Humans ; Candida albicans/genetics* ; CARD Signaling Adaptor Proteins/genetics* ; Mutation ; Encephalomyelitis

BACKGROUND: Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS: A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS: The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.
Humans ; Aspergillosis, Allergic Bronchopulmonary/complications* ; Aspergillus fumigatus/genetics* ; Asthma/genetics* ; Aspergillus ; Mutation/genetics* ; CARD Signaling Adaptor Proteins/genetics*

CARD Signaling Adaptor Proteins ; physiology ; Candidiasis ; genetics ; Genetic Predisposition to Disease ; Humans ; Interleukin-17 ; genetics ; Mutation ; STAT1 Transcription Factor ; genetics ; Toll-Like Receptor 3 ; genetics

OBJECTIVETo determine the CARD11 expression and its prognostic value in diffuse large B cell lymphoma (DLBCL).

METHODSThis retrospective study included previously untreated patients diagnosed with DLBCL from January 2007 to December 2012. Formalin-fixed, paraffin-embedded blocks of these patients were collected. Tissue microarray was built and expression of CARD11 was examined immunohistochemically. Subtype of DLBCL was determined by Hans algorithm (CD10, BCL6, MUM1). The pattern of CARD11 was further studied and their correlation with outcome was analyzed.

RESULTS79 patients with DLBCL were enrolled and two reactive lymph nodes were used as control. The positive rate of high CARD11 expression in DLBCL was 65.33%, which showed no significant associations with patients' characteristics. Positive CARD11 expression was associated with an inferior event free survival (EFS)(2- year EFS: 52.03%vs 86.12%,P=0.036). Even in patients with a high international prognostic index (IPI, 3-5 points), this difference still remained significant (Median EFS not reached vs 557 days,P=0.033).

CONCLUSIONDLBCL patients with high CARD11 expression had a shorter EFS compared with low level of CARD11. This difference remained significant when patients were in high IPI (3-5 points), which might indicate the value of CARD11 in stratification of high-risk DLBCL patients.

CARD Signaling Adaptor Proteins ; genetics ; metabolism ; Disease-Free Survival ; Guanylate Cyclase ; genetics ; metabolism ; Humans ; Lymphoma, Large B-Cell, Diffuse ; diagnosis ; genetics ; metabolism ; Prognosis ; Retrospective Studies

OBJECTIVETo explore the expression and significance of NLR family, pyrin domain containing 3 (NLRP3), apoptosis associated speck like protein containing a CRAD (ASC) and absent in melanoma 2 (AIM2) of patients with acute leukemia.

METHODSThe petipheral blood samples of 19 patients with ALL and 41 patients with ANLL as the AL group (each 20 cases of newly diagnosed, relapsed and complete remission group) and 20 cases of non-hematologic malignancies as the control group were collected from July 2013 to July 2014 in the First Affiliated Hospital of Gannan Medical University. The expression levels of NLRP3, ASC and AIM2 in peripheral blood plasma were determined by ELISA.

RESULTSThe expression levels of NLRP3, ASC and AIM2 in plasma of control and AL complete remission groups were significantly higher than those in newly diagnosed and relapsed groups, and were with statistical significance (P < 0.05), but there were no statistical signifirance between ALL and ANLL groups (P > 0.05).

CONCLUSIONThe expression of NLRP3, ASC and AIM2 is down-regulated in the patients with acute leukemia, which maybe play a role of anti-leukemia, and provide a laboratory evidence for diagnosis and treatment of patients with acute leukemia.

Acute Disease ; CARD Signaling Adaptor Proteins ; Carrier Proteins ; blood ; genetics ; Case-Control Studies ; Cytoskeletal Proteins ; blood ; genetics ; DNA-Binding Proteins ; blood ; genetics ; Humans ; Leukemia ; blood ; genetics ; Leukemia, Myeloid, Acute ; blood ; genetics ; NLR Family, Pyrin Domain-Containing 3 Protein

OBJECTIVETo determine the correlation between the expression of CARMA1 mRNA and MUM1 protein, as well as its effects on clinicopathological features and prognosis of diffuse large B cell lymphoma (DLBCL).

METHODSThe immunophenotype (CD20, CD79a, CD10, MUM1, Bcl6) and proliferation index of DLBCL cells were examined by immunohistochemistry (IHC). CARMA1 mRNA was detected by RT-PCR.

