Effect of Spatter Behavior on Mechanical Properties and Surface Roughness of Printed Parts during PBF-LM of 316L.

The spatter generated by the interaction between laser and powder during Powder Bed Fusion-Laser Melting (PBF-LM) can significantly affect the quality of printed parts. A high-speed camera is used to observe the dynamic process of spatter's behavior under different layer thickness and laser powers during the printing process, and to analyze the printed samples' surface roughness, microstructure, and mechanical properties. In terms of spatter image processing, employing an optical flow approach to track and quantify the number of spatters efficiently eliminates statistical redundancy and improves statistical correctness. It is found that under the same laser power, the number of spatters produced by the laser scan direction with the gas flow (LSD-W) is more than that by the laser scan direction against the gas flow (LSD-A), and the number of spatters produced increases with the increase of laser power. Analyzing the mechanical properties and surface roughness of the printed samples under different process parameters quantitatively reveals that differences in the spatter amount generated under different process parameters in the PBF-LM process is not the determining factor affecting the difference in tensile strength of printed parts. During LSD-W, the number of spatters generated at laser power of 170 W and layer thickness of 0.03 mm is 87, and the tensile strength of the printed sample is 618 MPa. During LSD-W, the number of spatters generated at laser power of 320 W and layer thickness of 0.05 mm is 211, and the tensile strength of the printed sample is 680 MPa. Instead, spatter generation has a more direct impact on the surface roughness of printed parts. The layer thickness is 0.03 mm, the laser power is 170 W, and (Ra = 2.372 µm) is the surface roughness of the sample. The layer thickness is 0.05 mm, the laser power is 320 W, and (Ra = 8.163 µm) is the surface roughness of the sample.

SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis.

Changes in neuronal activity modulate the vulnerability of motoneurons (MNs) in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). So far, the molecular basis of neuronal activity's impact in ALS is poorly understood. Herein, we investigated the impact of deleting the neuronal activity-stimulated transcription factor (TF) serum response factor (SRF) in MNs of SOD1G93A mice. SRF was present in vulnerable MMP9+ MNs. Ablation of SRF in MNs induced an earlier disease onset starting around 7-8 weeks after birth, as revealed by enhanced weight loss and decreased motor ability. This earlier disease onset in SRF-depleted MNs was accompanied by a mild elevation of neuroinflammation and neuromuscular synapse degeneration, whereas overall MN numbers and mortality were unaffected. In SRF-deficient mice, MNs showed impaired induction of autophagy-encoding genes, suggesting a potentially new SRF function in transcriptional regulation of autophagy. Complementary, constitutively active SRF-VP16 enhanced autophagy-encoding gene transcription and autophagy progression in cells. Furthermore, SRF-VP16 decreased ALS-associated aggregate induction. Chemogenetic modulation of neuronal activity uncovered SRF as having important TF-mediating activity-dependent effects, which might be beneficial to reduce ALS disease burden. Thus, our data identify SRF as a gene regulator connecting neuronal activity with the cellular autophagy program initiated in degenerating MNs.

Crosstalk of TetR-like regulator SACE_4839 and a nitrogen regulator for erythromycin biosynthesis.

TetR family transcriptional regulators (TFRs) are widespread in actinomycetes, which exhibit diverse regulatory modes in antibiotic biosynthesis. Nitrogen regulators play vital roles in modulation of primary and secondary metabolism. However, crosstalk between TFR and nitrogen regulator has rarely been reported in actinomycetes. Herein, we demonstrated that a novel TFR, SACE_4839, was negatively correlated with erythromycin yield in Saccharopolyspora erythraea A226. SACE_4839 indirectly suppressed erythromycin synthetic gene eryAI and resistance gene ermE and directly inhibited its adjacent gene SACE_4838 encoding a homologue of nitrogen metabolite repression (NMR) regulator NmrA (herein named NmrR). The SACE_4839-binding sites within SACE_4839-nmrR intergenic region were identified. NmrR positively controlled erythromycin biosynthesis by indirectly stimulating eryAI and ermE and directly repressing SACE_4839. NmrR was found to affect growth viability under the nitrogen source supply. Furthermore, NmrR directly repressed glutamine and glutamate utilization-related genes SACE_1623, SACE_5070 and SACE_5979 but activated nitrate utilization-associated genes SACE_1163, SACE_4070 and SACE_4912 as well as nitrite utilization-associated genes SACE_1476 and SACE_4514. This is the first reported NmrA homolog for modulating antibiotic biosynthesis and nitrogen metabolism in actinomycetes. Moreover, combinatorial engineering of SACE_4839 and nmrR in the high-yield S. erythraea WB resulted in a 68.8% increase in erythromycin A production. This investigation deepens the understanding of complicated regulatory network for erythromycin biosynthesis. KEY POINTS: • SACE_4839 and NmrR had opposite contributions to erythromycin biosynthesis. • NmrR was first identified as a homolog of another nitrogen regulator NmrA. • Cross regulation between SACE_4839 and NmrR was revealed.

