Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine.

Background: Atypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported. Case description: In this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML. Conclusion: Our case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT.

Effects of albumin and crystalloid priming strategies on red blood cell transfusions in on-pump cardiac surgery: a network meta-analysis.

BACKGROUND: In on-pump cardiac surgery, the albumin priming strategy could maintain colloid osmotic pressure better than crystalloid solutions and reduce excessive perioperative fluid balance. However, a high-quality meta-analysis is required to compare the safety of these approaches in perioperative red blood cell (RBC) transfusions. Owing to limited direct evidence, we conducted a network meta-analysis (NMA) to increase the pool of studies and provide indirect evidence. METHODS: The pre-defined primary outcomes were intraoperative and the first 24 h postoperative RBC transfusion volume in units. The pre-defined secondary outcome was postoperative blood loss (the first 24 h). We reviewed all randomized controlled trials comparing albumin, crystalloid, and artificial colloid priming strategies. Studies that only displayed pre-defined outcomes could be included. A pairwise meta-analysis was performed on studies that directly compared the pre-defined outcomes between albumin and crystalloids. Additionally, a random-effects network meta-analysis (NMA) model was employed to generate indirect evidence for the pre-defined outcomes between albumin and crystalloids. RESULTS: The literature search identified 830 studies,10 of which were included in the final analysis. Direct meta-analysis indicated that crystalloid priming significantly decreased total perioperative RBC transfusions (MD: -0.68U; 95%CI: -1.26, -0.09U; P = 0.02) and intraoperative RBC transfusions (MD: -0.20U; 95%CI: -0.39, -0.01U; P = 0.03) compared to albumin. Postoperative RBC transfusions showed a decreasing trend in the crystalloid group; however, the difference was not statistically significant. (MD: -0.16U; 95%CI: -0.45, 0.14U; P = 0.30). After including indirect evidence, the NMA results continued to demonstrate a higher RBC receiving with the albumin priming strategy compared to crystalloids, although the differences did not reach statistical significance. For postoperative blood loss, direct evidence showed no significant differences between albumin and crystalloid priming strategies. However, NMA evidence displayed that albumin exist higher probability of reducing postoperative blood loss than crystalloid. CONCLUSION: Both direct and NMA evidence indicated that the albumin priming strategy resulted in more perioperative RBC transfusions than crystalloids. Considering the additional blood management burden, the application of an albumin-priming strategy in on-pump cardiac surgery still needs more consideration.

An Explainable Machine Learning Model to Predict Acute Kidney Injury After Cardiac Surgery: A Retrospective Cohort Study.

Background: To derive and validate a machine learning (ML) prediction model of acute kidney injury (AKI) that could be used for AKI surveillance and management to improve clinical outcomes. Methods: This retrospective cohort study was conducted in Fuwai Hospital, including patients aged 18 years and above undergoing cardiac surgery admitted between January 1, 2017, and December 31, 2018. Seventy percent of the observations were randomly selected for training and the remaining 30% for testing. The demographics, comorbidities, laboratory examination parameters, and operation details were used to construct a prediction model for AKI by logistic regression and eXtreme gradient boosting (Xgboost). The discrimination of each model was assessed on the test cohort by the area under the receiver operator characteristic (AUROC) curve, while calibration was performed by the calibration plot. Results: A total of 15,880 patients were enrolled in this study, and 4845 (30.5%) had developed AKI. Xgboost model had the higher discriminative ability compared with logistic regression (AUROC, 0.849 [95% CI, 0.837-0.861] vs 0.803[95% CI 0.790-0.817], P<0.001) in the test dataset. The estimated glomerular filtration (eGFR) and creatine on intensive care unit (ICU) arrival are the two most important prediction parameters. A SHAP summary plot was used to illustrate the effects of the top 15 features attributed to the Xgboost model. Conclusion: ML models can provide clinical decision support to determine which patients should focus on perioperative preventive treatment to preemptively reduce acute kidney injury by predicting which patients are not at risk.

Reverse remodeling of left atrium assessed by cardiovascular magnetic resonance feature tracking in hypertrophic obstructive cardiomyopathy after septal myectomy.

