MTHFR C677T polymorphism, homocysteine, burden, and location of AMI and ACI.

OBJECTIVE: We aimed to investigate the relationship between homocysteine levels and MTHFR C677T polymorphisms and acute ischemic vascular events and focused on the differential effects of the MTHFR C677T polymorphisms on the burden and location of AMI and ACI. PATIENTS AND METHODS: 102 acute cerebral infarction (ACI) and acute myocardial infarction (AMI) patients who were admitted to the First Hospital of Jilin University in northeast China as the patient group, 83 healthy people who were hospitalized during the same period served as a control group. MTHFR C677T genotypes were identified via Polymerase Chain Reaction (PCR)-Fluorescent Probe Method. RESULTS: Patient group had higher serum homocysteine levels (p=0.013), lower serum folic acid (p<0.001), and Vit B12 levels (p=0.004) compared to the control group. Homocysteine levels in the patient group with the TT genotypes of the MTHFR C677T polymorphisms were higher than those with the CC and CT genotypes (p<0.05). Folic acid levels in the patients with TT genotypes were lower than those with the CC genotypes (p<0.05), but not in the control group (p>0.05). There were negative and significant associations between serum homocysteine levels and serum vitamin B12 levels in the control group (r=-0.234, p=0.033), but not between serum homocysteine levels and serum folic acid levels (r=-0.103, p=0.355). Conversely, there was a negative and significant association between serum homocysteine levels and serum folic acid levels in the patients' group (r=-0.257, p=0.01), but not between serum homocysteine levels and serum vitamin B12 levels (r=-0.185, p=0.64). No statistically significant differences in MTHFR C677T genotype and C/T alleles distribution were investigated between the patient and control group (p>0.05). The MTHFR C677T polymorphism did not differentially affect the burden and location of AMI and ACI. CONCLUSIONS: Homocysteine played a common role in atherosclerosis-related acute ischemic vascular events. These correlations were modified by MTHFR C677T polymorphisms and influenced by folic acid levels. The MTHFR C677T polymorphisms were not directly related to acute ischemic vascular events, nor did they differentially affect the burden and location of AMI and ACI.

[Effects of typical PKC subtypes on the proliferation of mouse pulmonary artery smooth muscle cells and the expression of ERK1/2 and Akt induced by hypoxia].