Intracellular fluorogenic supramolecular assemblies for self-reporting bioorthogonal prodrug activation.

A visual drug delivery system (DDS) is urgently needed for precision medicine. DDS-mediated bioorthogonal prodrug activation strategies have demonstrated remarkable advantages in enlarging a therapeutic index via the alleviation of adverse drug reactions. However, the events of bioorthogonal prodrug activation remain inaccessible. Here, we construct a self-reporting bioorthogonal prodrug activation system using fluorescence emission to interpret prodrug activation events. In designed reactive oxygen species (ROS)-instructed supramolecular assemblies, the bioorthogonal reaction handle of tetrazine carries a dual role as fluorescence quencher and prodrug activator. The subsequent inverse-electron-demand Diels-Alder (IEDDA) reaction simultaneously liberates fluorescence and active drugs, which form a linear relationship. Differentiated by their cellular redox status, ROS-instructed supramolecular assemblies form selectively in both tumor cells and cell spheroids. Upon prodrug treatment, the brightness of fluorescence reflects the liberation of active drugs, which further correlates with the cell survival rate. Therefore, a fluorescence-based visualizable DDS (VDDS) for bioorthogonal prodrug activation is demonstrated, which should be useful to elucidate the multi-step processes in drug delivery and determine prodrug activation efficacy.

A racemosin B derivative, C25, suppresses breast cancer growth via lysosomal membrane permeabilization and inhibition of autophagic flux.

Breast cancer is the most common malignancy among women worldwide. As conventional therapies are only partially successful in eradicating breast cancer, the development of novel strategies is a top priority. We previously showed that C25, a new racemosin B derivative, exerts its anti-cancer activity through inhibition of autophagy, but the underlying mechanism remained unknown. Here we show that C25 inhibits the growth of diverse breast cancer cell subtypes and effectively suppresses tumor progression in a xenotransplantation model of triple negative breast cancer. C25 acts as a lysosomotropic agent to induce lysosomal membrane permeabilization and inhibit autophagic flux, resulting in cathepsin release and cell death. In accordance, RNA sequencing and gene set enrichment analysis revealed that C25 induces pathways consistent with autophagy inhibition, cell cycle arrest and senescence. Interestingly, knockdown of TFEB or SQSTM1 reduced cell death induced by C25 treatment. Finally, we show that C25 synergizes with the chemo-therapeutics etoposide and paclitaxel to further limit breast cancer cell growth. Thus, C25 alone or in combination with other anti-neoplastic agents offers a novel therapeutic strategy for aggressive forms of breast cancer and possibly other malignancies.

Virtual manipulation of tail postures of a gliding barn owl (Tyto alba) demonstrates drag minimization when gliding.

Aerodynamic functions of the avian tail have been studied previously using observations of bird flight, physical models in wind tunnels, theoretical modelling and flow visualization. However, none of these approaches has provided rigorous, quantitative evidence concerning tail functions because (i) appropriate manipulation and controls cannot be achieved using live animals and (ii) the aerodynamic interplay between the wings and body challenges reductive theoretical or physical modelling approaches. Here, we have developed a comprehensive analytical drag model, calibrated by high-fidelity computational fluid dynamics (CFD), and used it to investigate the aerodynamic action of the tail by virtually manipulating its posture. The bird geometry used for CFD was reconstructed previously using stereo-photogrammetry of a freely gliding barn owl (Tyto alba) and we validated the CFD simulations against wake measurements. Using this CFD-calibrated drag model, we predicted the drag production for 16 gliding flights with a range of tail postures. These observed postures are set in the context of a wider parameter sweep of theoretical postures, where the tail spread and elevation angles were manipulated independently. The observed postures of our gliding bird corresponded to near minimal total drag.

