Sphingosine-1 phosphate receptor 1 (S1PR1) expression maintains stemness of acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) arises from leukemia stem cells (LSCs) and is maintained by cells which have acquired features of stemness. We compared transcription profiles of AML cells with/without stem cell features defined as in vitro clonogenicity and serial engraftment in immune-deficient mice xenograft model. We used multi-parameter flow cytometry (MPFC) to separate CD34+ bone marrow-derived leukemia cells into sphingosine-1 phosphate receptor 1 (S1PR1)+ and S1PR1- fractions. Cells in the S1PR1+ fraction demonstrated significantly higher clonogenicity and higher engraftment potential compared with those in the S1PR1- fraction. In contrast, CD34+ bone marrow cells from normal samples showed reduced clonogenicity in the S1PR1+ fraction compared with the S1PR1- fraction. Inhibition of S1PR1 expression in an AML cell line reduced the colony-forming potential of KG1 cells. Transcriptomic analyses and rescue experiments indicated PI3K/AKT pathway and MYBL2 are downstream mediators of S1PR1-associated stemness. These findings implicate S1PR1 as a functional biomarker of LSCs and suggest its potential as a therapeutic target in AML treatment.

[A new bibenzyl derivative from stems of Dendrobium officinale].

Eleven compounds were isolated from the 95% ethanol extract of the stems of Dendrobium officinale after water extraction by various modern chromatographic techniques, such as silica gel column chromatography(CC), octadecyl-silica(ODS) CC, Sephadex LH-20 CC, preparative thin layer chromatography(PTLC) and preparative high performance liquid chromatography(PHPLC). According to spectroscopic analyses(MS, 1D-NMR, 2D-NMR) combined with optical rotation data and calculated electronic circular dichroism(ECD), their structures were identified as dendrocandin Y(1), 4,4'-dihydroxybibenzyl(2), 3-hydroxy-4',5-dimethoxybibenzyl(3), 3,3'-dihydroxy-5-methoxybibenzyl(4), 3-hydroxy-3',4',5-trimethoxybibenzyl(5), crepidatin(6), alternariol(7), 4-hydroxy-3-methoxypropiophenone(8), 3-hydroxy-4,5-dimethoxypropiophenone(9), auriculatum A(10) and hyperalcohol(11). Among them, compound 1 was a new bibenzyl derivative; compounds 2 and 7-11 have not been previously reported from Dendrobium plants; compound 6 was reported from D.officinale for the first time. Compounds 3-6 exhibited potent antioxidant activity with IC_(50) values of 3.11-9.05 µmol·L~(-1) in ABTS radical scavenging assay. Compound 4 showed significant inhibitory effect on α-glucosidase, with IC_(50) value of 17.42 µmol·L~(-1), indicating that it boasted hypoglycemic activity.

Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification.

Background: Enoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified. Methods: In the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People's Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature. Results: By Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1- adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013-1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin. Conclusion: These bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.

Leukemic progenitor cells enable immunosuppression and post-chemotherapy relapse via IL-36-inflammatory monocyte axis.

Chemotherapy can effectively reduce the leukemic burden and restore immune cell production in most acute myeloid leukemia (AML) cases. Nevertheless, endogenous immunosurveillance usually fails to recover after chemotherapy, permitting relapse. The underlying mechanisms of this therapeutic failure have remained poorly understood. Here, we show that abnormal IL-36 production activated by NF-κB is an essential feature of mouse and human leukemic progenitor cells (LPs). Mechanistically, IL-36 directly activates inflammatory monocytes (IMs) in bone marrow, which then precludes clearance of leukemia mediated by CD8+ T cells and facilitates LP growth. While sparing IMs, common chemotherapeutic agents stimulate IL-36 production from residual LPs via caspase-1 activation, thereby enabling the persistence of this immunosuppressive IL-36­IM axis after chemotherapy. Furthermore, IM depletion by trabectedin, with chemotherapy and PD-1 blockade, can synergistically restrict AML progression and relapse. Collectively, these results suggest inhibition of the IL-36­IM axis as a potential strategy for improving AML treatment.

Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage.

