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Purpose: Drawing on affective events theory (AET), this study aims to investigate how and when leader voice solicitation affects employees' innovative behavior. Specifically, this study proposes that leader voice solicitation evokes employees' feelings of pride, which subsequently motivate employees' innovative behavior. Moreover, collectivism orientation plays a moderating role in this process. Design/methodology/approach: This study collected 251 supervisor–subordinate dyadic data in two phases and employed structural equational modeling (SEM) to test the hypotheses. Findings: The results revealed that employees' feelings of pride mediate the positive relationship between leader voice solicitation and employees' innovative behavior. Collectivism orientation intensifies the mediated relationship. Originality/value: This study extends the potential outcome variables of leader voice solicitation. Moreover, it introduces a novel theoretical perspective to explore the impact of leader voice solicitation on employees. Importantly, this study examines the mediating effect of pride and the moderating effect of collectivism orientation, deepening the understanding of how and when leader voice solicitation affects innovative behavior. [ABSTRACT FROM AUTHOR]

Secure k-Nearest Neighbor (k-NN) query aims to find k nearest data of a given query from an encrypted database in a cloud server without revealing privacy to the untrusted cloud and has wide applications in many areas, such as privacy-preserving machine learning and secure biometric identification. Several solutions have been put forward to solve this challenging problem. However, the existing schemes still suffer from various limitations in terms of efficiency and flexibility. In this paper, we propose a new encrypt-then-index strategy for the secure k-NN query, which can simultaneously achieve sub-linear search complexity (efficiency) and support dynamical update over the encrypted database (flexibility). Specifically, we propose a novel algorithm to transform the encrypted database and encrypted query points in the cloud. By indexing the transformed database using spatial data structures such as the R-tree index, our strategy enables sub-linear complexity for secure k-NN queries and allows users to dynamically update the encrypted database. To the best of our knowledge, the proposed strategy is the first to simultaneously provide these two properties. Through theoretical analysis and extensive experiments, we formally prove the security and demonstrate the efficiency of our scheme. [ABSTRACT FROM AUTHOR]

Background: Previous studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSCs acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC (AA-Exos) may play a key role in immunologic dissonance. Method: In this study, CD3 + T cells were collected and cocultured with AA-Exos and exosomes derived from HD-MSC (HD-Exos). The proliferation, differentiation and activation of CD3 + T cells were detected to compare the immunosuppressive effects between AA-Exos and HD-Exos. An immune-mediated murine model of AA was structured to compare the therapeutic effect of AA-Exos and HD-Exos. Furthermore, total RNA including miRNA from exosomes we purified and total RNA of CD3 + T cells were extracted for RNA-seq in order to construct the miRNA–mRNA network for interactions and functional analysis. Results: AA-Exos had impaired inhibition effects on CD3 + T cells in terms of cell proliferation, activation and differentiation compared with exosomes from HD-Exos. HD-Exos showed a more effective rescue of AA mice compared to AA-Exos. Importantly, we found some differentially expressed miRNA involved in immune response, such as miR-199, miR-128 and miR-486. The Gene Ontology analysis of differentially expressed genes (DEGs) revealed involvement of various cellular processes, such as lymphocyte chemotaxis, lymphocyte migration and response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes analysis illustrated upregulation of critical pathways associated with T cell function after coculturing with AA-Exos compared with HD-Exos, such as graft-versus-host disease, Th17 cell differentiation and JAK-STAT signaling pathway. A miRNA–mRNA network was established to visualize the interaction between them. Conclusion: In summary, AA-Exos had impaired immunosuppressive effect on T cells, less ability to rescue AA mice and differently expressed miRNA profile, which might partly account for the pathogenesis of AA as well as provide a new target of AA treatment. [ABSTRACT FROM AUTHOR]

Identity-based threshold signature (IDTS) is a forceful primitive to protect identity and data privacy, in which parties can collaboratively sign a given message as a signer without reconstructing a signing key. Nevertheless, most IDTS schemes rely on a trusted key generation center (KGC). Recently, some IDTS schemes can achieve escrow-free security against corrupted KGC, but all of them are vulnerable to denial-of-service attacks in the dishonest majority setting, where cheaters may force the protocol to abort without providing any feedback. In this work, we present a fully decentralized IDTS scheme to resist corrupted KGC and denial-of-service attacks. To this end, we design threshold protocols to achieve distributed key generation, private key extraction, and signing generation which can withstand the collusion between KGCs and signers, and then we propose an identification mechanism that can detect the identity of cheaters during key generation, private key extraction and signing generation. Finally, we formally prove that the proposed scheme is threshold unforgeability against chosen message attacks. The experimental results show that the computation time of both key generation and signing generation is <1 s, and private key extraction is about 3 s, which is practical in the distributed environment. [ABSTRACT FROM AUTHOR]