Bioorthogonal Disassembly of Tetrazine Bearing Supramolecular Assemblies Inside Living Cells.

Supramolecular assemblies are an emerging class of nanomaterials for drug delivery systems (DDS), while their unintended retention in the biological milieu remains largely unsolved. To realize the prompt clearance of supramolecular assemblies, the bioorthogonal reaction to disassemble and clear the supramolecular assemblies within living cells is investigated here. A series of tetrazine-capped assembly precursors which can self-assemble into nanofibers and hydrogels upon enzymatic dephosphorylation are designed. Such an enzyme-instructed supramolecular assembly process can perform intracellularly. The time-dependent accumulation of assemblies elicits oxidative stress and induces cellular toxicity. Tetrazine-bearing assemblies react with trans-cyclooctene derivatives, which lead to the disruption of π-π stacking and induce disassembly. In this way, the intracellular self-assemblies disassemble and are deprived of potency. This bioorthogonal disassembly strategy leverages the biosafety aspect in developing nanomaterials for DDSs.

Photofluorochromic water-dispersible nanoparticles for single-photon-absorption upconversion cell imaging.

Photofluorochromic diarylethene (DAE) molecules have been widely investigated due to their excellent fatigue resistance and thermal stability. However, the poor water solubility of DAEs limits their biological applications to some extent. Herein, we reported two kinds of water-dispersible DAE nanoparticles (DAEI-NPs and DAEB-NPs), in which DAE molecules were stabilized by the amphiphilic polymer DSPE-mPEG2000 using the nanoprecipitation approach. The fabricated nanoparticles retain well-controlled luminescence and fluorescence photoswitching properties in aqueous solution, which could be reversibly switched on and off under the alternating irradiation of ultraviolet (UV) and visible light. In addition, the closed-ring isomers of DAEB-NPs performed hot-band-absorption-based photon upconversion when excited by a 593.5 nm laser. Bearing excellent photophysical properties and low cytotoxicity, DAEB-NPs were applicable for upconversion cell imaging without high-excitation power density and free from oxygen removal. Additionally, the imaging process could be switched on by regulating the photofluorochromic nanoparticles.

Raptor wing morphing with flight speed.

In gliding flight, birds morph their wings and tails to control their flight trajectory and speed. Using high-resolution videogrammetry, we reconstructed accurate and detailed three-dimensional geometries of gliding flights for three raptors (barn owl, Tyto alba; tawny owl, Strix aluco, and goshawk, Accipiter gentilis). Wing shapes were highly repeatable and shoulder actuation was a key component of reconfiguring the overall planform and controlling angle of attack. The three birds shared common spanwise patterns of wing twist, an inverse relationship between twist and peak camber, and held their wings depressed below their shoulder in an anhedral configuration. With increased speed, all three birds tended to reduce camber throughout the wing, and their wings bent in a saddle-shape pattern. A number of morphing features suggest that the coordinated movements of the wing and tail support efficient flight, and that the tail may act to modulate wing camber through indirect aeroelastic control.

An immunotherapeutic approach to decipher the role of long non-coding RNAs in cancer progression, resistance and epigenetic regulation of immune cells.

Immunotherapeutic treatments are gaining attention due to their effective anti-tumor response. Particularly, the revolution of immune checkpoint inhibitors (ICIs) produces promising outcomes for various cancer types. However, the usage of immunotherapy is limited due to its low response rate, suggesting that tumor cells escape the immune surveillance. Rapid advances in transcriptomic profiling have led to recognize immune-related long non-coding RNAs (LncRNAs), as regulators of immune cell-specific gene expression that mediates immune stimulatory as well as suppression of immune response, indicating LncRNAs as targets to improve the efficacy of immunotherapy against tumours. Moreover, the immune-related LncRNAs acting as epigenetic modifiers are also under deep investigation. Thus, herein, is a summarised knowledge of LncRNAs and their regulation in the adaptive and innate immune system, considering their importance in autophagy and predicting putative immunotherapeutic responses.

