Plasma exosomes from patients with active thyroid-associated orbitopathy induce inflammation and fibrosis in orbital fibroblasts.

BACKGROUND: The pathogenesis of thyroid-associated orbitopathy (TAO) remains incompletely understand. The interaction between immunocytes and orbital fibroblasts (OFs) play a critical role in orbital inflammatory and fibrosis. Accumulating reports indicate that a significant portion of plasma exosomes (Pla-Exos) are derived from immune cells; however, their impact upon OFs function is unclear. METHODS: OFs were primary cultured from inactive TAO patients. Exosomes isolated from plasma samples of patients with active TAO and healthy controls (HCs) were utilized for functional and RNA cargo analysis. Functional analysis in thymocyte differentiation antigen-1+ (Thy-1+) OFs measured expression of inflammatory and fibrotic markers (mRNAs and proteins) and cell activity in response to Pla-Exos. RNA cargo analysis was performed by RNA sequencing and RT-qPCR. Thy-1+ OFs were transfected with miR-144-3p mimics/inhibitors to evaluate its regulation of inflammation, fibrosis, and proliferation. RESULTS: Pla-Exos derived from active TAO patients (Pla-ExosTAO-A) induced stronger production of inflammatory cytokines and hyaluronic acid (HA) in Thy-1+ OFs while inhibiting their proliferation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and single sample gene set enrichment analysis (ssGSEA) suggested that the difference in mRNA expression levels between Pla-ExosTAO-A and Pla-ExosHC was closely related to immune cells. Differential expression analysis revealed that 62 upregulated and 45 downregulated miRNAs in Pla-ExosTAO-A, with the elevation of miR-144-3p in both Pla-Exos and PBMCs in active TAO group. KEGG analysis revealed that the target genes of differentially expressed miRNA and miR-144-3p enriched in immune-related signaling pathways. Overexpression of the miR-144-3p mimic significantly upregulated the secretion of inflammatory cytokines and HA in Thy-1+ OFs while inhibiting their proliferation. CONCLUSION: Pla-Exos derived from patients with active TAO were immune-active, which may be a long-term stimulus casual for inflammatory and fibrotic progression of TAO. Our finding suggests that Pla-Exos could be used as biomarkers or treatment targets in TAO patients.

Navigation-guided nasal endoscopic surgery for acute vision loss caused by fibrous dysplasia: a case report and review of literatures.

BACKGROUND: Bone fibrous dysplasia is a benign disease of bone tissue dysplasia. Vision impairment is the commonest neurological complication of craniofacial fibrous dysplasia. Most of the vision loss caused by craniofacial fibrous dysplasia is usually a gradual process. Very few present with acute visual impairment as described in our case. CASE PRESENTATION: We report a patient with fibrous dysplasia presenting rapidly progressive visual loss in the left eye secondary to bone cyst formation. Transnasal endoscopic surgery guided by navigation with drainage and curettage of this bone cyst and orbital decompression resulted in progressive improvement in visual acuity that returned to normal 1 month post-operatively. CONCLUSIONS: In cases with acute visual loss due to fibrous dysplasia, emergency surgical treatment should be considered to preserve vision. In the surgical approach, navigation-guided nasal endoscopic surgery may be preferred because of its advantages.

Diagnostic and Biological Significance of KIR Expression Profile Determined by RNA-Seq in Natural Killer/T-Cell Lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is a rare, aggressive form of non-Hodgkin lymphoma that is generally incurable at more advanced stages with systemic involvement. Clonal diagnostic markers (eg, unique T- or B-cell receptor rearrangements) are not available for NKTCLs. Killer cell immunoglobulin like receptors (KIRs) are a family of type I transmembrane glycoproteins involved in the inhibition or activation of NK cells. A restricted expression profile of KIRs has been proposed as clonal markers of NK-cell proliferations. Here we evaluated the transcription profile of all KIR family genes and C-type lectin receptor genes using RNA sequencing on NKTCL cases (n = 17) and NK-cell lines (n = 3). The expression of all KIRs tended to be markedly reduced or absent in NKTCL, except for the KIR family member killer Ig-like receptor 2DL4 (KIR2DL4; alias CD158D), which was selectively overexpressed in the majority (59%) of cases. No specific expression pattern was observed for C-type lectin receptors. KIR2DL4 is an unusual member of the KIR family that recognizes human leukocyte antigen G and mediates NK-cell activation through inducing proliferation and survival pathways such as AKT and NF-κB. Stable knockdown of KIR2DL4 in two malignant NK-cell lines with high KIR2DL4 expression significantly reduced cell growth. Selective overexpression of KIR2DL4 and down-regulation of inhibitory KIRs may contribute to NKTCL pathogenesis.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.

Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4(-)/CD8(+), 1 was CD4(+)/CD8(-), and another was CD4(-)/CD8(-). T-cell receptor-γ chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name "indolent T-LPD of the GI tract" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.

MicroRNA expression profiling identifies molecular signatures associated with anaplastic large cell lymphoma.

Anaplastic large-cell lymphomas (ALCLs) encompass at least 2 systemic diseases distinguished by the presence or absence of anaplastic lymphoma kinase (ALK) expression. We performed genome-wide microRNA (miRNA) profiling on 33 ALK-positive (ALK[+]) ALCLs, 25 ALK-negative (ALK[-]) ALCLs, 9 angioimmunoblastic T-cell lymphomas, 11 peripheral T-cell lymphomas not otherwise specified (PTCLNOS), and normal T cells, and demonstrated that ALCLs express many of the miRNAs that are highly expressed in normal T cells with the prominent exception of miR-146a. Unsupervised hierarchical clustering demonstrated distinct clustering of ALCL, PTCL-NOS, and the AITL subtype of PTCL. Cases of ALK(+) ALCL and ALK(-) ALCL were interspersed in unsupervised analysis, suggesting a close relationship at the molecular level. We identified an miRNA signature of 7 miRNAs (5 upregulated: miR-512-3p, miR-886-5p, miR-886-3p, miR-708, miR-135b; 2 downregulated: miR-146a, miR-155) significantly associated with ALK(+) ALCL cases. In addition, we derived an 11-miRNA signature (4 upregulated: miR-210, miR-197, miR-191, miR-512-3p; 7 downregulated: miR-451, miR-146a, miR-22, miR-455-3p, miR-455-5p, miR-143, miR-494) that differentiates ALK(-) ALCL from other PTCLs. Our in vitro studies identified a set of 32 miRNAs associated with ALK expression. Of these, the miR-17∼92 cluster and its paralogues were also highly expressed in ALK(+) ALCL and may represent important downstream effectors of the ALK oncogenic pathway.

HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms.

HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, leading to low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell line led to apoptosis and G2/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its role in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis.

PRDM1 is a tumor suppressor gene in natural killer cell malignancies.

Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methylation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression--in particular, PRDM1α--in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-Cl9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathogenetic mechanism for NKCL.

Retinal peripapillary microvasculature in indirect traumatic optic neuropathy predicted prognosis of endoscopic trans-ethmosphenoid optic canal decompression.

PURPOSES: The purpose of this study is to quantify the alteration of retinal peripapillary microvasculature and structure in unilateral indirect traumatic optic neuropathy (ITON) and figure out predicted factors of visual improvement for ITON patients with endoscopic trans-ethmosphenoid optic canal decompression (ETOCD) after one month. METHODS: Twenty healthy controls and 72 unilateral ITON patients were included. Optical coherence tomography angiography was used to analyse radial peripapillary capillary (RPC) density, peripapillary retinal nerve fibre layer (pRNFL) thickness, superficial retinal capillary plexus (SRCP) and deep retinal capillary plexus (DRCP) density. Associations between preoperative parameters and postoperative best-corrected visual acuity (BCVA) were determined. The receiver operating characteristic (ROC) curves were used to figure out predicted factors of visual improvement for ITON after ETOCD one month. RESULTS: In ITON eyes, the preoperative global RPC density, pRNFL thickness and SRCP density were reduced compared with unaffected eyes (p ≤ 0.001). Multivariate linear regression showed that preoperative global RPC density (Standardized ß = -0.273), SRCP density (Standardized ß = -0.183), DRCP density (Standardized ß = -0.098) and preoperative BCVA (Standardized ß = 0.795) were associated with the postoperative BCVA (All p < 0.001). The area under the curve (AUC) of preoperative global RPC density to predict visual improvement after ETOCD was 0.816, while the AUCs of preoperative BCVA, global pRNFL thickness, SRCP and DRCP density were 0.575, 0.756, 0.516 and 0.615, respectively. CONCLUSIONS: The alteration of peripapillary area, especially the reduced RPC density, occurred in ITON eyes. The preoperative RPC density was associated with postoperative BCVA and was shown to be highly predictive for visual improvement after ETOCD one month.

Reduced contrast sensitivity function correlated with superficial retinal capillary plexus impairment in early stage of dysthyroid optic neuropathy.

