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Glucose oxidases (GODs) induce the catalyzation from β- d -glucose to gluconic acid in an oxygen-consuming process, providing a potential antibiotic substitution strategy. However, the inadequate properties of existing GODs in parallel hinder the antimicrobial capacity for industrial applications. In this study, PaGOD (WT) from Penicillium amagasakiense was enzymatically improved through computer-aided design based on energy optimization. Two thermostable variants A263P and K424F were selected and combined to generate variant A263P/K424F, superior in both thermostability (t 1/2 at 60 °C increased 2.6-fold) and catalytic efficiency (2.1-fold increase in catalytic efficiency), in comparison with the WT. The molecular dynamics simulations revealed the improved rigidity of A263P/K424F is attributed to the formation of hydrogen bonds within the flexible region and the newly-formed salt bridge Lys473: Asp477, following the increased ΔΔG. For improvement of antibacterial capacity, A263P/K424F impressively lower the half maximal inhibitory concentrations (IC 50) to 12 and 11 mg/L respectively for Escherichia coli and Staphylococcus aureus (86.4 % and 78.8 % lower than the WT, 65.7 % and 50 % lower than erythromycin). The results indicated that the antibacterial effects of GOD can be improved through in vitro molecular modification, which could be an effective strategy to address antibacterial requirements with antibiotic-free agents. • This study provides a potential antibacterial GOD for antibiotic substitution. • Antibacterial capacity was optimized by stabilizing the GOD for better properties. • Computer-aided design increased loop rigidity and remote interaction of target GOD. • The mutant exhibited better inhibition than erythromycin for some common bacteria. [ABSTRACT FROM AUTHOR]

China's mariculture is an indispensable part of the world's aquaculture and helps address food security issues in China and around the globe. However, this industry is facing a grand challenge from global warming. Therefore, it is urgent to assess the sensitivity of the main mariculture species and production modes to the increasing temperature. Here, we first extracted the coastal temperature data from 1465 grid cells (0.25 × 0.25 arcdegree) in the mariculture regions, and then compiled an upper thermal limit as well as culturing modes dataset of forty-two commercially important mariculture species. With these two datasets, we calculated the thermal safety margin (TSM) for each species across its aquaculture regions. Our results showed that several species with low TSMs were particularly sensitive to the current conditions and future warming, and some culturing regions face catastrophic consequences caused by high temperature and potential heatwaves. It is also noted that several mariculture modes like pond farming and mudflat ranching were more vulnerable compared to other mariculture modes. In summary, China's mariculture industry is sensitive to global warming at present and in the future. Our present study also provided tools to assess the risks in mariculture production and suggested solutions for future mitigation and adaptations. [ABSTRACT FROM AUTHOR]

We performed a nested case-control study to investigate the incidence, treatment, and prognosis of central nervous system (CNS) relapse after allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) and compared the outcomes of patients with CNS relapse following haploidentical donor (HID) HSCT versus identical sibling donor (ISD) HSCT. A total of 37 patients (HID-HSCT, 24; ISD-HSCT, 13) developed CNS relapse after transplantation between January 2009 and January 2019, with an incidence of 1.81%. The median time from transplantation to CNS relapse was 239 days. Pre-HSCT CNS involvement (HR 6.940, 95% CI 3.146–15.306, p <.001) was an independent risk factor for CNS relapse after allo-HSCT for AML. The 3-year overall survival (OS) for patients with CNS relapse was 60.3 ± 8.8%, which was significantly lower than that in the controls (81.5 ± 4.5%, p =.003). The incidence of CNS relapse was 1.64% for patients who received HID-HSCT and 2.55% for those who received ISD-HSCT (p =.193). There was no significant difference in OS between the HID-HSCT and ISD-HSCT subgroups among the patients with CNS relapse. In conclusion, CNS relapse is a rare but serious complication after allo-HSCT for AML, and the incidence and outcomes of patients with CNS relapse are comparable following HID-HSCT and ISD-HSCT. [ABSTRACT FROM AUTHOR]

