Minimal change disease associated with gastrointestinal stromal tumor accompanied by significantly elevated serum IgE level: a case report.

BACKGROUND: Minimal change disease (MCD) is a common cause of the nephrotic syndrome. Several studies have shown an increased incidence of cancer in patients with MCD. However, there are no reports on the association between MCD and gastrointestinal stromal tumor (GIST). CASE PRESENTATION: We report a case of a 66-year-old female with severe nephrotic syndrome and concomitant duodenal GIST. Immunoglobulin test showed a significant increase of IgE levels. The diagnosis of renal histopathology was MCD with subacute tubulointerstitial injury. The combination of preoperative Imatinib mesylate chemotherapy and tumor excision was accompanied by significant remission of proteinuria, and IgE level decreasing, without immunosuppressivetherapy. CONCLUSIONS: It is the first case report that MCD was associated with GIST and elevated IgE level. Clinically, in patients with elevated IgE level associated with nephrotic syndrome, the possibility of tumor must be taken into account when allergic factors are excluded.

EGFL6 promotes breast cancer by simultaneously enhancing cancer cell metastasis and stimulating tumor angiogenesis.

EGFL6, a member of the EGF-like superfamily, plays an important role during embryonic development and has been implicated in promotion of tumor angiogenesis without affecting wound healing. There is very little known about the function of EGFL6 in cancer cells. Here, we investigated whether EGFL6 plays a direct role in cancer cells in addition to the promotion of tumor angiogenesis. Our study showed that EGFL6 promoted epithelial-mesenchymal transition (EMT) and stemness of breast cancer cells and increased cell migration and invasion in cell culture studies. We also found that EGFL6 reduced apoptotic signaling in cancer cells and promoted tumor growth in vivo. Importantly, expression of EGFL6 in cancer cells and tumor endothelial cells not only increased tumor angiogenesis but also promoted migration of cancer cells. Such dual engagement of cancer and stromal cells suggests crosstalk mediated by EGFL6 in the tumor microenvironment. Blockade of EGFL6 using our novel anti-EGFL6 monoclonal antibody significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Silencing EGFL6 mRNA by shRNA transfection of cancer cells also significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Taken together, the results of this study indicate that targeting EGFL6 is a unique strategy for inhibiting both cancer cell metastasis and tumor angiogenesis.

Discrepant Clinical Significance of CD28+CD8- and CD4+CD25high Regulatory T Cells During the Progression of Hepatitis B Virus Infection.

Accumulating evidence demonstrates that CD8+CD28- regulatory T cells increase in chronic viral infection as well as tumorigenesis. However, it is still not clear about their characteristics in hepatitis B virus (HBV) infection. In addition, it is not understood whether this regulatory immune subset is distinct from CD4+CD25high regulatory T cells in the aspect of impact on or relationship to the progression of HBV infection. Hence, we investigated their dynamics and compared their correlations with clinical parameters in the chronic and advanced phases of HBV infection. The data showed that compared with healthy controls, the frequencies of CD28+CD8- and CD4+CD25high T cells increased in both chronic and advanced phases, while there is no significant difference between the two case groups. Interestingly, we found that in chronic phase, the frequency of CD8+CD28- subset was negatively correlated with the levels of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST), respectively, and did not present association with HBV DNA load, whereas that of CD4+CD25high T cells was positively correlated with HBV DNA load and the levels of ALT and AST, respectively. Amazingly, in advanced phase, the frequency of CD4+CD25high T cells was negatively correlated with HBV DNA load and the levels of ALT, respectively, while there is no significant correlation between the frequency of CD8+CD28- subset and those clinical parameters. Thereby, our findings demonstrated that CD28+CD8- and CD4+CD25high regulatory T cells might exert distinct effect on modulating antiviral immune responses and mitigate immunomediated liver damage in different phases of HBV infection, which represent potential prognostic markers and therapeutic targets for HBV-infected patients based on further exploration of detailed mechanism.

Membranous and Cytoplasmic Expression of PD-L1 in Ovarian Cancer Cells.