The persistence of leukemia stem cells (LSCs) is one of the leading causes of chemoresistance in acute myeloid leukemia (AML). To explore the factors important in LSC-mediated resistance, we use mass spectrometry to screen the factors related to LSC chemoresistance and defined IFN-γ-inducible lysosomal thiol reductase (GILT) as a candidate. We found that the GILT expression was upregulated in chemoresistant CD34+ AML cells. Loss of function studies demonstrated that silencing of GILT in AML cells sensitized them to Ara-C treatment both in vitro and in vivo. Further mechanistic findings revealed that the ROS-mediated mitochondrial damage plays a pivotal role in inducing apoptosis of GILT-inhibited AML cells after Ara-C treatment. The inactivation of PI3K/Akt/ nuclear factor erythroid 2-related factor 2 (NRF2) pathway, causing reduced generation of antioxidants such as SOD2 and leading to a shifted ratio of GSH/GSSG to the oxidized form, contributed to the over-physiological oxidative status in the absence of GILT. The prognostic value of GILT was also validated in AML patients. Taken together, our work demonstrated that the inhibition of GILT increases AML chemo-sensitivity through elevating ROS level and induce oxidative mitochondrial damage-mediated apoptosis, and inhibition of the PI3K/Akt/NRF2 pathway enhances the intracellular oxidative state by disrupting redox homeostasis, providing a potentially effective way to overcome chemoresistance of AML.

Two new dibenzyl derivatives from the stems of Dendrobium catenatum.

Two new dibenzyl derivatives, dendrocandins V-W (1-2), together with six known compounds (3-8), have been isolated from the dried stems of Dendrobium catenatum. Their structures were mainly elucidated on the basis of HRESIMS, one- and two-dimensional NMR techniques. The isolated compounds 5-8 were evaluated in vitro for their antioxidant and hypoglycemic activities. Compound 8 showed moderate potent DPPH scavenging activity with IC50 value of 34.45 ± 1.07 µM. And compounds 5, 7-8 exhibited significant ABTS radical scavenging activities with IC50 values of 10.03 ± 0.88, 5.32 ± 1.13 and 9.01 ± 1.39 µM. Compounds 6-7 showed potent α-glucosidase inhibitory activities with IC50 values of 36.05 ± 0.67 and 159.59 ± 0.86 µM.

Measuring the topological charge of terahertz vortex beams with a focal hyperbolic lens.

An efficient method is proposed to measure the topological charge (TC) of terahertz (THz) vortex beams with a focal hyperbolic (FH) lens at 0.1 THz. The FH lens is designed and fabricated by 3D printing. The diffraction fringes acquired in the focal plane of the FH lens can judge the number and sign of the TC. Furthermore, after the horizontal or vertical measurement curve is recorded by rotating the FH lens to a suitable angle, the TC value can then be simply and effectively identified. The TC value of the experiment measurement reaches 5. The experiment results are in excellent accord with the simulation.

Generating terahertz perfect optical vortex beams by diffractive elements.

An effective experiment scheme is proposed to generate the terahertz (THz) perfect optical vortex (POV) beams by diffractive elements at the frequency of 0.1THz. Two diffractive elements are designed and fabricated by 3D-printing to form the generation system. The ring radius of the generated beams is independent of the topological charge and positive linear relationship with the radial wave vector. By controlling the radial wave vector, the ring radius can be freely adjusted. The experiment results are shown to corroborate the numerical simulation ones. Such generated beams hold promise for developing the novel THz fiber communication systems.

Millimeter-wave SFCW SAR imaging system based on in-phase signal measurement with simplified transceiver.

A conventional millimeter-wave stepped frequency continuous wave (SFCW) synthetic aperture radar (SAR) imaging system generally utilizes IQ modulation technique to acquire the amplitude and phase of the waves scattered from a target object. Due to measure both in-phase signal and quadrature signal, the transceiver of the conventional system is complicate and costly, and the IQ imbalance problem makes the system difficult to calibrate. To reduce hardware complexity and enhance efficiency-cost ratio, a novel SFCW SAR imaging system only measuring in-phase signal is proposed and demonstrated. For lack of quadrature signal measurement, an algorithm based on Fourier transform is proposed to estimate the amplitude and phase. The ultimate images are obtained through an image-reconstruction algorithm, which uses the estimated amplitude and phase as input parameters. The proposed system is verified by both simulation and experiment, where the frequencies are set from 24GHz to 30GHz. The imaging results with high resolution and low noise are demonstrated. Compared to the conventional system, the image quality of the proposed system is almost identical, but the transceiver of the proposed system is greatly simplified.