BACKGROUND: Assessing the structure and function of left atrium (LA) is crucial in hypertrophic obstructive cardiomyopathy (HOCM) because LA remodeling correlates with atrial fibrillation. However, few studies have investigated the potential effect of myomectomy on LA phasic remodeling in HOCM after myectomy using cardiovascular magnetic resonance (CMR) feature tracking (FT). This study aims to evaluate the LA structural and functional remodeling with HOCM after myectomy by CMR-FT and to further investigate the determinants of LA reverse remodeling. METHODS: In this single-center study, we retrospectively studied 88 patients with HOCM who received CMR before and after myectomy between January 2011 and June 2021. Preoperative and postoperative LA parameters derived from CMR-FT were compared, including LA reservoir function (total ejection fraction [EF], total strain [εs], peak positive strain rate [SRs]), conduit function (passive EF, passive strain [εe], peak early negative strain rate [SRe]) and booster function (booster EF, active strain [εa], late peak negative strain rate [SRa]). Eighty-six healthy participants were collected for comparison. Univariate and multivariate linear regression identified variables associated with the rate of change of εa. RESULTS: Compared with preoperative parameters, LA reservoir function (total EF, εs, SRs), booster function (booster EF, εa, SRa), and SRe were significantly improved after myectomy (all P < 0.05), while no significant differences were observed in passive EF and εe. Postoperative patients with HOCM still had larger LA and worse LA function than healthy controls (all P < 0.05). After analyzing the rates of change in LA parameters, LA boost function, especially εa, showed the most dramatic improvement beyond the improvements in reservoir function, conduit function, and volume. In multivariable regression analysis, minimum LA volume index (adjusted ß = - 0.39, P < 0.001) and Δleft ventricular outflow tract (LVOT) pressure gradient (adjusted ß = - 0.29, P = 0.003) were significantly related to the rate of change of εa. CONCLUSIONS: Patients with HOCM after septal myectomy showed LA reverse remodeling with a reduction in LA size and restoration in LA reservoir and booster function but unchanged LA conduit function. Among volumetric and functional changes, booster function had the greatest improvement postoperatively. Besides, preoperative LAVmin index and ΔLVOT might be potential factors associated with the degree of improvement in εa.

Vesicular self-assembly of copolymer-grafted nanoparticles with anisotropic shapes.

Plasmonic nanovesicles show broad applications in areas such as cancer theranostics and drug delivery, but the preparation of nanovesicles from shaped nanoparticles remains challenging. This article describes the vesicular self-assembly of shaped nanoparticles, such as gold nanocubes grafted with amphiphilic block copolymers, in selective solvents. The nanocubes assembled within the vesicular membranes exhibit two distinctive packing modes, namely square-like and hexagonal packing, depending on the relative dimensions of the copolymer ligands and nanocubes. The corresponding optical properties of the plasmonic nanovesicles can be tuned by varying the length of the grafted copolymers and the size of the nanocubes. This work provides guidance for the fabrication of functional plasmonic vesicles for applications in catalysis, nanomedicines and optical devices.

Effect of Iron-Erythrocyte Metabolism-Related Indexes on Posttraumatic Growth in Patients on Maintenance Hemodialysis (MHD).

Purpose: To investigate the effect of iron-erythrocyte metabolism-related indexes on posttraumatic growth in MHD patients and their caregivers. Patients and Methods: A total of 170 pairs of MHD patients and their caregivers in Shanghai Changhai Hospital were enrolled in this research, which used sociodemographic characteristics, the Posttraumatic Growth Inventory (PTGI), the Perceived Social Support Scale (PSSS), and the Medical Coping Modes Questionnaire (MCMQ). The test data of 141 patients were retrieved from the hospital database. Results: Single-factor analysis showed that the PTGI score of patients with a mean corpuscular erythrocyte volume ≥ 100 fL was 85.4 ± 19.8 and those with a mean corpuscular erythrocyte volume lower than 100 fL were 70.6 ± 24.7; the PTGI scores of patients with reticulocytes >1.5% were 68.8 ± 25.8, and those with reticulocytes <1.5% were 78.4 ± 21.1; the PTGI scores of the caregivers whose serum iron was >10.6 µmol /L were 78.2 ± 21.6, and those with serum iron <10.6 µmol /L were 67.9 ± 22.8. The difference in MCMQ scores between the caregivers with transferrin saturation>50% and with transferrin saturation<20% was 18.9 ± 8.4. For the correlation test of serum iron, reticulocyte and PTGI scores for patients, the Pearson correlation coefficients were 0.239 and -0.193, respectively, and the correlation test between erythrocyte distribution width SD and the score of caregivers MCMQ scale, the Pearson correlation coefficient was 0.225; p for all was< 0.05, with significant differences. There was no significant difference in the scores of different scales for total iron binding capacity (TIBC) at different levels. Conclusion: The indexes related to iron erythrocyte metabolism in MHD patients are correlated with ruminant meditation of patients and their caregivers and promotion of posttraumatic growth. Good nutritional status, adequate hematopoietic material, and normal erythrocyte count and function are also important for them.