BACKGROUND: Expression of programmed death-ligand 1 (PD-L1) on tumor cells represents a powerful immune evasion pathway, but the role of intracellular or cytoplasmic PD-L1 has not been investigated in ovarian cancer cells. METHODS: Flow cytometry (FCM), Real-time PCR (qPCR), immunohistochemistry (IHC) and western blot were used to determine the expression of PD-L1 in ovarian cancer cells. The cytokines detected in the tumor or tumor associated macrophage (TAM) were used to treat cancer cells. PD-L1 blockade and silencing were used to elucidate the functional significance of cancer-related PD-L1 expression. RESULTS: Based on the results presented, PD-L1 was found variably expressed in the cytoplasm and the cell surface of both HO8910 and SKOV3 cells. TAM or IFN-γ, TNF-α, IL-10 and IL-6 released from TAM stimulated the expression of PD-L1 at the surface of the cancer cells. The IHC results were consistent with the data in vitro showing infiltration of TAM correlated with membranous PD-L1. The increases of PD-L1 at the surface were not due to a shift in the proportion of surface versus intracellular protein, but the contribution of extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K) pathway activation. As a consequence, inducible membranous PD-L1 expression on SKOV3 inhibited CD8+ T cell function, and cytoplasmic PD-L1 promoted cancer cell growth. Additionally, in mouse models, both PD-L1 and PD-1 mAb resulted in tumor growth inhibition and demonstrated a potential to decrease the number of PD-1+CD8+T cells. CONCLUSION: We conclude that TAM induced PD-L1 on the cancer cells represents an immune evasion mechanism. The observations confirm the therapeutic potential of PD-L1/PD-1 mAb to reactivate anti-tumor immunity in ovarian cancer.

Serum is an indispensable factor in the maintenance of the biological characteristics of sweat gland cells.

The tolerance of sweat gland cells for in vitro amplification and subcultivation is low as they are somatic cells. The present study aimed to formulate an optimal medium for the culture of human eccrine sweat gland cells (HESGCs) and to establish a method for induction of HESGCs proliferation, whilst maintaining the characteristics of sweat gland cells. HESGCs cultured in sweat gland (SG):keratinocyte growth medium­2 (KGM­2) (1:1) medium had a higher proliferation rate and a stable morphology compared with cells cultured in SG and KGM­2 medium only. Reverse transcription­quantitative polymerase chain reaction indicated that cells cultured in the SG:KGM­2 (1:1) medium exhibited higher expression levels of α­smooth muscle actin, keratin (K)77, carcinoembryonic antigen, K8, K18, ectodysplasin A receptor, c­Myc, Kruppel­like factor 4 and octamer­binding transcription factor 4 compared with cells cultured in SG only or KGM­2 only medium. Three­dimensional culture analysis revealed that HESGCs cultured in SG:KGM­2 1:1 medium differentiated into sweat gland­like structures, whereas cells cultured in KGM­2 only medium underwent cornification. The present study also determined that the maintenance of the biological characteristics of HESGCs occurred due to the presence of fetal bovine serum (FBS). Cells cultured in medium without FBS differentiated into keratinocytes. Therefore, the SG:KGM­2 (1:1) medium may be a suitable culture medium for HESGCs. In conclusion, this mixed medium is a valuable compound and should be considered to be a potential supplemental medium for HESGCs.

Urinary sediment miRNAs reflect tubulointerstitial damage and therapeutic response in IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN. METHODS: Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed. RESULTS: 1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group (p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group (p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN (p = 0.001, OR = 1.042). CONCLUSIONS: The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression.

Clinical Significance of Dynamics of Programmed Death Ligand-1 Expression on Circulating CD14+ Monocytes and CD19+ B Cells with the Progression of Hepatitis B Virus Infection.

Programmed death-1 (PD-1) expression has been revealed to be upregulated on T cells and contributes to T cell exhaustion in patients with hepatitis B virus (HBV) infection. In this study, we investigated the dynamic expression of programmed death ligand-1 (PD-L1), the ligand of PD-1, on circulating CD14+ monocytes and CD19+ B cells of HBV-infected patients at the stages of chronic HBV (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC), respectively. The results showed that compared with healthy controls, the levels of PD-L1 expression on CD14+ and CD19+ populations were both upregulated in CHB, LC, and HCC groups. Although there was no significant difference of PD-L1 expression on CD14+ population among three disease groups, further analysis demonstrated that the frequency of CD14+PD-L1+ population was negatively correlated with HBV DNA load, the levels of alanine aminotransaminase (ALT), and the levels of aspartate aminotransferase (AST), respectively, at CHB stage, while it did not present significant correlation with such parameters at LC stage and was only positively correlated with HBV DNA load at HCC stage. Similarly, the levels of PD-L1 expression on CD19+ population also did not present much difference among three disease groups. Intriguingly, the frequencies of CD19+PD-L1+ population at CHB and LCC stages were both positively correlated with the levels of ALT and AST, but they were not significantly correlated with HBV DNA load. Thereby, the current study elucidated the dynamics of PD-L1 expression on monocytes and B cells, along with the dynamic regulation of PD-1 on T cells, which had a close relationship during the progression of HBV infection. Collectively, our findings demonstrated that in the course of HBV infection development, PD-L1 expression on CD14+ monocytes and CD19+ B cells varied and significantly correlated with clinical parameters, which could be utilized as a potential clinical indicator.