Objective: To study the effects of specific isoforms of classic protein kinase C (cPKCs) on hypoxia-induced proliferation and the expression of ERK1/2 and Akt using drug intervention or virus transfection in vitro. Methods: Dynal MPC-1 magnetic particle concentrator was used to separate iron-containing pulmonary arterioles fragments, and the pulmonary artery smooth muscle cells (PASMCs) were primary cultured and identified. The cells were intervened by PKC agonist (PMA), PKCα inhibitor (safingol), PKCßⅠ inhibitor (Go6976) and PKCßⅡ inhibitor (LY333531) respectively, and the changes in protein expressions of cPKCs, and the phosphorylation levels of ERK1/2 and Akt were observed by immunoblotting under the condition of normal oxygen or hypoxia. The lentiviral vectors of PKCα and PKCß were used to specifically knock-down the activity of target genes by virus transfection techniques, and Western blotting was used to observe the protein expressions of cPKCs, and the phosphorylation levels of ERK1/2 and Akt in hypoxia-induced PASMCs in mice. Results: With Brdu method, the proliferation of PASMCs induced by hypoxia was significantly inhibited by safingol, Go6976 and LY333531 by inhibiting cPKCα, ßⅠ and ßⅡ respectively. Compared with the hypoxic control group, the rates of Brdu positive cells were (7.35±0.26)% vs (11.28±0.43)%, (3.76±0.25)% vs (7.98±0.28)% and (4.12±0.46)% vs (7.78±0.53)%. We also observed that PMA could significantly promote the proliferation of PASMCs under normoxic condition. Compared with the normoxia control group, the Brdu-positive cell rates were (9.65±0.47)% vs (6.34±0.52)%, (9.34±0.38)% vs (5.42±0.21)% and (7.78±0.53)% vs (4.12±0.46)%. In addition, after transfection with PKCα or PKCß lentiviral vector, the proliferation of PASMCs was significantly lower in hypoxia transfection group than in the control group. The rates of Brdu positive cells were (3.58±0.54)% vs (5.97±0.63)%, respectively. Using Western blotting, we also observed that after being inhibited by safingol, Go6976 and LY333531 respectively, the phosphorylation levels of ERK1/2 and Akt in PASMCs induced by hypoxia was significantly lower than the control group. After using safingol, the phosphorylation levels of ERK1/2 and Akt were (0.56±0.07) vs (1.08±0.13) and (0.49±0.04) vs (0.97±0.08). After using Go6976, the phosphorylation levels of ERK1/2 and Akt were (0.41±0.09) vs (0.79±0.10) and (0.48±0.09) vs (0.82±0.16), after using LY333531, the phosphorylation levels of ERK1/2 and Akt were (0.42±0.03) vs (0.87±0.06) and (0.34±0.07) vs (0.78±0.05). While PMA could promote the phosphorylation levels of ERK1/2 and Akt under normoxic condition, 1.25±0.12 vs 0.41±0.07 and 0.98±0.06 vs 0.37±0.08, respectively. Using transfection technique to specifically knock down the expression of cPKCα and ß, we found that under hypoxic conditions, transfection of PASMCs could significantly lower the phosphorylation levels of ERK1/2, its phosphorylation level was 0.29±0.06 vs 0.76±0.05, with no evident change in the phosphorylation levels of Akt. Conclusions: Hypoxia may lead to phosphorylation of ERK1/2 by promoting the protein expression of cPKCα, cPKCßⅠ and cPKCßⅡ respectively, which eventually induces abnormal proliferation of PASMCs from the distal pulmonary arteries, participating in the development of hypoxic pulmonary hypertension (HPH) of the mice. Regulation of the expression of cPKCα, cPKCßⅠ and cPKCßⅡ may help to attenuate the formation of pulmonary vascular remodeling. Target therapy based on cPKCs is expected to be a new direction for HPH therapy in the future.

Circular RNA circDENND4C facilitates proliferation, migration and glycolysis of colorectal cancer cells through miR-760/GLUT1 axis.

OBJECTIVE: Colorectal cancer is a common malignant tumor of the digestive tract, and its incidence is closely related to lifestyle inheritance and colorectal adenoma. Circular RNA (circRNA) has been proved to participate in the progression of colorectal cancer cells. Our study aimed to investigate the function and the underlying mechanism of circRNA circDENND4C in colorectal cancer cells. PATIENTS AND METHODS: The expression of circDENND4C, glucose transporter 1 (GLUT1), and miR-760 was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Western blot was used to measure the protein levels of GLUT1, the proliferation-related protein (Cyclin D1) and matrix metallopeptidase 9 (MMP-9). Cell Counting Kit-8 (CCK-8) assay and transwell assay were performed to evaluate cell proliferation and migration. The glucose uptake and lactate production were detected by the corresponding kits. The targets between circDENND4C and miR-760 and miR-760 and GLUT1 were predicted by starBase 3.0 and TargetScan, and then confirmed by Dual-Luciferase reporter assay. Animal experiment revealed the effect of circDENND4C on colorectal cancer cells in vivo. RESULTS: The expression of circDENND4C and GLUT1 was upregulated in colorectal cancer tissues and cells. Functionally, the knockdown of circDENND4C suppressed proliferation, migration, and glycolysis of colorectal cancer cells. Similarly, silence of GLUT1 also inhibited cell proliferation, migration, and glycolysis. Notably, the overexpression of GLUT1 reversed the functional effects of circDENND4C knockdown on colorectal cancer cells. More importantly, miR-760 acted as a direct target of circDENND4C, and miR-760 could bind to GLUT1, and circDENND4C regulated GLUT1 by sponging miR-760. Finally, circDENND4C knockdown decreased the growth of colorectal cancer cells in vivo. CONCLUSIONS: CircRNA circDENND4C accelerated proliferation, migration, and glycolysis of colorectal cancer cells through regulating GLUT1 by sponging miR-760.