Dexmedetomidine (DEX) is clinically used for sedation of patients in intensive care, which also has been shown to have a strong anti-inflammatory effect on a variety of diseases. Parthanatos is a newly discovered form of programmed cell death. Here, we aimed to explore whether DEX protects cardiomyocytes from parthanatos in chronic heart failure (CHF). The levels of malondialdehyde (MAD), total superoxide dismutase (SOD), and adenosine triphosphate (ATP) were measured by corresponding detection kits. CHF mice model was established by transverse aortic constriction (TAC). PARP-1 expression in cardiac tissues of wild-type CHF mice was evaluated by immunohistochemistry. Flow cytometry was used to detect the effect of N-methyl-N′-nitro-N′-nitrosoguanidine (MNNG) on cell death. Masson trichrome staining and hematoxylin and eosin staining were conducted in cardiac tissues to evaluate the histological changes. TUNEL and caspase-1 double-staining and caspase-1 and NLRP3 double-staining were conducted in cardiac tissues to evaluate the effect of DEX on cell death in vivo. The relative expression of parthanatos and NLRP3 inflammasome-related proteins was evaluated by western blotting. MNNG induced parthanatos in mouse HL-1 cardiomyocytes. MNNG-induced parthanatos was promoted by ROS production and NLRP3 inflammasome activation. DEX treatment suppressed MNNG-induced parthanatos via NLRP3 inflammasome activation mediated by ROS. Importantly, DEX inhibited pathological changes and parthanatos in CHF mice. DEX suppressed the ROS/NLRP3 signaling pathway in CHF mice. DEX inhibited parthanatos in cardiomyocytes and in CHF mice by regulating the ROS-mediated NLRP3 inflammasome activation. The PARP-1 activation and NLRP3 inflammasome activation induced by MNNG was inhibited by DEX treatment, thus the generation of ROS was further inhibited, suggesting the inhibitory effect of DEX treatment on parthanatos in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Introduction: Acquired aplastic anemia (AA), a heterogeneous bone marrow (BM) failure disease, is mainly mediated by the immune destruction of hematopoietic stem cells (HSCs). Given the predominant role of immunosuppressive therapy (IST) in AA, it is sensible to theorize that variants of cytokine genes might affect the outcome of IST. Methods: In this study, we analyzed three single nucleotide polymorphisms (SNPs) of interleukin (IL)‐10 gene in promoter region to clarify their relationship with susceptibility, clinical efficacy and prognosis of AA. Results: We observed that CT genotype of IL‐10 rs1800896 was associated with a decreased risk of AA (adjusted OR = 0.541 [95% CI 0.295–0.993], p =.047). Besides, the disease severity differed considerably by IL‐10 gene promoter genotypes and alleles. Furthermore, IL‐10 SNPs influenced efficacy of IST, with unfavorable response exhibited by rs1800871 and rs1800872 in dominant models (GG + AG vs. AA, adjusted OR = 0.409 [95% CI 0.178–0.943, p =.036] for rs1800871 and GG + GT vs. TT, adjusted OR = 0.396 [95% CI 0.173–0.909, p =.028] for rs1800872, respectively). Conclusion: The polymorphisms of IL‐10 promoter region were informatively genetic risk factors which might be conducive to the insights into the mechanisms of AA and the design of individual regimens. [ABSTRACT FROM AUTHOR]

Background: X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia (CSA), and is associated with the mutations in the 5-aminolevulinate synthase 2 (ALAS2). The genetic basis of more than 40% of CSA cases remains unknown. Methods: A two-generation Chinese family with XLSA was studied by next-generation sequencing to identify the underlying CSA-related mutations. Results: In the study, we identified a missense ALAS2 R204Q mutation in a hemizygous Chinese Han man and in his heterozygous daughter. The male proband presented clinical manifestations at 38 years old and had a good response to pyridoxine. Conclusions: XLSA, as a hereditary disease, can present clinical manifestations later in lives, for adult male patients with ringed sideroblasts and hypochromic anemia, it should be evaluated with gene analyses to exclude CSA. [ABSTRACT FROM AUTHOR]

Objectives: To clear the obscure conclusion on the prediction value of paroxysmal nocturnal haemoglobinuria (PNH) clones in severe aplastic anaemia (SAA) patients treated with immunosuppressive therapy (IST). Methods: We retrospectively analyzed 219 consecutive SAA patients treated with IST from October 2008 to October 2015 and evaluated the haematological responses to IST. Results: The presence of a PNH clone was detected in 55 (25.1%) patients prior to IST [37/88 by flow cytometry (FCM) and 18/131 by fluorescent aerolysin (FLAER)] and 27 disappeared after IST (23/37 in initial FCM group, 4/18 in initial FLAER group, p = 0.005). In patients without an initial clone, 12 (30.0%) cases in FCM and 17 (19.5%) in FLAER groups presented a PNH clone at least once after IST (p < 0.001). In patients with a pre-treatment PNH clone detected by FCM, the 3-, 6- and 12-month response rates were higher than patients without (p = 0.006; 0.002 and 0.002, respectively). And in FLAER group, the 3-month response rate was significantly higher in those with a prior clone (p = 0.017), however, the 6- and 12-month response rates showed no differences (p = 0.105, p = 0.144, respectively). By multivariate analysis, a shorter interval between diagnosis and treatment is associated with a better response and survival. Conclusions: A more reliable FLAER method allows us to draw a conclusion that PNH clone predicts a faster response but not a higher response rate to IST. Once a diagnosis is confirmed, the IST should be initiated as soon as possible. [ABSTRACT FROM AUTHOR]

