NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-ß in endometrial cancer.

OBJECTIVES: NLR family CARD domain containing 5 (NLRC5) could promote major histocompatibility complex class I (MHC-I)-dependent CD8+ T cell-mediated anticancer immunity. In this study, the immunosurveillance role and underlying mechanisms of NLRC5 in endometrial cancer (EC) were characterized. METHODS: CD8+ T cells were separated from healthy women's peripheral blood by using magnetic beads. The effect of NLRC5 and interferon-ß (IFN-ß) on immunosurveillance of EC were examined through a mouse tumor model and a CD8+ T cell-EC cell coculture system after NLRC5 overexpression and IFN-ß overexpression or depletion. The effect of NLRC5 on IFN-ß expression was examined with gain- and loss-of-function experiments. RESULTS: NLRC5 overexpression in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation and migration and promoted EC cell apoptosis and CD8+ T cell proliferation. In vivo, NLRC5 overexpression increased the proportion of CD8+ T cells and inhibited EC progression. Furthermore, IFN-ß overexpression in the EC cell and CD8+ T cell coculture system activated CD8+ T cell proliferation; however, genetic depletion of IFN-ß exerted the opposite effects. In addition, NLRC5 could negatively regulate IFN-ß expression in EC cells. Mechanistically, NLRC5 potentiated the antitumor responses of CD8+ T cells to EC by activating IFN-ß. CONCLUSIONS: Taken together, our findings demonstrated that NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-ß in EC, suggesting that genetically escalated NLRC5 and IFN-ß may act as potential candidates for the clinical translation of adjuvant immunotherapies to patients with EC.

Pattern-recognition receptors in endometriosis: A narrative review.

Endometriosis is closely associated with ectopic focal inflammation and immunosuppressive microenvironment. Multiple types of pattern recognition receptors (PRRs) are present in the innate immune system, which are able to detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in both intracellular and external environments. However, the exact role of PRRs in endometriosis and the underlying molecular mechanism are unclear. PRRs are necessary for the innate immune system to identify and destroy invasive foreign infectious agents. Mammals mainly have two types of microbial recognition systems. The first one consists of the membrane-bound receptors, such as toll-like receptors (TLRs), which recognize extracellular microorganisms and activate intracellular signals to stimulate immune responses. The second one consists of the intracellular PRRs, including nod-like receptors (NLRs) and antiviral proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) with helix enzyme domain. In this review, we mainly focus on the key role of PRRs in the pathological processes associated with endometriosis. PRRs recognize PAMPs and can distinguish pathogenic microorganisms from self, triggering receptor ligand reaction followed by the stimulation of host immune response. Activated immune response promotes the transmission of microbial infection signals to the cells. As endometriosis is characterized by dysregulated inflammation and immune response, PRRs may potentially be involved in the activation of endometriosis-associated inflammation and immune disorders. Toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), nod-like receptor family caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5), nod-like receptor family pyrin domain containing 3 (NLRP3), and c-type lectin receptors (CLRs) play essential roles in endometriosis development by regulating immune and inflammatory responses. Absent in melanoma 2 (AIM2)-like receptors (ALRs) and retinoic acid-inducible gene I-like receptors (RLRs) may be involved in the activation of endometriosis-associated immune and inflammation disorders. PRRs, especially TLRs, may serve as potential therapeutic targets for alleviating pain in endometriosis patients. PRRs and their ligands interact with the innate immune system to enhance inflammation in the stromal cells during endometriosis. Thus, targeting PRRs and their new synthetic ligands may provide new therapeutic options for treating endometriosis.

A case of CIC-rearranged sarcoma with CIC-LEUTX gene fusion in spinal cord.

A 16-year-old male was admitted to the hospital for weakness of both lower extremities. Magnetic resonance imaging revealed an intraspinal extramedullary subdural mass at the thoracic 9 level. Microscopically, the tumor cells were small to medium sized and round to ovoid in shape. They were distributed in diffuse sheets or showed nodular appearance. The nucleus of the tumor had mild-to-moderate atypia, with vesicular chromatin and prominent nucleoli. A smaller proportion of tumor cells demonstrated rhabdoid morphology. Focal myxoid stromal change was present, in which tumor cells exhibited spindle shapes. Approximately two mitoses were counted per 10 high-power fields. No necrosis was observed. The tumor cells were focal positive for CD99; multifocal positive for WT1; diffuse positive for nestin, synaptophysin, and D2-40; partial positive for GFAP; focal positive for desmin and SSTR2; and scattered positive for S-100 protein. The Ki-67 labeling index was approximately 20%. Genetic testing revealed CIC-LEUTX gene fusion. Considering the patient's history, clinical data, pathological findings and genetic findings, we rendered a rare tumor named CIC-rearranged sarcoma with CIC-LEUTX gene fusion.