Assessment of plasma B7-H3 levels in pediatric patients with different degrees of surgical stress.

BACKGROUND: Surgical stress initiates a series of host hormone, metabolism and immune responses, which predominantly affect the homeostatic mechanism of patients with major surgery. B7-H3 is a co-stimulatory molecule and has been shown to participate in both adaptive and innate immune responses. In this study we evaluated the clinical significance of plasma B7-H3 levels in pediatric patients with different types of operation and degrees of surgical stress. METHODS: A total of 48 children received pediatric general and cardiac surgery were recruited into this study. Based on the surgical stress scoring, children were divided into moderate stress (n = 14) and severe stress (n = 34) groups. Plasma B7-H3 levels were assessed at selected time points: before surgery, immediately after surgery, at day 1, day 3, and day 7 after surgery. Correlations between plasma B7-H3 levels and surgical stress scores were also examined. RESULTS: Plasma B7-H3 levels were significantly decreased in all 48 pediatric patients after surgery compared to the B7-H3 level before surgery (p < 0.01). Children with general surgery showed significant decreases in plasma B7-H3 immediately after surgery, and at day 3 and day 7 after surgery (p < 0.05, p < 0.01), whereas children with cardiac surgery showed reduced plasma B7-H3 immediately after surgery and at day 3 after surgery (p < 0.05). Plasma B7-H3 in cardiac surgery group was dropped much lower than that in general surgery group at day 1 (p < 0.05) and day 3 (p < 0.01) after surgery. Significantly reduced plasma B7-H3 was observed in the severe stress group, but not in the moderate stress group, immediately after surgery and at day 3 after surgery (p < 0.05), and severe stress group had significantly lower plasma B7-H3 levels than moderate stress group at day 1, day 3, and day 7 after surgery (p < 0.05). Furthermore, plasma B7-H3 levels at day 1 (p = 0.01) and day 3 (p = 0.025) after surgery correlated negatively with surgical stress scores. CONCLUSIONS: Plasma B7-H3 levels were decreased significantly in children subjected to pediatric general and cardiac surgery, which is closely associated with the severity of surgical stress. The negative correlation of plasma B7-H3 levels at day 1 and day 3 after surgery with surgical stress scoring implicates that the plasma B7-H3 level might be a useful biomarker for monitoring stress intensity during pediatric surgery.

[Therapeutic Effect of Combined Cytokines on Nonhuman Primate Model of Severe Haemopoietic Acute Radiation Sickness].

OBJECTIVE: To evaluate the therapeutic effects of combined administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-2 (rhIL-2) on radiation-induced severe haemopoietic acute radiation sickness (ARS) in rhesus monkeys, so as to provide experimental evidences for the effective clinical treatment. METHODS: Seventeen rhesus monkeys were exposed to 7.0 Gy (60)Co γ-ray total body irradiation (TBI) to establish severe haemopoietic ARS model, and were randomly divided into supportive care group, rhG-CSF+rhTPO treatment group and rhG-CSF+rhTPO+rhIL-2 treatment group. Survival time, general signs such as bleeding and infections, and peripheral blood cell counts in each group were monitored. Bone marrow cells were cultivated to examine the colony formation ability. The histomorphology changes of bone marrow were observed at 45 d post irradiation. RESULTS: After 7.0 Gy (60)Co γ-ray TBI, monkeys of supportive care group underwent tarry stool and emesis, then died in 12~18 d. The overall survival rate in this group was 16.7%. Gastrointestinal reactions of monkeys in two combined-cytokines treatment groups were inapparent. Combined-cytokines treatment induced 100% survival. Complete blood cells declined sharply after irradiation in each group, but two combined-cytokines treatment schemes could elevate the nadir of all blood cells, shorten the duration of pancytopenia and accelerate the recovery of hemogram. Compared with rhG-CSF+ rhTPO treatment, rhG-CSF+ rhTPO+ rhIL-2 treatment could increase the counts of lymphocytes and monocytes. The colony-formation rate of haemopoietic stem/progenitor cells in bone marrow dropped markedly at 2 d after irradiation. Combined-cytokines treatment promoted the ability of colony formation on day 29. Hematopoietic cells mostly disappeared in bone marrow of animals in supportive care group, but hematopoietic functions were recovered after cytokines were administrated. CONCLUSION: rhG-CSF+ rhTPO and rhG-CSF+ rhTPO+ rhIL-2 treatment can significantly promote hematopoiesis recovery, improve the quantity of life, simplify the supportive therapy, and enhance the survival rate of rhesus monkeys with severe haemopoietic ARS induced by 7.0 Gy (60)Co γ-ray exposure. Especially the application of rhIL-2 can accelerate the recovery of lymphocytes and monocytes and restore the immunological function. Thus, combination of rhG-CSF, rhTPO and rhIL-2 on the basis of supportive care is an efficient strategy to treat severe haemopoietic ARS.

