Anti-Acute Myeloid Leukemia Activity of CD38-CAR-T Cells with PI3Kδ Downregulation.

We previously constructed a nanobody-based anti-CD38 chimeric antigen receptor T (CD38-CAR-T) cell efficiently against multiple myeloma. As CD38 is also expressed on most tumor cells of acute myeloid leukemia (AML), we wondered about its efficacy in treating AML. In this study, we demonstrated that our CD38-CAR-T cells effectively lysed CD38+ AML cell lines, including NB4, U937, HL-60, THP-1 with an E:T (effector/target cells) ratio of 1:8, and primary AML cells from patients with a low E:T ratio of 1:16. Moreover, recent studies showed that inhibition of PI3Kδ could enhance CAR-T-cell efficacy. We constructed PI3Kδ-downregulated CD38-CAR-T cells with a CD38-CAR lentiviral vector containing short hairpin RNA (shRNA) sequences against PI3Kδ. CD38-CAR-T cells with PI3Kδ downregulation maintained their antileukemia function against both AML cell lines and primary AML cells while reducing the release of IL-2, IFN-γ, and TNF when co-culturing with AML cell lines. Both CD38-CAR-T and PI3Kδ-downregulated CD38-CAR-T-cell therapy significantly improved the survival of AML mice, whereas the latter had an even better effect on survival. In summary, our study demonstrated that CD38-CAR-T cells had promising activity against AML, and PI3Kδ downregulation in CD38-CAR-T cells could reduce some cytokines release without impairing their antileukemia function.

Activities of daily living predict periprocedural myocardial infarction and injury following percutaneous coronary intervention: a cross-sectional study.

BACKGROUND: In recent years, there has been growing interest in exploring the relationship between activities of daily living (ADL) and cardiovascular diseases. This retrospective cross-sectional study aimed to investigate the association of ADL measured by Barthel index (BI) with periprocedural myocardial infarction (PMI) and injury following percutaneous coronary intervention (PCI). METHODS: Enrolled patients were stratified into impaired and unimpaired ADL groups according to their BI scores. Logistic regressions were conducted to explore the association of ADL on admission with periprocedural myocardial injury and infarction. Restricted cubic spline (RCS) curve and subgroup analysis were also performed. RESULTS: Totally, 16.4% of patients suffered from PMI; the mean age was 65.8 ± 10.4 years old. RCS analysis showed that the morbidity of periprocedural myocardial infarction and injury showed a downward tendency with increasing BI scores. Multivariable logistic regression analysis demonstrated that impaired ADL was an independent risk factor for periprocedural myocardial infarction (OR = 1.190, 95% CI [1.041, 1.360], P = 0.011) and injury (OR = 1.131, 95% CI [1.017, 1.257], P = 0.023). Subgroup analysis showed that the association between ADL and PMI was founded in several subgroups, while the association between ADL and periprocedural myocardial injury was founded only in BMI ≥ 24 kg/m2 subgroup. CONCLUSION: Impaired ADL at hospital admission was an independent risk factor for periprocedural myocardial infarction and injury among patients following PCI.

A Novel RHCE*cE (c.827C>A) Allele, Containing the Single-Nucleotide Change, Encodes Altered c/E Antigens.

The RH blood group system is the most complex with over 50 antigens. So far over hundreds of RhCE variant alleles have been described resulting in weakened and/or partial expression of RhCE antigens [1], some variant Rh phenotypes are caused by exchange of genetic material between the RHD and RHCE genes, resulting in many hybrid genes, other phenotypes result from missense mutations. Variant alleles encode altered phenotypes with either weakened antigens, lacked antigens, or unexpected antigens. Besides, the mutation of RH blood group genes may lead to the changes of Rh antigen epitopes. RHCE gene mutations or polymorphisms may bring about altered RH antigens in quality and quantity [2]. Serologic weaknesses or discrepancies are regularly faced by blood transfusion laboratories, and molecular background explaining this feature can be precisely characterized only by the molecular biological methods.

The stabilization ability of NaA zeolite derived from fly ash for lead and cadmium in soil: Mechanisms and evaluation of effectiveness.

Developing technologies aimed at ecologically restoring is of great significance in addressing the problem of heavy metal pollution. In this study, NaA zeolites (FAZ) originated from fly ash with outstanding performance were prepared by alkali fusion hydrothermal method and used for the solidification and stabilization of heavy metals in soil. After systematic evaluation, it was found that FAZ may lower the leaching concentration of lead (Pb) in soil to <1 mg/kg and increase the stabilization rate of Pb to 80 % in the single Pb-contaminated soil, lower the leaching concentration of cadmium (Cd) in soil to <3 mg/kg and increase the stabilization rate of Cd to 60 % in the single Cd-contaminated soil, and lower the leaching concentration of Pb to 0.15 mg/kg and the leaching concentration of Cd to 0.74 mg/kg in PbCd complex polluted soil. Additionally, Pb stabilization rates reach 60 % and Cd stabilization rates reach 30 %, respectively. Ion exchange is primarily responsible for the adsorption and solidification of Pb and Cd in soil by FAZ. Generally, FAZ has a wide range of applications in the rehabilitation of contaminated soil and significantly lowers the level of heavy metal pollution in soil.

Innexin hemichannel activation by Microplitis bicoloratus ecSOD monopolymer reduces ROS.