Matteuinterins A-C, three new glycosides from the rhizomes of Matteuccia intermedia.

Phytochemical investigation on the rhizomes of Matteuccia intermedia C.Chr. led to the isolation of three new compounds, named matteuinterins A-C (1-3), together with seven known compounds (4-10). Their structures were elucidated by extensive NMR analyses and chemical derivatization. Compounds 5-10 were evaluated for their anti-inflammatory activities on PGE2 release in LPS-stimulated RAW 264.7 murine macrophages. Compounds 5 and 10 exhibited inhibitory effect on PGE2 production in LPS-activated murine macrophages with IC50 values of 17.8 ± 1.5 and 30.3 ± 2.1 µM, respectively.[Formula: see text].

TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance.

PURPOSE: The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all-trans retinoic acid (ATRA) resistance and uncover new potential therapeutic strategies to block the rapid progression of early death. EXPERIMENTAL DESIGN: The important role of TWIST1 in APL leukemogenesis was first determined by gain- and loss-of-function assays. We then performed in vivo and in vitro experiments to explore the interaction of TWIST1 and TRIB3 and develop a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL. RESULTS: We found that the epithelial-mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction. CONCLUSIONS: Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death.See related commentary by Peeke and Gritsman, p. 6018.

Leukemic IL-17RB signaling regulates leukemic survival and chemoresistance.

Secreted proteins provide crucial signals that have been implicated in the development of acute myeloid leukemia (AML) in the bone marrow microenvironment. Here we identify aberrant expressions of inflammatory IL-17B and its receptor (IL-17RB) in human and mouse mixed lineage leukemia-rearranged AML cells, which were further increased after exposure to chemotherapy. Interestingly, silencing of IL-17B or IL-17RB led to significant suppression of leukemic cell survival and disease progression in vivo. Moreover, the IL-17B-IL-17RB axis protected leukemic cells from chemotherapeutic agent-induced apoptotic effects. Mechanistic studies revealed that IL-17B promoted AML cell survival by enhancing ERK, NF-κB phosphorylation, and the expression of antiapoptotic protein B-cell lymphoma 2, which were reversed by small-molecule inhibitors. Thus, the inhibition of the IL-17B-IL-17RB axis may be a valid strategy to enhance sensitivity and therapeutic benefit of AML chemotherapy.-Guo, H.-Z., Niu, L.-T., Qiang, W.-T., Chen, J., Wang, J., Yang, H., Zhang, W., Zhu, J., Yu, S.-H. Leukemic IL-17RB signaling regulates leukemic survival and chemoresistance.

C-Methylated flavanones from the rhizomes of Matteuccia intermedia and their α-glucosidase inhibitory activity.

One new flavanonol, demethylmatteucinol (1), and nine new flavanone glucoside derivatives, matteflavosides H-J (2-4) and matteuinterates A-F (5-10), were isolated from the rhizomes of Matteuccia intermedia C.Chr., along with 21 known flavanones (11-31). Notably, all of them contain C-methylation in the A-ring. The structures of the compounds were elucidated by spectroscopic methods and chemical derivatization. The α-glycosidase inhibition assay indicated that compounds 12-17 showed potent inhibitory activity with IC50 values of 12.4-69.7 µM, which suggested their hypoglycemic effect.

Reduced graphene oxide-supported gold dendrite for electrochemical sensing of acetaminophen.

A new nanocomposite was developed based on reduced graphene oxide (RGO) supported gold dendrite and applied for amperometric detection of acetaminophen. The RGO-gold dendrite composite was prepared by self-assembly of poly (diallyldimethylammonium chloride) (PDDA) functionalized gold dendrite and poly (sodium 4-styrenesulfonate) (PSS) functionalized RGO. The composite electrode material was characterized by Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), Ultraviolet-vis spectroscopy (UV), X-ray diffraction (XRD), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). The RGO-gold dendrite composite exhibited enhanced conductivity, catalytic activity and stability for acetaminophen oxidation and determination. The RGO-gold dendrite based electrochemical sensor is competent for detecting acetaminophen with a linear range from 0.07 µM to 3000 µM with a detection limit of 0.005 µM (S/N = 3). Moreover, the sensor was applied for the detection of acetaminophen in tablets and urine samples, which holds great promise in pharmaceutical analysis.

Poly(3,6-diamino-9-ethylcarbazole) based molecularly imprinted polymer sensor for ultra-sensitive and selective detection of 17-ß-estradiol in biological fluids.

