PRTN3 variant correlates with increased autoantigen levels and relapse risk in PR3-ANCA versus MPO-ANCA disease.

A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.

Mutation-associated transcripts reconstruct the prognostic features of oral tongue squamous cell carcinoma.

Tongue squamous cell carcinoma is highly malignant and has a poor prognosis. In this study, we aimed to combine whole-genome sequencing, whole-genome methylation, and whole-transcriptome analyses to understand the molecular mechanisms of tongue squamous cell carcinoma better. Oral tongue squamous cell carcinoma and adjacent normal tissues from five patients with tongue squamous cell carcinoma were included as five paired samples. After multi-omics sequencing, differentially methylated intervals, methylated loop sites, methylated promoters, and transcripts were screened for variation in all paired samples. Correlations were analyzed to determine biological processes in tongue squamous cell carcinoma. We found five mutated methylation promoters that were significantly associated with mRNA and lncRNA expression levels. Functional annotation of these transcripts revealed their involvement in triggering the mitogen-activated protein kinase cascade, which is associated with cancer progression and the development of drug resistance during treatment. The prognostic signature models constructed based on WDR81 and HNRNPH1 and combined clinical phenotype-gene prognostic signature models showed high predictive efficacy and can be applied to predict patient prognostic risk in clinical settings. We identified biological processes in tongue squamous cell carcinoma that are initiated by mutations in the methylation promoter and are associated with the expression levels of specific mRNAs and lncRNAs. Collectively, changes in transcript levels affect the prognosis of tongue squamous cell carcinoma patients.

Corneal Adhesion Possesses the Characteristics of Solid and Membrane.

Adhesion behavior usually occurs in corneas associated with clinical treatments. Physiologically, an intact natural cornea is inflated by intraocular pressure. Due to the inflation, the physiological cornea has a mechanical property likeness to membrane. This characteristic is ignored by the classical theory used to analyze the adhesion behavior of soft solids, such as the Johnson-Kendall-Roberts (JKR) model. Performing the pull-off test, this work evidenced that the classical JKR solution was suitable for computing the corneal adhesion force corresponding to the submillimeter scale of contact. However, when the cornea was contacted at a millimeter scale, the JKR solutions were clearly smaller than the related experimental data. The reason was correlated with the membranous characteristic of the natural cornea was not considered in the JKR solid model. In this work, the modified JKR model was superimposed by the contribution from the surface tension related to the corneal inflation due to the intraocular pressure. It should be treated as a solid when the cornea is contacted at a submillimeter scale, whereas for the contact at a larger size, the characteristic of the membrane should be considered in analyzing the corneal adhesion. The modified JKR model successfully described the adhesion characteristics of the cornea from solid to membrane.

Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

Antitumor immune response is associated with favorable survival in GEP-NEN G3.

The tumor immune microenvironment (TME) represents a key determinant for responses to cancer treatment. However, the immune phenotype of highly proliferative gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is still largely elusive. In this retrospective study, we characterized the TME of high-grade (G3, Ki-67 > 20%) GEP-NEN. We analyzed formalin-fixed paraffin-embedded samples from 37 patients with GEP-NEN G3 by immunohistochemistry and multiplex immunofluorescence to address the abundance and spatial interaction of relevant immune subsets. We focused on the expression of immune checkpoint molecules PD-1 and PD-L1, the cytotoxic T-cell marker CD8, and the tumor-associated macrophage marker CD206. Findings were correlated with overall survival (OS) from the date of a cancer diagnosis. Patients with PD-L1-positive tumors (CPS ≥ 1) and intense PD-1+CD8+ immune cell infiltration showed the most favorable median OS. Multiplex immunofluorescence staining of ten representative tissue samples illustrated intratumoral heterogeneity of PD-L1 expression. Dense PD-1+CD8+ immune cell infiltrates were observed in PD-L1-positive tumor regions but not in PD-L1-negative regions. Proximity analysis revealed a spatial interaction between PD-1+CD8+ cells and PD-L1-positive cells. Our data suggest a pre-existing antitumor immune response in the TME in a subgroup of GEP-NEN G3. This supports a targeted clinical exploration of immunotherapeutic approaches.