Our understanding of the pathogenesis of immune thrombocytopenia (ITP) remains limited due to the complexity and heterogeneity of the disease. Recently, we observed that bone marrow mesenchymal stem cells (MSCs) derived from ITP patients exhibited growth defects and functional abnormalities that might be involved in the breakdown of self-tolerance. However, the underlying mechanism remains unclear. In this study, we profiled the expression of both mRNAs and miRNAs by utilizing the microarray technique and deciphered the mechanism underlying the impairment of MSCs derived from ITP patients (MSC-ITP). In total, we identified 740 genes and 32 miRNAs that were differentially expressed between ITP patients and controls. A compromised unfolded protein response (UPR) and decreased DNA transcription were shown to be significantly related to MSC-ITP. The interaction of miRNA with mRNA suggested that the cellular stress response, the UPR, and DNA transcription may be involved in the defects observed in MSC-ITP. Key differentially expressed genes were further validated by RT-PCR. Our results highlight that defects in the cellular stress response, as shown by a compromised UPR and differential DNA transcription, play key roles in causing the abnormalities observed in MSC-ITP. These data might contribute to a better understanding of the abnormal bone marrow niche and provide new insights into the pathogenesis of ITP. [ABSTRACT FROM AUTHOR]

Objectives: Ectopic pregnancies are among the leading causes of maternal morbidity and mortality in both developed and emerging nations, but tests for early, accurate, and convenient detection are lacking.Study Design: Between January 2013 and February 2015, 504 women with tubal pregnancy were prospectively recruited, and their clinical characteristics were recorded. Samples of peritoneal fluid were collected by culdocentesis, and venous blood was drawn from the antecubital vein. In samples from each source, levels of the following biochemical markers were measured: cancer antigen 125 (CA125), human chorionic gonadotropin (hCG), progesterone, vascular endothelial growth factor, and creatine kinase.Results: The ratios of biochemical markers in the peritoneal fluid and in the blood (Rp/v) were calculated. The median of Rp/v-CA125 and Rp/v-hCG were significantly lower in the ruptured ectopic pregnancy group than in the unruptured group. The optimal cutoff value to detect ectopic pregnancy rupture was 401.5U/mL as the upper limit for peritoneal CA125, with a sensitivity of 93.5% and specificity of 74.2%. The optimal cutoff value was 18.7 as the upper limit in the peritoneal fluid/blood ratio (Rp/v) of CA125, with a sensitivity of 77.5% and specificity of 68.4%.Conclusions: In countries with poor access to laparoscopy, culdocentesis is useful. In this study, culdocentesis provided additional information for management of abdominal pain when laparoscopy is not available. The authors propose Rp/v cutoff values that can be used conveniently and quickly to diagnose ruptured ectopic pregnancies and bleeding, enabling rapid and appropriate therapeutic responses. [ABSTRACT FROM AUTHOR]

Summary: Patients who receive allogeneic haematopoietic stem cell transplantation (allo‐HSCT) may develop sepsis, which result in a highly intensive care unit admission rate and mortality. Therefore, short‐term and long‐term prognostic models for sepsis after allo‐HSCT are urgently needed. We enrolled patients receiving allo‐HSCT who developed sepsis after allo‐HSCT at Peking University People's Hospital between 2012 and 2021, including 287 patients who received allo‐HSCT in 2018–2021 in the derivation cohort, and 337 patients in 2012–2017 in the validation cohort. Multivariate logistic regression analysis was used to identify prognostic factors, and these identified factors were incorporated into two scoring models. Seven independent factors (acute graft‐versus‐host disease (GVHD), chronic GVHD (cGVHD), total bilirubin, lactate dehydrogenase (LDH) and organ dysfunction [renal, lung and heart]) were included in the 6‐month prognostic model, and six factors (cGVHD, C‐reactive protein, LDH, organ dysfunction [lung, neurologic and coagulation]) were included in the 14‐day prognostic model. The area under the receiver operating characteristic curves, calibration plots and decision curve analysis demonstrated the robust predictive performance of the models, better than the Sequential Organ Failure Assessment score. Early identification of patients with high risk of 6‐month and 14‐day death may allow clinicians to provide timely treatments and improve the therapeutic effects. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo‐HSCT) and establish a prognostic model to identify post‐transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo‐HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo‐HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773–0.950), and the external AUC was 0.815 (95% CI, 0.708–0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients. [ABSTRACT FROM AUTHOR]