In this work, we reported the synthesis of 3, 6-diamino-9-ethylcarbazole and its application as a new monomer for preparation of molecularly imprinted polymer (MIP) electrochemical sensor. The as prepared MIP sensor exhibited ultrahigh sensitivity and selectivity for the detection of 17-ß-estradiol in attomolar levels (1 × 10-18molL-1). The sensor works by detecting the change of the interfacial impedance that is derived from recognition of 17-ß-estradiol on the MIP layer. The MIP sensor based on 3, 6-diamino-9-ethylcarbazole monomer revealed better performance than that of unmodified carbazole monomer. The monomer/template ratio, electropolymerization scanning cycles, and the incubation pH values were optimised in order to obtain the best detection efficiency. Under the optimised condition, the MIP sensor exhibits a wide linear range from 1aM to 10µM (1 × 10-18 ̶ 1 × 10-5molL-1). A low detection limit of 0.36aM (3.6 × 10-19molL-1) and a good selectivity towards structurally similar compounds were obtained. The proposed MIP sensor also exhibits long-term stability and applicability in human serum samples. These advantages enabled this MIP sensor to be a promising alternative of electrochemical sensor and may be extended to detection of other endogenous compounds.

Terahertz circular Airy vortex beams.

Vortex beams have received considerable research interests both in optical and millimeter-wave domain since its potential to be utilized in the wireless communications and novel imaging systems. Many well-known optical beams have been demonstrated to carry orbital angular momentum (OAM), such as Laguerre-Gaussian beams and high-order Bessel beams. Recently, the radially symmetric Airy beams that exhibit an abruptly autofocusing feature are also demonstrated to be capable of carrying OAM in the optical domain. However, due to the lack of efficient devices to manipulate terahertz (THz) beams, it could be a challenge to demonstrate the radially symmetric Airy beams in the THz domain. Here we demonstrate the THz circular Airy vortex beams (CAVBs) with a 0.3-THz continuous wave through 3D printing technology. Assisted by the rapidly 3D-printed phase plates, individual OAM states with topological charge l ranging from l = 0 to l = 3 and a multiplexed OAM state are successfully imposed into the radially symmetric Airy beams. We both numerically and experimentally investigate the propagation dynamics of the generated THz CAVBs, and the simulations agree well with the observations.

3D-printed diffractive elements induced accelerating terahertz Airy beam.

We first demonstrate the accelerating terahertz (THz) Airy beam with a 0.3-THz continuous wave. Two diffractive elements are designed and 3D-printed to form the generation system, which cannot only imprint the desired complex phase pattern but also perform the required Fourier transform (FT). We both numerically and experimentally demonstrate the propagation dynamics of the accelerating THz Airy beam and investigate its self-healing property during propagation in the free space. Our observations are in good agreement with the numerical simulations. Such an accelerating THz Airy beam could be able to develop novel THz imaging systems and robust THz communication links.

Discrimination of orbital angular momentum modes of the terahertz vortex beam using a diffractive mode transformer.

We present an efficient method to discriminate orbital angular momentum (OAM) of the terahertz (THz) vortex beam using a diffractive mode transformer. The mode transformer performs a log-polar coordinate transformation of the input THz vortex beam, which consists of two 3D-printed diffractive elements. A following lens separates each transformed OAM mode to a different lateral position in its focal plane. This method enables a simultaneous measurement over multiple OAM modes of the THz vortex beam. We experimentally demonstrate the measurement of seven individual OAM modes and two multiplexed OAM modes, which is in good agreement with simulations.

Generation of arbitrary order Bessel beams via 3D printed axicons at the terahertz frequency range.

We present the generation of arbitrary order Bessel beams at 0.3 THz through the implementation of suitably designed axicons based on 3D printing technology. The helical axicons, which possess thickness gradients in both radial and azimuthal directions, can convert the incident Gaussian beam into a high-order Bessel beam with spiral phase structure. The evolution of the generated Bessel beams are characterized experimentally with a three-dimensional field scanner. Moreover, the topological charges carried by the high-order Bessel beams are determined by the fork-like interferograms. This 3D-printing-based Bessel beam generation technique is useful not only for THz imaging systems with zero-order Bessel beams but also for future orbital-angular-momentum-based THz free-space communication with higher-order Bessel beams.