Experimental Study of the Wettability Characteristic of Thermally Treated Shale.

Extraction of shale gas from shale reservoirs is significantly affected by shale wettability. Recently, thermal recovery technologies (e.g., combustion) have been tested for shale gas recovery. This requires an understanding of the wettability change mechanism for thermally treated shale samples. In this study, the effect of combustion on shale wettability was investigated. Shale samples were first processed to obtain smooth surfaces and then combusted at temperatures of 200, 400, and 800 °C. The initial contact angles and dynamic behavior of water droplets on shale surfaces were recorded using the sessile drop method. It was found that pores and fractures were generated on the shale surfaces following high-temperature combustion. The pore volume and diameter increased with increasing combustion temperature, which improved the connectivity of hydrophilic pore networks. Compared to a raw shale sample, the shale sample combusted at 400 °C showed a smaller initial water contact angle and a more rapid decrease in the contact angle because of the oxidation of organic matter and generation of pore structures. Water droplets were found to completely spread over the surface of the shale sample combusted at 800 °C because of the generation of fractures. Moreover, the van der Waals potential between water droplets and combusted shale samples was determined to be stronger. However, the initial contact angle and dynamic behavior of water droplets did not show a significant change for the shale sample combusted at 200 °C. As a result, high-temperature combustion (≥400 °C) can be used to significantly improve the hydrophilicity of shale.

HIF1A activates the transcription of lncRNA RAET1K to modulate hypoxia-induced glycolysis in hepatocellular carcinoma cells via miR-100-5p.

Hepatocellular carcinoma (HCC) remains the primary cause of cancer-related death. Metabolic change is the major characteristic of cancer. The present study attempted to investigate the regulatory mechanisms of HCC energy metabolism from the perspective of noncoding RNA regulation of HIF1A and LDHA. The expression of miR-100-5p expression was significantly suppressed in HCC tissue samples and HCC cell lines under 1% O2-induced hypoxia. miR-100-5p overexpression significantly suppressed hypoxia-induced increases in lactate concentration and glucose uptake. Exposure to 1% O2 induced HIF1A protein and reduced miR-100-5p expression, while HIF1A silencing dramatically rescued miR-100-5p expression upon 1% O2 exposure. In addition, 1% O2-induced increases in lactate concentration and glucose uptake were also suppressed by HIF1A silencing. Next, by analyzing available data in TCGA, we found that lncRNA RAET1K was correlated with HIF1A and miR-100-5p.LncRNA RAET1K could downregulate the expression of miR-100-5p by acting as a sponge, while HIF1A bound the lncRNA RAET1K promoter region to activate its transcription. LncRNA RAET1K silencing significantly suppressed HCC cell proliferation and invasion and also suppressed hypoxia-induced increases in lactate concentration and glucose uptake, while miR-100-5p inhibition reversed the effects of lncRNA RAET1K silencing on hypoxia-induced glycolysis in HCC cells. Finally, the expression of HIF1A, lncRNA RAET1K, and LDHA was upregulated in HCC tissue specimens; the expression of miR-100-5p was negatively related to HIF1A, lncRNA RAET1K, and LDHA; and HIF1A, lncRNA RAET1K, and LDHA were positively correlated with each other. In conclusion, the HIF1A/lncRNA RAET1K/miR-100-5p axis modulates hypoxia-induced glycolysis in HCC cells and might affect HCC progression.

Severe polycystic liver diseases: hepatectomy or waiting for liver transplantation?: Two case reports.

