Chidamide Induces Epstein-Barr Virus (EBV) Lytic Infection and Acts Synergistically with Tenofovir to Eliminate EBV-Positive Burkitt Lymphoma.

Epstein-Barr virus (EBV) is a type of human γ-herpesvirus, and its reactivation plays an important role in the development of EBV-driven Burkitt lymphoma (BL). Despite intensive chemotherapy, the prognosis of relapsed/refractory BL patients remains unfavorable, and a definitive method to completely eliminate latent EBV infection is lacking. Previous studies have demonstrated that histone deacetylase (HDAC) inhibitors can induce the transition of EBV from latency to the lytic phase. The lytic activation of EBV can be inhibited by tenofovir, a potent inhibitor of DNA replication. Herein, we explored the antitumor effect and EBV clearance potential of a novel HDAC inhibitor called chidamide, combined with tenofovir, in the treatment of EBV-positive BL. In the study, chidamide exhibited inhibitory activity against HDAC. Moreover, chidamide inhibited BL cell proliferation, arrested cell cycle progression, and induced BL cell apoptosis primarily by regulating the MAPK pathways. Additionally, chidamide promoted the transcription of lytic genes, including BZLF1, BMRF1, and BMLF1 Compared with chidamide alone, the addition of tenofovir further induced growth arrest and apoptosis in EBV-positive BL cells and inhibited the transcriptions of EBV lytic genes induced by chidamide alone. Furthermore, our in vivo data demonstrated that the combination of chidamide and tenofovir had superior tumor-suppressive effects in a mouse model of BL cell tumors. The aforementioned findings confirm the synergistic effect of chidamide combined with tenofovir in inducing growth inhibition and apoptosis in EBV-positive BL cells and provide an effective strategy for eliminating EBV and EBV-associated malignancies. SIGNIFICANCE STATEMENT: High levels of Epstein-Barr virus (EBV)-DNA have consistently been associated with unfavorable progression-free survival and overall survival in EBV-associated lymphomas. Therefore, identifying novel strategies to effectively eradicate tumor cells and eliminate EBV is crucial for lymphoma patients. This study confirmed, for the first time, the synergistic effect of chidamide combined with tenofovir in the treatment of Burkitt lymphoma and the eradication of EBV virus.

Dielectric engineering enable to lateral anti-ambipolar MoTe2heterojunction.

Atomically two-dimensional (2D) materials have generated widespread interest for novel electronics and optoelectronics. Specially, owing to atomically thin 2D structure, the electronic bandgap of 2D semiconductors can be engineered by manipulating the surrounding dielectric environment. In this work, we develop an effective and controllable approach to manipulate dielectric properties of h-BN through gallium ions (Ga+) implantation for the first time. And the maximum surface potential difference between the intrinsic h-BN (h-BN) and the Ga+implanted h-BN (Ga+-h-BN) is up to 1.3 V, which is characterized by Kelvin probe force microscopy. More importantly, the MoTe2transistor stacked on Ga+-h-BN exhibits p-type dominated transfer characteristic, while the MoTe2transistor stacked on the intrinsic h-BN behaves as n-type, which enable to construct MoTe2heterojunction through dielectric engineering of h-BN. The dielectric engineering also provides good spatial selectivity and allows to build MoTe2heterojunction based on a single MoTe2flake. The developed MoTe2heterojunction shows stable anti-ambipolar behaviour. Furthermore, we preliminarily implemented a ternary inverter based on anti-ambipolar MoTe2heterojunction. Ga+implantation assisted dielectric engineering provides an effective and generic approach to modulate electric bandgap for a wide variety of 2D materials. And the implementation of ternary inverter based on anti-ambipolar transistor could lead to new energy-efficient logical circuit and system designs in semiconductors.