Bird wings act as a suspension system that rejects gusts.

Musculoskeletal systems cope with many environmental perturbations without neurological control. These passive preflex responses aid animals to move swiftly through complex terrain. Whether preflexes play a substantial role in animal flight is uncertain. We investigated how birds cope with gusty environments and found that their wings can act as a suspension system, reducing the effects of vertical gusts by elevating rapidly about the shoulder. This preflex mechanism rejected the gust impulse through inertial effects, diminishing the predicted impulse to the torso and head by 32% over the first 80 ms, before aerodynamic mechanisms took effect. For each wing, the centre of aerodynamic loading aligns with the centre of percussion, consistent with enhancing passive inertial gust rejection. The reduced motion of the torso in demanding conditions simplifies crucial tasks, such as landing, prey capture and visual tracking. Implementing a similar preflex mechanism in future small-scale aircraft will help to mitigate the effects of gusts and turbulence without added computational burden.

High aerodynamic lift from the tail reduces drag in gliding raptors.

Many functions have been postulated for the aerodynamic role of the avian tail during steady-state flight. By analogy with conventional aircraft, the tail might provide passive pitch stability if it produced very low or negative lift. Alternatively, aeronautical principles might suggest strategies that allow the tail to reduce inviscid, induced drag: if the wings and tail act in different horizontal planes, they might benefit from biplane-like aerodynamics; if they act in the same plane, lift from the tail might compensate for lift lost over the fuselage (body), reducing induced drag with a more even downwash profile. However, textbook aeronautical principles should be applied with caution because birds have highly capable sensing and active control, presumably reducing the demand for passive aerodynamic stability, and, because of their small size and low flight speeds, operate at Reynolds numbers two orders of magnitude below those of light aircraft. Here, by tracking up to 20,000, 0.3 mm neutrally buoyant soap bubbles behind a gliding barn owl, tawny owl and goshawk, we found that downwash velocity due to the body/tail consistently exceeds that due to the wings. The downwash measured behind the centreline is quantitatively consistent with an alternative hypothesis: that of constant lift production per planform area, a requirement for minimizing viscous, profile drag. Gliding raptors use lift distributions that compromise both inviscid induced drag minimization and static pitch stability, instead adopting a strategy that reduces the viscous drag, which is of proportionately greater importance to lower Reynolds number fliers.

FLI1 promotes protein translation via the transcriptional regulation of MKNK1 expression.

The disruption of protein translation machinery is a common feature of cancer initiation and progression, and drugs that target protein translation offer new avenues for therapy. The translation initiation factor, eukaryotic initiation factor 4E (eIF4E), is induced in a number of cancer cell lines and is one such candidate for therapeutic intervention. Friend leukemia integration 1 (FLI1) is a potent oncogenic transcription factor that promotes various types of cancer by promoting several hallmarks of cancer progression. FLI1 has recently been implicated in protein translation through yet unknown mechanisms. This study identified a positive association between FLI1 expression and mitogen­activated protein kinase (MAPK)­interacting serine/threonine kinase1 (MKNK1), the immediate upstream regulator of the eIF4E initiation factor. The short hairpin RNA (shRNA)­mediated silencing or overexpression of FLI1 in leukemic cell lines downregulated or upregulated MKNK1 expression, respectively. Promoter analysis identified a potent FLI1 binding site in the regulatory region of the MKNK1 promoter. In transient transfection experiments, FLI1 increased MKNK1 promoter activity, which was blocked by mutating the FLI1 binding site. FLI1 specifically affected the expression of MKNK1, but not that of MKNK2. The siRNA­mediated downregulation of MKNK1 downregulated the expression of survivin (BIRC5) and significantly suppressed cell proliferation in culture. FLI1 inhibitory compounds were shown to downregulate this oncogene through the suppression of MAPK/extracellular­regulated kinase (ERK) signaling and the subsequent activation of miR­145, leading to a lower MKNK1 expression and the suppression of leukemic growth. These results uncover a critical role for FLI1 in the control of protein translation and the importance of targeting its function and downstream mediators, such as MKNK1, for cancer therapy.