k-means clustering, which partitions data records into different clusters such that the records in the same cluster are close to each other, has many important applications such as image segmentation and genes detection. While the k-means clustering has been well-studied by a significant amount of works, most of the existing schemes are not designed for peer-to-peer (P2P) networks. P2P networks impose several efficiency and security challenges for performing clustering over distributed data. In this paper, we propose a novel privacy-preserving k-means clustering scheme over distributed data in P2P networks, which achieves local synchronization and privacy protection. Specifically, we design a secure aggregation protocol and a secure division protocol based on homomorphic encryption to securely compute clusters without revealing the privacy of individual peer. Moreover, we propose a novel massage encoding method to improve the performance of our aggregation protocol. We formally prove that the proposed scheme is secure under the semi-honest model and demonstrate the performance of our proposed scheme. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) have been widely accepted as the standard first-line treatments for severe aplastic anemia (SAA). However, most of the patients with SAA had a slim chance to access these strategies in developing countries. Here, we reported 10-year results in a cohort of 232 patients with SAA who received a novel IST of CsA, levamisole, and danazol (CsA&LMS-based regimen). The cumulative incidence of response was 52.1% at 6 months, 66.4% at 12 months, and 77.1% at 24 months. The 10-year overall survival (OS) and failure-free survival was 60.2% and 48.3%, respectively. Positive predictors of OS in multivariate analysis were higher pretreatment ANC, younger age, higher pretreatment absolute reticulocyte count (ARC), and response within 6 months. The probability of CsA&LMS discontinuation was 50.2% at 10 years. With a slow CsA&LMS taper, the actuarial risk for relapse was only 9.5%. The cumulative incidence of MDS/AML was 8.2% at 10 years. The long-term follow-up information demonstrated that the CsA&LMS regimen could be a promising strategy for patients with SAA in developing countries. [ABSTRACT FROM AUTHOR]

Cloud computing has been one of the critical solutions to reduce heavy storage and computation burden of biometric identification. To protect the privacy of biometric data against untrusted cloud servers, outsourced biometric databases are usually encrypted by users. Performing biometric identification over encrypted data without revealing privacy to cloud servers attracts more and more attention. Several secure biometric identification solutions have been proposed to solve this challenging problem. However, these schemes still suffer from various limitations, such as low search efficiency and heavy computation burden on users. In this paper, we propose a novel cloud-assisted biometric identification scheme based on the asymmetric scalar-product preserving encryption (ASPE) and spatial data structures such as the R-tree index, which simultaneously achieves sub-linear search efficiency and low computation burden on users. Specifically, we construct an R-tree index on the biometric dataset and encrypt the index with ASPE. Then we modify the original search algorithm in the R-tree index and design a secure search algorithm based on ASPE to find the nearest neighbor result over the encrypted R-tree index. Through theoretical analysis and extensive experiments, we demonstrate the effectiveness and efficiency of our proposed approach. [ABSTRACT FROM AUTHOR]

Nuclear protein 1 (NUPR1) is a stress-related small molecule and plays important roles in various tumors, including multiple myeloma (MM). Autophagy is essential for maintaining cellular homoeostasis in response to stress and, together with apoptosis, determines cell fate. Previous studies indicate that NUPR1 is involved in cancer progression of MM, but the underlying mechanisms have not been elucidated. In this study, we confirmed that NUPR1 and basal autophagy markers were highly expressed in the bone marrow of MM patients. The overexpression of NUPR1 was correlated with staging (both by Revised International Staging System [RISS] and Durie-Salmon [D-S] Staging System), levels of hemoglobin and calcium, and bone marrow plasma cell ratio in the MM patients. NUPR1 silencing reduced autophagy activities and induced apoptosis in U266 and RPMI 8226. We further observed a decrease in NUPR1 silencing-induced apoptosis in the presence of rapamycin, while an increase in apoptosis after chloroquine and 3-methyladenine treatment. Analysis of the mechanism indicated that PI3K/AKT/mTOR pathway was involved in autophagy-mediated apoptosis upon NUPR1 knockdown. In summary, our results demonstrate that NUPR1 silencing suppresses autophagy activities and induces autophagy-mediated apoptosis in MM cells through the PI3K/AKT/mTOR pathway, which exhibits potential as a treatment strategy for MM. [ABSTRACT FROM AUTHOR]