l-Asparaginase synergizes with etoposide via the PI3K/Akt/mTOR pathway in Epstein-Barr virus-positive Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive Epstein-Barr virus (EBV)-driven B-cell lymphoma characterized by the translocation and rearrangement of the c-Myc proto-oncogene. High-intensity multidrug chemotherapy regimens have a limited effect on the survival of refractory or relapsed BL patients, mainly owing to the high EBV load and drug resistance. l-asparaginase ( l-Asp) and etoposide (VP-16) play a beneficial role in EBV-related lymphoproliferative diseases; however, their roles and mechanisms in BL remain unclear. In this study, we found that VP-16 inhibited BL cell proliferation and arrested the cell cycle at the G2 /M phase. It also induced autophagy and activated the extrinsic and intrinsic apoptotic signaling pathways in BL cells. Mechanistically, VP-16 inhibited c-Myc expression and regulated the PI3K/Akt/mTOR signaling pathway. Notably, VP-16 also showed a specific synergistic effect with l-Asp to induce apoptosis in EBV-positive BL cells but not in EBV-negative BL cells. VP-16 combined with l-Asp further inhibited c-Myc expression and downregulated the PI3K/Akt/mTOR signaling pathway. Additionally, we found that VP-16 inhibited the expression of latent membrane protein 1 (LMP1), and in combination with l-Asp further decreased LMP1 expression in Raji cells. Our in vivo data also showed that the dual-drug combination significantly inhibited the growth of BL tumors and prolonged the survival of mice compared to VP-16 alone. In conclusion, this study provides new evidence that l-Asp may enhance the antitumor effect of VP-16 by inhibiting the PI3K/Akt/mTOR signaling pathway in EBV-positive BL cells.

The dynamics of forming a triplex in an artificial telomere inferred by DNA mechanics.

A telomere carrying repetitive sequences ends with a single-stranded overhang. The G-rich overhang could fold back and bind in the major groove of its upstream duplex, forming an antiparallel triplex structure. The telomeric triplex has been proposed to function in protecting chromosome ends. However, we lack strategies to mechanically probe the dynamics of a telomeric triplex. Here, we show that the topological dynamics of a telomeric triplex involves 3' overhang binding at the ds/ssDNA junction inferred by DNA mechanics. Assisted by click chemistry and branched polymerase chain reaction, we developed a rescue-rope-strategy for mechanically manipulating an artificial telomeric DNA with a free end. Using single-molecule magnetic tweezers, we identified a rarely forming (5%) telomeric triplex which pauses at an intermediate state upon unzipping the Watson-Crick paired duplex. Our findings revealed that a mechanically stable triplex formed in a telomeric DNA can resist a force of 20 pN for a few seconds in a physiological buffer. We also demonstrated that the rescue-rope-strategy assisted mechanical manipulation can directly rupture the interactions between the third strand and its targeting duplex in a DNA triplex. Our single-molecule rescue-rope-strategy will serve as a general tool to investigate telomere dynamics and further develop triplex-based biotechnologies.

Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells.

Cladribine is a purine nucleoside analog used to treat B-cell chronic lymphocytic leukemia and hairy cell leukemia, also functions as an inhibitor of DNA synthesis to block the repair of the damaged DNA. The therapeutic role of cladribine against diffuse large B-cell lymphoma cells (DLBCL) is still undefined. In the present study, we demonstrated that cladribine inhibited cell proliferation and induced G1 phase arrest in human DLBCL cells. Furthermore, we showed that cladribine induced apoptosis by decreasing the expression of c-FLIPL and increasing the expression of DR4 and the cleaved form of caspase8. Cladribine also upregulated the expression of Bax, and downregulated the expression of Mcl-1 and Bcl-2 in a dose-dependent manner. It also activated endoplasmic reticulum (ER) stress, and ATF4 expression was required for cladribine induced apoptosis. Also, we showed that suberoylanilide hydroxamic acid (SAHA) enhanced the pro-apoptotic role of cladribine. Collectively, cladribine activated extrinsic and intrinsic apoptotic signaling pathways via stimulating ER stress signaling pathway and eliciting synergistic effect with SAHA in DLBCL cells.

High expression of miR-338 is associated with poor prognosis in acute myeloid leukemia undergoing chemotherapy.