INTRODUCTION: Choice of treatment in patients with symptomatic polycystic liver diseases (PLD) remains controversial. Various surgical procedures aiming at eliminating symptomatic cysts are widely used in mild and advanced PLD patients, but liver transplantation is currently recommended as the only curative treatment especially in severe cases. PATIENT CONCERNS: Case 1: A 51-year-old male was admitted for severe eating disorder and dyspnea for 2 months. He had been diagnosed as PLD, PKD, and hypertension for 9 years, with only antihypertensive drug therapy. No significant family history could be traced.Case 2: A 54-year-old female was admitted to our hospital for ventosity during nearly 5 years. She had been diagnosed as PLD and hypertension for 22 years, for which only aspiration-sclerotherapy therapy was performed for multiple times. Both her mother and sister were diagnosed with PLD previously. DIAGNOSIS: They were diagnosed as PLD by medical history, family history, and computed tomography scan (multiple cysts dispersively presenting in the liver). INTERVENTIONS: The 2 patients underwent hepatectomy with fenestration, and were well recovered with no mortality. OUTCOMES: While case 1 only experienced relief of symptoms, case 2 experienced massive growth of hepatic parenchyma, which indicated positive prognosis and showed the possibility to avoid or at least postpone liver transplantation for a long time, considering the lack of liver parenchyma is one of the main reason for urgency of liver transplantation. CONCLUSION: Here we described subradical polycystic hepatectomy, a special form of hepatectomy with fenestration modified by us, as a safe and effective treatment to potentially achieve long-term effects in PLD patients.

The effectiveness of TDF versus ETV on incidence of HCC in CHB patients: a meta analysis.

BACKGROUND: It has been proved that nucleos(t) ide analogues (NAs) therapy could improve underlying liver disease and reduce the incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the difference of effectiveness in reducing HCC occurrence between tenofovir (TDF) and enticavir (ETV), two first-line NAs drugs, is still little known. This meta analysis aims to assess the efficacy in reducing incidence of HCC comparing tenofovir monotherapy with entecavir monotherapy among chronic hepatitis B (CHB) patients by analyzing their long-term clinical outcomes. METHODS: Databases including PubMed, Embase, Cochrane Central Register of Controlled Trial, and ISI Web of Science were fully investigated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For the included articles, two of the authors independently extracted and confirmed relevant data. Review Manager software (RevMan 5.3) was using for meta analysis. RESULTS: Seven articles with 3698 patients were finally included in this research, 1574 in tenofovir group and 2124 in entecavir group. For meta analysis, the incidence of HCC was significantly lower among the tenofovir group than entecavir group [rate ratio (95% CI) of 0.66 (0.49, 0.89), P = 0.008], while there was no statistical significance in incidence of death or transplantation [rate ratio (95% CI) of 0.78 (0.55, 1.13), P = 0.19], encephalopathy [risk ratio (95% CI) of 0.72 (0.45, 1.13), P = 0.15] or variceal bleeding [risk ratio (95% CI) of 0.71 (0.34, 1.50), P = 0.37] between the two groups. CONCLUSION: There is a better effect of tenofovir in reducing HCC incidence than entecavir, which indicates tenofovir should be used more widely while treating chronic hepatitis B patients. However before applying, randomized controlled trial and large prospective cohort study should be performed in the future.

Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy?

OBJECTIVE: Microvascular invasion (MVI) has been proved to be an independent risk factor for the recurrence of HCC. If promptly treated, the recurrence rate can be reduced and the total survival time can be prolonged. The aim of this study is to analyze the effect of sorafenib on the clinical outcomes in HCC patients with MVI after curative hepatectomy. METHODS: HCC patients who underwent hepatectomy and were pathologically diagnosed with MVI were retrospectively analyzed. Patients were divided into sorafenib group and control group. Sorafenib 400 mg, twice daily, was administered orally after surgery in the sorafenib group. The recurrence-free survival (RFS) and overall survival (OS) were observed during follow-up, and associated factors were analyzed using univariate and multivariate COX regression. RESULTS: There was no significant difference in demographics, clinical staging, and tumor index between sorafenib group (16 patients) and control group (33 matched patients). The RFS and OS were both longer in the sorafenib group, and the 3-years RFS rates of the sorafenib group and control group were 56.3% (9 of 16) and 24.2% (8 of 33), respectively (P=0.027). The 3-year OS rate of the sorafenib group was 81.3% (13 of 16), which was significantly higher than that of the control group (39.4%, P=0.006). The results of multivariate COX regression indicated that treatment with sorafenib was an independent associated factor for RFS and OS. CONCLUSION: We believe that using sorafenib therapy after curative hepatectomy in HCC patients with MVI is effective and beneficial as it can reduce recurrence and prolong the survival time.