[The prostate cancer precision screening program: a preliminary report after recruitment of 2 159 men].

Objective: The Chinese Anti-Cancer Association Genitourinary Cancer Committee Prostate Cancer Working Group released Consensus of prostate cancer (PCa) screening in 2017. This program aims to evaluate the methods and significance of prostate cancer precision screening in high risk population. Methods: A total of 2 159 eligible males enrolled from 13 community centers and 3 screening centers received PSA test from April 2017 to August 2018. Prostate-specific antigen (PSA) determination in serum with a cut-off of ≥4.0 ng/ml was the main screening test and indication for biopsy. The interviewer-administered questionnaire covered demographic characteristics and environmental exposure factors. The associations between these factors and prostate cancer risk were determined by multivariable unconditional logistic regression models. Results: Altogether, 271 cases (12.6%) had a confirmed PSA increase ≥ 4.0 µg/L (median 9.1, range 4.0-25.0). Subsequently, 57 subjects (21.0%) out of the 271 PSA-suspicious men underwent prostate biopsy, and 34 (59.6%) were confirmed as prostate cancer. Until now, the overall prostate cancer incidence in the first screening round was1.57%. There were no statistical differences in the distributions of PSA-suspicious and prostate cancer incidence between community centers and screening centers (P=0.578 and 0.735). Age (OR: 2.63; 95%CI: 1.84-3.75, P<0.001) and chronic prostatitis history (OR: 2.02; 95%CI: 1.55-2.63, P<0.001) were significantly associated with PSA level. After adjustment for these factors, older age (OR: 4.04; 95%CI: 1.71-9.59, P=0.002) and statins use (OR: 3.09; 95%CI: 1.25-7.69, P=0.015) were associated with an elevated risk of PCa. Conclusions: It is of substantial significance to screen prostate cancer in high risk population. Both community centers and screening centers methods are effective. Although largely underestimated, the incidence of PCa in the targeted Chinese population is higher than expected. Older men have a high risk of harboring PCa. Our study suggests a decreased risk of PCa in men with statins use. Prostate Cancer Precision Screening is promising to improve prostate cancer survival in China.

[Clinical analysis between trefoil factor 3 gene polymorphsims and susceptibility to papillary thyroid carcinoma].

Objective:To explore the relationships between trefoil factor 3（TFF3） gene polymorphisms and susceptibility to papillary thyroid carcinoma（PTC） in Han population of northern China. Method:A case-control study was performed in 123 PTC patients and 108 healthy controls. Four SNPs in the TFF3 gene, including rs225361, rs533093, rs9981660 and rs225439, were detected by gene sequencing. Result:Compared with healthy people, there was no significant difference in the genotype frequencies of rs225361, rs9981660, rs533093 and rs225439 alleles in the PTC group（P>0.05）. The CGTC and CGTT haploids of TFF3 gene were positively correlated with the occurrence of PTC, and CGCC and TGTC haploids were negatively correlated with the occurrence of PTC. TT genotype of rs9981660 had significant differences in the distribution of PTC with and without lymph node metastasis（P<0.05）. Conclusion:Polymorphisms in 4 SNP loci in the TFF3 gene may be unrelated to the occurrence of PTC. The CGTC, CGTT, CGCC and TGTC haploids in the TFF3 gene might be related to the development of PTC. The TT genotype at rs9981660 may be associated with lymph node metastasis of PTC.

[Chemotherapy combined with androgen-deprivation therapy in high-volume metastatic hormone sensitive prostate cancer: a short-term efficacy and safety analysis].