BACKGROUND: To assess the accuracy of contrast sensitivity function (CSF) in detecting dysthyroid optic neuropathy (DON) at an early stage in thyroid-associated ophthalmopathy (TAO) patients and to examine potential factors that may be linked to early visual impairments in these individuals. METHODS: A total of 81 TAO patients (50 non-DON and 31 DON), and 24 control subjects participated in the study. CSF was measured with the quick CSF (qCSF) method. Optical coherence tomography angiography (OCTA) images of the ganglion cell complex layer (GCCL), superficial and deep retinal capillary plexuses (SRCP and DRCP) in a 3 mm diameter area around the macula were evaluated. RESULTS: Compared with the controls, the area under the log contrast sensitivity function (AULCSF) and SRCP density were significantly reduced in non-DON and DON patients (all P < 0.05). The GCCL thickness of the DON patients was thinner than that of the controls and non-DON patients (all P < 0.05). The AULCSF was significantly correlated with spherical equivalent refractive error, muscle index, SRCP density and GCCL thickness in TAO patients, respectively (all P < 0.05). However, stepwise multi-regression analysis showed that the AULCSF was only significantly correlated with SRCP density (P < 0.001). Receiver operating characteristic curve analysis showed that the AULCSF produced the most accurate discrimination between non-DON and DON patients from the controls (AUC = 0.831, 0.987, respectively; all P < 0.001). CONCLUSIONS: CSF change in the early stage of DON is related to SRCP density. It can be an early indicator of visual impairments associated with DON in TAO patients.

Comparison of Two Tonometers in the Evaluation of 24-Hour Intraocular Pressure and Mean Ocular Perfusion Pressure in Patients with Thyroid-Associated Ophthalmopathy.

Purpose: The aim of the study is to compare a non-contact tonometer (NCT) and goldmann applannation tonometer (GAT) in the evaluation of intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) in patients with thyroid-associated ophthalmopathy (TAO). Methods: In this study, a total of 30 patients (16 females and 14 males) were recruited. All patients underwent a routine ophthalmic assessment and their medical history was acquired. Clinical assessment included the 24-hour measurement of intraocular pressure and blood pressure, an orbital computed tomography (CT) scan, and a visual field (VF）test. Patients were divided into two groups according to their visual field test results: a defect group with mean deviation (MD) of visual field -2 dB or lower and a normal group with MD over -2 dB. Results: Bland-Altman's analysis showed similar results of IOP at every time point and revealed an agreement of mean IOP between the two tonometers (the deviation in the mean IOP between the two tonometers was 1 mmHg, with 95% limits of agreement of 8.8 to -6.8 mmHg). The 24-hour MOPP SD value in NCT (2.28) and GAT (1.77) showed that the two instruments had the same diagnostic efficacy (100% sensitivity, 95.8% specificity). The areas under the receiver operator characteristic (ROC) curve of the 24-hour mean ocular perfusion pressure (MOPP) SD (GAT: 0.778, NCT: 0.713; z = 0.669, P=0.504), 24-hour MOPP fluctuation (GAT:0.683, NCT:0.757; z = 0.963, P=0.336) measured by GAT and NCT had no significant difference between the two tonometers. Conclusions: The measurement of IOPs, MOPPs, and their diagnostic efficacy of visual field defect showed consistency between NCT and GAT. The study highlights the importance of monitoring the 24-hour MOPP and IOP in TAO patients. Furthermore, it suggests that the less invasive NCT can replace GAT as a long-term monitoring device in TAO patients.

Selective deficits of S-cone in thyroid-associated ophthalmopathy patients without clinical signs of dysthyroid optic neuropathy.

Purpose: We explored whether thyroid-associated ophthalmopathy (TAO) patients without clinical signs of dysthyroid optic neuropathy (DON) would have a selective deficit mediated by S-cone. Methods: Thirty-two TAO patients without clinical signs of DON (non-DON, 42.03 ± 9.59 years old) and 27 healthy controls (41.46 ± 6.72 years old) participated in this prospective, cross-sectional study. All observers were tested psychophysically after passing color screening tests and a comprehensive ocular examination. Isolated L-, M-, and S-cone contrast thresholds were measured at 0.5 cyc/deg using Gabor patches. We calculated the area under the receiver operating characteristic (ROC) curve to quantify the ability of chromatic contrast sensitivity to detect the early visual function changes in non-DON patients. Results: S-cone contrast sensitivity in non-DON patients was found to be lower than that of healthy controls (P < 0.001), whereas the sensitivities to L- and M-cone Gabor patches were similar between these two groups (P = 0.297, 0.666, respectively). Our analysis of the ROC curve revealed that the sensitivity to S-cone had the highest index to discriminate non-DON patients from healthy controls (AUC = 0.846, P < 0.001). The deficit of S-cone was significantly correlated with muscle index in non-DON patients (R = 0.576, P = 0.001). Conclusion: There is a selective S-cone deficit in the early stage of TAO. S-cone contrast sensitivity could serve as a sensitive measure of visual impairments associated with early DON in patients with TAO.