Acute myeloid leukemia (AML) is a heterogeneous disease with unfavorable outcomes. MicroRNAs (miRNAs) are important regulators and prognostic factors involved in AML. To determine the clinical role of miR-338 in AML, a total of 164 adults with de novo AML were collected. These patients were classified into a chemotherapy group and an allogeneic hematopoietic stem cell transplantation (allo-HSCT) group according to the clinical treatment, and then each group was divided into two subgroups based on the median miR-338 expression values. We found that upregulated miR-338 positively correlates with higher frequencies of complex karyotype, RUNX1 mutation, and poor risk status. In the chemotherapy group, high expression of miR-338 was independently associated with shorter EFS and OS. However, no significant differences were observed between the two subgroups within the allo-HSCT group. We also divided all patients into two groups according to the median miR-338 expression values of the whole cohort. In the miR-338 high expression group, patients receiving allo-HSCT had longer OS and EFS than those receiving chemotherapy only. In contrast, patients receiving different therapies had similar OS and EFS in the miR-338 low expression group. Our study suggests that high expression of miR-338 is an adverse prognostic biomarker in patients with AML undergoing chemotherapy and may guide treatment decisions for AML. Furthermore, allo-HSCT could significantly overcome the negative effect of high miR-338 expression, but it seemed to be unbeneficial and unnecessary for low miR-338 expressions.

MiR-425 expression profiling in acute myeloid leukemia might guide the treatment choice between allogeneic transplantation and chemotherapy.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous disease. MicroRNAs function as important biomarkers in the clinical prognosis of AML. METHODS: This study identified miR-425 as a prognostic factor in AML by screening the TCGA dataset. A total of 162 patients with AML were enrolled for the study and divided into chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) groups. RESULTS: In the chemotherapy group, patients with high miR-425 expression had significantly longer overall survival (OS) and event-free survival (EFS) compared with patients with low miR-425 expression. In multivariate analyses, high miR-425 expression remained independently predictive of a better OS (HR = 0.502, P = 0.005) and EFS (HR = 0.432, P = 0.001) compared with patients with low miR-425 expression. Then, all patients were divided into two groups based on the median expression levels of miR-425. Notably, the patients undergoing allo-HSCT had significantly better OS (HR = 0.302, P < 0.0001) and EFS (HR = 0.379, P < 0.0001) compared with patients treated with chemotherapy in the low-miR-425-expression group. Mechanistically, high miR-425 expression levels were associated with a profile significantly involved in regulating cellular metabolism. Among these genes, MAP3K5, SMAD2, and SMAD5 were predicted targets of miR-425. CONCLUSIONS: The expression of miR-425 may be useful in identifying patients in need of strategies to select the optimal therapy between chemotherapy and allo-HSCT treatment regimens. Patients with low miR-425 expression may consider early allo-HSCT.

The effect of air stable n-doping through mild plasma on the mechanical property of WSe2 layers.

Two-dimensional transition metal dichalcogenides have been widely applied to electronic and optoelectronic device owing to their remarkable material properties. Many studies present the platform for regulating the contact resistance via various doping schemes. Here, we report the alteration of mechanical properties of few top layers of the WSe2 flake which are processed by air stable n-doping of N2O with a constant gas flow through mild plasma and present better manufacturability and friability. The single-line nanoscratching experiments on the WSe2 flakes with different doping time reveal that the manufacturable depths are positively correlated with the exposure time at a certain range and tend to be stable afterwards. Meanwhile, material characterization by x-ray photoelectron spectroscopy confirms that the alteration of mechanical properties is owing to the creation of Se vacancies and substitution of O atoms, which breaks the primary molecular structure of the WSe2 flakes. The synchronous Kelvin probe force microscopy and topography results of ROI nanoscratching of a stepped WSe2 sample confirmed that the depth of the degenerate doping is five layers, which was consistent with the single-line scratching experiments. Our results reveal the interrelationship of the mechanical property, chemical bonds and work function changes of the doped WSe2 flakes.