Background: Longitudinal studies have verified the pivotal role of mesenchymal stem/stromal cells (MSCs) in the bone marrow microenvironment for hematopoiesis and coordinate contribution to leukemia pathogenesis. However, the precise characteristics and alternation of MSCs during acquired aplastic anemia (AA) remain obscure. Methods: In this study, we originally collected samples from both healthy donors (HD) and AA patients to dissect the hematological changes. To systematically evaluate the biological defects of AA-derived MSCs (AA-MSCs), we analyzed alterations in cellular morphology, immunophenotype, multi-lineage differentiation, cell migration, cellular apoptosis, and chromosome karyocyte, together with the immunosuppressive effect on the activation and differentiation of lymphocytes. With the aid of whole genome sequencing and bioinformatic analysis, we try to compare the differences between AA-MSCs and HD-derived MSCs (HD-MSCs) upon the molecular genetics, especially the immune-associated gene expression pattern. In addition, the efficacy of umbilical cord-derived MSC (UC-MSC) transplantation on AA mice was evaluated by utilizing survivorship curve, histologic sections, and blood cell analyses. Results: In coincidence with the current reports, AA patients showed abnormal subsets of lymphocytes and higher contents of proinflammatory cytokines. Although with similar immunophenotype and chromosome karyotype to HD-MSCs, AA-MSCs showed distinguishable morphology and multiple distinct characteristics including genetic properties. In addition, the immunosuppressive effect on lymphocytes was significantly impaired in AA-MSCs. What is more, the cardinal symptoms of AA mice were largely rescued by systemic transplantation of UC-MSCs. Conclusions: Herein, we systematically investigated the signatures and efficacy of MSCs to dissect the alterations occurred in AA both at the cellular and molecular levels. Different from HD-MSCs, AA-MSCs exhibited multifaceted defects in biological characteristics and alterative molecular genetics in the whole genome. Our findings have provided systematic and overwhelming new evidence for the defects of AA-MSCs, together with effectiveness assessments of UC-MSCs on AA as well. [ABSTRACT FROM AUTHOR]

Conclusion: This study designed schemes to obtain distributed multiset intersection and union by exploiting LDP. In the schemes, the private items in each data owner’s set were sanitized to satisfy ϵ-LDP, and meanwhile the collector could derive a high-accuracy intersection and union from noisy sets. Through theoretical analysis and experiments, we presented that the proposed schemes enjoy good utility and strong robustness. [ABSTRACT FROM AUTHOR]

As a type of congenital microcytic hypochromic anemia, thalassemia trait is often confused with other conditions, such as congenital sideroblastic anemia (CSA) and iron deficiency anemia, before a specific work-up is performed. However, these tests, including hemoglobin (Hb) electrophoresis, gene mutations and Prussian blue staining after bone marrow aspirate, are relatively expensive, time-consuming and invasive. To find labor-saving parameters to facilitate differential diagnosis, we retrospectively analyzed the routine blood indexes of 59 thalassemia trait cases [22 α-thalassemia (α-thal), 36 β-thalassemia (β-thal) and one α/β-thal], 21 CSA patients, and 238 iron deficiency anemia controls. Significantly higher reticulocyte Hb equivalent (Ret-He) and lower red blood cell (RBC) distribution width (RDW) were prominent in thalassemia trait. Furthermore, RDW-standard deviation (SD) was independent of the severity of anemia in thalassemia trait, similar to Ret-He in CSA. In the context of the same grades of anemia, Ret-He combined with RDW was powerful in differentiation of thalassemia from CSA and iron deficiency anemia. By receiver operation curve (ROC) analysis, Ret-He had a specificity of 67.06% and a sensitivity of 76.92% with a cutoff value of 20.9 pg for thalassemia trait in mild anemia and a specificity of 84.09% and a sensitivity of 68.42% with a cutoff value of 19.1 pg for thalassemia trait in moderate anemia. Regarding CSA, Ret-He had 92.94% specificity and 60.00% sensitivity in mild anemia, with a cutoff value of 18.1 pg. Overall, Ret-He and RDW are two convenient indexes able to differentiate thalassemia from the other two microcytic anemias, CSA and iron deficiency anemia. [ABSTRACT FROM AUTHOR]

To investigate the therapeutic effect of glycyrrhizin arginine salt on rat cholestatic cirrhosis, we subjected male Sprague Dawley rats to common bile duct ligation for 14 days and treated them with distilled water (model group), arginine, or a low or high dose of glycyrrhizin arginine salt by gavage. A sham-operated group was used as a control group. Treatment with glycyrrhizin arginine salt substantially improved animal growth rates, reduced the ratio of liver weight to body weight and decreased total bilirubin, aspartate aminotransferase, 8-isoprostane and malondialdehyde compared with the values measured in the model group. The progress of liver fibrosis, as detected by hematoxylin and eosin and Masson’s trichrome staining, was slower in the glycyrrhizin arginine salt groups than in the model group or the arginine group. Reductions of bile salt pool size, hepatic hydroxyproline content and fibrosis score were also seen in the glycyrrhizin arginine salt groups compared with the model group. Furthermore, glycyrrhizin arginine salt significantly reduced the expression of transforming growth factor β 1 (TGF- β 1), α -smooth muscle actin, tumor necrosis factor- α and matrix metalloproteinases 2 and 9. Glycyrrhizin arginine salt also inhibited the expression of α -SMA and matrix metalloproteinases 2 and 9 in response to TGF- β 1 in LX-2 cells and primary rat hepatic stellate cells and mitigated the cytotoxicity induced by rat bile in HepG2 cells and primary rat hepatocytes. [ABSTRACT FROM AUTHOR]

