic diagnoses during routine endoscopic procedures.
Background This study aimed to show whether circulating bone morphogenetic proteins (BMPs) levels are associated with increased risk of mortality in patients with pulmonary arterial hypertension ...(PAH). Methods A total of 156 patients with PAH including 43 with heritable PAH (HPAH) and 113 with idiopathic PAH (IPAH) diagnosed by gene screening were enrolled in the study. Circulating BMPs were measured by ELISA in plasma samples from patients with HPAH (n = 43) and IPAH (n = 113) and from control subjects (n = 51). Clinical characteristics at baseline and long-term survival were compared according to the different BMP levels. Results Patients with HPAH had significantly higher BMP7 concentrations than patients with IPAH and control subjects (20.1 interquartile range (IQR), 9.4, 55.2 vs 6.5 IQR, 3.5, 11.7 and 2.5 IQR, 0.9, 6.6 pg/mL, respectively; P < .001). Elevated plasma BMP7 were associated with a higher risk of mortality after adjustment for sex, 6-minute walk distance, mean right atrial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output (HR, 1.904; 95% CI, 1.021-3.551; P = .043). Patients with IPAH with a BMP7 level > 7.85 pg/mL had a higher risk of mortality than those with a low BMP7 concentration ( P = .042, log-rank test). Conclusions Levels of circulating BMP7 correlate with mortality in PAH, and may be a predictor of disease in patients with HPAH and IPAH.
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