The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

Minimum-Consumption Discrimination of Quantum States via Globally Optimal Adaptive Measurements.

Reducing the average resource consumption is the central quest in discriminating non-orthogonal quantum states for a fixed admissible error rate ϵ. The globally optimal fixed local projective measurement for this task is found to be different from that for previous minimum-error discrimination tasks [S. Slussarenko et al., Phys. Rev. Lett. 118, 030502 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.030502]. To achieve the ultimate minimum average consumption, here we develop a general globally optimal adaptive strategy (GOA) by subtly using the updated posterior probability, which works under any error rate requirements and any one-way measurement restrictions, and can be solved by a convergent iterative relation. First, under the local measurement restrictions, our GOA is solved to serve as the local bound, which saves 16.6 copies (24%) compared with the previously best globally optimal fixed local projective measurement. When the more powerful two-copy collective measurements are allowed, our GOA is experimentally demonstrated to beat the local bound by 3.9 copies (6.0%). By exploiting both adaptivity and collective measurements, our Letter marks an important step toward minimum-consumption quantum state discrimination.

Experimental Demonstration of Inequivalent Mutually Unbiased Bases.

Quantum measurements based on mutually unbiased bases (MUBs) play crucial roles in foundational studies and quantum information processing. It is known that there exist inequivalent MUBs, but little is known about their operational distinctions, not to say experimental demonstration. In this Letter, by virtue of a simple estimation problem, we experimentally demonstrate the operational distinctions between inequivalent triples of MUBs in dimension 4 based on high-precision photonic systems. The experimental estimation fidelities coincide well with the theoretical predictions with only 0.16% average deviation, which is 25 times less than the difference (4.1%) between the maximum estimation fidelity and the minimum estimation fidelity. Our experiments clearly demonstrate that inequivalent MUBs have different information extraction capabilities and different merits for quantum information processing.

Identification and validation of 5-methylcytosine-associated genes in diffuse large B-cell lymphoma.

5-methylcytosine modifications play a significant role in carcinogenesis; however, studies exploring 5-methylcytosine-related genes in diffuse large B-cell lymphoma patients are lacking. In this study, we aimed to understand the potential role and clinical prognostic impact of 5-methylcytosine regulators in diffuse large B-cell lymphoma and identify a prognostic biomarker based on 5-methylcytosine-associated genes. Gene expression profiles and corresponding clinical information of diffuse large B-cell lymphoma patients and normal controls were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases. Diffuse large B-cell lymphoma was divided into three clusters according to the 5-methylcytosine regulators, and differentially expressed genes were screened among the three clusters. Univariate Cox and Lasso-Cox regression analyses were used to screen prognostic genes and construct a prognostic risk model. Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and time-dependent receiver operator characteristic curve analysis were used to evaluate prognostic factors. GSVA was used to enrich potential pathways associated with 5-methylcytosine modification patterns. SsGSEA and CIBERSORT were used to assess immune cell infiltration. Six 5-methylcytosine-related genes (TUBB4A, CD3E, ZNF681, HAP1, IL22RA2, and POSTN) were used to construct a prognostic risk model, which was proved to have a good predictive effect. In addition, univariate and multivariate Cox regression risk scores were independent prognostic factors for diffuse large B-cell lymphoma. Further analysis showed that the 5-methylcytosine risk score was significantly correlated with immune cell infiltration and immune checkpoint of diffuse large B-cell lymphoma. Our study reveals for the first time a potential role for 5-methylcytosine modifications in diffuse large B-cell lymphoma, provides novel insights for future studies on diffuse large B-cell lymphoma, and offers potential prognostic biomarkers and therapeutic targets for patients with diffuse large B-cell lymphoma.

Identification of a novel model based on ferroptosis-related genes for predicting the prognosis of diffuse large B-cell lymphomas.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. We aimed to build a ferroptosis-related gene (FRG) prognostic signature to predict the outcome of DLBCLs. METHODS: Our study retrospectively investigated the mRNA expression level and clinical data of 604 DLBCL patients from three GEO public datasets. We performed Cox regression analysis to extract the FRGs with prognostic values. ConsensusClusterPlus was used to categorize the DLBCL samples according to gene expression. The least absolute shrinkage and selection operator (LASSO) method and univariate Cox regression were implemented to construct the FRG prognostic signature. The association between the FRG model and clinical characteristics was also investigated. RESULTS: We identified 19 FRGs with potential prognostic values and classified the patients into clusters 1 and 2. Cluster 1 showed a shorter overall survival (OS) time than cluster 2. The two clusters had different patterns of infiltrating immune cells. LASSO was used to generate a six-gene risk signature (GCLC, LPCAT3, NFE2L2, ABCC1, SLC1A5, and GOT1), based on which a risk score formula and prognostic model were constructed for predicting the OS of DLBCL patients. Kaplan-Meier survival analysis proved that poorer OS was exhibited in the higher-risk patients stratified by the prognostic model in both the training and test cohorts. In addition, both the decision curve and the calibration plots showed that the nomogram had good agreement between the predicted results and actual observations. CONCLUSIONS: We developed and validated a novel FRG-based prognostic model which could help to predict the outcomes of DLBCL patient.