Efficacy and safety of TACE in combination with sorafenib for the treatment of TACE-refractory advanced hepatocellular carcinoma in Chinese patients: a retrospective study.

BACKGROUND: Transarterial chemoembolization (TACE) and sorafenib (SOR) are well-established treatments for hepatocellular carcinoma (HCC). This study evaluates the efficacy and safety of SOR combined with TACE in the treatment of patients with TACE-refractory, advanced-stage HCC. METHODS: This retrospective study included 61 patients with TACE-refractory advanced HCC. Patients were divided into TACE + SOR (n=30) and TACE (n=31) treatment groups. Patient demographic and clinical characteristics, overall survival (OS), time to progression (TTP), disease control rate (DCR), and adverse events (AEs) were compared between the two groups. RESULTS: Compared with TACE alone, the 5-year OS and TTP were prolonged in the TACE + SOR group (median OS: 17.9 vs 7.1 months, P<0.001; median TTP: 9.3 vs 3.4 months, P<0.001). Multivariate analysis showed that Child-Pugh class A (hazard ratio [HR], 0.234; 95% confidence interval [CI], 0.092-0.595), Eastern Cooperative Oncology Group performance status 1 (HR, 0.355; 95% CI, 0.153-0.826), alpha-fetoprotein <400 ng/mL (HR, 0.349; 95% CI, 0.177-0.689), and TACE + SOR treatment (HR, 0.151; 95% CI, 0.071-0.322) were independent, positive predictive factors of OS. CONCLUSION: The OS and TTP in the combined treatment group were significantly improved when compared with the TACE group. However, no significant difference in DCR was found between these two groups. While no AEs occurred in the TACE group, two patients in the TACE + SOR group experienced severe AEs which were effectively mitigated by lowering the dose of SOR. Thus, SOR in combination with TACE is a safe and effective treatment for advanced-stage, prior-TACE-resistant HCC.

Surveillance of the Antimicrobial Susceptibility of Neisseria gonorrhoeae Isolates Collected in Changsha, China from 2003 to 2015.

A total of 1,294 Neisseria gonorrhoeae isolates obtained in Changsha, China from 2003 to 2015 were examined for their susceptibility to penicillin (PEN), ciprofloxacin (CIP), spectinomycin (SPT), and ceftriaxone (CRO) using the disc diffusion method. In addition, the minimum inhibitory concentrations (MICs) of CRO for 460 isolates collected during 2008-2015 was determined by agar dilution method. Isolates with intermediate CRO susceptibility were additionally tested for azithromycin susceptibility. Results demonstrated that the rate of resistance to PEN and CIP were 77.5 % and 94.2 %, respectively. Only 4 SPT-resistant and 2 SPT-intermediate isolates were identified. No CRO-resistant isolates were identified, although the percentage with intermediate susceptibility increased from 1.8% in 2012 to 11.9% in 2015. Among these, 3 isolates showed no susceptibility to azithromycin with 2 isolates showing an MIC of 0.5 µg/mL and 1 isolate showing an MIC of 1.0 µg/mL. We recommend azithromycin for treating strains that demonstrate intermediate susceptible to CRO and azithromycin-susceptible N. gonorrhoeae isolates occurring in Changsha.

Gene-Specific DNA Methylation Changes Predict Remission in Patients with ANCA-Associated Vasculitis.