Acquired bone marrow failure syndromes (aBMFS) encompass a wide range of diseases. A study to investigate WT1 expression in BM was conducted in 387 patients with aBMFS in China. The WT1 level in patients with aplastic anemia (AA) was significantly lower than that in patients with paroxysmal nocturnal hemoglobinuria (PNH, p = .023) and myelodysplastic syndrome (MDS, p < .001). In addition, the WT1 level in patients with MDS significantly increased as the disease progressed to an advanced stage. Patients with hypoplastic MDS had a differentiated expression level of WT1 compared with that of NSAA (p < .001). Furthermore, post-treatment patients of AA with partial response (PR) or complete response (CR) status had relatively higher WT1 levels than those with naive AA (p = .017, p = .003, respectively). Thus, the WT1 expression level could be a useful genetic marker for routine clinical work in aBMFS. [ABSTRACT FROM AUTHOR]

Overwintering (OW) is the process by which rice passes through the winter season and germinates in the following spring. OW is also a typical quantitative inheritance trait. Currently, the molecular genetic basis of OW trait in Chinese perennial Dongxiang wild rice (DXWR) still remains to be known. In this study, a linkage map consisting of 139 simple sequence repeat (SSR) markers was constructed using an F2 population derived from a cross between DXWR and 93-11. This map covered the rice genome by approximately 1778.72 cM with approximately 12.80 cM average interval. The phenotype data of OW trait were investigated for QTL analysis in the following spring of 2017. The gene ontology (GO) annotation of the M-QTL was performed through the rice genome annotation project system. A major QTL-qOW6 was flanked by RM20069 (16,542,428 bp) and RM3498 (20,982,059 bp) on chromosome 6 and detected repeatedly by both inclusive composite interval and single-marker analysis mapping with an LOD score of 9.45 and explained 22.22% of phenotypic variance. In addition, two small QTLs (qOW2 and qOW3) controlling OW trait were detected on the second and third chromosomes, respectively. No epistatic interaction was detected between these QTLs, suggesting their unique genetic model. A total of 183 candidate genes at qOW6 locus were involved in 887 GO terms. Among them, 52 candidate genes were involved in response to stress. The other 28 candidate genes were related to cell membrane, which might affect the OW trait in perennial DXWR. These results may establish the foundation for understanding the genetic mechanism about OW trait and provide a novel gene resource for OW rice variety improvement. [ABSTRACT FROM AUTHOR]

Cloud can provide much convenience for big data storage and analysis. To enjoy the advantage of cloud service with privacy preservation, huge data is increasingly outsourced to cloud in encrypted form. Unfortunately, encryption may impede the analysis and computation over the outsourced dataset. Naïve Bayesian classification is an effective algorithm to predict the class label of unlabeled samples. In this paper, we investigate naïve Bayesian classification on encrypted large-scale dataset in cloud, and propose a practical and secure scheme for the challenging problem. In our scheme, all the computation task of naïve Bayesian classification are completed by the cloud, which can dramatically reduce the burden of data owner and users. We give a formal security proof for our scheme. Based on the theoretical proof, we can strictly guarantee the privacy of both input dataset and output classification results, i.e., the cloud can learn nothing useful about the training data of data owner and the test samples of users throughout the computation. Additionally, we not only theoretically analyze our computation complexity and communication overheads, but also evaluate our implementation cost by leveraging extensive experiments over real dataset, which shows our scheme can achieve practical efficiency. [ABSTRACT FROM AUTHOR]

By the design of suitable starting materials, a silver(I)-catalyzed epoxide ring-opening/1,2-acyl migration/cyclization cascade has been developed, which allowed us to systematically prepare unsymmetrical 3-formylfurans. Various 3-formylfurans were prepared in good to excellent yields. In addition, the distinct fluorescence properties of 3-formylfurans in solution and the solid state are disclosed. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia ( AA) is an immune-mediated bone marrow failure syndrome. 1 α,25-Dihydroxyvitamin D3 [1,25( OH)2D3], the biologically active metabolite of vitamin D, is a critical modulator of immune response via binding with vitamin D receptor ( VDR). Previous studies have established that 1,25( OH)2D3 and VDR were involved in the pathogenesis of some autoimmune diseases. In this study, we evaluated the involvement of 1,25( OH)2D3 and VDR on T-cell responses in AA. Plasma 25( OH)D3 levels were comparable between patients with AA and healthy controls. Surprisingly, VDR mRNA was significantly lower in untreated patients with AA than in healthy controls. Subsequent in vitro experiments revealed that 1,25( OH)2D3 treatment suppressed the proliferation of lymphocytes and inhibited the secretion of interferon- γ, tumor necrosis factor- α, and interleukin-17A, meanwhile promoting the production of transforming growth factor- β1 in patients with AA. Moreover, 1,25( OH)2D3 inhibited the differentiation of type 1 and Th17 cells but induced the differentiation of type 2 and regulatory T cells. Interestingly, VDR mRNA was elevated in healthy controls after 1,25( OH)2D3 treatment, but not in patients with AA. In conclusion, decreased expression of VDR might contribute to the hyperimmune status of AA and appropriate vitamin D supplementation could partly correct the immune dysfunction by strengthening signal transduction through VDR in patients with AA. [ABSTRACT FROM AUTHOR]

