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Background Generalised pustular psoriasis (GPP) is a systemic inflammatory disease that can be severe, debilitating, and life-threatening. Uncontrolled activation of interleukin-36 (IL-36) pro-inflammatory activity may underlie the pathogenesis of GPP. Currently, GPP-specific treatment options are limited. Objectives To evaluate the efficacy and safety of the anti-IL-36 receptor antibody imsidolimab in subjects with GPP. Methods In an open-label, single-arm, multiple-dose study, subjects with GPP were treated with imsidolimab to assess clinical efficacy, tolerability, and safety. Subjects received an intravenous (IV) imsidolimab 750 mg dose on Day 1, followed by 3 doses of subcutaneous (SC) imsidolimab 100 mg administered on Days 29, 57, and 85. The primary efficacy endpoint was the proportion of subjects that achieved a clinical response at Week 4 and Week 16 following treatment with imsidolimab as measured by the Clinical Global Impression (CGI) scale. Results A total of 8 patients were enrolled and 6 subjects completed the study. Responses were observed as early as Day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at Day 8, Day 29, and through Day 113. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. No subject discontinued the study due to a non-serious TEAE. Two subjects experienced serious adverse events (SAEs) and no deaths were reported. Conclusions Imsidolimab demonstrated a rapid and sustained resolution of symptoms and pustular eruptions in subjects with GPP. It was generally well-tolerated, associated with acceptable safety, and is advancing to Phase 3 trials. These data support targeting of IL-36 signalling with a specific antibody, imsidolimab, as a therapeutic option for this severely debilitating condition. The study was registered under EudraCT Number 2017-004021-33 and NCT 03619902.

Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is rare in clinical practice. It is a systemic inflammatory disease caused by a cytokine storm. Its clinical manifestations include thrombocytopenia, systemic edema, fever, bone marrow fibrosis, renal insufficiency, and organ enlargement. The high mortality rate of TAFRO syndrome is due to the difficulty of acquiring biopsy samples for diagnosis and the rapid disease progression. This disease is poorly understood by clinicians. Early detection, accurate diagnosis, and timely treatment play key roles in prolonging the survival of the patients. This review summarizes the latest progress in the pathogenesis, diagnostic criteria, and treatment regimens of TAFRO syndrome, aiming to help clinicians better understand TAFRO syndrome and improve its diagnosis and treatment.

Epstein-Barr virus (EBV) viremia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the impacts of early-onset EBV viremia in acute leukemia (AL) patients who underwent allo-HSCT with anti-thymocyte globulin (ATG)-containing myeloablative conditioning (MAC) regimen. Two hundred and ninety-six patients were included between January 2013 and December 2015. In 126 patients (42.6%) who developed early-onset EBV viremia, with a median time of 48 (range 18~99) days after allo-HSCT. The cumulative incidence of EBV viremia at 30 and 90 days after allo-HSCT were 4.1 and 39.9%, respectively. Prognostic analysis showed that the adjusted overall survival in early-EBVpos group was significantly lower than early-EBVneg group within the first 26.7 months after allo-HSCT [hazard ratio (HR), 1.63, P = 0.012], but significantly higher than those afterward (after 26.7 months: HR 0.11, P = 0.035); for the adjusted event-free survival, early-EBVpos group was significantly inferior in early-EBVpos group within the first 10.8 months after transplantation (HR: 1.55, P = 0.042), and this adverse effect was not detected any more after 10.8 months (HR: 0.58, P = 0.107). Compared with early-EBVneg group after adjusting by aGVHD and CMV viremia, HR for death from transplant-related mortality was 2.78-fold higher in patients with early-EBV viremia in piecewise constant Cox analysis (P = 0.006), and this adverse effect was not detected any more after the cut-point time (HR: 0.67, P = 0.361). No differences in terms of relapse and relapse mortality were observed between early-EBVpos and early-EBVneg group (P > 0.05). In conclusion, the impacts on transplant outcomes of early-EBV viremia were time-dependent, which may help to optimize management strategies for early-EBV viremia after allo-HSCT, especially in AL patients with ATG-containing MAC regimen.

Visible light-driven photocatalytic oxidation technology has shown great potential for effective removal of organic pollutants from water and mitigation of energy crises at the same time. The highly effective and economic b-Fe2O3/BiOCl0.875Br0.125 photocatalyst was prepared by a facile hybrid compositing method with b-Fe2O3 and BiOCl0.875Br0.125 to overcome relatively high material cost and limited catalytic efficiency. Characterization techniques, such as XRD, SEM and XPS were used to study the purity and crystallization characteristics of the as-prepared photocatalyst. Furthermore, taking rhodamine b (RhB) as a simulated organic pollutant, the photocatalytic property of b-Fe2O3/BiOCl0.875Br0.125 with different Bi content was further evaluated by static catalytic degradation test under visible-light. The results indicated that the photocatalytic efficiency of the novel composites increases with the improvement of Bi content. Additionally, in comparison to equal mass of pure phase BiOCl0.875Br0.125, when the Bi content reached to 30%, a comparable and even better photocatalysis performance was achieved by the as-prepared b-Fe2O3/BiOCl0.875Br0.125. The hybrid b-Fe2O3/BiOCl0.875Br0.125 has a potential cost advantage in practical water treatment, and provide an attractive method for fabricating efficient visiblelight- driven photocatalysts.