Objective: To investigate the short-term efficacy and adverse events of chemotherapy combined with androgen-deprivation therapy in high-volume metastatic hormone sensitive prostate cancer. Methods: From March 2015 to August 2017, 55 patients with high-volume metastatic hormone sensitive prostate cancer were enrolled at Department of Urology, Fudan University Shanghai Cancer Center receiving chemotherapy combined with androgen-deprivation therapy. The age was 65(8) years (M(Q(R))) (range: 46 to 79 years). Patients were enrolled in the study for continuous androgen-deprivation therapy (medical or surgical castration), combined with docetaxel 75 mg/m(2) intravenous injection on the first day, repeated every 21 days (6 cycles). Endpoints included overall survival, progression-free survival of prostate cancer, prostate specific antigen (PSA) response rate, and adverse events. Results: The follow-up time was 21.2(11.7) months. The PSA value before chemotherapy was 144.9(415.3) µg/L. The days in patients undergoing androgen deprivation therapy before chemotherapy was 14(23) days. Four patients (7.3%) presented 0 in Eastern Cooperative Oncology Group scoring system and 51 patients(92.7%) presented 1. Thirty-nine patients (70.9%) completed more than 6 cycles of combined chemotherapy, 17 patients (30.9%) showed PSA<0.2 µg/L at 6 months after treatment, and 14 patients (25.5%) showed PSA<0.2 µg/L at 12 months after treatment. Twenty-eight patients (50.9%) had grade 3 to 4 neutropenia and 1 patient (1.8%) developed infectious neutropenia and died. Nausea and vomit occurred in 16 patients (29.1%). Twelve patients (21.8%) underwent dose adjustment due to adverse events in blood system. Conclusions: The short-term effect was confirmed in high-volume metastatic hormone sensitive prostate cancer using chemotherapy combined androgen-deprivation therapy, and the long-term effect remains to be seen. Myelosuppression during chemotherapy requires close attention, and taking timely examination is recommended.

Radial forearm flaps with venous compromise: correlations between salvage techniques and their rates of success.

We retrospectively analysed the reliability of anastomosis of the deep venous system as a salvage technique for a free radial forearm flap that has developed venous compromise. The primary predictors were the salvage techniques, which comprised anastomosis of the deep venous system and a repeat of the original anastomosis, and the primary outcome measure was the rate of success. The potential confounders included original venous outflow, the original causes of the venous compromise, and the number of venous anastomoses. The chi squared test, Fisher's exact test, and the Cochran-Mantel-Haenszel test were used for statistical analysis as appropriate. The final sample comprised 42 patients who required re-exploration for venous compromise. The salvage rates were 15/18 when anastomosis of the deep venous system was chosen as a salvage technique and 9/24 and when the original anastomosis was done again (p=0.003, OR 2.222, 95% CI 1.274 to 3.876). The salvage rate of venous compromise was higher in patients who had anastomoses of the deep venous system than in those in whom the original anastomosis was repeated.

[Use of prostate health index in diagnosing prostate cancer in Chinese men].

Objective: To investigate the value of prostate health index (PHI) in the diagnosis of prostate cancer in patients with total prostate specific antigen (tPSA) <20 µg/L. Methods: Totally 1 135 patients with tPSA<20 µg/L and prostate biopsy indications at Department of Urology, Fudan University Shanghai Cancer Center from March 2013 to April 2016 were enrolled in this study. They were tested for serum tPSA, free prostate specific antigen and prostate specific antigen isoform 2, from which PHI was calculated. Diagnostic efficacy of PHI and tPSA were evaluated using receiver operating characteristic (ROC) curve analysis. The detection rates of prostate cancer were calculated in different ranges of PHI. Subgroup analysis of 716 patients, who were aged 50 or above with tPSA in the range of 4 to 10 µg/L and digital rectal examination negative, was performed. Results: In the biopsied objects with tPSA<20 µg/L, PHI was significantly higher in prostate cancer patients than that in non-cancer patients (48.4(37.4) vs. 26.5(16.9), U=52 674.00, P=0.000), PHI was also significantly higher in high-grade prostate cancer patients than that of low-grade prostate cancer patients (44.5(30.8) vs. 56.4(42.5), U=23 314.00, P=0.000). The area under the curve (AUC) of PHI for diagnosing prostate cancer was significantly higher than that of tPSA (0.771 vs. 0.627, P=0.000). When PHI was in the range of <27, 27 to <36, 36 to <55 and ≥55, the probability of prostate cancer was 9.4% (95%CI: 7.0% to 12.2%), 16.3% (95%CI: 12.2% to 20.8%), 31.0% (95%CI: 25.9% to 37.3%) and 66.4% (95%CI: 58.9% to 74.2%), respectively. Subgroup analysis showed that the AUC of PHI in diagnosing prostate cancer was significantly higher than that of tPSA (0.764 vs. 0.569, P=0.000). When PHI was in the range of <27, 27 to <36, 36 to <55 and ≥55, the probability of prostate cancer was 8.1% (95%CI: 5.4% to 11.3%), 14.0% (95%CI: 9.1% to 19.9%), 30.8% (95%CI: 23.6% to 38.7%) and 78.8% (95%CI: 66.7% to 88.9%), respectively. Conclusion: PHI is superior to tPSA in the diagnosis of prostate cancer in Chinese men with tPSA<20 µg/L.