ANCA-associated vasculitis is an autoimmune condition characterized by vascular inflammation and organ damage. Pharmacologically induced remission of this condition is complicated by relapses. Potential triggers of relapse are immunologic challenges and environmental insults, both of which associate with changes in epigenetic silencing modifications. Altered histone modifications implicated in gene silencing associate with aberrant autoantigen expression. To establish a link between DNA methylation, a model epigenetic gene silencing modification, and autoantigen gene expression and disease status in ANCA-associated vasculitis, we measured gene-specific DNA methylation of the autoantigen genes myeloperoxidase (MPO) and proteinase 3 (PRTN3) in leukocytes of patients with ANCA-associated vasculitis observed longitudinally (n=82) and of healthy controls (n=32). Patients with active disease demonstrated hypomethylation of MPO and PRTN3 and increased expression of the autoantigens; in remission, DNA methylation generally increased. Longitudinal analysis revealed that patients with ANCA-associated vasculitis could be divided into two groups, on the basis of whether DNA methylation increased or decreased from active disease to remission. In patients with increased DNA methylation, MPO and PRTN3 expression correlated with DNA methylation. Kaplan-Meier estimate of relapse revealed patients with increased DNA methylation at the PRTN3 promoter had a significantly greater probability of a relapse-free period (P<0.001), independent of ANCA serotype. Patients with decreased DNA methylation at the PRTN3 promoter had a greater risk of relapse (hazard ratio, 4.55; 95% confidence interval, 2.09 to 9.91). Thus, changes in the DNA methylation status of the PRTN3 promoter may predict the likelihood of stable remission and explain autoantigen gene regulation.

Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

BACKGROUND: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by destructive vascular inflammation. Two prominent ANCA autoantigens are myeloperoxidase (MPO) and proteinase 3 (PR3), and transcription of MPO and PRTN3, the genes encoding the autoantigens, is associated with disease activity. We investigated whether patients with AAV have alterations in histone modifications, particularly those associated with transcriptional activation, at MPO and PRTN3. RESULTS: We identified a network of genes regulating histone modifications that were differentially expressed in AAV patients compared to healthy controls. We focused on four genes (EHMT1 and EHMT2, ING4, and MSL1) and found their expression correlated with expression of MPO and PRTN3. Methylation of histone H3K9, catalyzed by EHMT1 and EHMT2 and associated with gene silencing, was most depleted at MPO and PRTN3 in patients with active disease and the highest MPO and PRTN3 expression. Acetylation of histone H4K16, modified by complexes containing ING4 and MSL1 and associated with gene activation, was most enriched at MPO and PRTN3 in patients with active disease and the highest MPO and PRTN3 expression. Methylation at H3K4, a mark of transcriptional activation, was enriched at MPO and PRTN3 in patients and healthy controls. CONCLUSIONS: MPO and PRTN3 in neutrophils of AAV patients with active disease have a distinct pattern of histone modifications, which implicates epigenetic mechanisms in regulating expression of autoantigen genes and suggests that the epigenome may be involved in AAV pathogenesis.

Dysregulation of autoantigen genes in ANCA-associated vasculitis involves alternative transcripts and new protein synthesis.

Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcriptional dysregulation results in a variety of mRNA processing events from the PRTN3 gene locus. In addition to elevated levels of PR3 message, leukocyte RNA from patients contained PR3 transcripts with an alternative 3' untranslated region. Furthermore, we detected usage of an alternative transcription start site within intron 1 of the PRTN3 gene locus that coincided with active disease (odds ratio, 3.3; 95% confidence interval, 1.3 to 8.4; P=0.01). This promoter may be developmentally regulated, because it was active in normal human bone marrow, multiple leukemia cell lines, MCF-7 cells, and subjects after GM-CSF treatment but not subjects with a neutrophil left shift. This transcript, which lacks exon 1 of PRTN3, encodes a 24-kD protein (p24(PR3/MBN)) with a sequence similar to that previously described for myeloblastin. Notably, PR3, p24(PR3/MBN), and MPO were synthesized in cultured neutrophils from patients with active ANCA-associated vasculitis, indicating that increased transcription results in newly synthesized autoantigens in peripheral neutrophils of patients. The synthesis of p24(PR3/MBN) seems to expand the autoantigen repertoire, because immunoblots showed that sera from patients recognized p24(PR3/MBN). These findings emphasize the importance of transcriptional dysregulation of the autoantigen in autoimmune disease.