3D computational models explain muscle activation patterns and energetic functions of internal structures in fish swimming.

How muscles are used is a key to understanding the internal driving of fish swimming. However, the underlying mechanisms of some features of the muscle activation patterns and their differential appearance in different species are still obscure. In this study, we explain the muscle activation patterns by using 3D computational fluid dynamics models coupled to the motion of fish with prescribed deformation and examining the torque and power required along the fish body with two primary swimming modes. We find that the torque required by the hydrodynamic forces and body inertia exhibits a wave pattern that travels faster than the curvature wave in both anguilliform and carangiform swimmers, which can explain the traveling wave speeds of the muscle activations. Notably, intermittent negative power (i.e., power delivered by the fluid to the body) on the posterior part, along with a timely transfer of torque and energy by tendons, explains the decrease in the duration of muscle activation towards the tail. The torque contribution from the body elasticity further clarifies the wave speed increase or the reverse of the wave direction of the muscle activation on the posterior part of a carangiform swimmer. For anguilliform swimmers, the absence of the aforementioned changes in the muscle activation on the posterior part is consistent with our torque prediction and the absence of long tendons from experimental observations. These results provide novel insights into the functions of muscles and tendons as an integral part of the internal driving system, especially from an energy perspective, and they highlight the differences in the internal driving systems between the two primary swimming modes.

Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity.

BACKGROUND: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS: Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.

Comprehensive analysis of Helicobacter pylori infection-associated diseases based on miRNA-mRNA interaction network.

Helicobacter pylori (H. pylori) infection remains a cause of significant morbidity and mortality worldwide. Comprehensive understanding of the pathogenic mechanism of H. pylori and its interaction with host will contribute to developing novel prophylactical and therapeutical strategies. Here, we first determined microRNA (miRNA) levels in H. pylori-infected patients with gastritis, duodenal ulcer, gastric cancer or mucosa-associated lymphoid tissue lymphoma using miRNA data sets. Thirty-four differentially expressed miRNAs were identified and functional enrichment analysis of those miRNA target genes revealed that H. pylori infection were strongly associated with pathway in cancer and regulation of mRNA synthesis. Using disease connectivity analysis of 28 hub genes, we found that H. pylori may increase the risk of many extragastric diseases (e.g. cardiovascular disease, hemic and lymphatic diseases and nervous system disease). Altogether, our integrated analysis provided a new method to predict pathogen-human disease connectivity based on miRNA-mRNA interaction network and indicated anti-H. pylori therapy as an effective means of human diseases prevention.

Synthesis of novel guttiferone E and xanthochymol derivatives with cytotoxicities by inducing cell apoptosis and arresting the cell cycle phase.

The mixture of GX (guttiferone E and xanthochymol), an inseparable polycyclic polyprenylated acylphloroglucinol (PPAP), showed moderate cytotoxic activities. The chemical transformation of GX yielded three different types of PPAPs (1, 2, and 3/4). A series of analogs were prepared, and the structures of the 40 newly synthesized compounds were elucidated by 1D and 2D NMR and HR-ESI-MS. The derivatives were screened in vitro for antiproliferative activity against five human cancer cell lines: human leukemic cell lines (HEL and K562), cervical cancer cell line (Hela), human breast adenocarcinoma cell line (MCF-7), and human non-small cell lung cancer cell line (A549), using the MTT assay, and most of the derivatives showed good cytotoxic activities. Noticeably, compound 2, a novel tautomer with a hemiketal, exhibited selective cytotoxic activities against HEL (IC50 = 4.79 ±â€¯0.23 µM) and K562 (IC50 = 7.69 ±â€¯0.34 µM) leukemia cells. The mechanism studies indicated that compound 2 induced apoptosis and arrested the cell cycle at the G0/G1 phase in the HEL cell line. Furthermore, compound 2 activated the intrinsic pathway by reducing the expression of anti-apoptotic protein Bcl-2 and cell cycle-specific cyclin D1 and by enhancing the pro-apoptotic protein Bax. Moreover, the caspase-3 and PPRP1 levels were also upregulated. Our present results suggest that compound 2 is a potential candidate for developing novel anti-leukemia agents in the future.