Patients with hepatitis B‐related cirrhosis complicated with thrombocytopenia have a higher risk of bleeding, which may lead to higher mortality. We aimed to explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) in the treatment of hepatitis B‐related cirrhosis complicated with severe thrombocytopenia. Patients with hepatitis B‐related compensated liver cirrhosis complicated with severe thrombocytopenia were divided into four groups according to the treatment method for thrombocytopenia. Platelet counts, the appearance of bleeding symptoms and adverse events were evaluated during the observation period. Also during the observational period, the platelet counts in the prednisone group, rhTPO group and prednisone plus rhTPO group were higher than those in the no treatment group. Patients without splenomegaly reacted better to rhTPO. Fewer bleeding events of grade 2 or worse were observed in the three treatment groups compared to the no treatment group. The platelet counts at baseline and treatment with rhTPO and/or prednisone were factors associated with bleeding events of grade 2 or worse in multivariate analysis. There could be a potential advantage for the use of rhTPO plus prednisone based on higher platelet counts and fewer bleeding events. Treatment with rhTPO was more effective in patients without splenomegaly. [ABSTRACT FROM AUTHOR]

Recent findings have shown that the level of interleukin‐35 (IL‐35) is abnormal in several autoimmune diseases. Nonetheless, whether IL‐35 participates in the pathogenesis of immune thrombocytopenia (ITP) remains unclear. The current study investigates whether IL‐35 modulates megakaryopoiesis. The results show that IL‐35 receptors are progressively expressed on bone marrow megakaryocytes during the in vitro differentiation of CD34+ progenitors. IL‐35 increases the number of megakaryocyte colony‐forming units through the Akt pathway. The level of bone marrow IL‐35 is reduced in ITP patients, and the decreased level of IL‐35 may inhibit megakaryopoiesis. Then, the potential causes of decreased IL‐35 in ITP patients are explored. The primary type of cell that secretes IL‐35, known as IL‐35‐producing regulatory T cells (iTr35), is reduced in ITP patients. Bone marrow mesenchymal stem cells (MSCs) from ITP patients exhibit an impaired capability of inducing iTr35 due to enhanced apoptosis, which may contribute to the reduced level of bone marrow IL‐35 in ITP patients. Iguratimod promotes megakaryocyte development and differentiation by elevating the expression of IL‐35 receptors on megakaryocytes. Iguratimod improves response rates and reduces bleeding symptoms in corticosteroid‐resistant ITP patients. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) can cause end-organ diseases including pneumonia, gastroenteritis, retinitis, and encephalitis in hematopoietic stem cell transplantation recipients. Potential differences among different CMV diseases remain uncertain. This study aimed to compare the clinical characteristics, risk factors, and mortality among different CMV diseases. A retrospective nested case-control study was performed based on a cohort of 3862 patients who underwent haploidentical hematopoietic stem cell transplantation at a single-center. CMV diseases occurred in 113 (2.92%) of 3862 haplo-HSCT recipients, including probable CMV pneumonia (CMVP, n = 34), proven CMV gastroenteritis (CMVG, n = 34), CMV retinitis (CMVR, n = 31), probable CMV encephalitis (CMVE, n = 7), and disseminated CMV disease (Di-CMVD, n = 7). Most (91.2%) cases of CMVG developed within 100 days, while most (90.3%) cases of CMVR were late onset. Refractory CMV infection and CMV viral load at different levels were associated with an increased risk of CMVP, CMVG, and CMVR. Compared with patients without CMV diseases, significantly higher non-relapse mortality at 1 year after transplantation was observed in patients with CMVP and CMVR, rather than CMVG. Patients with CMVP, Di-CMVD, and CMVE had higher overall mortality after diagnosis than that of patients with CMVG and CMVR (61.7%, 57.1%, 40.0% vs 27.7%, 18.6%, P = 0.001). In conclusion, the onset time, viral dynamics, and mortality differ among different CMV diseases. The mortality of CMV diseases remains high, especially for CMVP, Di-CMVD, and CMVE. [ABSTRACT FROM AUTHOR]

Summary: The abnormal immunomodulatory functions of mesenchymal stem cells (MSCs) have been implicated in the development of immune thrombocytopenia (ITP). Recent studies have suggested important effects of complement on immune cell function. However, whether complement modulates bone marrow MSCs function in ITP is poorly defined. Tacrolimus has recently been applied to the treatment of autoimmune diseases. Here, we explored whether impaired ITP‐MSCs could be targeted by tacrolimus. Our results showed that the Nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome was activated in ITP MSCs with complement deposition (MSCs‐C+) and initiated caspase‐1‐dependent pyroptosis. Transcriptome sequencing results showed abnormal fatty acid metabolism in MSCs‐C+. Enhanced fatty acid β‐oxidation and reactive oxygen species production activated the NLRP3 inflammasome. Adipocytes derived from MSCs‐C+ secreted less adiponectin. Adiponectin promoted the differentiation of megakaryocytes and inhibited the destruction of platelets. Tacrolimus inhibited NLRP3 inflammasome activation and MSCs‐C+ pyroptosis in vitro and in vivo. Tacrolimus plus danazol elicited a higher sustained response than danazol monotherapy in corticosteroid‐resistant patients with ITP. Our findings demonstrate that the activation of the NLRP3 inflammasome in ITP MSCs mediated by complement could be inhibited by tacrolimus, which might be a potential new therapy for ITP. [ABSTRACT FROM AUTHOR]