Familial gigantiform cementoma: distinctive clinical features of a large Chinese pedigree.

Familial gigantiform cementoma is a rare benign fibrocemento-osseous lesion of the jaws that can cause severe facial deformity. It has an autosomal dominant mode of inheritance, but varies in its phenotype. It is more common in white, African, and East-Asian patients. Here we report what is to our knowledge the first distinctive Chinese family with familial gigantiform cementoma involving 4 generations and 13 patients, and which suggests that the tumour presents with 3 distinctive growth phrases.

Protein kinase D1 inhibits breast cancer cell invasion via regulating matrix metalloproteinase expression.

PURPOSE: This study aimed to explore the role of protein kinase D1 (PKD1) in breast cancer invasion. MATERIALS AND METHODS: The relative expression of PKD1mRNA and protein in human invasive breast cancer tissue samples and normal samples, as well as breast cancer cell lines, were detected. Constitutively-active PKD1 and PKD1 specific shRNA were expressed in the MD-MB-231 and MCF-7 cells, respectively. The role of PKD1 in the invasive behavior of breast cancer cell line was evaluated by matrix metalloproteinase (MMP) expression. RESULTS: The results showed that PKD1, as a serine/threonine kinase, is downregulated significantly in invasive ductal carcinoma and metastatic invasive ductal carcinoma tissue than the normal tissue and the low expression of PKD1 is also found in breast cancer cell line MD-MB-231. The MMP2 and MMP9 expression in PKD1 constitutively-active MD-MB-231 cells and MCF-7 knockdown cells were decreased and increased respectively. CONCLUSION: The authors confirmed that PKD1 was downregulated in invasive breast cancer. PKD1 can negatively regulate the MMP expression and may serve as a potential therapeutic target.

Screening for key genes associated with invasive ductal carcinoma of the breast via microarray data analysis.

The aim of this study was to identify key genes related to invasive ductal carcinoma (IDC) of the breast by analyzing gene expression data with bioinformatic tools. Microarray data set GSE31138 was downloaded from Gene Expression Omnibus, including 3 breast cancer tissue samples and 3 normal controls. Differentially expressed genes (DEGs) between breast cancer and normal control were screened out (FDR < 0.05 and |logFC| > 2). Coexpression between genes was examined with String, and a network was then constructed. Relevant pathways and diseases were retrieved with KOBAS. A total of 56 DEGs were obtained in the IDC of the breast compared with normal controls. A gene coexpression network including 27 pairs of genes was constructed and all the genes in the network were upregulated. Further study indicated that most of the genes in the coexpression network were enriched in ECM-receptor interaction (COL4A2, FN1, and HMMR) and nucleotide excision repair (CETN2 and PCNA) pathways, and that the most significantly related disease was autoimmune lymphoproliferative syndromes. A number of DEGs were acquired through comparative analysis of gene expression data. These findings are beneficial in promoting the understanding of the molecular mechanisms in breast cancer. More importantly, some key genes were revealed via gene coexpression network analysis, which could be potential biomarkers for IDC of the breast.

Polymorphisms at long non-coding RNAs and prostate cancer risk in an eastern Chinese population.