PTPN22 R620W polymorphism and ANCA disease risk in white populations: a metaanalysis.

OBJECTIVE: No clear consensus has been reached on the PTPN22 R620W polymorphism and anti-neutrophil cytoplasmic antibody (ANCA) disease, especially when stratified by ANCA specificity and disease phenotypes. METHODS: A metaanalysis was conducted on the PTPN22 R620W polymorphism across 4 studies in 1399 white patients with ANCA disease and 9934 normal control subjects. RESULTS: Overall, metaanalysis showed a statistically significant association between the A allele and ANCA disease in all subjects (OR 1.44, 95% CI 1.26-1.64, p < 0.00001), and stratification by disease category indicated the A allele was associated with granulomatosis with polyangiitis (Wegener's; GPA; OR 1.72, 95% CI 1.35-2.20, p < 0.0001) and microscopic polyangiitis (MPA; OR 1.53, 95% CI 1.08-2.15, p = 0.02) as compared to controls. However, when stratified by ANCA specificity, the association of the A allele was statistically evident among those with proteinase 3 (PR3) ANCA disease (OR 1.74, 95% CI 1.25-2.430, p = 0.001), with the same trend but not statistically associated with myeloperoxidase ANCA disease (OR 1.94, 95% CI 0.64-5.85, p = 0.24). The marked associations were also demonstrated between this allele with lung (OR 1.69, 95% CI 1.21-2.36, p = 0.002), ENT (OR 2.03, 95% CI 1.45-2.84, p < 0.0001), skin (OR 2.55, 95% CI 1.69-3.84, p < 0.0001), and peripheral neuropathy involvement (OR 2.12, 95% CI 1.39-3.22, p = 0.0005). CONCLUSION: The PTPN22 620W allele confers susceptibility to the occurrence and development of ANCA disease in whites, with specific evidence among subsets with GPA, MPA, and PR3 ANCA.

Serum pepsinogen reference intervals in apparently healthy Chinese population with latex enhanced turbidimetric immunoassay.

AIM: Serum pepsinogen (sPG) has been used to help in diagnosing atrophic corpus gastritis and in screening for gastric cancer non-invasively. There are as yet no reports on sPG reference intervals (RIs) with latex enhanced turbidimetric immunoassay (LIA). In this study, we established the RIs for sPG in a healthy Chinese population using LIA. METHODS: Serum PGI and PGII levels in a healthy population (aged 17-80 years) were measured simultaneously using LIA. RIs were determined following Clinical Laboratory and Standards Institute C28-A3 guidelines using a non-parametric method. RESULTS: 95% RIs in men (ng/mL) were: ≤40 years old, 25.53-100.76 for PGI and ≤24.42 for PGII; 41-50 years old, 26.62-124.74 for PGI and ≤26.81 for PGII; and 51-80 years old, 30.40-153.25 for PGI and ≤32.62 for PGII. Corresponding RIs for women (ng/mL) were: ≤40 years old, 21.20-87.44 for PGI and ≤25.53 for PGII; and 41-80 years, 26.40-127.46 for PGI and ≤30.18 for PGII. 95% RI for PGI/PGII in both men and women at any age was ≥2.51. CONCLUSIONS: We established the RIs for sPG using LIA in a healthy Chinese population, which can provide a reference for clinical and laboratory studies.

The reference intervals for HE4, CA125 and ROMA in healthy female with electrochemiluminescence immunoassay.