Background: Cytomegalovirus (CMV) infection of the central nervous system (CNS) is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Cases presentation: Two patients with drug-resistant CMV encephalitis after allo-HSCT were successfully treated with donor CMV-specific cytotoxic T lymphocytes (CTLs). In the first case, a 27-year-old male who received haploidentical transplantation to treat T-cell acute lymphoblastic leukemia (T-ALL), developed CMV encephalitis during the time of the ganciclovir maintenance treatment. After intravenous foscarnet and donor CMV-specific CTLs, CMV-DNA of CSF became undetectable and the abnormal signs of brain magnetic resonance imaging (MRI) were limited. Another case, a 57-year-old female with acute myeloid leukemia (AML) who underwent haploidentical transplantation, also developed CMV encephalitis during the maintenance treatment of the ganciclovir. After administering donor CMV-specific CTLs intrathecally, the CMV load of the CSF decreased.Conclusions: The intravenous/intratheca administration of donor CMV-specific CTLs may be a safe and effective treatment for CMV encephalitis, especially for patients who suffered from drug-resistant CMV infection.

Excessively high concentration of inorganic salts in the groundwater is the main threat for residents to drink directly in the remote areas of northwestern China. In this paper, nano-porous membrane process was proposed to removal of diverse ions in such raw water. Through the response surface methodology (RSM), the effects of multiple factors on permeate flux and ion rejection rates were analysed, and the application scope of nanofiltration for various water resource was evaluated. It was found that the factors affecting permeate flux, chloride removal and nitrate removal (response value) followed some typical sequences, and the operating pressure was always the most influential factor. Besides, nanoporous membrane process showed predominant performance in the removal of sulphate, chloride and fluoride; the rejection rates were over 99%, 97% and 95%, respectively, and the produced water could completely satisfy the relevant national standards for drinking water. However, nitrate removal rate was seldom over 80%, and it reduced obviously with the increasing initial concentration of nitrate, thus the nitrate content of raw water should be controlled within 40 mg.L-1.

The problem of cyanobacteria blooms during potable water production has generated wide concern. Ferrate(VI) serving as a pre-oxidation tactic was first applied to enhance conventional Fe(II) coagulation for Microcystis aeruginosa-laden water treatment at lab scale. Results demonstrated that ferrate(VI) pre-oxidation could successfully destabilize algae cells through destroying the protective organic layer. The residual ferrate(VI) together with post-added Fe(II) could provoke a comproportionation reaction, where large amounts of Fe hydrolyzates [Fe(OH)3] are formed. The in-situ Fe(OH)3 with abundant reactive surface is responsible for the promotion of flocs growth by facilitating the clustering and cross-linking of algal organic matters (AOM) and cyanobacteria cells, simultaneously resulting in satisfactory reductions in OD680, turbidity and UV254. Overdose of ferrate(VI) could cause severe cell destruction along with the release of intracellular organic matter (IOM), which may impair the water quality by increasing the concentration of dissolved organic carbon (DOC) and the disinfection by-products formation potential (DBPFP). Meanwhile, considering the Fe residual in settled water, the optimal ferrate(VI) dose (20 µM) and Fe(II) dose (80 µM) were proposed. Besides, the synergistic effect of both the degradation by ferrate(VI) and the adsorption by in-situ Fe(OH)3 contributed to the removal of DOC and Microcystin-LR. This study suggests that ferrate(VI) might be a potential candidate for pre-treatment to assist Fe(II) coagulation when addressing algae-laden water.

T cells play crucial roles in our immunity against hematological tumors by inducing sustained immune responses. Flow cytometry-based detection of a limited number of specific protein markers has been routinely applied for basic research and clinical investigation in this area. In this study, we combined flow cytometry with the simple integrated spintip-based proteomics technology (SISPROT) to characterize the proteome of primary T cell subtypes in the peripheral blood (PB) from single multiple myeloma (MM) patients. Taking advantage of the integrated high pH reversed-phase fractionation in the SISPROT device, the global proteomes of CD3+, CD4+ and CD8+ T cells were firstly profiled with a depth of >7 000 protein groups for each cell type. The sensitivity of single-shot proteomic analysis was dramatically improved by optimizing the SISPROT and data-dependent acquisition parameters for nanogram-level samples. Eight subtypes of T cells were sorted from about 4 mL PB of single MM patients, and the individual subtype-specific proteomes with coverage among 1 702 and 3 699 protein groups were obtained from as low as 70 ng and up to 500 ng of cell lysates. In addition, we developed a two-step machine learning-based subtyping strategy for proof-of-concept classifying eight T cell subtypes, independent of their cell numbers and individual differences. Our strategy demonstrates an easy-to-use proteomic analysis on immune cells with the potential to discover novel subtype-specific protein biomarkers from limited clinical samples in future large scale clinical studies.