MicroRNA-150 negatively regulates the function of CD4(+) T cells through AKT3/Bim signaling pathway.

Donor-derived CD4(+) T lymphocytes are the major effector cells directly involved in the development of graft-versus-host disease (GVHD). As a negative regulator of immune cell differentiation and development, microRNA-150 (miR-150) induces immunological tolerance in CD4(+) T cells after transplantation. However, the specific mechanisms have not been fully elucidated. In this study, we demonstrated that miR-150 is capable of not only inhibiting proliferation and activation of CD4(+) T cells but also promoting apoptosis. Mechanistically, miR-150 targets v-akt murine thymoma viral oncogene homolog 3 (AKT3), and subsequently downregulates B-cell lymphoma 2 (Bcl-2) interacting mediator of cell death (BIM). We have also demonstrated that re-expression of AKT3 reversed miR-150-mediated inhibition of CD4(+) T lymphocyte development. Therefore, we conclude that miR-150 negatively regulates CD4(+) T cell function by inhibiting the AKT3/BIM signaling pathway. These findings also suggest that manipulating the levels of miRNA-150 could be a valuable strategy in prevention and/or treatment of acute graft-versus-host disease.

Accurate calibration and uncertainty estimation of the normal spring constant of various AFM cantilevers.

Measurement of force on a micro- or nano-Newton scale is important when exploring the mechanical properties of materials in the biophysics and nanomechanical fields. The atomic force microscope (AFM) is widely used in microforce measurement. The cantilever probe works as an AFM force sensor, and the spring constant of the cantilever is of great significance to the accuracy of the measurement results. This paper presents a normal spring constant calibration method with the combined use of an electromagnetic balance and a homemade AFM head. When the cantilever presses the balance, its deflection is detected through an optical lever integrated in the AFM head. Meanwhile, the corresponding bending force is recorded by the balance. Then the spring constant can be simply calculated using Hooke's law. During the calibration, a feedback loop is applied to control the deflection of the cantilever. Errors that may affect the stability of the cantilever could be compensated rapidly. Five types of commercial cantilevers with different shapes, stiffness, and operating modes were chosen to evaluate the performance of our system. Based on the uncertainty analysis, the expanded relative standard uncertainties of the normal spring constant of most measured cantilevers are believed to be better than 2%.

Synthesis and evaluation of novel isoxazolyl chalcones as potential anticancer agents.

A series of novel isoxazolyl chalcones were synthesized and evaluated for their activities in vitro against four types of human non-small cell lung cancer cells, including H1792, H157, A549 and Calu-1 cells. The preliminary biological screening showed that compounds 5d and 5f-i exhibited significant cytotoxicity, particularly, compounds 5f and 5h were identified as the most potent anticancer agents with IC50 values 1.35-2.07 µM and 7.27-11.07 µM against H175, A549 and Calu-1 cell lines, respectively. Compounds 5f-i could induce apoptosis in A549 cells by death receptor 5 (DR5) mediated extrinsicpathways. The preliminary structure-activity relationship study showed that compounds bearing electron withdrawing groups (EWG) at the 2-position of the phenyl ring in Ar group were more effective than those with EWG at 4-position. These results further demonstrated that the scaffolds designed in this work might lead to the discovery of novel anti-lung cancer agents.

Investigation on blind tip reconstruction errors caused by sample features.

Precision measurements of a nanoscale sample surface using an atomic force microscope (AFM) require a precise quantitative knowledge of the 3D tip shape. Blind tip reconstruction (BTR), established by Villarrubia, gives an outer bound with larger errors if the tip characterizer is not appropriate. In order to explore the errors of BTR, a series of simulation experiments based on a conical model were carried out. The results show that, to reconstruct the tip precisely, the cone angle of the tip characterizer must be smaller than that of the tip. Furthermore, the errors decrease as a function of the tip cone angle and increase linearly with the sample radius of curvature, irrespective of the tip radius of curvature. In particular, for sharp (20 nm radius) and blunt (80 nm radius) tips, the radius of curvature of the tip characterizer must be smaller than 5 nm. Based on these simulation results, a local error model of BTR was established. The maximum deviation between the errors derived from the model and the simulated experiments is 1.22 nm. Compared with the lateral resolution used in the above simulated experiments (4 nm/pixel), it is valid to ignore the deviations and consider the local error model of BTR is indeed in quantitative agreement with the simulation results. Finally, two simulated ideal structures are proposed here, together with their corresponding real samples. The simulation results show they are suitable for BTR.

