The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia.

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.

Possible Role of Cellular Polyamine Metabolism in Neuronal Apoptosis.

Recent studies have shown that cellular levels of polyamines (PAs) are significantly altered in neurodegenerative diseases. Evidence from in vivo animal and in vitro cell experiments suggests that the cellular levels of various PAs may play important roles in the central nervous system through the regulation of oxidative stress, mitochondrial metabolism, cellular immunity, and ion channel functions. Dysfunction of PA metabolism related enzymes also contributes to neuronal injury and cognitive impairment in many neurodegenerative diseases. Therefore, in the current work, evidence was collected to determine the possible associations between cellular levels of PAs, and related enzymes and the development of several neurodegenerative diseases, which could provide a new idea for the treatment of neurodegenerative diseases in the future.

Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor.

BACKGROUND: Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable. METHODS: The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. RESULTS: DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. CONCLUSIONS: DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID. CLINICALTRIALS: gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Correlation between Transforming Growth Factor-ß and Periapical Lesions in Patients with Chronic Apical Periodontitis.

Objective: To examine the expression of transforming growth factor-ß (TGF-ß) in the periapical granulation tissue and serum of patients with chronic apical periodontitis and to conduct immunohistochemical analysis so as to explore the relationship between TGF-ß and the degree of periapical lesions. Methods: Periapical granulation tissues of 20 cases of chronic apical periodontitis were collected as the experimental group. Healthy gingival tissues without eruption of third molars of 5 cases were collected as the control group. Immunohistochemistry, enzyme-linked immunosorbent assay, and real-time PCR (RT-PCR) were utilized to determine the expression of TGF-ß mRNA and protein, and the difference in the expression of TGF-ß was compared between groups. In the experimental group, oral CBCT was taken to measure the periapical bone resorption area. Spearman's correlation method was applied to analyze the correlation between TGF-ß protein and gene expression levels and periapical bone resorption area. Results: Immunohistochemistry and enzyme-linked immunosorbent assay demonstrated that the expression of TGF-ß protein in chronic apical periodontitis tissue and serum was higher than that in the controls (P < 0.05). RT-PCR revealed that the expression of TGF-ß mRNA was higher in chronic apical periodontitis tissue than that of the controls (P < 0.05). Spearman's correlation analysis showed that in the experimental group, the mRNA expression of TGF-ß was positively correlated with the periapical bone resorption area (P < 0.01), and the protein expression level was not correlated with the periapical bone resorption area (P < 0.05). Conclusion: The increased expression of TGF-ß in the periapical granulation tissue and serum of patients with chronic apical periodontitis has a certain correlation with the progression of periapical periodontitis. The correlation between TGF-ß at the mRNA level and the degree of early stage disease as well as the high expression of TGF-ß in inflammatory cells in immunohistochemistry have confirmed that TGF-ß promotes bone resorption in early periapical periodontitis, and its mechanism of action deserves further investigation.

Methylcobalamin Alleviates Neuronal Apoptosis and Cognitive Decline Induced by PM2.5 Exposure in Mice.

BACKGROUND: Fine particulate matter (particulate matter 2.5, PM2.5) is considered one of the harmful factors to neuronal functions. Apoptosis is one of the mechanisms of neuronal injury induced by PM2.5. Methylcobalamine (MeCbl) has been shown to have anti-apoptotic and neuroprotective effects. OBJECTIVE: The current work tried to explore the neuroprotective effects and mechanisms that MeCbl protects mice against cognitive impairment and neuronal apoptosis induced by chronic real-time PM2.5 exposure. METHODS: Twenty-four 6-week-old male C57BL/6 mice were exposed to ambient PM2.5 and fed with MeCbl for 6 months. Morris water maze was used to evaluate the changes of spatial learning and memory ability in mice. PC12 cells and primary hippocampal neurons were applied as the in vitro model. Cell viability, cellular reactive oxygen species (ROS) and the expressions of apoptosis-related proteins were examined. And cells were stained with JC-1 and mitochondrial membrane potential was evaluated. RESULTS: In C57BL/6 mice, MeCbl supplementation alleviated cognitive impairment and apoptosis-related protein expression induced by PM2.5 exposure. In in vitro cell model, MeCbl supplementation could effectively rescue the downregulation of cell viability induced by PM2.5, and inhibited the increased levels of ROS, cellular apoptosis, and the expressions of apoptosis related proteins related to PM2.5 treatment, which may be associated with modulation of mitochondrial function. CONCLUSION: MeCbl treatment alleviated cognitive impairment and neuronal apoptosis induced by PM2.5 both in vivo and in vitro. The mechanism for the neuroprotective effects of MeCbl may at least be partially dependent on the regulation of mitochondrial apoptosis.

Recent Advances on Possible Association Between the Periodontal Infection of Porphyromonas gingivalis and Central Nervous System Injury.

Chronic periodontitis caused by Porphyromonas gingivalis (P. gingivalis) infection generally lasts for a lifetime. The long-term existence and development of P. gingivalis infection gradually aggravate the accumulation of inflammatory signals and toxic substances in the body. Recent evidence has revealed that P. gingivalis infection may be relevant to some central nervous system (CNS) diseases. The current work collects information and tries to explore the possible relationship between P. gingivalis infection and CNS diseases, including the interaction or pathways between peripheral infection and CNS injury, and the underlying neurotoxic mechanisms.

[Corrigendum] Integrated transcriptomic and epigenetic data analysis identifies aberrant expression of genes in acute myeloid leukemia with MLL­AF9 translocation.

Following the publication of this paper, the authors have realized that the final article did not indicate in the Authors' Contribution section that Fangce Wang and Zheng Li made equal contributions to this work (FW and ZL performed most of the statistical analyses and drafted the initial version of the manuscript). Therefore, the affiliations for this paper should have been written as follows (changes are highlighted in bold): FANGCE WANG1*, ZHENG LI1*, GUANGMING WANG1, XIAOXUE TIAN1, JIE ZHOU1, WENLEI YU1, ZHUOYI FAN1, LIN DONG1, JINYUAN LU1, JUN XU2, WENJUN ZHANG1 and AIBIN LIANG1. 1Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092; 2Medical Center for Stem Cell Engineering and Transformation, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China. *Contributed equally. The authors confirm that there are no further errors in the paper, and all the authors agree to this correction. The authors and the Editor apologize for any inconvenience caused. [the original article was published in Molecular Medicine Reports 21: 883­893, 2020, DOI: 10.3892/mmr.2019.10849].

Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLL­AF9 translocation.

Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLL­AF9 translocation and identified potential new targets for the therapy of AML with MLL­AF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLL­AF9­associated chromatin immunoprecipitation sequencing (ChIP­Seq) data was analyzed and identified binding sites for MLL­AF9 and wild type MLL (MLL WT). The ChIP­Seq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLL­AF9 leukemia cells and normal hematopoietic cells at MLL­AF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL­AF9 direct target genes. Upon validation using RNA­Seq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLL­AF9 were identified and further confirmed in MLL­AF9 mouse model using reverse transcription­quantitative polymerase chain reaction. These genes may have a critical role in AML with MLL­AF9 translocation.

Propagation dynamics of Janus vortex waves.

We study the propagation dynamics of Janus vortex wave under the action of a focusing lens based upon the formula of focused circular vortex Airy beams. Two dark foci would be generated under the action of a lens, and thus a perfect light hollow bottle could be formed. By controlling corresponding parameters, we could control the focal position and the relative intensity between the two focal intensities. The off-axis optical vortex (OV) would rotate rapidly in two focal regions, but keep still in the lens focus region. The angular displacement of OV in each focusing process is nearly π/2. (Note that the angular displacement for an off-axis OV in single focusing process of Gaussian beam is nearly π.) Two same OVs would repel to each other, but two opposite OVs would attract each other and annihilate at first focus plane in Janus vortex waves.

Targeting RAD51 enhances chemosensitivity of adult T­cell leukemia­lymphoma cells by reducing DNA double­strand break repair.

RAD51, is a key homologous recombination protein that repairs DNA damage and maintains gene diversity and stability. Previous studies have demonstrated that the over­expression of RAD51 is associated with chemotherapy resistance of tumor cells to chemotherapy, and enhanced activity of DNA damage repair (DDR) systems contributes to resistance of adult T­cell leukemia­lymphoma (ATL) resistance to chemotherapy. Thus, targeting RAD51 is a potential strategy for the sensitization of ATL cells to chemotherapeutic drugs by inducing DNA damage. In general, cells can repair minor DNA damage through DDR; however, serious DNA damage may cause cell toxicity in cells which cannot be restored. In the present, down regulation of RAD51 by shRNA and imatinib sensitized Jurkat cells to etoposide by decreasing the activity of homologous recombination (HR). We found that the suppression of RAD51 by shRNA inhibited tumor cells proliferation and enhanced apoptosis of Jurkat cells after etoposide treatment. Importantly, downregulation of RAD51 by imatinib obviously increased the apoptosis of Jurkat cell after etoposide treatment. These results demonstrated that RAD51 may be of great value to as a novel target for the clinical treatment of adult T­cell leukemia­lymphoma (ATL), and it may improve the survival of leukemia patients.

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in T-Cell Acute Lymphoblastic Leukemia (T-ALL) [corrected].

BACKGROUND/AIMS: T-Cell Acute Lymphoblastic Leukemia (T-ALL) [corrected] is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. METHODS: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. RESULTS: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. CONCLUSION: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

Propagation characteristics of partially coherent circular Airy beams.

The abruptly autofocusing properties of partially coherent circular Airy beam (CAB) with different spatial coherent length are theoretically investigated in this paper. It is found that, as spatial coherent length decreases, the size of the focal spot would increase and the focal intensity would decrease. But the abruptly autofocusing property for partially coherent CAB is still quite obvious, when comparing with the common partially coherent Gaussian beam under the same conditions; and its autofocusing position is less easily influenced by coherence. The influences of initial radius r0 and decaying parameter a on the autofocusing property have also been investigated in the end.

A three­lncRNA signature for prognosis prediction of acute myeloid leukemia in patients.

Long non-coding RNAs (lncRNAs) are transcripts characterized by >200 nucleotides, without validated protein production. Previous studies have demonstrated that certain lncRNAs have a critical role in the initiation and development of acute myeloid leukemia (AML). In the present study, the subtype­specific lncRNAs in AML was identified. Following the exclusion of the subtype­specific lncRNAs, the prognostic value of lncRNAs was investigated and a three­lncRNA expression­based risk score [long intergenic non­protein coding RNA 926, family with sequence similarity 30 member A and LRRC75A antisense RNA 1 (LRRC75A­AS1)] was developed for AML patient prognosis prediction by analyzing the RNA­seq data of AML patients from Therapeutically Available Research to Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA) projects. In the training set obtained from TARGET, patients were divided into poor and favorable prognosis groups by the median risk score. The prognostic effectiveness of this lncRNA risk score was confirmed in the validation set obtained from TCGA by the same cut­off. Furthermore, the lncRNA risk score was identified as an independent prognostic factor in the multivariate analysis. As further verification of the independent prognostic power of the lncRNA risk score, stratified analysis was performed by a cytogenetics risk group and revealed a consistent result. The prognostic predictive ability of the risk score was compared with the cytogenetics risk group by time­dependent receiver operating characteristic curves analysis. It was revealed that the combination of the lncRNA risk score and cytogenetics risk group provided a higher prognostic value than a single prognostic factor. The present study also performed co­expression analysis to predict the potential regulatory mechanisms of these lncRNAs in a cis/trans/competing endogenous RNA manner. The results suggested that LRRC75A­AS1 was highly associated with the target genes of transcription factors tumor protein 53 and ETS variant 6. Overall, these results highlighted the use of the three­lncRNA expression­based risk score as a potential molecular biomarker to predict the prognosis in AML patients.

Abruptly autofocusing property of circular Airy vortex beams with different initial launch angles.

Controlling the trajectory of circular Airy beams (CABs) by negative launch angles would greatly reduce their abruptly autofocusing property. By numerically simulating the propagation of a circular Airy vortex beam with different initial launch angles, we demonstrate in this paper that a larger topological charge of optical vortex (OV) is quite helpful to enhance the abruptly autofocusing property under different launch angles (especially for negative launch angles), without affecting the focal position and trajectory. Two opposite OVs would attract each other and partially overlap in the focal plane of CAB under different launch angles, causing even stronger autofocusing. As the distance between two OVs increases, the focal intensity contrast would decrease, especially for a beam with positive launch angles, whose autofocusing property decreases much more quickly with the distance.

Propagation characteristics of the modified circular Airy beam.

We have proposed a kind of modified circular Airy beam (MCAB) based upon a modification of the Fourier spectrum of circular Airy beams (CAB) in this paper. Unlike most abruptly autofocusing beams, the position of peak intensity of MCAB can be moved to any rings behind. Two apodization parameters are introduced to describe the propagation characteristics of MCAB. It is found that the focal position, focal trajectory and the size of focal spot do not change with the apodization parameters; but the abruptly autofocusing property will be greatly enhanced if appropriately apodization parameters are chosen. Comparing with the common CAB and the previous blocked CAB, the MCAB shows better abruptly autofocusing property. It may have more applications in various fields.

SIRT1 downregulation enhances chemosensitivity and survival of adult T-cell leukemia-lymphoma cells by reducing DNA double-strand repair.