Hypoxia-Responsive Molecular Probe Lighted up by Peptide Self-Assembly for Cancer Cell Imaging.

Hypoxia is a characteristic feature of most solid tumors, which promotes the proliferation, metastasis, and invasion of tumors and stimulates the resistance of cancer treatments, leading to the serious consequences of tumor recurrence. The exploration of hypoxia detection technology will aid tumor diagnosis and treatment. Fluorescence imaging technology is an accurate and efficient hypoxia detection technology. It has attracted significant research interest, but designing novel fluorescence probes, especially stimuli-responsive probes with high sensitivity and low toxicity is still challenging. In this work, we report a hypoxia-responsive molecular bioprobe lighted up by peptide self-assembly, which contains aggregationinduced emission (AIE) fluorescent molecule TPE, hypoxia-responsive azo group (-N═N-), the self-assembling peptide GFFY, and targeting ligand RGD. The resulting peptide derivative TPE-GFFY-N═N-EERGD forms supramolecular nanofibers but emit weak fluorescence because the azobenzene moiety can effectively quench the fluorescence of the TPE dye. However, the fluorescence-quenched nanofibers could be lighted up dramatically when the azo group is reduced. More importantly, this "turn-on" supramolecular fluorescence bioprobe enables effective detecting tumor hypoxia due to the overexpressed azoreductase in the tumor microenvironment. This work affords a paradigm of designing environmentsensitive fluorescent molecular probes for tumor hypoxia imaging.

Network Pharmacologic Analysis of Dendrobium officinale Extract Inhibiting the Proliferation of Gastric Cancer Cells.

Globally, gastric cancer (GC) is one of the three most deadly cancers. Dendrobium officinale (D. officinale) is a traditional Chinese medicine (TCM), and its extract can significantly inhibit the proliferation of gastric cancer cells. However, there are no unified conclusions on its potential active components and possible mechanisms of action. This paper aims at exploring the potential active components, targets, and cell pathways of D. officinale extract in inhibiting the proliferation of gastric cancer cells by using network pharmacology and cytology experiments. In this paper, UPLC-MS/MS was used to identify the main chemical components in the extracts of D. officinale, and the an ADME model was used to screen the potential active components. Network pharmacology methods such as target prediction, pathway identification, and network construction were used to determine the mechanism through which the D. officinale extract inhibited gastric cancer cell proliferation. MTT assays, fluorescence confocal microscopy, clone formation, and flow cytometry were used to verify the inhibitory activity of the D. officinale extract on gastric cancer cell proliferation in vitro. The UPLC-MS/MS analysis identified 178 chemical components from the D. officinale extract. Network pharmacology analysis showed that 13 chemical components had the potential to inhibit the proliferation of gastric cancer cells, with the possible involvement of 119 targets and 20 potential signaling pathways. In vitro experiments confirmed that the D. officinale extract could significantly inhibit the proliferation of gastric cancer cells. Therefore, we believe that the D. officinale extract can inhibit the proliferation of gastric cancer cells through effects on multiple components, multiple targets, and multiple pathways.

Synthesis and Manipulation of Single-Crystalline Lithium Nickel Manganese Cobalt Oxide Cathodes: A Review of Growth Mechanism.

Lithium nickel manganese cobalt oxide (NMC) cathodes are of great importance for the development of lithium ion batteries with high energy density. Currently, most commercially available NMC products are polycrystalline secondary particles, which are aggregated by anisotropic primary particles. Although the polycrystalline NMC particles have demonstrated large gravimetric capacity and good rate capabilities, the volumetric energy density, cycling stability as well as production adaptability are not satisfactory. Well-dispersed single-crystalline NMC is therefore proposed to be an alternative solution for further development of high-energy-density batteries. Various techniques have been explored to synthesize the single-crystalline NMC product, but the fundamental mechanisms behind these techniques are still fragmented and incoherent. In this manuscript, we start a journey from the fundamental crystal growth theory, compare the crystal growth of NMC among different techniques, and disclose the key factors governing the growth of single-crystalline NMC. We expect that the more generalized growth mechanism drawn from invaluable previous works could enhance the rational design and the synthesis of cathode materials with superior energy density.

Molecular and expression characterization of Toll-like receptor family genes from the Anadara sativa (Bivalvia, Arcidae) transcriptome.