Objectives Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by CCND1/IGH rearrangement. We reported a case of MCL harboring both CCND1/IGH and MYC/IGH rearrangements that also presented with an aggressive clinical course. Methods Biopsy specimens were evaluated by morphological staining, immunohistochemistry, flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). Results Morphological and immunohistochemical staining of gallbladder samples demonstrated blastoid variant MCL. However, in the bone marrow sample, FISH indicated rearrangements in CCND1/IGH and MYC/IGH. Flow cytometry identified two groups of malignant lymphocytes. We sorted these two groups of cells. NGS then revealed that both cell types carried CCND1/IGH rearrangements and TP53 mutations. Furthermore, the CD19+/CD10+ cells carried additional MYC/IGH rearrangement and NOTCH2 mutation. Conclusions The rearrangement of MYC and a mutation in NOTCH2 probably induced the transformation of MCL cells in this patient. This uncommon double-hit MCL case clearly demonstrates a transformation process.

Central nervous system complications (CNSCs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and may be a significant source of morbidity and mortality. We performed a retrospective study of 153 pediatric patients who underwent allo-HSCT to determine CNSC type, incidence, and impact on survival. A total of 34 patients (22.2%) developed CNSCs. The cumulative incidence of CNSCs at 100 days and 3 years was 18.30 and 22.73%, respectively. The most common CNSC was calcineurin inhibitor (CNI)-associated neurotoxicity (50.0%). Risk factors for CNSCs were the time from diagnosis to HSCT ≥4.8 months (p = 0.032) and the development of acute graft-versus-host disease (aGVHD) grade III–IV (p = 0.002). CNSCs after allo-HSCT negatively impacted overall survival (hazard ratio [HR] 1.97, p = 0.043) and nonrelapse mortality (HR 4.84, p < 0.001). In conclusion, CNSCs after allo-HSCT are associated with poor outcomes; patients with severe aGVHD and/or late transplantation should be given more attention.

This paper considers combining a proof of concept (POC) study and a dose finding (DF) study where the POC and the DF share the same primary endpoint. An example based on real study conditions shows that compared to a conventional design the proposed adaptive design tests more active doses, with a smaller sample size and a shorter overall duration leading to a budget saving of 30% in study operations. Keywords: Adaptive design, Dose finding, Proof of concept, Seamless design, Budget saving

In this study, we compared the efficacy of mitoxantrone in combination with intermediate-dose cytarabine (HAM) with that of high-dose cytarabine alone (HiDAC) as consolidation regimens in non-acute promyelocytic leukemia (APL) acute myeloid leukemia patients with favorable and intermediate cytogenetics. A total of 62 patients from Shenzhen People's Hospital were enrolled in this study. All patients enrolled received standard induction chemotherapy and achieved the first complete remission (CR1). In these patients, 24 received HiDAC and 38 received HAM as consolidation. The median relapse free survival (RFS) and overall survival (OS) were similar between these two consolidation regimens. Even in subgroup analysis according to risk stratification, the combination regimen conferred no benefit in longterm outcome in patients with favorable or intermediate cytogenetics. However, in patients receiving HAM regimen, the lowest neutrophil count was lower, neutropenic period longer, neutropenic fever rate higher, and more platelet transfusion support was required. HAM group also tended to have higher rate of sepsis than HiDAC group. According to our results, we suggest that combination treatment with mitoxantrone and intermediate-dose cytarabine has limited value as compared to HiDAC, even in young non-APL AML patients with favorable and intermediate cytogenetics.