OBJECTIVES: Human epididymis protein 4 (HE4) is a tumor marker in diagnosing ovarian cancer. Together with cancer antigen 125 (CA125) and the risk of ovarian malignancy algorithm (ROMA) score, it can improve sensitivity and specificity. There are no reports about the serum HE4 reference intervals (RIs) with electrochemiluminescence immunoassay (ECLIA). The RI of ROMA hasn't been established yet. In this study, we establish the RIs for serum HE4, CA125 and ROMA in healthy Chinese female with ECLIA. METHODS: Serum HE4 and CA125 concentrations in healthy female (age ranged from 21 to 81 years) were simultaneously measured with ECLIA on Roche Cobas E601 system. The RIs were determined following CLSI C28-A3 guidelines using a nonparametric method. RESULTS: The upper limits of the 95% percentile intervals were 82.62 pmol/L for HE4, 30.91 U/mL for CA125 and 19.27 for ROMA. The reference limits for HE4, CA125 and ROMA were 65.87 pmol/L, 32.23 U/mL, 13.14 for premenopausal women, and 90.76 pmol/L, 27.52 U/mL, 25.46 for postmenopausal women respectively. CONCLUSION: We established the RIs for serum HE4, CA125 and ROMA with ECLIA in healthy Chinese female. It provided a reference for clinical and laboratory studies.

Reference intervals for serum creatinine levels in the healthy geriatric population.

BACKGROUND: There are few reliable reference values of enzymatically assayed serum creatinine (Scr) levels categorized within a small age interval in the healthy geriatric population. The aim of this study was to establish the reference intervals (RIs) for Scr in the elderly population. METHODS: Healthy, elderly Chinese Han ethnic individuals aged between 60 and 89 years old were recruited for this study. We stratified the reference individuals by gender and age (60-69, 70-79 and 80-89 years), and the Scr values were measured by an enzymatic method. The central 95 percentile RIs were determined using non-parametric statistical methods. RESULTS: The Scr values in the elderly population show a Gaussian distribution and age/sex related differences. The RIs for Scr in the reference population with respect to age (ranges of 60-69, 70-79 and 80-89 years) were 52.9-94.5, 57.3-106.2 and 59.0-110.8 µmol/L for males, respectively, and 44.3-75.4, 47.1-85.5 and 45.1-90.9 µmol/L for females, respectively. CONCLUSIONS: We have established the RIs for Scr measured with an enzymatic method in the healthy Chinese Han ethnic elderly population, which can provide a reference for both clinical and laboratory studies.

High basal activity of the PTPN22 gain-of-function variant blunts leukocyte responsiveness negatively affecting IL-10 production in ANCA vasculitis.

Consequences of expression of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gain-of-function variant were evaluated in leukocytes from patients with anti-neutrophil cytoplasmic autoantibody (ANCA) disease. The frequency of the gain-of-function allele within the Caucasian patient cohort was 22% (OR 1.45), compared to general American Caucasian population (16.5%, p = 0.03). Examination of the basal phosphatase activity of PTPN22 gain-of-function protein indicated persistently elevated activity in un-stimulated peripheral leukocytes, while basal activity was undetectable in leukocytes from patients without the gain-of-function variant. To examine consequences of persistently high PTPN22 activity, the activation status of ERK and p38 MAPK were analyzed. While moderate levels of activated ERK were observed in controls, it was undetectable in leukocytes expressing PTPN22 gain-of-function protein and instead p38MAPK was up-regulated. IL-10 transcription, reliant on the ERK pathway, was negatively affected. Over the course of disease, patients expressing variant PTPN22 did not show a spike in IL-10 transcription as they entered remission in contrast to controls, implying that environmentally triggered signals were blunted. Sustained activity of PTPN22, due to the gain-of-function mutation, acts as a dominant negative regulator of ERK activity leading to blunted cellular responsiveness to environmental stimuli and expression of protective cytokines.