Innate immunity plays an important role in invertebrates because it provides the first line of protection by recognizing invading microbial pathogens and then activating downstream signaling pathways. However, until now, increasing reports of clam diseases did not include those of Anadara sativa, which are widely distributed and economically important maritime clams. In the present study, transcriptome libraries of untreated (termed H) and Vibrio anguillarum-challenged (termed HV) A. sativa hepatopancreases were constructed and sequenced using the Illumina HiSeq4000 platform. In total, we obtained 78,012,510 and 84,937,516 clean reads from 80,006,030 to 86,871,742 raw data reads, respectively, assembled by different software programs. Furthermore, 150,274 unigenes were generated from 196,003 transcripts, with an N50 length of 1088 bp, and then annotated with the SwissProt, NR, NT, PFAM, KO, GO, KOG and KEGG databases. Moreover, 3982 differentially expressed unigenes (H vs HV) were determined, with 3583 upregulated and 399 downregulated genes. Among these differentially expressed unigenes, 207 unigenes were found using KEGG annotation in 16 immune-related signaling pathways, such as Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I-like receptor (RLR) signaling pathways. Finally, we selected 11 full-length TLRs and classified them into 3 groups, namely, one V-TLR, four Ls-TLR and six sP-TLR; furthermore, we validated the increased expression patterns of the 11 TLRs in response to LPS injection. In summary, these results revealed multiple findings on potential immune-related genes, such as the differential expression analysis and annotation based on the A. sativa transcriptome in response to V. anguillarum stimulation, and explored the molecular and expression characterization of A. sativa TLRs, which provide new insights into the innate immune responses and defense mechanisms in shellfish.

Performance of polyvinyl pyrrolidone-isatis root antibacterial wound dressings produced in situ by handheld electrospinner.

Antibacterial dressings are an increasingly important tool for the prevention and management of wound infections, particularly in light of concerns surrounding conventional drug-resistant antibiotics. Handheld electrospinning devices provide opportunities for the rapid application of antibacterial dressing materials to wounds, but spinning formulations need to be compatible with live biological surfaces. We report the development of a new antibacterial formulation compatible with handheld electrospinning, and its manufacture directly on a wound site. Nanofibrous dressing mats were produced from polyvinyl pyrrolidone (PVP) containing isatis root (Indigowoad root or Ban-Lan-Gen), a traditional Chinese medicine, commonly used for the treatment of infectious disease. The resulting wound dressing mats of PVP/isatis root exhibited well-defined fibrous structures and excellent surface wetting, and permeability characteristics. The presence of isatis root conferred antibacterial activity against gram negative and gram positive strains. Moreover, in a Kunming mouse skin injury model, direct electrospinning of PVP/isatis root formulations on to wound sites produced near complete wound closure after 11 days and epidermal repair in histological studies.

In Situ Electrospun Zein/Thyme Essential Oil-Based Membranes as an Effective Antibacterial Wound Dressing.

Wound dressings are an important element in promoting the healing of wounds. Electrospun fibrous materials have a highly porous structure and controllable antibacterial activity and are therefore popular as potential wound dressings. However, electrospun fibrous wound dressings are usually conveniently packaged for immediate use but cannot accommodate irregularly shaped wounds, and their misuse runs the risk of causing a secondary injury to the wound. To overcome these issues, in situ electrospun zein/thyme essential oil (TEO) nanofibrous membranes are proposed as a potential type of wound dressing and applied for wound management through an in situ electrospinning process, which uses a portable electrospinning device. The as-spun zein/TEO membranes show high gas permeability up to 154 ± 20.9 m2/s and superhydrophilicity with a 0° contact angle. With the addition of TEO, good antibacterial effects are also imparted onto the membrane to prevent infection. Moreover, the in situ electrospinning can directly deposit the zein/TEO membranes onto the site of the wound to accommodate the shape of the wound with increased convenience and perceived comfort. Experiments carried out on mice suggest that the in situ electrospun zein/TEO membrane greatly promotes the wound healing process within 11 days. The study results, therefore, suggest that wound dressings in the form of in situ electrospun zein/TEO membranes can be used to facilitate wound healing.

Fabrication of hexahedral Au-Pd/graphene nanocomposites biosensor and its application in cancer cell H2O2 detection.