Background: Primary central nervous system diffuse large B cell lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS). PCNSL has distinct molecular features,most of which harbor MYD88, CD79b and/or PIM1 mutation. Up to date,there is few study focusing on molecular classification of PCNSL. The clinicopathologic and prognostic significance of molecular classification in PCNSL remains unknown. Methods: Targeted exome sequencing covering 413 genes was conducted on 40 cases of PCNSL. The techniques of performing transcriptional sequencing on FFPE tumor tissue samples was also used following the “K.TotalRNA” protocol. All patients enrolled received high-dose methotrexate-based (HD-MTX) chemoimmunotherapy. Then, a molecular classification methodology in PCNSL patients by bioinformatic analysis was developed. Results: Targeted deep sequencing on the coding regions revealed that MYD88, CD79b and PIM1 were the three most commonly mutated genes in PCNSL patients. All cases were clustered into two molecular subgroups. Patients with PIM1 and/or CD79b mutation were clustered into the so-called CDP group; while patients without PIM1 and CD79b mutation were clustered into the so-called nonCDP group. The 2-year PFS rate was 50.0% and 29% for CDP group and nonCDP group, respectively (P=0.107). And the 2-year OS rate was 76% and 40% for CDP group and nonCDP group, respectively (P=0.037). Patients in CDP group had a prolonged long-term survival compared with those in nonCDP group. Univariate and multivariate analysis revealed that age less than 60, no Myc/Bcl2/Bcl6 double expression by immunohistochemical staining (IHC), and CDP subgroup by NGS were three independent risk factors indicating favorable OS. PyClone analysis revealed that tumor cells of nonCDP group were genetically more heterogeneous than those of CDP group. RNA sequencing analysis revealed that a total of 131 genes were significantly differentially expressed between CDP and nonCDP groups. GO enrichment analysis of these genes suggested that the major categories of biological processes that significantly altered between the two groups mainly related to drug metabolism, suggesting that tumor cells of the two groups may have different drug metabolism mechanism. Results of the PyClone analysis and RNA sequencing partially explained the different treatment sensitivity between these two groups. Conclusion: We developed a new molecular methodology to divide PCNSL into CDP and nonCDP groups, based on the mutational status of CD79b and PIM1. According to our result, PCNSL patients without PIM1 and CD79b mutation had unfavorable long-term survival after HD-MTX based chemoimmunotherapy, possibly due to their clonal heterogeneity and their different drug metabolism mechanism. Citation Format: Jihao Zhou, Min Zuo, Peng Ke, Qi Shen, Lifeng Li, Yaping Xu, Lina Hu, Guoqiang Li, Chun Feng, Xuan Gao, Yanfang Guan, Xuefeng Xia, Xinyou Zhang, Yuhua Huang. PIM1 and CD79b mutation status impact outcome in primary central nervous system DLBCL after high-dose methotrexate-based chemoimmunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 666.

Magnetic Fe3O4 nanoparticles were synthesized and used as peroxymonosulfate (PMS) activator in the presence of ultrasound (US) irritation for azo dye degradation in this study. At pH 7.0 and temperature 298K, Fe3O4 nanoparticles were able to activate PMS under ultrasound irritation to produce sulfate radicals for acid orange 7 (AO7) removal in 30min. Higher catalysts dosage, neutral pH as well as optimum values of PMS dosage and ultrasound power favored the AO7 degradation. Fe3O4 displayed excellent stability and reusability in the US/PMS system. Both of the sulfate radicals and hydroxyl radicals were produced in the reaction and sulfate radicals were the dominant according to the scavenging tests and electron paramagnetic resonance (ESR) tests. The mechanisms of ultrasound irritation enhanced PMS activation in the presence of Fe3O4 were proposed based on the results and literatures.

Objectives Congenital dysfibrinogenemia is a rare hereditary disease characterized by normal antigen level but lower function level of fibrinogen. Patients with congenital dysfibrinogenemia usually present as bleeding and/or thrombotic events. In this study, we explored the genetic abnormality and clinical treatment of a Chinese family with dysfibrinogenemia. Methods This study was conducted in Jan 2015 to Jan 2016 in the Second Medical College (Shenzhen People's Hospital, Jinan University, Shenzhen, Guangdong Province, P.R. China. Coagulation function test were used to screen patients in this family. For all family members, DNA from peripheral blood was isolated. Whole-genome exon sequencing was carried out to screen possible mutations. And sanger sequencing was employed to further confirm the mutation in patients. Results The proband is a woman who had anemia and increased menstruation. Hypofibrinogenemia was found after admission. However, a pulmonary embolism occurred after the fibrinogen replacement treatment. Whole exon sequencing was conducted afterward. A candidate mutation in FGA gene (c.103C>A) was identified and validated in the woman and in two siblings. Conclusion From this case, we learned that1) point mutation of c.103C>A is the pathogenesis for congenital dysfibrinogemia in this family; 2) thromboprophylaxis should always be in consideration when fibrinogen replacement is conducted. Prospective studies are needed to determine the best fibrinogen replacement strategy in order to achieve adequate hemostasis while minimize risk of thrombosis.

INTRODUCTION AND OBJECTIVES:Vibegron is a novel, once-daily, oral β3-adrenoceptor (AR) agonist in development for treatment of patients (pts) with overactive bladder (OAB). Vibegron is highly selec...

A bifunctional membrane modified by BiOCl0.875Br0.125 and polydopamine (PDA) was developed in the current study and employed for the photocatalytic degradation of roxarsone (ROX) under visible-light and simultaneous immobilization of the released inorganic arsenic by sorption. Characterization techniques, such as FESEM, XRD, FTIR-ATR, DRS and XPS were used to characterize as-prepared membranes so as to analyze their structural and functional attributes. Dynamic cyclic experiments indicated that a satisfactory degradation efficiency of ROX (∼100%) could be achieved by the photocatalytic process within 5 h. Simultaneously, the released inorganic arsenic could be completely converted to As(V) and eventually immobilized onto the surface of membrane. The critical reactive oxidation species (ROS) including O2−, h+ and OH contributed to the photodegradation of ROX, and the PDA coating played multiple roles as an adhesive interface, an electron transfer layer, and an active adsorptive layer. Additionally, based on the HPLC-AFS and GC–MS analysis, the major degradation products were detected and the mechanism of ROX degradation and simultaneous arsenic immobilization by BiOCl0.875Br0.125/PDA functionalized PVDF membranes (BPMs) was given, and the reaction pathway of ROX during the photocatalytic/filtration process was also taken into consideration. Combined with the exceptional photocatalytic property and high adsorption capacity of arsenic, the fabricated BPMs may open new opportunities for the control of ROX in water treatment.

// Yu Jing 1,* , Xiangshu Jin 1,* , Lixin Wang 1,2,* , Liping Dou 1 , Quanshun Wang 1 , Yushi Yao 1 , Shimei Lian 3 , Jihao Zhou 1 , Haiyan Zhu 1 , Zilong Yao 1 , Lijun Gao 1 , Lili Wang 1 , Yonghui Li 1 , Xuefeng Bai 4 , Meiyun Fang 5 and Li Yu 1 1 Department of Hematology, Chinese PLA General Hospital, Beijing, China 2 Department of Hematology, Navy General Hospital of PLA, Beijing, China 3 Department of Hematology, Dalian Municipal Central Hospital, Affiliated Hospital of Dalian Medical University, Dalian, China 4 Department of Pathology and Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH, USA 5 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, China * These authors have contributed equally to this work Correspondence to: Li Yu, email: // Meiyun Fang, email: // Keywords : decitabine, haploidentical lymphocyte infusion, Induction therapy, acute myeloid leukemia Received : November 01, 2015 Accepted : July 16, 2016 Published : August 10, 2016 Abstract In this study, we first initiated a multicenter, single-arm, phase-II clinical trial using decitabine (DAC) (20mg/m 2 for five days) based chemotherapy, followed by haploidentical lymphocyte infusion (HLI) that was applied as induction therapy for elderly patients with AML. Furthermore, the role of HLI infusion was explored in a mouse model. The clinical trial included 29 elderly patients (median age: 64, range 57-77) with AML. Sixteen cases achieved complete remission (CR) and 9 cases achieved partial remission (PR) after the first treatment cycle. Of the patients with PR, 5 subjects achieved remission after the second induction, which brings the overall CR rate to 72.4%. The 2-year overall survival (OS) and disease-free survival (DFS) was 59.6% and 36.9% respectively. The treatment regimen was well tolerated with only one patient died of severe pneumonia one month after the first treatment. In the mouse experiment, we found that DAC/HLI significantly enhanced the survival of leukemic mice. These results suggested that DAC-based chemotherapy combined with HLI is an alternative first line induction therapy for elderly patients with AML. This trial is registered at ClinicalTrials.gov (NCT01690507).

In order to eliminate the harm of the algal blooms to the safety of the drinking water production, Fe(II)/peroxymonosulfate (PMS) process was applied as simultaneous oxidation coupled with coagulation to enhance the removal of Microcystis aeruginosa (M. aeruginosa). In comparison with Fe(II)/H2O2 and Fe(II)/persulfate process, the higher removal rate of algae cells and faster settling speed were obtained in Fe(II)/PMS treatment. The removal rate of optical density at 680 nm (OD680), turbidity and dissolved organic carbon (DOC) reached up to 92.3%, 91.1% and 58.3% with the sequential addition of 90 μM Fe(II) and 50 μM PMS in 20 min. The moderate oxidation capacity of PMS in weak alkaline environment lead to the low ratios of damaged cells and algal organic matters (AOMs) release. The aggregation of the in situ formed Fe3O4 could significantly promote the generation and settleability of larger flocs. This study demonstrated that Fe(II)/PMS process might be a promising technology towards algae-laden water treatment.

Multiple myeloma (MM) remains incurable. The MM microenvironment supports MM cells’ survival and immune escape. Because myeloid-derived suppressor cells (MDSCs) is important in the MM microenvironment, and demethylating agent decitabine (DAC) can deplete MDSCs in vitro and in vivo, we hypothesized that DAC treatment could inhibit MM by depleting MDSCs in the MM microenvironment. In this study, we used the mouse IL6 secreting, myeloma cell line MPC11 as a model. MDSCs were sorted using magnetic beads and cultured. A transwell coculture assay was used to mimic the microenvironment in vitro. And MPC11-bearing mice model was used to observe the efficacy of DAC treatment in vivo. In vitro coculture assay indicated that MPC11 cells showed significantly lower proliferation rate, less IL6 production and more apoptosis when they were cocultured with bone marrow cells without MDSCs (nonMDSCs) or DAC-treated bone marrow cells (DAC BMs) than with MDSCs or PBS-treated bone marrow cells (CTR BM). Supplementation with M-MDSCs rescued the inhibitory effect of DAC BMs, while additional NOHA supplementation further antagonized the rescue effect of M-MDSCs. In MPC11-bearing mice, the combined treatment of DAC with anti-Gr1 antibody showed synergistic effect on inhibiting tumor growth and promoting T cell infiltration in the tumor tissue. M-MDSC reinfusion also antagonized the efficacy of DAC treatment. DAC treatment can inhibit myeloma cell proliferation and induce enhanced autologous T cell immune response by depleting M-MDSCs in the MM microenvironment. We believe that DAC treatment could improve the prognosis of MM in future.

Background Acute graft-versus-host disease (aGVHD) remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper cells including Th17 play key roles in aGVHD pathogenesis. Donor regulatory T cell (Tregs) adoptive therapy reduces aGVHD without weakening graft-versus-leukemia effect (GVL) in both mouse and human, although the purification and ex vivo expansion of Tregs in clinical scenarios remain costly and technically demanding. Hypoxia-inducible factor 1 alpha (HIF-1α) is a key molecule switch that attenuates Treg but promotes Th17 development. However, whether pharmacological inhibition of HIF-1α reduces aGVHD via increasing Treg development and diminishing Th17 responses remains unexplored. Methods By using alloantigen-specific mixed lymphocyte culture and murine models of aGVHD and GVL, we evaluated the impacts of HIF-1α inhibition by echinomycin on the alloantigen-specific CD4 T cell responses ex vivo, as well as on aGVHD and GVL effect following allo-HSCT. Results Ex vivo echinomycin treatment resulted in increased number of Tregs in the culture as well as reduced alloantigen-specific Th17 and Th1 responses. In vivo echinomycin treatment reduced GVHD scores and prolonged survival of mice following allo-HSCT, which is associated with increased number of donor Tregs and reduced number of Th17 and Th1 in lymphoid tissues. In murine model of leukemia, echinomycin treatment preserved GVL effect and prolonged leukemia free survival following allo-HSCT. Conclusions Echinomycin treatment reduces aGVHD and preserves GVL effect via increasing donor Treg development and diminishing alloantigen-specific Th17 and Th1 responses following allo-HSCT, presumably via direct inhibition of HIF-1α that results in preferential Treg differentiation during alloantigen-specific CD4 T cell responses. These findings highlight pharmacological inhibition of HIF-1α as a promising strategy in GVHD prophylaxis. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1132-9) contains supplementary material, which is available to authorized users.

Immune thrombocytopenia (ITP) is a disease characterized by isolated thrombocytopenia. Abnormal effector T cell activation is an important mechanism in the pathogenesis of ITP. Regulatory T cells (Treg) have a strong immunosuppressive function for T cell activation and their importance in the pathophysiology and clinical treatment of ITP has been confirmed. Myeloid-derived suppressor cells (MDSCs) are other immunosuppressive cells, which can also suppress T cell activation by secreting arginase, iNOS and ROS, and are essential for Treg cells’ differentiation and maturation. Therefore, we speculate that MDSCs might also be involved in the immune-dysregulation mechanism of ITP. In this study, we tested MDSCs and Treg cells in peripheral blood samples of twenty-five ITP patients and ten healthy donors. We found that MDSCs and Treg cells decreased simultaneously in active ITP patients. Relapsed ITP patients showed lower MDSCs levels compared with new patients. All patients received immunosuppressive treatment including dexamethasone alone or in combination with intravenous immune globulin. We found that MDSCs’ level after treatment correlated with platelet recovery. Our study is the first that focused on MDSCs’ role in ITP. Based on our results, we concluded that circulating MDSCs could predict disease activity and treatment response in ITP patients. This preliminary conclusion indicates a substantial significance of MDSCs in the pathophysiology and clinical treatment of ITP, which deserves further investigation.

Additional file 1. Additional figures.

The immunoregulatory effect of demethylating agent decitabine (DAC) has been recognized recently. However, little is known about its impact on immune tolerance. In this study, we aimed to determine the impact of DAC on the immune tolerance induced by tumor cells. The effects of DAC on immune cells in vivo were measured by flow cytometry. Myeloid-derived suppressor cells (MDSCs) were sorted using magnetic beads and cultured in vitro. The mixed lymphocyte reaction was used to determine the immunoregulatory effect of DAC in vitro. An adoptive transfusion mouse model was established to evaluate the effect in vivo. We found that DAC treatment significantly depleted MDSCs in vivo by inducing MDSCs apoptosis. When given at a low dose, the immune effector cells were less affected by the treatment, except for MDSCs. The mixed lymphocyte reaction in vitro showed that T-cell responses were enhanced when MDSCs were depleted. Supplementation of MDSCs would attenuate this T-cell activation effect. Using an adoptive transfusion mouse model, we further demonstrated in vivo that DAC treatment could induce autologous anti-tumor immune response by depleting MDSCs. This study is the first to illustrate DAC’s immunoregulatory effect on immune tolerance. The disruption of immune tolerance is due to MDSCs depletion that induces an autologous immune response in vivo. By depleting MDSCs, DAC treatment removes one of the obstacles affecting anti-tumor immune activation and warrants further experimental and clinical studies to explore its potential utility in combination with various anti-tumor immunotherapies in the future.

In this paper, we study the bioequivalence (BE) inference problem motivated by pharmacokinetic data that were collected using the serial sampling technique. In serial sampling designs, subjects are independently assigned to one of the two drugs; each subject can be sampled only once, and data are collected at K distinct timepoints from multiple subjects. We consider design and hypothesis testing for the parameter of interest: the area under the concentration–time curve (AUC). Decision rules in demonstrating BE were established using an equivalence test for either the ratio or logarithmic difference of two AUCs. The proposed t-test can deal with cases where two AUCs have unequal variances. To control for the type I error rate, the involved degrees-of-freedom were adjusted using Satterthwaite's approximation. A power formula was derived to allow the determination of necessary sample sizes. Simulation results show that, when the two AUCs have unequal variances, the type I error rate is better controlled by t...

Botulinum toxin treatment has been investigated as a minimally invasive alternative to oral medications in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (LUTS/BPH).To explore the efficacy of onabotulinumtoxinA 100 U, 200 U, and 300 U versus placebo in men with LUTS/BPH in a phase 2 dose-ranging study.A multicenter double-blind randomized, placebo-controlled 72-wk study enrolled men ≥ 50 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥ 12, total prostate volume (TPV) 30-100ml, and maximum flow rate (Q(max)) 5-15 ml/s.Single transperineal (n=63) or transrectal (n=311) administration of placebo (n=94) or onabotulinumtoxinA 100 U (n=95), 200 U (n=94), or 300 U (n=97) into the prostate transition zone.The primary efficacy end point was a change from baseline in IPSS at week 12. Secondary end points were Q(max), TPV, and transition zone volume (TZV). Analysis of covariance and the Cochran-Mantel-Haenszel method assessed the efficacy and proportion of IPSS responders. Adverse events (AEs) were assessed.Significant improvements from baseline in IPSS, Q(max), TPV, and TZV were observed for all groups, including placebo, at week 12 (p0.001), with no significant differences between onabotulinumtoxinA and placebo. However, in an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with onabotulinumtoxinA 200 U in prior α-blocker users (n=180) at week 12. AEs were comparable across all groups.Reductions in LUTS/BPH symptoms were seen in all groups, including placebo, with no significant between-group differences owing to a large placebo effect from the injectable therapy. The findings from the post hoc analysis in men previously treated with α-blockers will be further explored in an appropriately designed study.http://www.Clinical Trials.gov; NCT00284518.

Magnetic Fe

Aims We assessed the effects of onabotulinumtoxinA (BOTOX®) on clinical and urodynamic variables in patients with idiopathic overactive bladder (OAB) and urinary urgency incontinence (UUI) with or without detrusor overactivity (DO), inadequately managed with anticholinergics. Methods Three hundred thirteen patients with OAB were randomized to double-blind intradetrusor injection with placebo (n = 44) or 1 of 5 onabotulinumtoxinA doses (50–300 U; n = 269). Primary efficacy variable was change from baseline in UUI episodes/week at week 12. Urodynamic assessments at baseline and weeks 12 and 36 included maximum cystometric capacity (MCC) and volume at first involuntary detrusor contraction (IDC). Results 76.0% of patients had baseline DO. Changes from baseline in MCC and volume at first IDC with onabotulinumtoxinA ≥100 U were superior to placebo at week 12, generally decreasing by week 36. Significant dose-dependent increases in MCC were observed for all onabotulinumtoxinA doses at week 12, and for 150, 200, and 300 U at week 36. Data suggested a dose–response relationship. At week 12 on diary, 15.9% of placebo and 29.8–57.1% of onabotulinumtoxinA 50–300 U recipients, respectively, did not demonstrate UUI. OnabotulinumtoxinA doses >150 U were more commonly associated with post-void residual urine volumes >200 ml. Conclusions Improvements in urodynamic parameters and clinical outcomes generally trended together following onabotulinumtoxinA treatment. This therapy improved key urodynamic parameters in patients with idiopathic OAB and UUI, with no differences in outcomes between those with and those without baseline DO. Therefore, successful idiopathic OAB treatment with onabotulinumtoxinA does not appear to be related to pretreatment finding of DO. 30:556–562, 2011. © 2011 Wiley-Liss, Inc.

Clinical trials demonstrate that onabotulinumtoxinA reduces upper limb post-stroke spasticity, with therapeutic response influenced by injected dose. Individual studies provide limited insight regarding muscle group-specific dose-response relationships. Our objective was to characterize dose-response relationships between onabotulinumtoxinA and muscle tone in specific upper limb muscles. Individual patient data from seven multicenter, randomized, double-blind, placebo-controlled trials were pooled. Of 544 post-stroke patients enrolled, 362 received onabotulinumtoxinA and 182 received placebo, injected into the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and/or biceps brachii (BB). Ashworth Scale score change at week 6 (AshworthCBL) was the primary outcome measure for muscle tone. For a broader analysis of response, AshworthCBL/onabotulinumtoxinA dosage relationships were characterized using three techniques: (1) AshworthCBL plotted as a function of onabotulinumtoxinA dose in Units (U) [dose-response curve]; (2) mean AshworthCBL per onabotulinumtoxinA dose depicting the responses seen with specific dose injection clusters/groups for each specific muscle group; and (3) onabotulinumtoxinA dose estimated to produce a mean 1-point decrease in AshworthCBL as an indicator of clinically meaningful benefit of treatment. Increasing onabotulinumtoxinA doses produced greater AshworthCBLs (muscle tone improvements). The maximal week 6 response (E(max)) model indicated a saturating dose-response relationship, with mean E(max) AshworthCBL values of -1.48, -1.48, -0.63, -0.77, and -0.61 in the FCR, FCU, FDS, FDP, and BB, respectively. OnabotulinumtoxinA doses estimated to produce a mean 1-point decrease in AshworthCBL were: 22.5U, 18.4U, 66.3U, 42.5U in the FCR, FCU, FDS, and FDP, respectively, and not determinable in the BB. These analyses demonstrate a saturating effect of greater muscle tone improvements with increasing onabotulinumtoxinA doses in post-stroke spasticity patients. These findings suggest potentially effective onabotulinumtoxinA doses in selected muscle groups in this study population.

An innovative probabilistic rule is proposed to predict the clinical significance or clinical insignificance of DDI. This rule is coupled with a hierarchical Bayesian model approach to summarize substrate/inhibitor's PK models from multiple published resources. This approach incorporates between-subject and between-study variances into DDI prediction. Hence, it can predict both population-average and subject-specific AUCR. The clinically significant DDI, weak DDI, and clinically insignificant inhibitions are decided by the probabilities of predicted AUCR falling into three intervals, (-infinity, 1.25), (1.25, 2), and (2, infinity). The main advantage of this probabilistic rule to predict clinical significance of DDI over the deterministic rule is that the probabilistic rule considers the sample variability, and the decision is independent of sampling variation; while deterministic rule based decision will vary from sample to sample. The probabilistic rule proposed in this paper is best suited for the situation when in vivo PK studies and models are available for both the inhibitor and substrate. An early decision on clinically significant or clinically insignificant inhibition can avoid additional DDI studies. Ketoconazole and midazolam are used as an interaction pair to illustrate our idea. AUCR predictions incorporating between-subject variability always have greater variances than population-average AUCR predictions. A clinically insignificant AUCR at population-average level is not necessarily true when considering between-subject variability. Additional simulation studies suggest that predicted AUCRs highly depend on the interaction constant K(i) and dose combinations.

The effect of food on the oral bioavailability of sunitinib malate (SU11248, an oral, multi-targeted tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activities) was assessed in a randomized open-label, two-way crossover study. A 50-mg dose of SU11248 was administered to 16 healthy subjects after a 10-h fast in one period and after a high-fat, high-calorie meal in the other period. The 90% confidence intervals (CIs) for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were within the 80-125% bioequivalence range, indicating the absence of a food effect. SU11248 exposure increased slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, AUC0-last and AUC0-infinity both 112%). There was a delay in the formation/absorption of the active metabolite SU12662 in the fed state (mean Cmax decreased 23%), but exposure remained unaffected (90% CIs for AUC0-last and AUC0-infinity were within 80-125%). These results indicate that SU11248 can be administered with or without food.

Higher-order crossover designs have drawn considerable attention in clinical trials, because of their ability to test direct treatment effects in the presence of carry-over effects. The important question, when applying higher-order crossover designs in practice, is how to choose a design with both statistical and cost efficiencies from various alternatives. In this paper, we propose a general cost function and compare five statistically optimal or near-optimal designs with this cost function for a two-treatment study under different carry-over models. Based on our study, to achieve both statistical and cost efficiencies, a four-period, four-sequence crossover design is generally recommended under the simple carry-over or no carry-over models, and a three-period, two-sequence crossover design is generally recommended under the steady-state carry-over models. Copyright © 2005 John Wiley & Sons, Ltd.

Cancer‑testis antigens (CTAs) are a group of tumor‑associated antigens restricted to male germ cells under normal physiological conditions. CTAs are expressed in certain types of tumors and thus are a novel target for immunotherapy. Nuclear RNA export factor 2 (NXF2) is a CTA of which the expression pattern, regulation and clinical significance are unclear. In the present study, following treatment with a demethylating agent, decitabine, NXF2 expression was detected in the majority of the NXF2‑negative acute leukemia cell lines, but not in healthy donor samples. This finding was confirmed by western blot analysis. Eight primary acute leukemia bone marrow samples were treated with decitabine in vitro, and results showed that NXF2 expression was significantly upregulated. In another nine acute myeloid leukemia or myelodysplastic syndrome patients, it was noted that the expression of NXF2 was upregulated in all patients following the first cycle of decitabine, which suggested that NXF2 was activated by decitabine treatment in vivo. Furthermore, NXF2 expression in acute leukemia cells was demonstrated to be regulated by CpG island hypermethylation. To the best of our knowledge, this is the first study to demonstrate that NXF2 is activated by demethylation in acute leukemia cells in vitro and in vivo. NXF2 may therefore serve as a novel target for immunotherapy against acute leukemia.