Enhancement of CD4(+) T cell response and survival via coexpressed OX40/OX40L in Graves' disease.

OX40/OX40L pathway plays a very important role in the antigen priming T cells and effector T cells. In the present study, we aimed to examine the involvement of OX40/OX40L pathway in the activation of autoreactive T cells in patients with Grave's disease (GD). We found that OX40 and OX40L were constitutively coexpressed on peripheral CD4(+) T cells from GD patients using flow cytometry analysis. The levels of OX40 and OX40L coexpression on CD4(+) T cells were shown to be correlated with TRAbs. Cell proliferation assay showed that blocking OX40/OX40L signal inhibited T cell proliferation and survival, which suggested that OX40/OX40L could enhance CD4(+) T cell proliferation and maintain their long-term survival in GD by self-enhancing loop of T cell activation independent of APCs. Confocal microscopy and coimmunoprecipitation analysis further revealed that OX40 and OX40L formed a functional complex, which may facilitate signal transduction from OX40L to OX40 and contribute to the pathogenesis of GD.

Renal Light Chain Deposition Associated with the Formation of Intracellular Crystalline Inclusion Bodies in Podocytes: A Rare Case Report.

We herein report the case of an elderly woman with bone pain and proteinuria as the main clinical manifestations. The patient was diagnosed with the IgG κ type of multiple myeloma. Her renal pathology consisted of widespread κ light chain protein deposition associated with the formation of large quantities of rod-like crystals in podocytes. This phenomenon is very rare. We explored the significance of this crystal formation via a detailed and descriptive analysis and also performed a literature review, thus providing data to increase the available information about this type of disease.

Dysmorphic erythrocytes are superior to hematuria for indicating non-diabetic renal disease in type 2 diabetics.

AIMS/INTRODUCTION: There are sparse and limited studies on erythrocyte morphology in renal biopsy identifying nephropathic patients among type 2 diabetics. The present study sought to clarify the predictive value of dysmorphic erythrocytes in type 2 diabetics with non-diabetic renal disease and influences on hematuria. MATERIALS AND METHODS: We examined 198 patients with type 2 diabetes who underwent kidney biopsies between 2012 and 2013. Hematuria was defined as >3 or >10 red blood cells per high-power field (RBCs/hpf) in urine sediment. If >80% of the erythrocytes were dysmorphic, glomerular hematuria was diagnosed. Clinical findings and predictive value of dysmorphic erythrocytes were compared between patients with hematuria (n = 19) and those without (n = 61). The potential risk factors for hematuria among diabetic nephropathy patients were also screened. RESULTS: There was a statistically significant difference between the diabetic nephropathy group and the non-diabetic renal disease group (6.6 vs 16.8%; P = 0.04) when the demarcation point of hematuria was 10 RBCs/hpf. When the definition of hematuria was based on an examination of urinary erythrocyte morphology, a marked difference was seen (3.3 vs 24.8%; P < 0.001). Glomerular hematuria showed high specificity and a positive predictive value (0.97 and 0.94, respectively) in non-diabetic renal disease. A multivariate analysis showed that nephrotic syndrome was significantly associated with hematuria (odds ratio 3.636; P = 0.034). CONCLUSIONS: Dysmorphic erythrocytes were superior to hematuria for indicating non-diabetic renal disease in type 2 diabetics. Nephrotic syndrome was an independent risk factor for hematuria.

The increase of circulating PD-L1-expressing CD68(+) macrophage in ovarian cancer.

Tumor-associated macrophages (TAMs) have been characterized as a critical population of immunosuppressive cells in a variety of tumor types. PD-L1 (also termed B7-H1) has been described to exert co-inhibitory and immune regulatory functions. Here, in ovarian cancer, PD-L1 is selectively overexpressed on some TAM compared that of benign ovarian disease. When expanding the data in peripheral blood, the proportion of PD-L1(+)CD68(+) cell among CD68(+) cells and the intensity of PD-L1 staining on CD68(+) cell in healthy group were similar to that observed in ovarian cyst group; instead, these two measures were significantly higher in ovarian cancer group, thereafter related to TNM stage. Interestingly, intracellular levels of IL-10, IL-6, TNF-α, and IFN-γ in PD-L1(+)CD68(+) macrophage were higher than those in PD-L1(-)CD68(+) macrophage, especially IL-6 expression. Based on the PD-L1 receptor PD-1 expression on tumor-infiltrating cytotoxic cells, our data supported that expression of PD-L1 on TAM promoted apoptosis of T cells via interaction with PD-1 on CD8(+)T cells. Taken together, these results suggested that PD-L1-expressing macrophage represents a novel suppressor cell population in ovarian cancer, which contributes immune escape of ovarian cancer.

Expression of PD-L1 on CD4+CD25+Foxp3+ Regulatory T Cells of Patients with Chronic HBV Infection and Its Correlation with Clinical Parameters.

Regulatory T cells (Tregs) play a pivotal role in suppressing specific antiviral immune responses during the progression of chronic hepatitis B virus infection (CHB) as well as tumorigenesis. Programmed death-1 ligand-1 (PD-L1) expressed on Tregs can transduce an inhibitory signal into effector T cells through interacting with programmed death-1 (PD-1). However, in CHB patients, the clinical significance of PD-L1 expression on Tregs has not been clearly described. This study investigated the frequency of circulating Tregs and PD-L1 expression on Tregs and analyzed their correlations with clinical parameters. The data show that both the frequency of CD4+CD25+FoxP3+ Tregs and PD-L1 expression on Tregs in the peripheral blood increased significantly in CHB patients when compared with healthy controls. At the same time, it is shown that PD-L1 expression on Tregs was positively correlated with the percentage of Tregs in CHB patients. Moreover, the results demonstrated that both Treg frequency and PD-L1 expression on Tregs positively correlated with the levels of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST), both of which are indicators of the extent of liver injury. Taken together, these findings suggest that PD-L1 on Tregs might contribute to progression of hepatitis B virus infection through mediating the inhibitory function of Tregs. Thereby, blockade of interaction between Treg-expressing PD-L1 and PD-1 on effector T cells may be adopted as a potential therapeutic approach in CHB.

The role of LGR5 and ALDH1A1 in non-small cell lung cancer: Cancer progression and prognosis.

The Leucine rich repeat containing G protein coupled receptor 5 (LGR5), may be a candidate marker of non-small cell lung cancer (NSCLC) cells with stem cell-like properties. Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of NSCLC stem cell markers. To identify the relationship of LGR5 and ALDH1A1 in NSCLC, we analyzed the expression of LGR5 and ALDH1A1 in NSCLC samples, and determined their clinical significance. We performed quantitative RT-PCR for LGR5 and ALDH1A1 expression in 24 NSCLC patients, and showed that LGR5 and ALDH1A1 mRNA were frequently increased in NSCLC tissues in comparison to that in adjacent normal tissues (p = 0.0005 and p < 0.0001, respectively). Besides, the expression of LGR5 and ALDH1A1 mRNA has a significant correlation (r = 0.416, P = 0.0483). The expression of LGR5 and ALDH1A1 in 109 NSCLC tumors and 50 adjacent normal tissues were detected by immunohistochemistry. Positive LGR5 and ALDH1A1 expression was defined in 28.4% and 41.3% of the NSCLC tumors, respectively. Further analysis indicated that 24 of these LGR5⁺ (24/31) samples expressed ALDH1A1(r = 0.3883, p < 0.0001), we also found co-localization of LGR5 and ALDH1A1 in tumor tissue samples. LGR5 and ALDH1A1 expression was significantly associated with higher pathological TNM stage of the disease (stage I + II and III + IV) (P = 0.0311 and p = 0.0221, respectively), the co-expression of LGR5 and ALDH1A1 was associated with nodal status (p = 0.0424). High expression of LGR5 or ALDH1A1 was related to poor prognosis (P = 0.0125 and p = 0.0410, respectively), and NSCLC patients with co-expression of LGR5 and ALDH1A1 had a poorer prognosis than the others (P = 0.0011). Both of them can be an independent risk factor of a poorer prognosis (P = 0.016 and P = 0.024, respectively). The expression of LGR5 and ALDH1A1 were closely associated with the tumorigenicity, metastasis and poor prognosis of NSCLC, and LGR5⁺ cells in NSCLC were likely to be the cancer cells with stem cell-like properties due to the significant correlation between LGR5 and ALDH1A1.