3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss. [ABSTRACT FROM AUTHOR]

The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide (CLA) enantiomers as CYP3A4 substrates were investigated. The apparent permeability coefficients ( P app ) of (−) and (+)CLA were higher in the absorptive direction than those in the secretory direction with efflux ratios (ER) of 0.709 ± 0.411 and 0.867 ± 0.250 (×10 −6 cm/s), respectively. Their bidirectional transports were significantly reduced by 75.6–87.5% after treatment with verapamil (a P -glycoprotein inhibitor) that increased the rate of metabolism by CYP3A4, whereas the CYP3A4 inhibitor ketoconazole treatment markedly enhanced the basolateral to apical flux of (−) and (+)CLA with ERs being 2.934 ± 1.432 and 1.877 ± 0.148(×10 −6 cm/s) respectively. These changes could be blocked by the duel CYP3A4/ P -glycoprotein inhibitor cyclosporine A, consequently, P app values for CLA enantiomers in both directions were significantly greater than those obtained by using verapamil or ketoconazole, and their ERs were similar to those following (−) or (+)-isomer treatment alone. Furthermore, the uptake of (−)CLA was more than that of (+)CLA in the transfected cells. Incubation with ketoconazole decreased the intracellular concentrations of the two enantiomers. This effect disappeared in the presence of a CYP3A4 inducer dexamethasone. These results indicated that CYP3A4 could influence P -gp efflux, transport and uptake of CLA enantiomers as CYP3A4 substrates and that a duel inhibition to CYP3A4/ P -glycoprotein could enhance their absorption and bioavailability, which provides new insight into the efflux-metabolism alliance and will benefit the clinical pharmacology of (−)CLA as a candidate drug for treatment of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

The (−)- and (+)-clausenamide (CLA) enantiomers have different pharmacokinetic effects in animals, but their association with putative stereoselective regulation of P-glycoprotein (P-gp) remains unclear. Using three cells expressing P-gp—Caco-2, KBv and rat brain microvessel endothelial cells(RBMEC), this study investigated the association of CLA enantiomers with P-gp. The results showed that the rhodamine 123 (Rh123) accumulation, an indicator of P-gp activity, in Caco-2, KBv and RBMECs was increased by (−)CLA (1 or 5 μmol/L) at 8.2%–28.5%, but reduced by (+)CLA at 11.7%–25.9%, showing stereoselectivity in their regulation of P-gp activity. Following co-treatment of these cells with each CLA enantiomer and verapamil as a P-gp inhibitor, the (+)-isomer clearly antagonized the inhibitory effects of verapamil on P-gp efflux, whereas the (−)-isomer had slightly synergistic or additive effects. When higher concentrations (5 or 10 μmol/L) of CLA enantiomers were added, the stimulatory effects of the (+)-isomer were converted into inhibitory ones, leading to an enhanced intracellular uptake of Rh123 by 24.5%–58.2%; but (−)-isomer kept its inhibition to P-gp activity, causing 30.0%–63.0% increase in the Rh123 uptake. The biphasic effects of (+)CLA were confirmed by CLA uptake in the Caco-2 cells. (+)CLA at 1 μmol/L had significantly lower intracellular uptake than (−)CLA with a ratio[(−)/(+)] of 2.593, which was decreased to 2.167 and 1.893 after CLA concentrations increased to 2.5 and 5 μmol/L. Besides, in the non-induced KB cells, (+)CLA(5 μmol/L) upregulated P-gp expression at 54.5% relative to vehicle control, and decreased Rh123 accumulation by 28.2%, while (−)CLA(5 μmol/L) downregulated P-gp expression at 15.9% and increased Rh123 accumulation by 18.0%. These results suggested that (−)CLA could be a P-gp inhibitor and (+)CLA could be a modulator with concentration-dependent biphasic effects on P-gp activity, which may result in drug—drug interactions when combined with other P-gp substrate drugs. [ABSTRACT FROM AUTHOR]