Aplastic anemia (AA) is a bone marrow failure syndrome that is caused largely by profound quantitative and qualitative defects of hematopoietic stem and progenitor cells. However, the mechanisms underlying these defects remain unclear. Under conditions of stress, autophagy acts as a protective mechanism for cells. We therefore postulated that autophagy in CD34+ hematopoietic progenitor cells (HPCs) from AA patients might be impaired and play a role in the pathogenesis of AA. To test this hypothesis, we tested autophagy in CD34+ cells from AA samples and healthy controls and investigated the effect of autophagy on the survival of adult human bone marrow CD34+ cells. We found that the level of autophagy in CD34+ cells from AA patients was significantly lower than in age/sex-matched healthy controls, and lower in cases of severe AA than in those with non-severe AA. Autophagy in CD34+ cells improved upon amelioration of AA but, compared to healthy controls, was still significantly reduced even in AA patients who had achieved a complete, long-term response. We also showed that although the basal autophagy in CD34+ cells was low, the autophagic response of CD34+ cells to “adversity” was rapid. Finally, impaired autophagy resulted in reduced differentiation and proliferation of CD34+ cells and sensitized them to death and apoptosis. Thus, our results confirm that autophagy in CD34+ cells from AA patients is impaired, that autophagy is required for the survival of CD34+ cells, and that impaired autophagy in CD34+ HPCs may play an important role in the pathogenesis of AA. [ABSTRACT FROM AUTHOR]

Clinical and experimental evidence suggests an immune-mediated pathophysiology in subjects with lower-risk myelodysplastic syndromes (MDS) in whom immunosuppressive therapy may be effective. The novel immunosuppressive strategy of cyclosporine A (CsA) alternately combined with levamisole (LMS; CsA + LMS regimen) can dramatically improve the response rate and survival in aplastic anemia from those of our previous study. Herein, we retrospectively analyzed the data of 89 lower-risk MDS patients who received the CsA + LMS regimen. A total of 63 patients (70.8%) achieved either complete remission or hematological improvement at 4 months. Overall, 51, 41 and 19 patients had erythroid, platelet and neutrophil responses, respectively. Following the CsA + LMS regimen, 6 patients progressed to more advanced MDS at a median interval of 5 months (range, 3-42 months). The estimated 24-month progression-free survival was 82.2% (95% CI, 72.84-91.56) for all patients. Within the median follow-up of 18.5 months (range, 7.0-61.0), 6 patients died. In conclusion, the CsA + LMS regimen alleviated cytopenias and improved survival and freedom from evolution, suggesting that it could be reserved as an alternative choice for lower-risk MDS. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective Recently enhanced T-helper type 17 (Th17) immune responses and deficient CD4+ CD25hiFoxP3+ regulatory T cells (Tregs) have been reported in acquired aplastic anemia ( AA). Interleukin-21 ( IL-21), a CD4+ T-cell-derived proinflammatory cytokine, modulates the balance between Th17 cells and Tregs. However, its role in AA remains unclear. Methods IL-21 gene expression was examined by quantitative real-time PCR. Cytokines in plasma and cell culture supernatants were detected by ELISA. Cytokines-producing T cells and Tregs were evaluated by flow cytometry. Results IL-21 mRNA levels in circulating CD4+ T cells and IL-21 levels in blood plasma were markedly increased in patients with newly diagnosed AA. Moreover, elevated IL-21-producing CD4+ T cells were accompanied by Th17 cells accumulation and Tregs decrease, and correlated with AA activity. In vitro, IL-21 not only inhibited the expression of FoxP3, but also induced the expression of IL-17 in CD4+ T cells of AA patients. More importantly, we found that T cells within the bone marrow (BM) of AA patients were in a heightened activation state, which may be related to IL-21. Conclusion Our data suggested a critical role of IL-21 in breaking immune homeostasis in AA by promoting Th17 cells, activating BM T cells and suppressing Tregs. [ABSTRACT FROM AUTHOR]

Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children. To characterize the clinical presentations and survival, we performed a retrospective analysis of pediatric patients. Methods: We reviewed 55 pediatric patients with PNH referred to our hospital from January 1990 through June 2012 to assess clinical presentations, survival, and differences among subcategories. Results: The overall survival 10 years after diagnosis estimated via the Kaplan-Meier method was 77.6%. The cohort of patients was divided into subcategories of classic PNH, PNH/aplastic anemia (AA), and subclinical PNH (PNH-sc)/AA based on the recently proposed PNH working clinical classification. We found that patients with classic PNH and PNH/AA had larger PNH clones and many more parameters of hemolysis, but patients with PNH-sc/AA had smaller PNH clones, fewer parameters of hemolysis, and a higher rate of bone marrow failure. Our results revealed a high rate of bone marrow failure and a low rate of hemoglobinuria at presentation. Furthermore, thrombotic events were not observed in our patients, which is significantly different from the rate seen in Caucasian patients. Additionally, pediatric patients with PNH may develop bone marrow cytogenetic abnormalities. Conclusion: This study provides insight into Chinese pediatric PNH patients and may aid in setting up individualized therapeutic regimens. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (AA) is the most common condition linked to transfusion dependence. We conducted a cohort study to explore patterns of the dynamic evolution of iron burden, and to identify the risk factors for iron overload (IO) in 550 AA patients. Of the participants, 13 % presented with IO when diagnosed, including 7 % of patients without a history of transfusion and 22 % of those receiving transfusions. Male patients [hazard ratio (HR) = 3.85, 95 % confidence interval (CI) 1.77-8.36], adults (HR = 3.04, 95 % CI 1.21-7.63), and patients with high transfusion burdens (more than eight units; HR = 11.30, 95 % CI 4.45-28.70) experienced a significantly higher risk of IO. Furthermore, we found a sharply increasing risk of IO within the first 2 years, especially in males, patients with large number of lifetime transfusions, and patients not responding to treatment. More interestingly, after transfusion independence, a significant seesaw effect between erythropoiesis and iron burden was not noted until 6 months later, which continued over 3 years. In contrast to female patients, children, and patients with lower transfusion burdens, male subjects, adults, and subjects with high transfusion burdens experienced a pattern of slow decline in iron burden. AA incurred a high risk of progression to IO and showed distinct patterns in the evolution of iron burden. In light of these data, we offer suggestions for decision-making regarding who should undergo iron chelation and when. [ABSTRACT FROM AUTHOR]

Idiopathic aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. Immune abnormalities such as decreased lymphocyte counts, inverted CD4/CD8 T-cell ratio and increased IFN-γ-producing T cells have been found in AA. CD30, a surface protein belonging to the tumor necrosis factor receptor family and releasing from cell surface as a soluble form (sCD30) after activation, marks a subset of activated T cells secreting IFN-γ when exposed to allogeneic antigens. Our study found elevated BM plasma levels of sCD30 in patients with SAA, which were closely correlated with disease severity, including absolute lymphocyte count (ALC) and absolute netrophil count (ANC). We also noted that sCD30 levels were positively correlated with plasma IFN-γ levels and CD4/CD8 T-cell ratio in patients with SAA. In order to explain these phenomena, we stimulated T cells with alloantigen in vitro and found that CD30+ T cells were the major source of IFN-γ, and induced CD30+ T cells from patients with SAA produced significantly more IFN-γ than that from healthy individuals. In addition, increased proportion of CD8+ T cells in AA showed enhanced allogeneic response by the fact that they expressed more CD30 during allogeneic stimulation. sCD30 levels decreased in patients responded to immunosuppressive therapy. In conclusion, elevated BM plasma levels of sCD30 reflected the enhanced CD30+ T cell-mediated immune response in SAA. CD30 as a molecular marker that transiently expresses on IFN-γ-producing T cells, may participate in mediating bone marrow failure in AA, which also can facilitate our understanding of AA pathogenesis to identify new therapeutic targets. [ABSTRACT FROM AUTHOR]

The appropriate management of patients with moderate aplastic anemia (mAA) remains to be unclear and controversial. A cohort of 118 patients with mAA received a novel immunosuppressive strategy of cyclosporine alternately combined with levamisole (CSA and LMS regimen), which included 42 newly diagnosed and 76 chronic (disease duration >6 months) cases. CSA and LMS regimen was orally administrated with the initial dose of CSA 3 mg/kg per day in adults or 5 mg/kg per day in children, and LMS 150 mg per day in adults or 2.5 mg/kg per day in children, continued for 12 more months after achieving maximal hematologic response, followed by a slow tapering. The overall response rates were of 100 and 86.8 % for newly diagnosed and chronic group, respectively. The 24-month progression-free survival were 95.2 % (95 % confidence intervals [CI], 85.9-100 %) and 93.6 % (95 % CI, 86.9-100 %) for newly diagnosed and chronic group, respectively ( P = 0.50). The 2-year event-free survival for the patients in newly diagnosed group (86.6 %; 95 % CI, 70.4-100 %) was superior to that in chronic group (57.0 %; 95 % CI, 43.5-70.4 %, P = 0.001). To date, 11 patients relapsed and no patients evolved to clonal disorders. Thus, CSA and LMS regimen represents a promising immunosuppressive strategy for mAA. [ABSTRACT FROM AUTHOR]