The role of B7-H1 in gastric carcinoma: clinical significance and related mechanism.

The aim of this study was to investigate the role of co-stimulatory molecule B7-H1 in gastric carcinoma, to assess its clinical significance, and to explore related mechanism. Expression of B7-H1 and interferon gamma (IFN-γ) was evaluated by immunohistochemistry in 205 gastric carcinoma tissues and nonmalignant para-carcinoma tissues and 30 normal tissues. Expression data were correlated with clinicopathologic features of the patients. Furthermore, gastric carcinoma cell line SGC7901, MGC803, and AGS were employed to assess the expression of B7-H1 under the stimulation of IFN-γ. There was no detectable or weak amount of B7-H1 in normal tissue, while 43 % (88/205) of gastric carcinoma tissues and nonmalignant para-carcinoma tissues were confirmed with B7-H1 positive (p < 0.01). High B7-H1 expression was significantly associated with the age (p < 0.01), alcohol (p < 0.05), carcinoma location (p < 0.01), and differentiation (p < 0.05). Moreover, IFN-γ and CD3(+) T cells infiltration were found in carcinoma tissues, but not in normal tissues. In addition, the expression of B7-H1 was also found in gastric carcinoma cell lines (SGC7901, MGC803 and AGS), and IFN-γ could increase its expression. Our data suggest that B7-H1 may represent a new early diagnostic marker for patients with well-differentiated gastric carcinoma. Furthermore, given its immune-inhibitory function, B7-H1 may represent a potential target in the treatment of gastric carcinoma.

Validation of a differential diagnostic model of diabetic nephropathy and non-diabetic renal diseases and the establishment of a new diagnostic model.

BACKGROUND: The aims of the present study were to validate the differential diagnostic model of diabetic nephropathy (DN) and non-diabetic renal diseases (NDRD) established in 2003 and to establish a new diagnostic model suitable for the current clinical characteristics of DN. METHODS: We examined 200 patients with Type 2 diabetes who underwent kidney biopsy from 2004 to 2012. The 2003 differential diagnostic model based on the data collected from 1993 to 2003 was evaluated by the diagnostic test and changes in the clinical differentiation parameters of DN and NDRD were analyzed. Logistic regression, receiver operating characteristics (ROC) curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analysis were applied. RESULTS: The 2003 diagnostic model showed an accuracy of 77.5%. A significantly elevated incidence of hematuria, longer history of diabetes, and reduced level of glycated hemoglobin (HbA1c) were observed in the DN group from 2004 to 2012 compared with DN group from 1993 to 2003. Histories of diabetes mellitus (Dm), systolic blood pressure (Bp), HbA1c (Gh), hematuria (Hu), diabetic retinopathy (Dr), and hemoglobin (Hb) are independently related to DN. Thus, a new diagnostic model was constructed as follows: PDN = exp (0.846 + 0.022 Dm + 0.033Bp + 2.050 Gh-2.664 Hu-0.078 Hb + 2.942Dr)/[1 + exp (0.846 + 0.022 Dm + 0.033 Bp + 2.050 Gh-2.664 Hu-0.078 Hb + 2.942 Dr)].Validation tests determined that the accuracy of the new model were 90.9%. CONCLUSIONS: Changes in people with DN, clinical characteristics have reduced the diagnostic efficacy of the 2003 diagnostic model. The newly established model can provide a better, more current differentiation between DN and NDRD.

The compromised inflammatory response to bacterial components after pediatric cardiac surgery is associated with cardiopulmonary bypass-suppressed Toll-like receptor signal transduction pathways.