The incidence of herpes zoster (HZ) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is significantly higher than that of the general public. Although routine antiviral prophylaxis is recommended, late-onset HZ has been highlighted, yet limited information is known about its clinical features and predictors. Here, we conducted a retrospective nested case-control study to identify patients with late-onset HZ, defined as a diagnosis of HZ after 1 year of transplantation, among allo-HSCT recipients between 2012 and 2017 at Peking University People's Hospital. Three controls were matched for each patient. A total of 201 patients developed late-onset HZ. Age over 20 years, absence of neutrophil engraftment by 14 days, mental disorders, immunosuppressant use at 1 year, and a peripheral CD4+/CD8+ ratio ≥0.5 at 1 year were independent risk factors, among which the CD4+/CD8+ ratio demonstrated good discriminative power for predicting late-onset HZ. For patients with a CD4+/CD8+ ratio <0.5, patient age, neutrophil engraftment time, mental disorders, and immunosuppressant use were potential risk factors. A stratification algorithm was accordingly established, classifying the transplant recipients into three risk groups. Whether the algorithm could facilitate the administration of posttransplant antiviral prophylaxis merits further validation. • Late-onset herpes zoster is not rare after HSCT despite routine prophylaxis. • A higher CD4+/CD8+ ratio predicts the occurrence of late-onset HZ. • Age, NE engraftment, mental disorder, and immunosuppression are risk factors. • A risk stratification algorithm is suggested to facilitate long-term HZ prevention. [ABSTRACT FROM AUTHOR]

With the rapid development of the triple play, mobile devices can access various video information on Internet by using 3G networks. However, it is not convenient for users that there are various kinds of video formats. An advanced task scheduling algorithm supporting dynamic loading balance (ADLBA) is proposed based on the research and analysis of Linux Virtual Server (LVS). We implement to prove its feasiblity and practicality. [ABSTRACT FROM AUTHOR]

Thrombocytopenia is a common complication of human cytomegalovirus (HCMV) infection in immunocompromised hosts, which contributes to poor prognosis even in patients receiving antiviral treatment. Here, we investigated the megakaryo/thrombopoiesis process, including the involvement of the c‐Mpl/IEX‐1 pathway, after HCMV infection, identified receptors mediating the interaction between megakaryocytes (MKs) and HCMV, and explored novel therapeutic targets. Our data shows that HCMV directly infects megakaryocytes in patients with HCMV DNAemia and influences megakaryopoiesis via the c‐Mpl/IEX‐1 pathway throughout megakaryocyte maturation, apoptosis, and platelet generation in vivo and in vitro. After treatment with inhibitors of PDGFRα and αvβ3, the HCMV infection rate in MKs was significantly reduced, suggesting that IMC‐3G3 and anti‐αvβ3 are potential therapeutic alternatives for viral infection. In summary, our study proposes a possible mechanism and potential treatments for thrombocytopenia caused by HCMV infection and other viral diseases associated with abnormal hemostasis. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is regarded as a curative therapy for majority of hematologic malignancies and some non-malignant hematologic diseases. Venous thromboembolism (VTE) has become increasingly recognized as a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). To show the characteristics of VTE after haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) and make comparisons with matched related donor HSCT (MRD-HSCT). A retrospective nested case-control study design was used, cases with VTE and matched controls were selected, with 3534 patients underwent HID-HSCT and 1289 underwent MRD-HSCT. During follow-up, 114 patients with VTE were identified. The incidence of VTE in HID-HSCT group was similar to that of MRD-HSCT group (2.4% versus 2.3%, P = 0.92). In HID-HSCT group, VTE occurred at a median time of 92.5 days, which was earlier than MRD-HSCT group (243.5 days). For HID-HSCT, advanced disease status, cardiovascular risk factors, acute graft-versus-host disease (aGVHD), and relapse were the independent risk factors for VTE. For MRD-HSCT, cardiovascular risk factors, aGVHD, and relapse were associated with VTE. Overall survival (OS) of patients following HID-HSCT and MRD-HSCT were similar, but the OS in patients with VTE was significantly lower than patients without VTE. There was no statistical difference in the incidence of VTE after HID-HSCT compared with MRD-HSCT. The development of VTE adversely impacted the OS after allo-HSCT. • The incidence of VTE in HID-HSCT is similar to that in MRD-HSCT. • Prior VTE, cardiovascular risk factors, GVHD and relapse are associated with VTE after allo-HSCT. • The development of VTE adversely impacts overall survival after allo-HSCT. [ABSTRACT FROM AUTHOR]