The chalcone 2'-hydroxy-4',5'-dimethoxychalcone activates death receptor 5 pathway and leads to apoptosis in human nonsmall cell lung cancer cells.

Natural chalcones have been proved to inhibit cancer cells with therapeutic potential, but the underlying molecular mechanism is still largely unexplored. Here, we identified a novel chalcone, 2'-hydroxy-4',5'-dimethoxychalcone (HDMC) and demonstrated that HDMC induced apoptosis in various nonsmall cell lung cancer cells. Further study showed that HDMC elevated cellular reactive oxygen species (ROS) levels, thus inducing expressions of ATF4 and C/EBP homologous protein (CHOP). Then, death receptor 5 (DR5) was upregulated through ATF4-CHOP axis and eventually resulted in apoptosis. We also found that downregulation of c-FLIPL contributed to HDMC-induced apoptosis. In conclusion, HDMC induces apoptosis in human nonsmall cell lung cancer cells via activation of DR5 signaling pathway, and ROS-mediated ATF4-CHOP axis is involved in the process. Our results further supported the potential for HDMC to be developed as a new antitumor agent for cancer therapy or chemoprevention.

A Combination of CPI-0610 and SAHA Induces Apoptosis through STAT3 and p38 Signalling Pathways in Diffuse Large B-cell Lymphoma Cells.

BACKGROUND: Although immunotherapies have greatly improved diffuse large B-cell lymphoma (DLBCL) prognosis, a proportion of patients remain to be relapsed or refractory. Therefore, the identification of novel therapeutic targets and drugs is urgently required. Inhibition of the bromodomain and extra-terminal (BET) proteins has been a promising therapeutic strategy for various haematologic cancers. CPI-0610 is a potent and selective BET inhibitor. The effects of CPI-0610 in DLBCL cells have not been reported yet. AIMS: The aim of this study was to assess the effects of CPI-0610 in DLBCL and its underlying mechanisms. METHODS: DLBCL cells were treated with CPI-0610, followed by measuring cell viability, cell cycle, apoptosis, autophagy, and specific cell signaling pathways. Moreover, immunodeficient mice were engrafted with SUDHL2 cells and then treated with CPI-0610 for analysis of tumor burden. We also analyzed the synergistic effect of CPI-0610 with histone deacetylase inhibitor suberoylanilide hydroxamic acid. RESULTS: The present study demonstrated that CPI-0610 displayed cell cytotoxicity by arresting the G1 cell cycle and inducing endogenous and exogenous apoptotic pathways. Additionally, CPI-0610 decreased BRD4 and c-Myc expressions and affected MAPK, JAK/STAT, and AKT signalling pathways in human DLBCL cells. An in vivo experiment exhibited that CPI-0610 decreased the primary tumour growth of the DLBCL xenograft model. Furthermore, the use of CPI-0610 in combination with suberoylanilide hydroxamic acid exhibited a specific synergistic effect in inducing apoptosis through the regulation of STAT3 and p38. CONCLUSION: Targeting BET may be an effective therapeutic strategy and potentiated by a combination with histone deacetylase inhibition in DLBCL.

Associations among risk perception, health efficacy, and health behaviors for cardiovascular disease: an application of risk perception attitude framework.