Most chemotherapy drugs used for the treatment of adult T-cell leukemia-lymphoma (ATL) cause cell death directly by inducing DNA damage, which can be repaired via several DNA repair pathways. Enhanced activity of DNA damage repair systems contributes to ATL resistance to chemotherapies. Targeting DNA repair pathways is a promising strategy for the sensitization of ATL cells to chemotherapeutic drugs. in the present study, inhibition of SIRT1 deacetylase by shRNA sensitized Jurkat cells to etoposide by reducing the activity of non-homologous end joining (NHEJ) and homologous recombination (HR). Silencing of SIRT1 deacetylase by shRNA resulted in enhanced apoptosis and cell cycle arrest, while reduced colony formation of Jurkat cells after etoposide treatment was accompanied by elevated acetylation of FOXO1. Furthermore, inhibition of SIRT1 led to decreased activity of DNA damage repair by NHEJ and HR, accompanied by increased Ku70 acetylation. Furthermore, SIRT1 downregulation prolonged the survival time of Jurkat-xenografted mice. These results suggested that SIRT1 promotes DNA double­strand repair pathways in Jurkat cells by deacetylating Ku70, and increases cell proliferation by deacetylating FOXO1. The results suggest that SIRT1 is a potential target for the development of combinatorial treatment for ATL.

Photoluminescence and low-threshold lasing of ZnO nanorod arrays.

We report on the photoluminescence (PL) and lasing characteristics of ZnO nanorod arrays (NRAs) fabricated by hydrothermal process on nanocrystalline ZnO seeded Si and post-growth annealing. The morphology of the ZnO NRAs was examined by field emission scanning electron microscopy and the structure was characterized by x-ray diffraction, Fourier-transform infrared and Raman scattering spectroscopy. The properties of light emission were studied by continuous wave (CW) and 30 ps pulsed ultraviolet excitation. The ZnO NRAs consist of aligned nanorods and are nanocrystalline with wurtzite structure and c-axis orientation. At room temperature, the ZnO NRAs are capable of emitting strong CW PL and pulsed stimulated emission, with the latter showing obvious lasing characteristics. The threshold for lasing was observed to be ~16 kW/cm(2).

Infrared and raman spectroscopic studies of optically transparent zirconia (ZrO2) films deposited by plasma-assisted reactive pulsed laser deposition.

Plasma-assisted pulsed laser deposited zirconia (ZrO(2)) films were studied by Fourier transform infrared (FT-IR) and Raman spectroscopy for structural characterization and thermal stability in combination with optical characterization by spectroscopic ellipsometry and optical transmission measurements. Only the monoclinic ZrO(2) phase was positively identified from the infrared and Raman spectra of the as-deposited ZrO(2) films, which show excellent optical transparency from the ultraviolet to the near infrared as revealed by optical characterization. The as-deposited ZrO(2) films are free of any SiO(x) interfacial layer when deposited on silicon. The prepared ZrO(2) films exhibit good thermal stability in their structural, optical, and interfacial properties up to 900 °C. Upon annealing above 1100 °C, a silicon oxide interfacial layer forms due to the oxidation of the silicon substrate surface by the oxygen diffused from the oxide film to the silicon substrate at high temperatures.

Electronic structures and excitonic transitions in nanocrystalline iron-doped tin dioxide diluted magnetic semiconductor films: an optical spectroscopic study.

Nanocrystalline iron-doped tin dioxide (Sn(1-x)Fe(x)O(2)) films with x from 0 to 0.2 were prepared on c-sapphire substrates by pulsed laser deposition. X-ray diffraction and Raman scattering analysis show that the films are of the rutile structure at low compositions and an impurity phase related to Fe(2)O(3) appears until the x is up to 0.2, suggesting the general change of lattice structure due to the Fe ion substitution. The dielectric functions are successfully determined from 0.0248 to 6.5 eV using the Lorentz multi-oscillator and Tauc-Lorentz dispersion models in the low and high photon energy regions, respectively. With increasing Fe composition, the highest-frequency transverse optical phonons E(u) shifts towards a lower energy side and can be well described by (608 - 178x) cm(-1). From the transmittance spectra, the fundamental absorption edge is found to be decreased with the Fe composition due to the joint contributions from SnO(2) and Fe(2)O(3). It can be observed that the doped films exhibit evident excitonic excitation features, which are strongly related to the Fe doping. Among them, the 6A(1g)→ 4T(2g) transition contributes to the onset of optical absorption. Moreover, the remarkable intensity reduction and a red-shift trend with the doping composition, except for the pure film, can be testified by the photoluminescence spectra. It can be concluded that the replacement of Sn with the Fe ion could induce the 2p-3d hybridization and result in the electronic band structure modification of the Sn(1-x)Fe(x)O(2) films.