PURPOSE: Cardiopulmonary bypass (CPB) during pediatric cardiac surgery often elicits a systemic inflammatory response followed by a compromised immune response, which has been attributed to the morbidity of postoperative infection; however, the underlying mechanism(s) has not yet been fully elucidated. We hypothesized that CPB inhibits the activation of Toll-like receptor (TLR) signal transduction pathways, thereby causing an immunosuppressive state after pediatric cardiac surgery. METHODS: We examined 20 children with congenital heart disease undergoing pediatric cardiac surgery. RESULTS: Cardiopulmonary bypass differentially affected lipopolysaccharide (LPS)- or bacterial lipoprotein (BLP)-stimulated ex vivo production of proinflammatory and anti-inflammatory cytokines, with significantly diminished tumor necrosis factor α, interleukin (IL) 1ß, IL-6, and IL-8, but substantially enhanced IL-10 production. Consistent with the reduced inflammatory response, CPB strongly inhibited LPS- or BLP-activated TLR signal transduction pathways in monocytes with down-regulated expression of CD14, TLR4, and TLR2 and with suppressed phosphorylation of nuclear factor κB p65, p38, and extracellular signal-regulated kinase 1/2. CONCLUSIONS: These results indicate that CPB during pediatric cardiac surgery causes substantially reduced production of inflammatory cytokines in response to bacterial component LPS or BLP stimulation, which is associated with CPB-induced suppression of TLR-mediated signal transduction pathways. This reduced inflammatory response after CPB in children with congenital heart disease may predispose them to an increased risk of postoperative infection.

Clinical significance of the induction of macrophage differentiation by the costimulatory molecule B7-H3 in human non-small cell lung cancer.

B7-H3, a member of the B7 family of molecules, is expressed in certain types of human cancer and is important in tumor development and progression. Although several studies have reported that the expression of B7-H3 is correlated with poor outcomes in patients with cancer, its exact role in cancer remains unknown. In the present study, the expression levels of B7-H3 in the pathological specimens of 105 patients treated for non-small cell lung cancer (NSCLC) were examined by immunohistochemistry. A high expression level of B7-H3 was observed in 46.9% of the 105 NSCLC tissue specimens. These patients demonstrated a more advanced tumor grade and a shorter survival time. In addition, we also examined the levels of tumor-associated macrophages (TAMs) in NSCLC tissues and observed that the levels were positively correlated with the expression of B7-H3, and that higher levels of macrophages were associated with lower levels of infiltrating T cells and a shorter survival time. These results demonstrated that TAMs are important in the evasion of tumor immune surveillance in NSCLC. Furthermore, through knockdown of B7-H3 by RNA interference, we observed that soluble B7-H3 was capable of inducing macrophages to express higher levels of macrophage mannose receptor (MMR) and lower levels of human leukocyte antigen (HLA)-DR, as well as higher levels of interleukin-10 (IL-10) and lower levels of IL-1ß in vitro. These observations are characteristic of an anti-inflammatory/reparatory (alternative/M2) phenotype. Therefore, our data suggests that B7-H3 proteins are involved in the progression of NSCLC by inducing the development of monocytes into anti-inflammatory cells.

Aging promotes progression of IgA nephropathy: a systematic review and meta-analysis.

BACKGROUND: There has been considerable interest in whether old age is associated with IgA nephropathy (IgAN) progression, which is still controversial. METHODS: We searched multiple databases for studies published from 1980 to 2012. The inclusion criteria were case-control, cohort studies published in any language. The included studies needed to have an older group. IgAN was proven by biopsy. RESULTS: We included 9 studies with a total of 6,543 patients. The meta-analyses of other risk factors between the older group (>50 years old) and the non-older group (15-50 years old) found significant differences in the presence of hypertension, proteinuria, serum cholesterol levels and baseline renal function. In the overall analysis, compared to the non-older group, older age significantly increased the incidence of developing end-stage renal disease [ESRD; relative risk (RR) random model 1.95; 95% CI: 1.27-3.01]. In the subgroup analyses, we found the age limit and traditional risk factors of IgAN may be the sources of heterogeneity between studies. Moreover, the RR (2.56) of the Asian countries was much higher than the RR (1.11) of the European countries. CONCLUSIONS: This comprehensive review revealed that old age is a real risk factor for IgAN progression to ESRD. The incidence of ESRD in the older IgAN patients was 1.95 times higher than that in the non-older IgAN patients. Moreover, the risk of IgAN progression to ESRD of the older patients in Asia was higher than that of the older patients in Europe.