Background: There is currently a pervasive prevalence of cardiovascular disease (CVD) risk worldwide and an inadequate amount of action is being taken to promote healthy lifestyle habits. The risk perception attitude (RPA) framework, which classifies individuals based on their risk perception and efficacy belief, enables us to predict their preventive behaviors. We applied the RPA framework to analyze CVD prevention behaviors among Chinese adults and extended its application to CVD objective risk. Methods: A cross-sectional survey was performed in two sites in Zhejiang Province, from March to August 2022, which contained self-reported CVD risk perception, objective CVD risk, efficacy belief, physical activity, healthy diet, and covariates. We used the RPA framework to categorize participants into four groups, then analysis was conducted to estimate inter-group differences in healthy behaviors. We further conducted a hierarchical logistic regression analysis with individuals' health behaviors as the dependent variable, using three blocks of independent variables. Results: Among 739 participants, healthy physical activity and healthy diet had significant differences among four RPA groups, post hoc tests clarified that the proportion of respondents with healthy PA in the responsive group (61.6%) was significantly higher than that in the other three groups. Risk perception and efficacy belief significantly predicted health behavior against CVD; the relationship between absolute CVD risk and health behavior was moderated by efficacy belief. Conclusions: Early CVD risk screening is crucial, but tailored support and a proper understanding of personal risk are essential to promote healthy behaviors. Developing communication and behavioral counseling intervention strategies on the basis of the RPA framework has the potential to promote healthy behaviors for CVD prevention.

Thymosin ß4 Exerts a Cytoprotective Function and Attenuates Liver Injury in Murine Hepatic Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation.

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening complication that may occur after hematopoietic stem cell transplantation (HSCT). Hepatic sinusoidal endothelial cell (HSEC) injury and liver fibrosis are key mechanisms of HSOS. Thymosin ß4 (Tß4) is an active polypeptide that functions in a variety of pathologic and physiologic states, including inflammation regulation, anti-apoptosis, and anti-fibrosis. In this study, we found that Tß4 can stimulate HSEC proliferation, migration, and tube formation in vitro via activation of pro-survival signaling AKT (protein kinase B). In addition, Tß4 resisted γ irradiation-induced HSEC growth arrest and apoptosis in parallel with upregulation of anti-apoptotic protein B cell lymphoma extra-large (Bcl-xL) and B cell lymphoma-2 (Bcl-2), which may be associated with activation of AKT. More importantly, Tß4 significantly inhibited irradiation-induced pro-inflammatory cytokines in parallel with negative regulation of TLR4/MyD88/NF-κB and MAPK p38. Meanwhile, Tß4 reduced intracellular reactive oxygen species production and upregulated antioxidants in HSECs. Additionally, Tß4 inhibited irradiation-induced activation of hepatic stellate cells by downregulating the expression of fibrogenic markers α-SMA, PAI-1, and TGF-ß. In a murine HSOS model, levels of circulating alanine aminotransferase, aspartate aminotransferase, total bilirubin, and pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α were significantly reduced after administration of Tß4 peptide; furthermore, Tß4 treatment successfully ameliorated HSEC injury, inflammatory damage, and fibrosis of the murine liver. Taken together, our findings indicate that Tß4 stimulates proliferation and angiogenesis of HSECs, exerts a cytoprotective effect, and attenuates liver injury in a murine HSOS model, suggesting that its use may be a potential strategy to prevent and treat HSOS after HSCT.

Application of the NU-1000 coated SPME fiber on analysis of trace organochlorine pesticides in water.

Herein, a novel solid-phase microextraction (SPME) fiber based on the NU-1000 sorbent was developed for direct immersion extraction of organochlorine pesticides (OCPs) in water samples. As a kind of metal-organic framework, the NU-1000 possessed the mesoporous channels which were beneficial for the mass transfer of target analytes. Extraction equilibrium was achieved rapidly with the optimal extraction time of 30 min. The NU-1000 coated fiber with a high specific surface area showed better extraction efficiencies than commercial fibers (65 µm PDMS/DVB or 85 µm PA) towards OCPs, with the enrichment factors of the NU-1000 coated fiber 2-20 times higher than the latter. NU-1000 coated fiber showed higher extraction efficiencies toward polycyclic aromatic hydrocarbons (PAHs) than OCPs and nitrobenzenes. This indicated that π-π interaction and CH-π interaction between pollutants and aromatic groups of the NU-1000 contributed to the high extraction efficiencies. Under the optimal conditions (extraction at 40 °C for 30 min and desorption at 260 °C for 6 min), the NU-1000 coated fiber coupled with gas chromatography-mass spectrometry (GC-MS) exhibited satisfied analytical performance on analysis of OCPs, with a wide linear range (0.1-2000 ng L-1), low limits of detections (LODs, 0.011-0.058 ng L-1), and good reproducibility and repeatability. The established method has been successfully applied to the determination of OCPs in surface water with good sensitivity and recoveries, which proved the great promise of the NU-1000 on the extraction of organic pollutants with conjugated groups.