• The incidence of immune-mediated neuropathies (IMN) following haploidentical hematopoietic stem cell transplantation was reported. • Cytomegalovirus viremia and chronic graft-versus-host disease were identified as independent risk factors of post-transplant IMN. •T The outcomes of patients with post-transplant IMN were described. Immune-mediated neuropathies (IMNs) following hematopoietic stem cell transplantation have been described recently, which, excluding Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, may present with atypical patterns. This retrospective, nested, case-control study reviewed data from 3858 patients who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) during the past 10 years at a single center, and 40 patients (1.04%) with IMN following haplo-HSCT were identified. Chronic graft-versus-host disease (cGVHD) (P =.043) and cytomegalovirus (CMV) viremia (P =.035) were recognized as independent risk factors for the development of IMN after haplo-HSCT. There were no significant differences in overall survival (P =.619), disease-free survival (P =.609), nonrelapse mortality (P =.87), or the incidence of relapse (P =.583) between patients with and without IMN after haplo-HSCT. However, patients with post-transplant IMN were at higher risk of developing cGVHD (P =.012) than patients who did not develop IMN. Twenty-four of the 40 patients with IMN (60%) attained neurologic improvement after treatments including vitamins B 1 and B 12 and/or immunomodulatory agents. However, 19 (47.5%) patients still had persistent motor/sensory deficits despite receiving timely treatment. More studies are needed to help develop standardized diagnostic and therapeutic strategies for patients with post-transplant IMN. [ABSTRACT FROM AUTHOR]

ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients. [ABSTRACT FROM AUTHOR]

Summary: Immune thrombocytopenia (ITP) is an autoimmune disease. Mesenchymal stem cells (MSCs) play important roles in the physiology and homeostasis of the haematopoietic system, including supporting megakaryocytic differentiation from CD34+ haematopoietic progenitor cells. Tumour necrosis factor alpha‐induced protein 3 (TNFAIP3, also termed A20) plays a key role in terminating NF‐κB signalling. Human genetic studies showed that the polymorphisms of the TNFAIP3 gene may contribute to ITP susceptibility. In this study, we showed a significant decrease in TNFAIP3 and increase in NF‐κB/SMAD7 in ITP‐MSCs. In co‐cultures with CD34+ cells, NF‐κB was overexpressed in MSCs from healthy controls (HC‐MSCs) after transfection with NFKBIA (IκB)‐specific short hairpin (sh)RNAs, resulting in MSC deficiency and a reduction in megakaryocytic differentiation and thrombopoiesis. Knockdown of TNFAIP3 expression using TNFAIP3‐specific shRNAs in HC‐MSCs affected megakaryocytopoiesis. However, IKBKB knockdown corrected megakaryocytopoiesis inhibition in the ITP‐MSCs by decreasing NF‐κB expression. Amplified TNFAIP3 expression in ITP‐MSCs by TNFAIP3 cDNA can facilitate megakaryocyte differentiation. shRNA‐mediated knockdown of SMAD7 expression rescued the impaired MSC function in ITP patients. Therefore, we demonstrate that a pathological reduction in TNFAIP3 levels induced NF‐κB/SMAD7 pathway activation, causing a deficiency in MSCs in ITP patients. The ability of ITP‐MSCs to support megakaryocytic differentiation and thrombopoiesis of CD34+ cells was impaired. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To explore the possible risk factors for the occurrence and mortality of thrombotic microangiopathy (TMA) with concomitant acute graft‐vs‐host disease (aGVHD) and to investigate outcomes and treatments of this disorder after allo‐HSCT. Methods: Fifty cases diagnosed with TMA with concomitant aGVHD and 150 controls were identified from a cohort composed of 3992 patients who underwent allo‐HSCT from 2008 to 2016. Results: Grade III‐IV aGVHD (P = .000), acute kidney injury (AKI) (P = .033), and hypertension (P = .028) were significant independent risk factors associated with the occurrence of TMA with concomitant aGVHD. A haptoglobin level below normal (P = .013), a maximum volume of diarrhea >2500 mL/d (P = .015), and bloody diarrhea (P = .049) were significant markers for death in both univariate and multivariate analyses. Patients diagnosed with TMA with concomitant aGVHD had a lower overall survival (OS), a higher non‐relapse mortality (NRM), but a lower risk of relapse. Conclusions: Thrombotic microangiopathy with concomitant aGVHD is a significant complication after allo‐HSCT, with a worse outcome, including significantly lower OS and higher NRM. There are specific risk factors associated with occurrence and mortality of this complication. [ABSTRACT FROM AUTHOR]

Noroviruses are a common cause of acute gastroenteritis outbreaks in institutions including schools and kindergartens around the world. An outbreak caused by GII.P16-GII.2 norovirus in a kindergarten in Lianyungang, Jiangsu Province, China is reported here. An epidemiological investigation was conducted, and pathogen detection was performed. The descriptive analysis indicated that this outbreak in middle class 1 had a point source. Twenty cases of acute gastroenteritis occurred in this class within a period of 8.5 h; the attack rate was 52.6% (20/38). Airborne transmission via the air conditioning unit in a confined restroom could have played a critical role in this outbreak. Sequence analysis of GII-positive samples confirmed that the norovirus GII.P16-GII.2 variant was the etiological agent of this outbreak. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease in which dendritic cells (DCs) play a crucial role in the breakdown of self-tolerance. Studies have identified the function of mesenchymal stem cells (MSCs) in promoting the development of regulatory DCs (regDCs). Our previous work revealed that MSCs in ITP exerted senescence, apoptosis, and impaired immunosuppressive effects on T and B cells. However, it is unclear whether the effects of MSCs on regDC induction are altered in ITP. Our data demonstrated that MSCs in ITP were impaired in inhibiting CD1a+ DC and CD14+ DC differentiation from CD34+ hematopoietic progenitor cells (CD34+ HPCs). DCs differentiated with MSCs in ITP exhibited an increased expression of costimulatory molecules CD80/CD86 and secretion of proinflammatory interleukin-12 (IL-12). Accordingly, the tolerogenic characteristics were deficient in DCs induced by MSCs in ITP. DCs differentiated with MSCs in ITP exhibited an impaired ability to inhibit CD3+ T cell proliferation, to suppress T helper (Th)1 cell differentiation, and to induce anergic and regulatory T cells (Tregs). The expression of Notch signaling components was measured in MSCs in ITP. Reduced expression of the ligand Jagged-1, the receptor Notch-1 intracellular domain (NICD-1), and the target gene Hes-1 was identified in MSCs in ITP. The addition of biologically active Jagged-1 to CD34+ HPCs was observed to promote regDC differentiation. When cultured on Jagged-1-coated plates, MSCs in ITP showed an enhancement of the Notch-1 pathway activation, Jagged-1 expression, and the function in inducing regDCs. Pretreatment with all-trans retinoic acid (ATRA) was found to partially restore the capacity of MSCs in both ITP patients and healthy controls in inducing CD34+-derived regDCs. Our data elucidated that MSCs in ITP were impaired in inducing CD34+-regDCs, associated with the Notch-1/Jagged-1 signaling pathway. ATRA could partially correct the impairment of MSCs, suggesting that ATRA could serve as a potential therapeutic alternative for ITP. [ABSTRACT FROM AUTHOR]

The role ofHelicobacter pylori(H. pylori) infection on thrombocytopenia in chronic hepatitis B (CHB) related compensatory cirrhotic patients is unknown. We conducted an observational study to determine whetherH. pyloriplays a role in these patients. A total of 255 patients from three centers in China were enrolled in the study. All patients received nucleoside analogs (NA) therapy and were screened forH. pyloriinfection. Patients were divided into three groups based on theirH. pyloriinfection status and the therapy administered: patients withoutH. pyloriinfection who received NA therapy alone (N = 146); patients withH. pyloriinfection who received NA therapy alone (n = 48); and patients withH. pyloriinfection who receivedH. pylorieradication combined with NA therapy (N = 61). We observed that in CHB compensatory cirrhotic patients withH. pyloriinfection, the platelets count was significantly lower relative to uninfected patients (31 versus 60 × 109/L,p < 0.01). During a 2-year follow-up, the elevation in platelet count was significantly higher in HBV/H. pylorico-infected patients who received the NA andH. pylorieradication treatment compared to the other two groups (p < 0.01). It suggested thatH. pyloriinfection and eradication treatment combined with NA were independent risk factors associated with platelets response during treatment of thrombocytopenia in CHB compensatory cirrhosis (p < 0.01). In conclusion,H. pyloriinfection may associate with thrombocytopenia in CHB compensatory cirrhosis.H. pylorieradication combined with NA treatment may prove to be beneficial to CHB compensatory cirrhotic patients with thrombocytopenia who are infected withH. pylori. [ABSTRACT FROM PUBLISHER]