BACKGROUND: Controversial data on the association of single-nucleotide polymorphisms (SNPs, rs3787016G>A and rs10773338G>A) in long non-coding RNA (lncRNA) with prostate cancer risk were emerged. Considering possible genetic differences among populations, we conducted the present study to clarify these discrepancies and re-validate these results in an eastern Chinese population and thus provide clues for new therapeutic targets of prostate cancer. METHODS: Genotypes of these two SNPs from 1015 ethnic Han Chinese patients with prostate cancer and 1032 cancer-free controls were determined by Taqman assays. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations. RESULTS: The association of rs3787016 A variant genotypes with a significantly higher prostate cancer risk were found (adjusted OR = 1.418, 95% CI = 1.090-1.844 for AA vs GG). Stratification analysis indicated that the risk of rs3787016 variant AG/AA genotypes was more evident in younger subjects, ever smoking, patients with Gleason score ⩾ 7(4+3) and highly aggressive status. All these risks were not present for rs10773338G>A. CONCLUSIONS: These findings suggested that lncRNA SNPs may contribute to prostate cancer risk in an eastern Chinese population. Larger and well-designed studies with different ethnic populations are warranted to validate our findings.

Protein tyrosine phosphatase SHP2 regulates TGF-ß1 production in airway epithelia and asthmatic airway remodeling in mice.

BACKGROUND: Transforming growth factor (TGF)-ß1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-ß1 production and thus a potential regulator of airway remodeling. OBJECTIVES: To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling. METHODS: The airways of Shp2(flox/flox) mice were infected with recombinant adenovirus vectors expressing a Cre recombinase-green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-ß1. RESULTS: Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-ß1 production by these cells correlated with the extent of shp2 gene expression. CONCLUSIONS: SHP2 activities in airway epithelial cells appear to modulate TGF-ß1 production and, in turn, regulate allergic airway remodeling following allergen provocation. CLINICAL IMPLICATIONS: Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP2 represents a potentially novel therapeutic target for the treatment of asthmatics. CAPSULE SUMMARY: Airway epithelial protein tyrosine phosphatase SHP2 appears to modulate TGF-ß1 activities as part of one or more cellular pathways leading to regulating the airway remodeling and lung dysfunction occurring in mouse models of allergic respiratory inflammation.

RAGE upregulation and nuclear factor-kappaB activation associated with ageing rat cardiomyocyte dysfunction.

Evidence suggests that ageing is a major risk factor for cardiac dysfunction. Interactions between advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) are known to cause chronic cellular activation, including activation of nuclear factor-kappaB (NF-kappaB), which has been implicated as a causal factor in the ageing process. To assess whether cardiomyocyte contractile function and the interaction of AGEs with RAGE in the heart are altered in ageing, 25- and 2-month-old male rats were compared. Mechanical properties were assessed in ventricular myocytes using an edge-detection system, including peak twitch amplitude (PTA), time-to-PTA (TPS), time-to-75% relengthening (TR75) and maximal velocity of shortening/relengthening (+/-dL/dt) in ventricular myocytes. AGEs were detected by using a fluorescence assay. The expression of RAGE and NF-kappaB was assessed through a Western blot analysis. Compared with young myocytes, aged myocytes displayed a prolonged TR75 at 1 Hz. With increasing stimulus frequency (from 2 to 4 Hz), aged myocytes' PTA was significantly reduced relative to young myocytes. Aged rat hearts displayed high level of AGEs, RAGE upregulation and NF-kappaB activation. These findings demonstrate impaired cardiomyocyte relaxation and reduced tolerance to increased stimulus frequency in aged rats, which might be associated with enhanced AGEs, RAGE expression, and NF-kappaB activation.

Diagnostic accuracy of tumour markers for malignant pleural effusion: a meta-analysis.