Comparative study of CD4 and CD45RO T cells and CD20 B cells in cerebrospinal fluid of syphilitic meningitis and tuberculous meningitis patients.

This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p < 0.05). After medical therapy, there was a significantly decline trend of the CD4 T-cell proportion in both groups (p < 0.05). The proportion of CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p < 0.05). After medical therapy, the positive ratio of CD45RO T cells was increased in the CSF of both group patients (p < 0.05). The proportion of CD20B cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM.

Common Polymorphisms Within QPCT Gene Are Associated with the Susceptibility of Schizophrenia in a Han Chinese Population.

A recent genome-wide association study conducted in Caucasians has identified glutaminyl-peptide cyclotransferase (QPCT) gene as a susceptibility gene for schizophrenia, as its common single nucleotide polymorphism (SNP) rs2373000 was significantly associated with the risk of this disease. To date, this finding has not been validated in other populations or ethnic groups. The aim of this study was to investigate the association of common SNPs spanning QPCT gene with the susceptibility of schizophrenia in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. A total of 6 tagSNPs including rs2373000 was selected and then genotyped in our sample. Although the relation between rs2373000 and the risk of schizophrenia was not successfully replicated, we showed for the first time that the minor allele (C) of rs3770752 was associated with a reduced risk of schizophrenia (odds ratio (OR) = 0.645; 95 % confidence interval (CI) 0.486-0.855; P corrected = 0.012) in our cohorts. Meanwhile, this allele seemed to modify the schizophrenia risk through a dominant manner (CC + CT vs. TT, OR = 0.625; 95 % CI 0.457-0.854; P corrected = 0.03). In addition, we found that the minor allele (T) of rs3770748 remarkably reduced the schizophrenia risk via a recessive manner (TT vs. TC + CC, OR = 0.618; 95 % CI: 0.449-0.851; P corrected = 0.03). Taken together, these findings demonstrate a significant association between common SNPs within QPCT gene and schizophrenia risk in a Han Chinese population, suggesting QPCT gene may represent a susceptibility gene for this disease.

A multiple cavity malignancy involving the renal capsule, pleura and meninges: A case report and review of the literature.

Malignant renal subcapsular effusions commonly arise from primary or metastatic renal neoplasms. The current case report presents a rare case of malignancy with a massive renal subcapsular effusion accompanied by a malignant pleural effusion of an unknown primary site, which underwent progression to carcinomatous meningitis during chemotherapy. The type of adenocarcinoma present was determined by effusion cytology. Intravenous chemotherapy (docetaxel plus oxaliplatin and gemcitabine plus cisplatin) were administered; however, the disease still progressed. Time to progression was 9 months during treatment of gefitinib. Comprehensive therapies, including intracavity chemotherapy, immunotherapy and gefitinib, were shown to be effective and prolonged the patient's survival time.

[Ageing related changes of insulin secretion and insulin sensitivity among normal glucose tolerance individuals in China].

OBJECTIVE: To explore the aging-related changes of insulin secretion and insulin sensitivity among normal glucose tolerance (NGT) individuals in China. METHODS: A total of 34 293 individuals were recruited. All of them were described as NGT by 75 g oral glucose tolerance test (75 g OGTT) according to the diagnostic criterion of WHO, 1999. HOMA-ß, ΔI(30)/ΔG(30), InsAuc30/GluAuc30, InsAuc120/GluAuc120 were calculated to estimate insulin secretion; HOMA-IR and Matsuda index measured to estimate insulin sensitivity; Disposition index: DI(30) and DI(120) were used to estimate ß-cell function. RESULTS: HOMA-ß, ΔI(30)/ΔG(30), InsAuc30/GluAuc30 and InsAuc120/GluAuc120 were all lower in the elder group then the younger group (P trend < 0.05). The mean HOMA-ß dropped from 192 ± 16 (20 - 29 years) to 115 ± 7 (70 or elder) among men and from 162 ± 8 (20 - 29 years) to 120 ± 12 (70 or elder) among women. The mean ΔI(30)/ΔG(30) dropped from 20.0 ± 2.0 (20 - 29 years) to 8.6 ± 0.6 (70 or elder) among men and from 22.4 ± 1.6 (20 - 29 years) to 12.5 ± 1.7 (70 or elder) among women. The above index were negatively correlated with age in univariate linear regression (P < 0.05), the results among men and overall still existed after adjusted for BMI and waist circumference in multivariate linear regression, while the relation between HOMA-ß and age disappeared among women. Matsuda Index was positively correlated with age (ß = 0.02, P = 0.001) and HOMA-IR were negatively correlated with age (ß = -0.01, P = 0.001) among men even after adjusted for BMI and waist circumference and the above correlation between Matsuda Index/HOMA-IR and ageing was not significant until adjusted for BMI and waist circumference in multivariate linear regression. Among women HOMA-IR (ß = -0.01, P = 0.000), Matsuda index (ß = 0.03, P = 0.000). DI(30) and DI(120) were negatively correlated with age in both univariate and multivariate linear regression. CONCLUSIONS: The basal, postchallenge insulin secretion and postchallenge islet compensatory function decreases with ageing, while insulin sensitivity does not deteriorate with ageing and its related change of body composition and weight gain.

Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains.

Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Overexpression of tumor necrosis factor-α (TNF-α) occurs in the AD brain. Recent clinical studies have shown that the anti-TNF-α therapy improves cognition function of AD patients rapidly. However, the underlying mechanism remains elusive. The present study investigates the effects of intracerebroventricular injection of the monoclonal TNF-α antibody, Infliximab, on the pathological features of AD in the APP/PS1 double transgenic mice. We found that Infliximab administration reduced the levels of TNF-α, amyloid plaques, and tau phosphorylation as early as three days after daily injection of 150 µg Infliximab for three days. The number of CD11c-positive dendritic-like cells and the expression of CD11c were found to be increased concurrently after Infliximab injection. These data suggested that the CD11c-positive dendritic-like cells might contribute to the Infliximab-induced reduction of AD-like pathology. Furthermore, our results support the use of anti-TNF-α for the treatment of AD.

[Predictive value of sonographic features in preoperative evaluation of malignant thyroid nodules].

OBJECTIVE: To retrospectively evaluate the diagnostic accuracy of ultrasonographic (US) features for the pre-operative differentiation of benign and malignant thyroid nodules by using pathological diagnosis as the reference standard. METHODS: A total of 1501 patients with 2123 thyroid nodules (1864 malignant, 259 benign) diagnosed intra-operatively and undergoing pre-operative ultrasonography at our hospital were recruited. The following characteristics of US images were evaluated: nodule size, shape, margin, echotexture, echogenicity, presence and type of calcification, blood flow inside or around nodules and the presence of ipsilateral cervical lymphadenectasis. RESULTS: (1) The risk of malignancy was higher in a solitary nodule than in a non-solitary nodule [16.7% (109/653) vs 10.2% (150/1470), P=0.000]. The mean diameter of benign nodules was larger than that of malignant nodules [(2.4±1.4) vs (2.1±1.9) cm, P=0.009]. (2) Microcalcification, irregular shape, ill-defined border, solid and hypoechogenicity were more common in malignant nodules. Irregular shape had the highest sensitivity and positive predictive value while microcalcification had the highest diagnostic accuracy. (3) Nodules with a rich blood flow inside tended to have a higher risk of malignancy. The distribution pattern of blood flow around the nodules was not associated with the differentiation of benign and malignant thyroid nodules. Nodules with the presence of ipsilateral cervical lymphadenectasis had a higher risk of malignancy than those without lymphadenectasis [28.3% (80/283) vs 9.6% (92/963), P<0.01]. (4) If microcalcification, irregular shape, ill-defined border, solid, hypoechogenicity and the presence of ipsilateral cervical lymphadenectasis were treated as the characteristics of malignancy, a higher frequency of these characteristics was correlated with a higher risk of malignancy. CONCLUSION: Despite a lack of specific US imaging characteristics in malignant thyroid nodules, microcalcification and irregular shape appear closely correlated with malignancy. A combined use of conventional US characteristics may improve the accuracy of differential diagnosis.

A novel mouse model of human breast cancer stem-like cells with high CD44+CD24-/lower phenotype metastasis to human bone.

BACKGROUND: A satisfactory animal model of breast cancer metastasizing to bone is unavailable. In this study, we used human breast cancer stem-like cells and human bone to build a novel "human-source" model of human breast cancer skeletal metastasis. METHODS: Human breast cancer stem-like cells, the CD44+/CD24-/lower subpopulation, was separated and cultured. Before injection with the stem-like cells, mice were implanted with human bone in the right or left dorsal flanks. Animals in Groups A, B, and C were injected with 1 x 10(5), 1 x 10(6) human breast cancer stem-like cells, and 1 x 10(6) parental MDA-MB-231 cells, respectively. A positive control group (D) without implantation of human bone was also injected with 1 x 10(6) MDA-MB-231 cells. Immunohistochemistry was performed for determination of CD34, CD105, smooth muscle antibody, CD44, CD24, cytokine, CXC chemokine receptor-4 (CXCR4), and osteopontin (OPN). mRNA levels of CD44, CD24, CXCR4, and OPN in bone metastasis tissues were analyzed by real-time quantitative polymerase chain reaction (PCR). RESULTS: Our results demonstrated that cells in implanted human bones of group B, which received 1 x 10(6) cancer stem-like cells, stained strongly positive for CD44, CXCR4, and OPN, whereas those of other groups showed no or minimum staining. Moreover, group B had the highest incidence of human bone metastasis (77.8%, P = 0.0230) and no accompaniment of other tissue metastasis. The real-time PCR showed an increase of CD44, CXCR4, and OPN mRNA in metastatic bone tissues in group B compared with those of groups C and D, however the expression of CD24 mRNA in group B were the lowest. CONCLUSIONS: In the novel "human source" model of breast cancer, breast cancer stem-like cells demonstrated a higher human bone-seeking ability. Its mechanism might be related to the higher expressions of CD44, CXCR4, and OPN, and the lower expression of CD24 in breast cancer stem-like cells.

RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins.

The RIG-G gene, originally isolated from an acute promyelocytic leukemia cell line NB4, codes for a 60-kDa cytoplasmic protein that is induced by all-trans retinoic acid (ATRA) treatment along with the induction of morphological differentiation of NB4 cells. Here, we provide evidence that ectopic expression of Rig-G in U937 cells can lead to a significant accumulation of cells at G(1)/S transition. Growth arrest seems to occur by modulating several major cell cycle regulatory players. Interestingly, Rig-G alters JAB1 cellular distribution through interacting with this protein and increases the intracellular level of p27 by preventing it from the JAB-1-dependent and ubiquitin/proteasome-mediated degradation. Furthermore, we demonstrate a role of Rig-G for c-myc down-regulation that results in an up-regulation of p21, tightly associated with cell cycle arrest. In addition, our studies reveal that Rig-G is a direct target of STAT1, a key transcription factor in regulating IFN responses, and may be one of the first experimentally proven molecular mediators for the antiproliferative effect of IFN-alpha. Considering that IFN-alpha and ATRA synergistically inhibit growth along the intracellular pathways triggered by the two compounds in many cell types, we suggest that Rig-G may also represent one of the key molecular nodes of signaling cross-talk between ATRA and IFN-alpha.

[A clinical study on the effect of Yinxing Damo combined with betahistine hydrochloride injection on vertebral basilar artery ischemic vertigo].

OBJECTIVE: To evaluate the therapeutic efficacy of Yinxing Damo (YXDM) combined with Betahistine Hydrochloride Injection (BHI) on vertebra basilar artery ischemic vertigo (VBIV). METHODS: Ninety patients with VBIV were randomly divided into two groups; 45 patients (the treated group) were treated with YXDM and BHI intravenous dripping, once a day for 14 days. Another 45 patients (control group) were treated with Xueshuantong and BHI intravenous dripping, once daily for 14 days. The clinical syndromes and the index of the transcranial Doppler (TCD) and hemorheology were observed. RESULTS: The total effective rate was 100% in the treated group, which was better than that in the control group 90.5%, (P < 0.05). The indexes of TCD and hemorheology in the treated group were obviously improved after treatment, (P < 0.01). CONCLUSION: YXDM combined with BHT injection had better effect in treating patients with VBIV is an ideal drug for VBIV.

Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk.

Acute promyelocytic leukemia (APL) is characterized by the specific chromosome translocation t(15;17) with promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) fusion gene and the ability to undergo terminal differentiation as an effect of all-trans retinoic acid (ATRA). Recently, arsenic trioxide (As(2)O(3)) has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. At the cellular level, As(2)O(3) triggers apoptosis and a partial differentiation of APL cells in a dose-dependent manner; both effects are observed in vivo among patients with APL and APL animal models. To further explore the mechanism of As(2)O(3)-induced differentiation, the combined effects of arsenic and a number of other differentiation inducers on APL cell lines (NB4 and NB4-R1) and some fresh APL cells were examined. The data show that a strong synergy exists between a low concentration of As(2)O(3) (0.25 microM) and the cyclic adenosine monophosphate (cAMP) analogue, 8-CPT-cAMP, in fully inducing differentiation of NB4, NB4-R1, and fresh APL cells. Furthermore, cAMP facilitated the degradation of As(2)O(3)-mediated fusion protein PML-RARalpha, a process considered to play a key role in overcoming the differentiation arrest of APL cells. On the other hand, cAMP could significantly inhibit cell growth by modulating several major players in G(1)/S transition regulation. Interestingly, H89, an antagonist of protein kinase A, could block the differentiation-inducing effect of As(2)O(3) potentiated by cAMP. These results thus support the existence of a novel signaling cross-talk for APL maturation, which may deepen understanding of As(2)O(3)-induced differentiation in vivo, and thus furnish insights for new therapeutic strategies.