Engineering of Oxidized Line Defects on CVD-Grown MoS2 Flakes.

Defect engineering is a promising means to create patterns on two-dimensional (2D) materials to enable unconventional properties. However, defects usually exist abundantly and randomly on 2D materials, which makes it difficult to tune the properties in a controllable manner. Therefore, it is highly desirable to find out the formation mechanism and controllable fabrication method of defects on 2D materials. In this report, we systematically investigated the line defects on monolayer MoS2 formed by introducing oxygen during the CVD growth. The line defects were formed due to the overoxidation of the MoS2 flake along crystal boundaries, which bulged out of the surface and had the same surface potential as the basal plane. Therefore, the MoS2 flake with line defects maintained the optical and electrical integrity but exhibited distinct properties as compared to the pristine one. By controlling the oxygen concentration during CVD growth, the density of the line defects can be precisely controlled to implement controllable property tuning. Moreover, during the transfer process, the MoS2 flake was easily broken along the line defects, which increased the active sites to achieve enhanced hydrogen evolution reaction performance. This work is expected to inspire the development of patterned functional 2D materials by defect engineering.

The Acetyltransferase KAT5 Inhibitor NU 9056 Promotes Apoptosis and Inhibits JAK2/STAT3 Pathway in Extranodal NK/T Cell Lymphoma.

BACKGROUND: Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive malignant non- Hodgkin's lymphoma (NHL) with a poor prognosis. Therefore, novel therapeutic biomarkers and agents must be identified for the same. KAT5 inhibitor, NU 9056, is a small molecule that can inhibit cellular proliferation; however, its role in ENKTL has not been studied. OBJECTIVE: The present study investigated the effect of NU 9056 in ENKTL cells and explored the possible molecular mechanism for its antitumour effect. METHODS: The role of NU 9056 in ENKTL cells was investigated through the Cell Counting Kit-8 assay, flow cytometry, Western blot, and real-time quantitative polymerase chain reaction assay. RESULTS: NU 9056 inhibited ENKTL cell proliferation and induced G2/M phase arrest. NU 9056 also induced apoptosis by upregulating DR4, DR5, and caspase 8 expressions. Additionally, NU 9056 increased the expression of Bax, Bid, and cytochrome C and decreased the expression of Bcl-2, Mcl-1, and XIAP. Furthermore, NU 9056 activated endoplasmic reticulum (ER) stress and inhibited the JAK2/STAT3 signalling pathway. The p38 mitogen-activated protein kinase (MAPK) signalling pathway was also activated by NU 9056, and the ERK signalling pathway was suppressed in natural killer/T cell lymphoma cells. CONCLUSION: NU 9056 inhibited cell proliferation, arrested cell cycle in the G2/M phase, and induced apoptosis through the stimulation of ER stress, thus inhibiting the JAK2/STAT3 signalling pathway and regulating MAPK pathways in ENKTL cells.

A Novel Prognostic Index Model for Adult Hemophagocytic Lymphohistiocytosis: A Multicenter Retrospective Analysis in China.

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from the Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cutoff points of continuous variables; univariate and multivariate Cox analyses were used for variable selection, and the Kaplan-Meier curve was used to analyze the value of variables on prognosis. The C-index, Brier Score, and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio, and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in the derivation and validation cohorts by using a bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH.