ALBERT

Description: Nonlinear ultrasonic Lamb waves are popular to characterize the nonlinearity of materials. However, the widely used nonlinear Lamb mode suffers from two associated complications: inherent dispersive and multimode natures. To overcome these, the symmetric Lamb mode (S0) at low frequency region is explored. At the low frequency region, the S0 mode is little dispersive and easy to generate. However, the secondary mode still exists, and increases linearly for significant distance. Numerical simulations and experiments are used to validate the nonlinear features and therefore demonstrate an easy alternative for nonlinear Lamb wave applications.

Description: This paper describes a five-phase fault-tolerant modular in-wheel permanent-magnet synchronous machine (PMSM) for electric vehicles. By adopting both the analytical and finite-element methods, the magnetic isolation abilities of some typical slot/pole combinations are analyzed, and a new fractional-slot concentrated winding topology that features hybrid single/double-layer concentrated windings and modular stator structure is developed. For the proposed hybrid single/double-layer concentrated windings, feasible slot/pole combinations are studied for three-, four-, and five-phase PMSMs. A five-phase in-wheel PMSM that adopts the proposed winding topology is designed and compared with the conventional PMSM, and the proposed machine shows advantages of large output torque, zero mutual inductances, low short-circuit current, and high magnetic isolation ability. Some of the analysis results are verified by experiments.

Description: Ultrasonic guided waves are useful to assess the integrity of a structure from a remote location. Recently, tomography techniques have been developed to quantitatively estimate the thickness map of plate-like structures based on the dispersion characteristics of guided waves. In many applications only limited locations are available to place transducers. The missing viewing angles lead to artifacts which can degrade the image quality. To address this problem, this paper applies the regularization method to synthesize the missing components. The regularization technique is performed by an adaptive threshold approach to the limited view reconstruction. The effectiveness of this method combined with the full waveform inversion method is demonstrated by using numerical simulations as well as experiments on an irregularly shaped defect and two flat-bottom defects. The results indicate that the additional components obtained from the regularization method can significantly reduce the artifacts, leading to better reconstruction accuracy.

Description: Background: Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms underlying PGF remain to be elucidated, which increases the difficulty of managing PGF. In murine study, effective cross-talk between hematopoietic stem cells (HSCs) and bone marrow (BM) micro-environment plays an important role in hematopoiesis. HSCs occupy a hypoxic BM micro-environment to protect them from oxidative stress, whereas excessive reactive oxygen species (ROS) could inhibit HSCs self-renewal and induce HSCs exhaustion resulting in hematopoietic dysfunction. We recently reported that the impaired BM micro-environment may contribute to the occurrence of PGF post-HSCT using a prospective nested case-control study (Kong Y, et al. Biol Blood Marrow Transplant. 2013;19:1465-1473). Nevertheless, it is largely unknown whether the quantitatively and functionally impaired HSCs pre- and post-HSCT operate in the occurrence of PGF in allotransplants patients. Aims: To investigate whether the quantitative and functional abnormalities of the donor BM CD34+ cells pre- and post-HSCT are involved in the pathogenesis of PGF. Methods: The hematopoietic reconstitution activities of the CD34+ cells, sorted from the donors' BM of PGF and good graft function (GGF) patients, were evaluated in xenografted NOD-Prkdcscid IL2rgnull mice as an indicator of donors' HSCs function. To further investigate the effect of oxidative stress on normal hematopoiesis post-HSCT, the BM CD34+ cells of GGF allotransplant patients were treated of hydrogen peroxide (H2O2) with or without antioxidant N-acetyl-L-cysteine (NAC) in vitro. Subsequently, a prospective nested case-control study was performed enrolling 15 patients with PGF, 30 matched patients with GGF after allo-HSCT and their healthy donors. Quantification of the frequency, intracellular ROS levels, and cell cycle status of the BM CD34+ cells were analyzed by flow cytometry pre- and post-HSCT. Colony-forming capacity was investigated in CD34+ cells post-HSCT in vitro. The study was approved by the Ethics Committee of Peking University People's Hospital and written informed consent was obtained from all subjects. Results: The hematopoietic reconstitution activity of the BM CD34+ cells in NOD-Prkdcscid IL2rgnull mice demonstrated no significant differences between the donors of PGF and GGF patients. In the subsequent in vitro study, increased ROS were found to play an important role in the exhaustion of the quiescent BM CD34+ cells of GGF patients, whereas treatment of ROS-abrogated CD34+ cells with the antioxidant NAC could partially, but significantly restore the exhaustion and colony-forming capacity of CD34+ cells. In the prospective nested case-control study, all patient- and therapy-related variables were similar between patients with PGF and GGF. Polymerase chain reaction DNA fingerprinting of the STRs confirmed 100% donor chimerism in these patients. The frequency, intracellular ROS levels and cell cycle status of the transplanted donor BM CD34+ cells showed no remarkable differences pre-HSCT. Nevertheless, the percentage of CD34+ cells post-HSCT and their colony-forming capacity, especially the quiescent CD34+ CD38low fraction, decreased remarkably in PGF patients when compared to that in GGF patients. Notably, significantly increased ROS levels were observed in CD34+ and CD34+ CD38low fractions of PGF patients post-HSCT. Summary/Conclusion: Although the frequency and function of the transplanted donor BM CD34+ cells of PGF were demonstrated normal pre-HSCT, the increased levels of ROS and exhaustion of the quiescent CD34+ cells may operate in PGF post-HSCT. Our preliminary data indicate that an impaired BM micro-environment which may hamper the hematopoietic reconstitution of the donor HSCs in the recipients, rather than the defective donor HSCs, was involved in the occurrence of PGF. Therefore, novel therapeutic approaches, such as antioxidative therapy to maintain hypoxia BM micro-environment, promise to facilitate hematopoietic recovery in PGF. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), and the Beijing Municipal Science and Technology Program (grant nos. Z141100000214011& Z151100004015164& Z151100001615020). Disclosures No relevant conflicts of interest to declare.

Description: Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure.T cell homeostasis is critical to determine the potency of the GVT effect. Cytotoxic T lymphocyte antigen-4 (CTLA-4 or CD152) is a T cell activation negative regulator. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT. Patients and Methods: In this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 154 acute leukemia patients after related HLA-haplotype-mismatched transplantation. The four SNP genotypes (-1661, -318, CT60 and +49) were determined by TaqMan SNP genotyping assays. Results: Recipients of donors with +49 GG showed significantly lower OS (69.1% vs. 85.6%, P=0.024) and higher incidence of III-IV aGVHD (10.0% vs. 2.1%, P=0.032) than those with GA + AA(Fig.1,Fig.2). Multivariate analyses showed that +49GG was an independent risk factor for OS (HR:0.457,95%CI=0.227-0.920,P=0.028). Patients receiving mDLI showed significantly lower OS with +49 GG donor than those with AG+AA (P=0.011).The haplotype analysis revealed only three haplotypes in the donor population -1661/-318/CT60/+49 i.e.,ACGG,ACAA and GTGA,the frequencies were 64.3%, 19.5%, and 16.2%, respectively.Donors with and without the ACGG/ACGG haplotype had the same effect on transplant outcome as those with +49 GG and +49 AG+AA. Conclusion: The CTLA-4 +49 GG and the haplotype ACGG/ACGG reduced the overall survival and increased the aGVHD after allo-HSCT from the related HLA-haplotype-mismatched donor,knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for donor selection and individual application of immunosuppressive agents and immunotherapy. CONFLICT OF INTEREST The authors declare no conflict of interest. Disclosures No relevant conflicts of interest to declare.

Description: Background: Poor graft function (PGF), a kind of bone marrow (BM) failure syndrome, is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, the exact mechanisms underlying PGF remain unclear. The BM immune micro-environment is considered to be involved in the regulation of murine hematopoiesis. Dysregulated T cell response was found to suppress proliferation and induce apoptosis of hematopoietic progenitor cells in patients with aplastic anemia. Therefore, we conducted a study to analyze the alteration of T cell subpopulations in BM micro-environment of allotransplant patients. Aims: To compare the cellular compositions and function of T cells in BM micro-environment between patients with PGF and good graft function (GGF) after allo-HSCT in Peking University Institute of Hematology. Methods: Using a prospective nested case-control study, the active phenotype and memory phenotype of CD4+ T cells and CD8+ T cells in BM were analyzed by flow cytometry in 12 patients with PGF, 36 matched patients with GGF after allo-HSCT, and 15 healthy donors (HDs). Furthermore, the cytokine secretion function of CD4+ T cells and CD8+ T cells were evaluated after simulation and the level of eight Th1 and Th2 cytokines in BM plasma were detection by cytometric beads assay. Results: The demographic and clinical characteristics were similar between allo-HSCT patients with PGF and those with GGF. Although the PGF patients presented a significant lymphopenia, a notable increased percentage of activated CD8+ T cells was detected in the BM of PGF patients when compared to that in GGF patients (61.7% versus 35.0%, P =.02). Moreover, the in vitro cytokine stimulated tests demonstrated a significant higher proportion of Tc1 in PGF patients (46.1% versus 20.3% versus 28.4%, P

Description: Objectives: SNPs of CTLA-4 have been shown to be important risk factors associated with autoimmune disease and malignancy , the objectives of this study were to explore the association of CTLA-4 SNPs with the development of myeloma and to evaluate the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4 SNPs. Methods: Peripheral blood samples from 86 MM patients and 154 controls were obtained for the investigation of CTLA4 polymorphisms, The five SNP genotypes of CTLA-4, namely, -1772(rs733618),-1661 (rs4553808), -318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were determined by TaqMan SNP genotyping assays (Applied Biosystems) , Results: Some of the CTLA-4 polymorphisms display frequencies that are different among the different ethnic groups. The Kaplan-Meier analysis revealed that patients with rs733618 GG showed a significantly lower DFS (0% vs. 57.4%, P = 0.020) and OS (46.3% vs. 83.3%, P = 0.026) than those with GA+AA in MM patients after Botizomib based therapy. Multivariate analyses showed that rs733618 GG were risk factor for OS (HR= 0.025; 95% CI= 0.004-0.161;P=0.000). The incidence of nonhematologic grade 3/4 adverse events was significantly increased in the rs 4553808 GA+GG group compared to AA group(P=0.036). Conclusion: In summary, CTLA-4 rs733618 GG reduced the progression-free survival and overall survival in MM patients after Botizomib based therapy,knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for MM therapy. The exact effect of the CTLA-4 polymorphism and haplotype on MM therapy outcome should be determined in different cohorts with substantially larger number of subjects. Correspondence: Professor X-J Huang, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking-Tsinghua Center for Life Sciences, 11 Xizhimen South Street, Beijing 100044, P.R. China. E-mail: huangxiaojun@bjmu.edu.cn The first 2 authors contributed equally to this work. Disclosures No relevant conflicts of interest to declare.