The extracellular superoxide dismutases (ecSODs) secreted by Microplitis bicoloratus reduce the reactive oxygen species (ROS) stimulated by the Microplitis bicoloratus bracovirus. Here, we demonstrate that the bacterial transferase hexapeptide (hexapep) motif and bacterial-immunoglobulin-like (BIg-like) domain of ecSODs bind to the cell membrane and transiently open hemichannels, facilitating ROS reductions. RNAi-mediated ecSOD silencing in vivo elevated ROS in host hemocytes, impairing parasitoid larva development. In vitro, the ecSOD-monopolymer needed to be membrane bound to open hemichannels. Furthermore, the hexapep motif in the beta-sandwich of ecSOD49 and ecSOD58, and BIg-like domain in the signal peptides of ecSOD67 were required for cell membrane binding. Hexapep motif and BIg-like domain deletions induced ecSODs loss of adhesion and ROS reduction failure. The hexapep motif and BIg-like domain mediated ecSOD binding via upregulating innexins and stabilizing the opened hemichannels. Our findings reveal a mechanism through which ecSOD reduces ROS, which may aid in developing anti-redox therapy.

Metro-access integrated network based on optical OFDMA with dynamic sub-carrier allocation and power distribution.

We propose and demonstrate a novel optical orthogonal frequency-division multiple access (OFDMA)-based metro-access integrated network with dynamic resource allocation. It consists of a single fiber OFDMA ring and many single fiber OFDMA trees, which transparently integrates metropolitan area networks with optical access networks. The single fiber OFDMA ring connects the core network and the central nodes (CNs), the CNs are on demand reconfigurable and use multiple orthogonal sub-carriers to realize parallel data transmission and dynamic resource allocation, meanwhile, they can also implement flexible power distribution. The remote nodes (RNs) distributed in the user side are connected by the single fiber OFDMA trees with the corresponding CN. The obtained results indicate that our proposed metro-access integrated network is feasible and the power distribution is agile.

[Effect of Myeloma-Derived Exosomes on Surface Activating Receptors of NK Cells].

OBJECTIVE: To investigate the effect of myeloma-derived exosomes on surface activating receptors of NK cells, and to explore the mechanism of the function defect of NK cells. METHODS: The exosomes from the supernatant of multiple myeloma cell lines RPMI8226 and U266 were extracted by ultracentrifugation, and the size of them was identified under electron microscope; the human primary NK cells were extracted, and were co-cultured with the myeloma-derived exosomes (40 µg/ml), then the expression levels of surface activating receptors NKp46, NKp30 and NKG2D of NK cells at 0,1,4 and 24 hours were detected by flow cytometry. RESULTS: The exosomes showed small vesicular, sized 30-100 nm under electron microscope. The expression of surface activating receptors of NK cells declined at different degree after co-cultured with myeloma-derived exosomes. CONCLUSION: Myeloma-derived exosomes can inhibit the expression of surface activating receptors of NK cells.

Dendritic cells in semen of infertile men: association with sperm quality and inflammatory status of the epididymis.

OBJECTIVE: To determine whether dendritic cells (DCs) are present in semen and whether their abundance and activation correlate with sperm quality and inflammatory status of the male genital tract. DESIGN: In vitro prospective study. SETTING: University hospital laboratory. PATIENT(S): Eighty infertile men and twelve control fertile men were enrolled in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The percentages of DCs, intracellular staining of cytokines, and spermatozoa DNA fragmentation index were assessed by flow cytometry. Seminal cytokines, neutral α-glucosidase, zinc, and fructose were measured with commercial kits. RESULT(S): A significant number of CD11c(+) HLA-DR(+) DCs were detected in ejaculates from patients with chronic inflammation of genital tract, which was negatively correlated with spermatozoa motility, vitality, and DNA integrity. Intracellular staining of cytokines of seminal DCs showed enhanced ability to secrete inflammatory cytokines (interleukin [IL] 23p19, tumor necrosis factor [TNF]-related apoptosis-inducing ligand [TRAIL], and TNF-α). Furthermore, a significant correlation was found between DCs and the seminal concentrations of IL-6, IL-17, IL-23, TRAIL, and neutral α-glucosidase, the marker of epididymal function, in the inflammatory group but not in the noninflammatory and fertile groups. CONCLUSION(S): The abundance and activation of seminal DCs of infertile men may be closely associated with poor epididymal function and sperm quality.

Construction of protein profile classification model and screening of proteomic signature of acute leukemia.

The French-American-British (FAB) and WHO classifications provide important guidelines for the diagnosis, treatment, and prognostic prediction of acute leukemia, but are incapable of accurately differentiating all subtypes, and not well correlated with the clinical outcomes. In this study, we performed the protein profiling of the bone marrow mononuclear cells from the patients with acute leukemia and the health volunteers (control) by surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI_TOF_MS). The patients with acute leukemia were analyzed as unitary by the profiling that were grouped into acute promyelocytic leukemia (APL), acute myeloid leukemia-granulocytic (AML-Gran), acute myeloid leukemia-monocytic (AML-Mon) acute lymphocytic leukemia (ALL), and control. Based on 109 proteomic signatures, the classification models of acute leukemia were constructed to screen the predictors by the improvement of the proteomic signatures and to detect their expression characteristics. According to the improvement and the expression characteristics of the predictors, the proteomic signatures (M3829, M1593, M2121, M2536, M1016) characterized successively each group (CON, APL, AML-Gra, AML-Mon, ALL) were screened as target molecules for identification. Meanwhile, the proteomic-based class of determinant samples could be made by the classification models. The credibility of the proteomic-based classification passed the evaluation of Biomarker Patterns Software 5.0 (BPS 5.0) scoring and validated application in clinical practice. The results suggested that the proteomic signatures characterized by different blasts were potential for developing new treatment and monitoring approaches of leukemia blasts. Moreover, the classification model was potential in serving as new diagnose approach of leukemia.