Background: Previous reports showed that outcome of rabbit antithymocyte globulin (rATG) was not satisfactory as the first-line therapy for severe aplastic anemia (SAA). We explored a modifying schedule of administration of rATG. Design and Methods: Outcomes of a cohort of 175 SAA patients, including 51 patients administered with standard protocol (3.55 mg/kg/d for 5 days) and 124 cases with optimized protocol (1.97 mg/kg/d for 9 days) of rATG plus cyclosporine (CSA), were analyzed retrospectively. Results: Of all 175 patients, response rates at 3 and 6 months were 36.6% and 56.0%, respectively. 51 cases received standard protocol had poor responses at 3 (25.5%) and 6 months (41.2%). However, 124 patients received optimized protocol had better responses at 3 (41.1%, P = 0.14) and 6 (62.1%, P = 0.01). Higher incidences of infection (57.1% versus 37.9%, P = 0.02) and early mortality (17.9% versus 0.8%, P<0.001) occurred in patients received standard protocol compared with optimized protocol. The 5-year overall survival in favor of the optimized over standard rATG protocol (76.0% versus. 50.3%, P<0.001) was observed. By multivariate analysis, optimized protocol (RR = 2.21, P = 0.04), response at 3 months (RR = 10.31, P = 0.03) and shorter interval (<23 days) between diagnosis and initial dose of rATG (RR = 5.35, P = 0.002) were independent favorable predictors of overall survival. Conclusions: Optimized instead of standard rATG protocol in combination with CSA remained efficacious as a first-line immunosuppressive regimen for SAA. [ABSTRACT FROM AUTHOR]

Although all patients with paroxysmal nocturnal hemoglobinuria (PNH) have acquired mutations in the phosphatidylinositol glycan class-A(PIG-A)gene, their clinical courses are highly variable. We reviewed 280 PNH cases referred to our hospital from January 1990 through June 2010 to assess clinical presentations, prognostic factors influencing survival, difference among subcategories, and clinical significance of PNH clone size. The overall survival at 10 years after diagnosis estimated by Kaplan-Meier was 77.6%. Both univariate and multivariate analyses identified risk factors affecting survival, including age >40 years, absolute neutrophil count<0.5 × 10 cells/L, development of thrombotic events, evolution to myelodysplastic syndrome or acute myelogenous leukemia, and recurrent infections. The cohort of patients were divided into subcategories of classic PNH, PNH/AA, and PNH-sc/AA based on the recent proposed PNH working clinical classification, hemoglobinuria as the initial symptomatic manifestation was high up to 82.0% in classic PNH subcategory, whereas only as low as 1.4% in PNH-sc/AA subcategory; the frequencies of infectious (26.0%) and bleeding symptoms (14.0%) in classic PNH subcategory were significantly less than those in PNH/AA (25.3% and 51.7%, respectively) and PNH-sc/AA (48.3% and 83.2%, respectively) subcategories. Our results revealed that large PNH clone was associated with increased risks for hemoglobinuria and thrombosis, whereas small PNH clone was associated with bone marrow failure. Thus, this study may shed insights into Chinese PNH patients to set up individually therapeutic regimens. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 10-year-old girl who was diagnosed with Iron-refractory iron deficiency anaemia (IRIDA), an autosomal recessive genetic disorder caused by mutation in TMPRSS6 gene. It reports that to confirm the diagnosis of IRIDA, the hormone hepcidin level in serum was measured using enzyme-linked immunosorbent assay and TMPRSS6 mutations were screened by DNA sequencing. Further it mentions that she was given glucocorticoids which leads to decrease in serum hepcidin.

The article reports the use of immunosuppressant drug cyclosporin in combination with antihelminthic drug levamisole for aplastic anaemia. It mentions that the treatment was done with immunosuppressive therapy (IST) by anti-thymocyte globulin (ATG), infusion of horse or rabbit-derived antibodies against human T cells, and cyclosporin. Several tables related to patient's characteristics and the pretreatment blood count and results of patients are depicted.

Summary: Securely performing nearest neighbor query over encrypted data in cloud is an important topic in the area of cloud computing, for which Wang et al recently put forward a scheme (ie, CloudBI‐II) to address the challenging security problem: resisting the collusion of cloud server and query users. In this paper, we propose an efficient attack method that indicates CloudBI‐II will reveal the difference vectors under the collusion attack. Furthermore, we show that the difference vector disclosure will result in serious privacy breach and, thus, attain an efficient attack method to break CloudBI‐II. Namely, CloudBI‐II cannot achieve their declared security. Through theoretical analysis and experiment evaluation, we confirm that our proposed attack approach can fast recover the original data from the encrypted data set in CloudBI‐II. Finally, we provide an enhanced scheme that can efficiently resist the collusion attack. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning megaloblastic anemia in China.