Objectives The aim of this study was to investigate the role of prostacyclin (PGI 2 ) in prolonged isolated thrombocytopenia (PT) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the effect of PGI 2 on the activation and aggregation of platelets in PT. Methods We enrolled 37 patients with PT and 36 controls following allo-HSCT in this study. Platelet aggregation and activation and PGI 2 levels were measured. Endothelial progenitor cells (EPCs) from either PT or control patients were cultured ex vivo with serum from either PT or control patients. PGI 2 secretions were then measured. PGI 2 was added to the platelets ex vivo , and platelet aggregation and activation and PI3K/Akt phosphorylation were analyzed. Results A higher PGI 2 level was observed in the PT patients. The activation and aggregation of platelets were significantly lower in the PT patients. EPCs from PT patients cultured in PT serum secreted higher levels of PGI 2 , and PGI 2 inhibited platelet activation and aggregation in a concentration-dependent manner ex vivo . PI3K/Akt phosphorylation of platelets was regulated by PGI 2 after allo-HSCT. Disease status, serum PGI 2 level and platelet aggregation were independent risk factors in patients with PT after allo-HSCT. Conclusions Higher PGI 2 levels and lower platelet activation and aggregation occurred simultaneously in PT patients. PGI 2 inhibited platelet activation and aggregation, probably by regulating the phosphorylation of PI3K/Akt. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6 × DBA/2) F1 (BDF1, H-2b × d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-α and IL-17A expression and enhanced IFN-γ expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT. [ABSTRACT FROM AUTHOR]

B-cell acute lymphoblastic leukemia (B-ALL) in adults is a very challenging disease. Relapse following remission after induction chemotherapy remains the major barrier to patient survival. ADAM28 is overexpressed in several human tumors and is related to cell proliferation and lymph node metastasis. To date, no information has been available on the prognostic role of ADAM28 in B-ALL. Fifty consecutive patients with de novo B-ALL and 22 healthy donors were enrolled in this study and were followed for 2.8 years. Our data suggested that ADAM28 expression in B-ALL patients was significantly increased ( P < 0.0001). Patients experiencing disease relapse exhibited significantly increased ADAM28 expression, compared with those with favorable outcomes ( P = 0.0094). Notably, ADAM28 overexpression was associated with lower probabilities of relapse-free survival (RFS) and event-free survival (EFS) ( P < 0.001) and was a significant prognostic factor ( P < 0.001). In vitro , the PI3K/Akt pathway inhibitor, as well as arsenic trioxide (ATO), down-regulated ADAM28 expression. Our results were the first to indicate that ADAM28 overexpression in B-ALL patients is correlated with relapse. ADAM28 overexpression is potentially regulated by the PI3K/Akt pathway. These data demonstrate that ADAM28 might serve as a novel biomarker for evaluating relapse in B-ALL and as a potential therapeutic target in B-ALL patients. [ABSTRACT FROM AUTHOR]

No effective treatment has been identified for patients of liver cirrhosis (LC) associated with hepatitis B virus (HBV) and severe thrombocytopenia. We aimed to explore the effectiveness and safety of low-dose prednisone or cyclosporine A (CsA) combined with nucleoside analog (NA) in patients with severe thrombocytopenia associated with HBV-related LC. We included 145 consecutive compensated HBV-associated LC patients with severe thrombocytopenia between 1 January 2006 and 31 December 2013. We divided the patients into three groups by treatment strategy, including NA only (n = 57), NA plus prednisone (n = 46), and NA plus CsA (n = 42). We analyzed the platelet counts, bleeding events, liver function, replication of HBV, and outcomes in each group. At all time points during this observation, the platelet counts in prednisone or CsA group were higher than those in the NA only group. There are significant differences in the cumulative rates of bleeding events among the three groups. The platelet counts and treatment were factors associated with bleeding events in multivariate analysis. The differences in HBV-DNA negative rates, HBV-DNA elevated rates, normal serum alanine transaminase rates, serum alanine transaminase elevated more than two times the baseline rates, and HBeAg seropositive conversion ratio among the groups did not reach statistical significance. The adverse events in our study were, in general, mild and balanced among the three treatment groups. Treatment with low-dose prednisone or CsA plus NA could elevate the platelet counts and reduce the risk of bleeding events in HBV LC with severe thrombocytopenia. [ABSTRACT FROM PUBLISHER]