Endoscopic Transconjunctival Deep Lateral Wall Decompression for Thyroid-associated Orbitopathy: A Minimally Invasive Alternative: Transconjunctival Endoscopic with Wall Decompression for TAO.

PURPOSE: To investigate the feasibility, efficacy, and safety of endoscopic transconjunctival transorbital deep lateral wall decompression for thyroid-associated orbitopathy (TAO). DESIGN: Prospective single-surgeon interventional case series. METHODS: Twenty-two patients (39 orbits) diagnosed with thyroid-associated orbitopathy without dysthyroid optic neuropathy were enrolled in this study. All patients underwent endoscopic transconjunctival transorbital deep lateral wall decompression for proptosis reduction. The data, including measurement on exophthalmometry, volumetric change on computed tomography, and surgery-related complications, were analyzed. RESULTS: We observed a proptosis reduction (mean, 3.42 ± 0.87 mm; range, 2.10-5.52 mm) and a corresponding decrease in the bony volume of the greater wing of the sphenoid bone (mean, 1.89 ± 0.81 cm3; range, 0.56-3.79 cm3) postoperatively. Preexisting diplopia improved in 5 patients (22.73%). Transient zygomaticotemporal hypoesthesia developed in all patients, and cerebrospinal fluid leakage occurred in 1 orbit (2.56%). No patient complained of temporal hollowing, oscillopsia, or new-onset or worsening diplopia during follow-up. CONCLUSIONS: Endoscopic transconjunctival transorbital deep lateral wall decompression is an effective and minimally invasive treatment for proptosis reduction in patients with thyroid-associated orbitopathy. The surgery-related complications with this technique were fewer compared with traditional approaches.

Elevated pulse pressure correlated with reduced retinal peripapillary capillary in thyroid-associated ophthalmology with visual field defect.

Purpose: To quantify the retinal vessel density in thyroid-associated ophthalmology (TAO) patients with visual field (VF) defect and examine its associations with mechanical and system vascular risk factors for underlying pathogenesis of VF defect in TAO. Methods: The cohort was composed of 62 TAO eyes (39 with VF defect and 23 without VF defect). The pulse pressure (PP), intraocular pressure (IOP), ophthalmic rectus muscular index (MI), superficial retinal capillary plexus (SRCP), radial peripapillary capillary (RPC) density, and other related parameters were measured. The associations among these factors and VF mean deviation (MD) were analyzed. Results: In TAO patients with VF defect, reduced RPC density, higher PP, and larger horizontal and vertical MI were found (all P < 0.03) when compared to TAO patients without VF defect. The RPC density was correlated with VF MD value (r = 0.242, P = 0.029), while SRCP density was not (P = 0.419). In univariable general estimating equation (GEE) analysis with RPC density as the outcome, PP and its fluctuation showed a significant association (both P < 0.04). In the final RPC model with multivariable GEE analysis, only PP (ß = -0.082, P = 0.029) showed significance while PP fluctuation (P = 0.080) did not. Conclusions: The elevated PP was correlated with reduced retinal peripapillary perfusion in TAO resulting in VF defect. These data suggested that the system vascular factor may be important in the pathogenesis of reduced retinal perfusion resulting in visual impairment in TAO.

Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis.

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.

Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8+ T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8+ T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8+ T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.

PRDM1 decreases sensitivity of human NK cells to IL2-induced cell expansion by directly repressing CD25 (IL2RA).

IL2 receptor signaling is crucial for human NK cell activation and gain of effector functions. The molecular mechanisms involved in termination of IL2 activation are largely unknown in human NK cells. PR/SET domain 1 was previously reported to decrease cell growth and increase apoptosis in an IL2-dependent manner in malignant NK cell lines, suggesting the possibility of down-regulation of IL2 signaling pathway gene(s) through direct transcriptional repression. Using ChIP-Seq, we identified a PRDM1 binding site on the first intron of CD25 (IL2RA), which codes for the IL2 receptor subunit regulating sensitivity to IL2 signaling, in primary NK cells activated with engineered K562 cells or IL2. Ectopic expression of PRDM1 down-regulated CD25 expression at transcript and protein levels in two PRDM1 nonexpressing NK cell lines. shRNA-mediated knockdown of CD25 in two malignant NK cell lines led to progressive depletion of NK cells in low IL2 concentrations. By contrast, ectopic CD25 expression in primary human NK cells led to progressive increase in cell number in CD25-transduced cells in low IL2 concentrations. Altogether these results reveal a pivotal role of PRDM1 in inhibition of IL2-induced NK cell expansion through direct repression of CD25 in activated human NK cells. These observations provide additional support for the role of PRDM1 in attenuation of NK cell activation and growth, with implications on neoplastic transformation or NK cell function when it is deregulated.

Prevalence and risk factors associated with chronic kidney disease in adults over 40 years: a population study from Central China.

AIM: Chronic kidney disease (CKD) poses a serious public health problem worldwide. Population-based studies determining the prevalence of this disease in China have been limited in several large developed cities. In the present study, a population-based screening study in Henan, a representative province in Central China, was conducted in order to quantify the prevalence of CKD and identify the associated risk factors for this disease in a population of developing areas of China. METHODS: Residents (n = 4156) over 40 years old in four major cities of Henan Province were interviewed and their albuminuria, reduced renal function, haematuria and blood pressure were measured. Associations between age, components of metabolism syndrome and indicators of CKD were examined. RESULTS: Among these subjects, the prevalence rates of albuminuria, haematuria and reduced renal function were 4.51%, 6.28% and 1.53%, respectively. Approximately 10.49% of the subjects had at least one indicator of kidney damage. The awareness rate of this disease in subjects with CKD was only 9.50%. Hypertension, diabetes and hyperuricaemia were three independent risk factors for CKD. CONCLUSION: The high prevalence and low awareness of CKD in the studied population suggest that CKD is a severe public health problem in Central China. Effectively preventive and therapeutic interventions are needed.

[Level of CD4(+) CD25(high) CD127(low/-) regulatory T cells in transitional cell carcinoma patients and its clinical significance].

OBJECTIVE: To evaluate the expressions of CD4+ CD25high CD127low/- regulatory T cells (Treg) in peripheral blood from patients with transitional cell carcinoma (TCC) in urinary system. METHODS: The proportion of Treg population in CD4+ T cells from 93 patients with transitional cell carcinoma was evaluated. And flow cytometry was employed to analyze different clinicopathologic characteristics and detect the pre- and post-operative changes in 38 patients with benign urinary diseases and 37 healthy subjects. RESULTS: The proportion of Treg population in CD4+ T cells in peripheral blood of patients with TCC significantly increased as compared with those with benign urinary diseases and healthy subjects. There was a strong correlation between the proportion of Treg and tumor recurrence, quantity, lymph node metastasis (P < 0. 01) as well as pathological stage; no correlation was found between the proportion of Treg and clinical TNM stage (P > 0. 05). The proportion of Treg was also different at pre- and post-operation (P < 0. 05). CONCLUSION: CD4+ CD25high CD127low/- regulatory T cells in peripheral blood from patients with TCC significantly increased as compared with that in patients with benign urinary diseases and in healthy subjects. It may be responsible for immune suppression in TCC patients. Tumor resection could decrease the proportion of Treg in peripheral blood, but the long-term change in immune function requires further investigations.

Two new species of Rhabdocoela (Polycystididae and Trigonostomidae) from China.

Two new species of Rhabdocoela, namely Alcha sinensis n. sp. (Polycystididae) and Trigonostomum sinensis n. sp. (Trigonostomidae), were discovered from the intertidal zone of eastern Shenzhen City, China. For A. sinensis n. sp., the stylet consists of two symmetrical triangular plates and one lamellar plate. All three plates are jagged at their posterior ends. The anterior end of the stylet connects to a thick muscular layer, which causes its movement. For T. sinensis n. sp., the copulatory organ consists of a long-tubular stylet and two "T"-shaped plates (plate I and plate II). The stylet bends 120° at 25% of its length from the base and extends straight distally. Two "T" plates are connected to each other and surround the stylet. Plate I is hook-shaped at its distal end, and plate II has a similar length but only half the width of plate I. The phylogenetic (18S rDNA and 28S rDNA) results also support the establishment of these two new species. On the basis of the molecular phylogeny and morphology of the copulatory organ and bursa appendage, we propose a new categorization of the species of Trigonostomum.