CHST15 gene germline mutation is associated with the development of familial myeloproliferative neoplasms and higher transformation risk.

Herein, we describe the clinical and hematological features of three genetically related families predisposed to myeloproliferative neoplasms (MPNs). Using whole-exome sequencing, we identified a c.1367delG mutation(p.Arg456fs) in CHST15 (NM_001270764), a gene encoding a type II transmembraneglycoproteinthat acts as a sulfotransferase and participates in the biosynthesis of chondroitin sulfate E, in germline and somatic cells in familial MPN. CHST15defects caused an increased JAK2V617F allele burden and upregulated p-Stat3 activity,leading to an increase in the proliferative and prodifferentiation potential of transgenic HEL cells. We demonstrated that mutant CHST15 is able to coimmmunoprecipitate the JAK2 protein,suggesting the presence of a CHST15-JAK2-Stat3 signaling axis in familial MPN. Gene expression profiling showed that the FREM1, IFI27 and C4B_2 genes are overexpressed in familial MPN, suggesting the activation of an "inflammatory response-extracellular matrix-immune regulation" signaling network in the CHST15 mutation background.We thus concluded that CHST15 is a novel gene that predisposes to familial MPN and increases the probability of disease development or transformation.

Coagulation Factor XIII Subunit A Is a Biomarker for Curative Effects and Prognosis in Malignant Solid Tumors, Especially Non-small Cell Lung Cancer.

BACKGROUND: The expression of coagulant factor XIII subunit A (FXIII-A) is significantly increased in some types of cancer cells and tumor-associated macrophages (TAMs). However, few studies on plasma FXIII-A in cancer patients have been conducted and have shown contradictory results, so the relationship of plasma FXIII-A with the progression and prognosis of malignant tumors is still unknown. This study explored the association of plasma FXIII-A with a curative effect and the prognosis of patients with malignant solid tumors. METHODS: We monitored plasma FXIII-A before and during systemic therapy and assessed its relationship with the curative effect and prognosis of malignant solid tumors, especially non-small cell lung carcinoma (NSCLC), by propensity-adjusted, multivariable logistic regression analysis and survival curve, in a prospective study of 1147 patients with different types of malignant solid tumors. The influencing factors of plasma FXIII-A were also analyzed. RESULTS: We found that D-dimer (D2) = 1 mg/L was the inflection point for the association between FXIII-A and D2: FXIII-A was significantly negatively correlated with D2 (r = -0.39, p < 0.01) and FDP (r = -0.40, p < 0.01) in D2 > 1 mg/L but uncorrelated with D2 or FDP in D2 ≤ 1 mg/L, which provided a method to find a more realistic plasma FXIII-A level. Plasma FXIII-A was positively correlated with age, platelets, lymphocytes, monocytes and carcinoembryonic antigen (CEA). It was found for the first time that plasma FXIII-A was abnormally significantly increased (FXIII-A > 150%) in post-therapy patients, especially in NSCLC and lung metastasis patients, and the incidence of FXIII-A > 150% in lung adenocarcinoma was 16 times higher than that in lung squamous carcinoma. FXIII-A > 150% proved to be an independent risk factor for disease progression in NSCLC patients (OR=5.74, 95% CI: 1.20-27.60, p = 0.029), predicting poor efficacy. The marked decrease in plasma FXIII-A (FXIII-A < 40%) was related to coagulation disorders and poor prognosis with a short survival time (median survival time of 4 months). CONCLUSIONS: Plasma FXIII-A has the potential to be a real-time biomarker with bidirectional indicator effects to assess curative effects and prognosis in malignant solid tumors, especially NSCLC.

microRNA-630 Regulates Underglycosylated IgA1 Production in the Tonsils by Targeting TLR4 in IgA Nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerular disease. The characteristic pathology involves immune complexes formed by the deposition of IgA1 and underglycosylated IgA1 aggregates in the mesangial area, which may be accompanied by the deposition of IgG and/or IgM and complement components. However, the molecular mechanisms of IgAN remain unclear. In the present study, microarray analysis showed that the expression of microRNA-630 (miR-630) was significantly reduced in palatal tonsils from IgAN patients compared with chronic tonsillitis. Additionally, bioinformatic analysis showed that Toll-like receptor 4 (TLR4) was the predicted target gene of miR-630 and was regulated by miR-630. When miR-630 was overexpressed in palatal tonsil mononuclear cells from IgAN patients, the expression of TLR4 was reduced and the content of IgA1 in the cell culture supernatant was decreased, and the level of galactosylation in the IgA1 hinge region was increased. Moreover, immunohistochemical analysis showed that the expression of TLR4 in IgAN patients was significantly increased. After knocking down the expression of TLR4, both the concentration of IgA1 and the binding force of IgA1 with broad bean lectin were significantly reduced in IgAN. Furthermore, the mechanism study demonstrated that TLR4 might regulate the expression of IL-1ß and IL-8 through NF-κB signaling pathway to modulate the concentration of IgA1 and the glycosylation level of IgA1. This interesting finding may offer new insight into the molecular mechanism of IgAN.

Metabolomics window into the role of acute kidney injury after coronary artery bypass grafting in diabetic nephropathy progression.

INTRODUCTION: Metabolomics has emerged as a valuable tool to discover novel biomarkers and study the pathophysiology of diabetic nephropathy (DN). However, the effect of postoperative acute kidney injury (AKI) on diabetes mellitus (DM) to chronic DN progression has not been evaluated from the perspective of metabolomics. METHODS: A group of type 2 diabetes mellitus (T2DM) inpatients, who underwent off-pump coronary artery bypass grafting (CABG), were enrolled in our study. According to whether postoperative AKI occurred, patients were grouped in either the AKI group (AKI, n = 44) or the non-AKI group (NAKI, n = 44). Urine samples were collected from these patients before and 24 h after operation. Six patients from the AKI group and six patients from the NAKI group were chosen as the pilot cohort for untargeted metabolomics analysis, with the goal of identifying postoperative AKI-related metabolites. To understand the possible role of these metabolites in the chronic development of renal injury among T2DM patients, trans-4-hydroxy-L-proline and azelaic acid were quantified by targeted metabolomics analysis among 38 NAKI patients, 38 AKI patients, 46 early DN patients (DN-micro group), and 34 overt DN patients (DN-macro group). RESULTS: Untargeted metabolomics screened 61 statistically distinguishable metabolites in postoperative urine samples, compared with preoperative urine samples. Via Venn diagram analysis, nine of 61 were postoperative AKI-related metabolites, including trans-4-hydroxy-L-proline, uridine triphosphate, p-aminobenzoate, caffeic acid, adrenochrome, δ-valerolactam, L-norleucine, 5'-deoxy-5'-(methylthio) adenosine, and azelaic acid. By targeted metabolomics analysis, the level of trans-4-hydroxy-L-proline increased gradually from the NAKI group to the AKI, DN-micro, and DN-macro groups. For azelaic acid, the highest level was found in the NAKI and DN-micro groups, followed by the DN-macro group. The AKI group exhibited the lowest level of azelaic acid. CONCLUSIONS: The detection of urinary trans-4-hydroxy-L-proline after AKI could be treated as an early warning of chronic DN progression and might be linked to renal fibrosis. Urinary azelaic acid can be used to monitor renal function noninvasively in DM and DN patients. Our results identified markers of AKI on DM and the chronic progression of DN. In addition, the progression of DN was associated with AKI-like episodes occurring in DM.

The role of hypertriglyceridemia and treatment patterns in the progression of IgA nephropathy with a high proportion of global glomerulosclerosis.

PURPOSE: Many studies have focused on finding predictors for mild IgAN progression. However, the cases of severe IgAN with a high proportion of global glomerulosclerosis have received inadequate attention. METHODS: A group of 172 primary IgAN patients with 50-75% global glomerulosclerosis was studied retrospectively between April 2007 and October 2017. Patients were divided into three groups according to the serum triglyceride tertiles: < 1.42 µmol/L (Group 1), 1.42-2.29 µmol/L (Group 2), and > 2.29 µmol/L (Group 3). Groups 1 and 2 comprised non-hypertriglyceridemia subjects, while Group 3 was defined as the hypertriglyceridemia (HTG) group. The patients were followed for 4-96 months (median 39.43 months). The study end point was defined as a 50% decline in estimated glomerular filtration rate (eGFR) or ESRD. RESULTS: A high proportion of global glomerulosclerosis is not absolutely correlated with severe clinical features and poor renal outcome. In our retrospective observation, eGFR decreased by less than 10% of the baseline during follow-up in 43.6% of the patients. However, in our patients with HTG, the cumulative renal survival rate was significantly lower compared to those without HTG. Multivariate Cox regression analysis also showed that triglyceride is an independent predictor of poor renal outcomes. Furthermore, in the HTG group, the cumulative renal survival rates were higher in patients treated with Tripterygium wilfordii Hook F (TwHF) compared to those without TwHF. CONCLUSIONS: A high proportion of global glomerulosclerosis combined with HTG at biopsy have better predictive validity for the disease progression of IgAN than global glomerulosclerosis alone. TwHF may partially affect the renal outcome of severe IgAN with HTG, and this may relate to its regulation of lipid metabolism and immunoinflammatory response.

RNF8 is responsible for ATRA resistance in variant acute promyelocytic leukemia with GTF2I/RARA fusion, and inhibition of the ubiquitin-proteasome pathway contributes to the reversion of ATRA resistance.

BACKGROUND: GTF2I-RARA is a newly identified RARA fusion gene in variant acute promyelocytic leukemia (APL) patients with t(7;17)(q11;q21). Clinical manifestation in the patient showed that it is a sort of ATRA-insensitive oncogene and is different from the classic PML-RARA in terms of therapeutic reaction. METHODS: To reveal the functional characteristics and regulating mechanism of the GTF2I-RARA fusion gene, we established a GTF2I-RARA-transfected HL60 cell model and examined its sensitivity to ATRA by western blot, MTT assay, flow cytometry, and Wright-Giemsa staining. Coimmunoprecipitation and confocal microscopy were used to examine the binding of GTF2I-RARA and transcriptional corepressors. We also performed ChIP-seq to search for potential target genes. Immunoprecipitation, ubiquitination assay, western blot, luciferase assay, and real-time PCR were used to analyze the effects of RNF8 on RARA. Flow cytometry and Wright-Giemsa staining were used to study the effect of MG132 and ATRA on the GTF2I-RARA-transfected HL60 cell model. RESULT: We confirmed resistance of GTF2I-RARA to ATRA. Compared with PML-RARA, GTF2I-RARA has a higher affinity to HDAC3 under ATRA treatment. Using the ChIP-sequencing approach, we identified 221 GTF2I-RARA binding sites in model cells and found that the RING finger protein 8 (RNF8) is a target gene of GTF2I-RARA. RNF8 participates in disease progression and therapy resistance in APL with the GTF2I-RARA transcript. Elevated RNF8 expression promotes the interaction between RARA and RNF8 and induces RARA Lys-48 linkage ubiquitylation and degradation, resulting in attenuated transcriptional activation of RARA. CONCLUSION: Our results suggest that RNF8 is a key GTF2I-RARA downstream event. Using the combination of MG132 and ATRA to treat GTF2I-RARA-HL60 cells, a synergistic effect leading to GTF2I-RARA-HL60 cell differentiation was confirmed. Taken together, the targeting of RNF8 may be an alternative choice for treatment in variant APL with GTF2I-RARA fusion.

Functional Role of SUV39H1 in Human Renal Tubular Epithelial Cells Under High-glucose Ambiance.

SUV39H1, the histone methyltransferase (HMTase) of histone H3 lysine 9 trimethylation (H3K9me3), is a known transcriptional repressor of inflammatory genes. The effect of SUV39H1 on inflammatory gene promoters under high-glucose stimulation in vascular smooth muscle cells (VSMCs), macrophages, and cardiomyocytes has been studied, but how SUV39H1 functions in renal tubules under diabetic conditions is unclear. Renal biopsy specimens of ten diabetic nephropathy (DN) subjects and seven non-DN minimal change diseases (MCD) subjects were collected. SUV39H1, IL-6, and MCP-1 expression in renal tissues were measured using immunohistochemical, while SUV39H1, H3K9me3, IL-6, and MCP-1 in human proximal tubular epithelial cells (HK-2) under varying glucose conditions were assayed by Western blot and ELISA. SUV39H1 was overexpressed in HK-2 cells; the regulation of SUV39H1 and H3K9me3 on NF-κB, IL-6, MCP-1, caspase 3, and apoptosis was measured. SUV39H1 was expressed more in diabetic human renal tubules. HK-2 cells with high glucose up-regulated IL-6 and MCP-1 in a dose- and time-dependent manner, and SUV39H1 expression was reduced with greater glucose and prolonged stimulation. Expression of H3K9me3 was synchronized with SUV39H1. Moreover, overexpression of SUV39H1 in high glucose environment was accompanied with increased H3K9me3 and decreased inflammation and apoptosis. SUV39H1 dysregulation may be involved in DN progression. Overexpression of SUV39H1 may reduce renal inflammation and apoptosis via epigenetic modulation, thus plays a protective role in DN.

Vibration Induces BAFF Overexpression and Aberrant O-Glycosylation of IgA1 in Cultured Human Tonsillar Mononuclear Cells in IgA Nephropathy.

Objective. To investigate the influence of in vitro vibratory stimulation of human tonsillar mononuclear cells (TMCs). Methods. Fourteen IgA nephropathy (IgAN) patients with chronic tonsillitis (CT) and 12 CT patients with no renal pathology were enrolled. Group A TMCs were collected after 24 hours of culture and used to determine baseline levels. TMCs in groups B, C, D, E, and F were exposed to vibratory stimulation (60 Hz) for 0 (as the control group), 1, 3, 5, and 10 minutes, respectively. Results. Baseline concentrations of B-cell-activation factor (BAFF) and IgA1, BAFF mRNA expression, and aberrant O-glycosylation IgA1 level were higher in the IgAN group as compared to that in the CT group, and all increased after vibratory stimulation. Baseline mRNA expressions of core ß1,3-galactosyltransferase (C1GALT1) and core ß1,3GalT-specific molecular chaperone (Cosmc) were lower in the IgAN group; the levels decreased further after vibratory stimulation. Conclusion. In patients with IgAN, vibratory stimulation of TMCs appears to induce IgA1 secretion through activation of BAFF release and to aberrant O-glycosylation IgA1 by suppressing C1GALT1 and Cosmc expression. In vitro vibratory stimulation of human TMCs mimics the vibratory simulation of palatine tonsils produced by vocal cords during phonation.

Two novel compound heterozygous mutations associated with types I and II protein C deficiency with unusual phenotypes.

INTRODUCTION: We diagnosed two Chinese hereditary PC deficiency families and identified two novel compound heterozygous mutations (p.Arg194Cys/Gly324Ser and p.Glu274X/Asp297His) in the protein C (PROC) gene. The probands were classified as types I and II PC deficiency. The aim of this article is to access the influence of the mutations on PC activity, antigen and protein structure, and to evaluate whether there is abnormal PC localization. MATERIALS AND METHODS: Genomic DNA of all family members was extracted, PCR amplified, and sequenced. The mutant PC expression plasmids were constructed. Expression assays, intracellular localization, and molecular modeling were performed. RESULTS: Proband 1, a type II PC defect, harbored a compound heterozygous mutation, p.Arg194Cys/Gly324Ser in the PROC gene, underwent two thromboembolic events. Expression assays indicated that the p.Arg194Cys mutant lead to decreased PC activity and normal PC Ag levels. Intracellular localization showed that both p.Arg194Cys and p.Gly324Ser co-localized with the endoplasmic reticuli and the Golgi apparatus. Molecular modeling suggested that the p.Gly324Ser mutation disturbed the interaction between the heavy and light chains of the PC protein. Proband 2, a type I PC defect, harbored a compound heterozygous PROC gene mutation, p.Glu274X/Asp297His, presented with recurrent spontaneous abortion and right popliteal vein thrombosis. Expression results were in accordance with the PC changes of the patient, and existed in defective PC transport. Structural model suggested p.Glu274X lead to disulfide bond between heavy and light chain cannot form. CONCLUSIONS: Our results confirm that two novel compound heterozygous PROC gene mutations are causative on the two PC deficiency families.

Potential diagnostic biomarkers for IgA nephropathy: a comparative study pre- and post-tonsillectomy.