RESULTSCARMA1 mRNA was detected in 76 of 89 (85.40%) cases with DLBCL. The level of CARMA1 mRNA was higher in MUM1-postive group than in MUM1-negative group. No correlation was found in the expression intensity between the two molecules (P = 0.084). Ki67 positive rate was higher in MUM1(+) cases than in MUM1(-) ones (P = 0.030). There was no difference between MUM1(+) and MUM1(-) cases in sex, median age, staging, primary site and other clinicopathological features. In 58 CARMA1 mRNA positive cases, low expression cases showed more in earlier stage and more males. No difference in survival status was identified between cases with and without MUM1 expression, over- and low-expression of CARMA1 mRNA, as well as over- and low-expression of CARMA1 mRNA among 58 cases with MUM1 expression.

CONCLUSIONThe expression of CARMA1 mRNA is likely associated with the expression of MUM1 and shows male predominance in DLBCL. The expression of CARMA1 may be involved with pathogenesis and progression of ABC-like DLBCL. The two molecules correlated somewhat with some clinicopathological features, but not with survival of DLBCL.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; CARD Signaling Adaptor Proteins ; genetics ; metabolism ; Chromosomal Proteins, Non-Histone ; genetics ; metabolism ; Female ; Guanylate Cyclase ; genetics ; metabolism ; Humans ; Lymphoma, Large B-Cell, Diffuse ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Multiple Myeloma ; genetics ; metabolism ; pathology ; Neoplasm Staging ; Young Adult

MHC class II expression is controlled mainly at transcriptional level by class II transactivator (CIITA), which is a non-DNA binding coactivator and serves as a master control factor for MHC class II genes expression. Here, we describe the function of a novel splice-isoform of CIITA, DC-expressed caspase inhibitory isoform of CIITA (or DC-CASPIC), and we show that the expression of DCCASPIC in DC is upregulated upon lipopolysaccharides (LPS) induction. DC-CASPIC localizes to mitochondria, and protein-protein interaction study demonstrates that DC-CASPIC interacts with caspases and inhibits its activity in DC. Consistently, DC-CASPIC suppresses caspases-induced degradation of nitric oxide synthase-2 (NOS2) and subsequently promotes the synthesis of nitric oxide (NO). NO is an essential regulatory molecule that modulates the capability of DC in stimulating T cell proliferation/activation in vitro; hence, overexpression of DC-CASPIC in DC enhances this stimulation. Collectively, our findings reveal that DC-CASPIC is a key molecule that regulates caspases activity and NO synthesis in DC.
Alternative Splicing ; Amino Acid Sequence ; Animals ; Base Sequence ; CARD Signaling Adaptor Proteins ; genetics ; metabolism ; Cell Line ; Dendritic Cells ; drug effects ; immunology ; metabolism ; Humans ; In Vitro Techniques ; Lipopolysaccharides ; pharmacology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mitochondria ; metabolism ; Molecular Sequence Data ; Nitric Oxide ; biosynthesis ; Nitric Oxide Synthase Type II ; metabolism ; Nuclear Proteins ; genetics ; metabolism ; Protein Isoforms ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; T-Lymphocytes ; immunology ; metabolism ; Trans-Activators ; genetics ; metabolism ; Up-Regulation ; drug effects

AIMTo determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion.

METHODOLOGYA lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA).

RESULTSWe show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC.

CONCLUSIONThe CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.

Adaptor Proteins, Signal Transducing ; antagonists & inhibitors ; physiology ; B-Cell CLL-Lymphoma 10 Protein ; CARD Signaling Adaptor Proteins ; antagonists & inhibitors ; physiology ; Carcinoma, Squamous Cell ; pathology ; Caspase Inhibitors ; Caspases ; physiology ; Cell Line, Tumor ; Chemokine CXCL12 ; antagonists & inhibitors ; physiology ; Enzyme Activation ; drug effects ; Gene Silencing ; Genetic Vectors ; genetics ; Humans ; I-kappa B Kinase ; drug effects ; I-kappa B Proteins ; metabolism ; Isoenzymes ; antagonists & inhibitors ; Lentivirus ; genetics ; Membrane Proteins ; antagonists & inhibitors ; physiology ; Mouth Neoplasms ; pathology ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; NF-KappaB Inhibitor alpha ; NF-kappa B ; antagonists & inhibitors ; physiology ; Neoplasm Invasiveness ; Neoplasm Proteins ; antagonists & inhibitors ; physiology ; Phosphorylation ; Plasmids ; genetics ; Protein Kinase C ; antagonists & inhibitors ; Receptors, CXCR4 ; physiology ; Tumor Necrosis Factor-alpha ; pharmacology