BACKGROUND: The role of tumour markers such as carbohydrate antigen (CA) 125, CA 15-3, CA 19-9 and CYFRA 21-1 (a fragment of cytokeratin 19) in differentiating malignant pleural effusions (MPE) from benign effusions is not yet clear. METHODS: After a systematic review of English language studies, sensitivity, specificity and other measures of accuracy of pleural concentrations of CA 125, CA 15-3, CA 19-9 and CYFRA 21-1 or their combinations in the diagnosis of MPE were pooled using random effects models. Summary receiver operating characteristic curves were used to summarise overall test performance. RESULTS: Twenty-nine studies met the inclusion criteria for the analysis. The summary estimates of the sensitivity and specificity of these tumour markers were as follows: CA 125, 0.48/0.85; CA 15-3, 0.51/0.96; CA 19-9, 0.25/0.96; CYFRA 21-1, 0.55/0.91 for diagnosing MPE. The estimated summary receiver operating characteristic curves showed that the performance of pleural CA 125 and CA 19-9 measurement in the diagnosis of MPE was limited, whereas that of CA 15-3 and CYFRA 21-1 was better. When two or more of the above four tumour markers were combined, or combined with carcinoembryonic antigen, the sensitivity and specificity were all increased to different extents. CONCLUSIONS: The current evidence does not recommend using one tumour marker alone for the diagnosis of MPE, but the combination of two or more tumour markers seems to be more sensitive. The results of tumour marker assays should be interpreted in parallel with clinical findings and the results of conventional tests.

CD4CD25 regulatory T lymphocytes in allergy and asthma.

Allergic asthma is characterized by airway hyper-responsiveness and chronic mucosal inflammation mediated by CD4(+) Th2 lymphocytes. Regulatory CD4(+)CD25(+) T cells are important components of the homeostasis of the immune system, as impaired CD4(+)CD25(+) T cell activity can cause autoimmune diseases and allergy. The mechanism of suppression by CD4(+)CD25(+) T cells remains controversial; different in vivo and in vitro studies raise possible roles for the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta, forkhead transcription factor Foxp3, glucocorticoid-induced tumor necrosis factor receptor, cytotoxic lymphocyte associated antigen-4, 4-1BB costimulator receptor, a CD4-related molecule LAG-3, and neuropilin-1. Current data suggest that Th2 responses to allergens are normally suppressed by CD4(+)CD25(+) T cells. Suppression by CD4(+)CD25(+) T cells is decreased in allergic individuals. Furthermore, CD4(+)CD25(+) T cells play a key role in regulating airway eosinophilic inflammation. The immunomodulatory properties of CD4(+)CD25(+) T cells do extend to Th2 responses, most notably by limiting the development of a proinflammatory CD4(+) Th2 phenotype characterized by reduced cytokine production. An understanding of the roles of CD4(+)CD25(+) T cells in vivo could provide better insight into the design of novel approaches to modulate the chronic airway inflammatory reaction evident in bronchial asthma.

Effects of allergen inhalation and oral glucocorticoid on serum soluble CTLA-4 in allergic asthmatics.

BACKGROUND: The serum soluble cytotoxic T lymphocyte associated antigen-4 (sCTLA-4) concentration is significantly elevated in patients with asthma, and sCTLA-4 concentration correlate with the severity of asthma. The aim of the present study was to investigate effects of allergen inhalation and oral glucocorticoid on concentration of serum sCTLA-4 in patients with allergic asthma. METHODS: Allergen inhalation challenge was conducted in allergic asthmatics with isolated early asthma response and those with dual asthma response. In a randomized, double-blind, placebo-controlled, parallel group fashion, prednisolone or placebo was give orally once a day for 2 weeks. Venous blood samples were collected before and after allergen inhalation or prednisolone administration for obtaining sera. The serum sCTLA-4 concentrations were determined using enzyme-linked immunosorbent assay. RESULTS: The serum sCTLA-4 concentrations in the dual responder group increased from 29.0 (14.5-43.7) microg/l [median (25-75 percentiles)] before allergen inhalation to 44.0 (24.3-61.3) microg/l 24 h after allergen inhalation. In the isolated early responders, there were no significant increase in serum sCTLA-4 concentrations after allergen inhalation compared with baseline levels. There was a significant decrease in serum sCTLA-4 concentrations after 2 weeks of glucocorticoid therapy [22.0 (15.5-31.0) microg/l] compared with baseline values [37.0 (19.5-53.0) microg/l], whereas there was no significant difference in the placebo group. CONCLUSION: This study has demonstrated that serum sCTLA-4 concentrations increased after allergen inhalation in sensitized asthmatic subjects, and that serum sCTLA-4 concentrations were downregulated by prednisolone therapy.