OBJECTIVE: The proteins BAFF, ST6GALNAC2, C1GALT1, and COSMC in peripheral blood mononuclear cells (PBMCs) and plasma levels of IgA1 and galactose-deficient IgA1 (Gd-IgA1) are potential biomarkers for IgAN nephropathy. In this study, we comparatively studied the changes of those biomarkers before and after tonsillectomy. METHODS: Peripheral blood samples were obtained from 16 IgAN patients with pre- and post-tonsillectomy. IgAN was diagnosed based on results from analysis of percutaneous renal biopsy tissue. Peripheral blood samples from three patients without renal diseases (non-IgAN), before and after tonsillectomy, and 16 healthy controls were also examined. BAFF, ST6GALNAC2, C1GALT1, and COSMC mRNA levels in PBMCs were detected using real-time PCR. Plasma IgA1 content was measured by ELISA. Gd-IgA1 levels were determined using the VV lectin-ELISA method. RESULTS: BAFF, ST6GALNAC2, C1GALT1, and COSMC mRNA levels and the plasma concentrations of IgA1 and Gd-IgA1 in IgAN patients before tonsillectomy were significantly higher than those in healthy controls (P < 0.05). Tonsillectomy significantly increased the expression of BAFF and ST6GALNAC2, and plasma IgA1 level, while it downregulated that of C1GALT1 and COSMC (P < 0.05). However, in non-IgAN patients, tonsillectomy did not affect the mRNA levels of BAFF, ST6GALNAC2, C1GALT1, and COSMC, plasma IgA1 content and Gd-IgA1 level. Positive correlations were established between BAFF and IgA1 (r = 0.604, P < 0.01) and between ST6GALNAC2 and Gd-IgA1 (r = 0.623, P < 0.01). CONCLUSIONS: Tonsillectomy changes the mRNA levels of BAFF, ST6GALNAC2, C1GALT1, and COSMC in PBMCs, as well as the plasma IgA1 level in IgAN patients. BAFF and ST6GALNAC2 might regulate IgA1 secretion and O-glycosylation.

Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review.

Acute promyelocytic leukemia (APL) is characterized by the generation of the promyelocytic leukemia-retinoic acid (RA) receptor α (PML-RARα) fusion gene. PML-RARα is the central leukemia-initiating event in APL and is directly targeted by all-trans-RA (ATRA) as well as arsenic. In classic APL harboring PML-RARα transcripts, more than 90% of patients can achieve complete remission when treated with ATRA combined with arsenic trioxide chemotherapy. In the last 20 years, more than 10 variant fusion genes have been found and identified in APL patients. These variant APL cases present different clinical phenotypes and treatment outcomes. All variant APL cases show a similar breakpoint within the RARα gene, whereas its partner genes are variable. These fusion proteins have the ability to repress rather than activate retinoic targets. These chimeric proteins also possess different molecular characteristics, thereby resulting in variable sensitivities to ATRA and clinical outcomes. In this review, we comprehensively analyze various rearrangements in variant APL cases that have been reported in the literature as well as the molecular characteristics and functions of the fusion proteins derived from different RARα partner genes and their clinical implications.

Efficacy of triptolide on the apoptosis of tonsillar mononuclear cells from patients with IgA nephropathy.

AIMS: This study aimed to evaluate the extent of apoptosis of tonsillar mononuclear cells (TMCs) derived from patients with IgA nephropathy (IgAN) and the effects of triptolide (TP) on the apoptosis of these TMCs. METHODS: TMCs were isolated from tonsillar tissues of patients with IgAN or chronic tonsillitis (control group). Rates of TMCs apoptosis were measured by annexin V-fluorescein isocyanate (FITC)/propidium iodide (PI)-labeled flow cytometry (FCM). Expression levels of Bcl-2 family proteins were quantified by immunohistochemistry of fixed tonsillar sections and Western blot analyzes of TMCs lysates. TMCs from IgAN patients were treated 10, 20, or 30 ng/mL TP for 24 h and then evaluated for viability by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, for the percentage of apoptotic cells by FCM, and for the relative expression levels of Bcl-2 family proteins by Western blot analysis. RESULTS: Compared to TMCs from the control group, TMCs from the IgAN group demonstrated lower rates of apoptosis, higher expression levels of the anti-apoptosis proteins Bcl-2 and Bcl-xL, and lower expression levels of the pro-apoptosis protein Bax. Treatment of IgAN patient-derived TMCs with 10, 20, or 30 ng/mL TP for 24 h suppressed the viability and promoted the apoptosis of TMCs in a dose-dependent manner. Western blot analysis revealed a TP dose-dependent decrease in Bcl-2 and Bcl-xL expression levels, in parallel with increased Bax protein levels. CONCLUSION: TMCs from IgAN patients may be in a state of inhibited apoptosis mediated by Bcl-2 family proteins, which may be reversed by TP treatment.