Tailor-made PL-UC-C3 nanoparticles for fluorescence/computed tomography imaging-guided cascade amplified photothermal therapy.

BACKGROUND: Development of the burgeoning number of photothermal therapy (PTT) agents has drawn a huge amount of interest, since PTT treatment is a powerful and effective alternative to traditional treatments. Optimal PTT agents should integrate some essential preconditions including negligible systemic toxicity, deep penetration into tumor tissues, and maximum laser energy absorbance. Unfortunately, only few of the PTT agents reported could meet all of the above mentioned conditions. METHODS: Here, we report a brand new PTT agent through the encapsulation of NaGdF4:Yb,Tm@ NaGdF4:Yb (UCNPs) and an organic compound (C3) into poly-e-caprolactone-polyethylene-polyglycol (PCL-PEG) (PL-UC-C3 NPs). RESULTS: UCNPs as an up-conversion material and C3 as a PTT agent both feature low cytotoxicity, and most importantly, UCNPs with superior conversion efficiency could efficiently absorb the energy of a 980 nm laser, transform the near-infrared laser light into visible light, and translate the palingenetic visible light to C3. The usage of a 980 nm laser ensures a deeper penetration and lower energy, while the highly efficient absorption and transformation process confers a cascade amplified hyperthermia for tumor treatment. CONCLUSION: In this regard, our research provides a powerful and robust breakthrough for florescence/computed tomography imaging-guided PTT treatment, lighting up the clinical application in cancer treatment.

Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.

E26 transformation-specific (ETS) gene family contains a common DNA-binding domain, the ETS domain, responsible for sequence-specific DNA recognition on target promoters. The Fli-1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline-like compounds including 4'-demethoxy-3',4'-methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli-1 transactivation ability. These compounds altered expression of Fli-1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline-like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli-1-driven mouse model. Mechanistically, the compounds blocked c-Raf-MEK-MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli-1 protein synthesis. Consistent with its high expression in myelomas, B-cell lymphoma, and B chronic lymphocytic leukemia (B-CLL), pharmacological inhibition of Fli-1 by the flavagline-like compounds or genetic knock-down via shRNA significantly hindered proliferation of corresponding cell lines and patients' samples. These results uncover a critical role of Fli-1 in growth and survival of various hematological malignancies and point to flavagline-like agents as lead compounds for the development of anti-Fli-1 drugs to treat leukemias/lymphomas overexpressing Fli-1.

Associations Between XPD Lys751Gln Polymorphism and Leukemia: A Meta-Analysis.

Objectives: The aim of the present study was to define the potential relationship between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphisms and the risk of leukemia. Methods: A comprehensive search of Pubmed, Web of Science, EBSCO, the Cochrane Library and China National Knowledge Infrastructure was conducted to identify original articles published before March 2017 concerning the association between XPD Lys751Gln polymorphisms and leukemia risk. A literature quality assessment was performed using the Newcastle-Ottawa Scale. Heterogeneity across studies was assessed using I2 statistics. Random- or fixed-effects models were used to calculate pooled odds ratios (ORs) in the presence or absence of heterogeneity, respectively. Sensitivity analysis was used to assess the influence of individual studies on the pooled estimate. Publication bias was investigated using funnel plots and Egger's regression test. All data analyses were performed using Stata 14.0 and Revman 5.3. Results: Fourteen studies with a total of 7525 participants (2,757 patients; 4,768 controls) were included in this meta-analysis. We found that XPD Lys751Gln polymorphisms significantly increased the risk of developing leukemia in both dominant OR = 1.21, 95%CI [1.10-1.35], P ≤ 0.001) and heterozygote (OR = 1.22, 95%CI [1.09-1.36], P ≤ 0.001) model. An allele model showed a borderline significant increase in leukemia risk (OR = 1.13, 95%CI [1.00-1.27], P = 0.05). A subgroup analysis revealed a consistent association between XPD Lys751Gln polymorphisms and leukemia risk for some genetic models in Caucasian populations, adult or chronic groups, and in almost all models of childhood or acute groups. Conclusion: Our results indicate that XPD Lys751Gln polymorphism increases the risk of leukemia, especially in childhood and acute cases.