Currently, real time monitoring of chemical substances in vivo and in vitro has gained enormous attraction, and many researches reports have been focused on the design and construction of high-performance biosensor devices. In this work, a high-performance sensor was constructed by taking advantage of the excellent electrochemical activity and high-index facets of Au-Pd nanocubes and the large surface of rGO. Glassy carbon electrodes (GCEs) were modified by both Au-Pd nanocubes and rGO nanocomposites via physical adsorption. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) were utilized to characterize and identify this unique nanostructure. These three-dimensional nanocomposites possess a high electroactive surface area and an excellent electrical conductivity, which resulted in favorable electroreduction activity toward H2O2 with a lower detection limit of 4 nM, a wide linear range from 0.005 µM to 3.5 mM and a rapid response time. Furthermore, the proposed sensor exhibited desirable performance in the detection of endogenous H2O2 in human serum samples and real-time monitoring of H2O2 released from living breast cancer cell lines. In summary, this work not only provides a potential method to construct a physiological and pathological H2O2 biosensor but also makes a valuable contribution to the early diagnosis of different cancers.

Regional disparities in warm season rainfall changes over arid eastern-central Asia.

Multiple studies have reported a shift in the trend of warm season rainfall over arid eastern-central Asia (AECA) around the turn of the new century, from increasing over the second half of the twentieth century to decreasing during the early years of the twenty-first. Here, a closer look based on multiple precipitation datasets reveals important regional disparities in these changes. Warm-season rainfall increased over both basin areas and mountain ranges during 1961-1998 due to enhanced moisture flux convergence associated with changes in the large-scale circulation and increases in atmospheric moisture content. Despite a significant decrease in warm-season precipitation over the high mountain ranges after the year 1998, warm season rainfall has remained large over low-lying basin areas. This discrepancy, which is also reflected in changes in river flow, soil moisture, and vegetation, primarily results from disparate responses to enhanced warming in the mountain and basin areas of AECA. In addition to changes in the prevailing circulation and moisture transport patterns, the decrease in precipitation over the mountains has occurred mainly because increases in local water vapor saturation capacity (which scales with temperature) have outpaced the available moisture supply, reducing relative humidity and suppressing precipitation. By contrast, rainfall over basin areas has been maintained by accelerated moisture recycling driven by rapid glacier retreat, snow melt, and irrigation expansion. This trend is unsustainable and is likely to reverse as these cryospheric buffers disappear, with potentially catastrophic implications for local agriculture and ecology.

Trimetallic AuPtPd nanocomposites platform on graphene: Applied to electrochemical detection and breast cancer diagnosis.

Recently, great efforts have been made to use biosensors for the early diagnosis of cancer. Specifically, using a biomarker to detect H2O2 in physiological conditions is of great significance for understanding the signal transduction pathways and achieving early cancer diagnosis. In this work, we report an innovative H2O2 sensor that was fabricated by trimetallic AuPtPd nanocomposites platform on reduced graphene oxide (rGO) nanosheets with the modification of the rGO and trimetallic AuPtPd nanoparticles on a glassy carbon electrode (GCE) by physical adsorption. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) were utilized to characterize and identify these unique nanocomposites. In addition, the electrochemical properties of the proposed sensor were evaluated by cyclic voltammetry and chronoamperometry. Electrochemical research has demonstrated that the AuPtPd/rGO-modified GCE showed excellent electrocatalytic activity towards the reduction of H2O2, including a wider linear range from 0.005 µM to 6.5 mM, a low detection limit of 2 nM, good selectivity and acceptable repeatability. Moreover, the sensor can monitor the release of H2O2 release from living cancer cells. Therefore, this study not only improves simplicity, sensitivity and quantitatively for detection H2O2 in cells at nM level but also provides a foundation for the biological and biomedical applications such as the early diagnosis of cancer.

Evolutionary and functional analysis of Cyclina sinensis c-Jun AP-1 gene in response to LPS stimulation.

The transcription factor activator protein-1 (AP-1) plays an essential and critical role in the regulation of numerous downstream genes involved in various physiological and chemical responses. In this study, we identified a full-length cDNA of the c-Jun AP-1 gene (termed Csc-Jun) from the transcriptome library in Cyclina sinensis. The cDNA contains an 825-bp open reading frame that encodes a 274-amino acid protein sequence, including a characteristic Jun transcription factor domain and a highly conserved basic leucine zipper (bZIP) signature that shares 90% identity to that of Ruditapes philippinarum. Furthermore, a phylogenetic analysis using MrBayes and PhyML software (with Bayesian and maximum likelihood approaches, respectively) revealed that the c-Jun AP-1 family genes might be involved in adapting to various environments in different invertebrates. We implemented the PAML software with the maximum likelihood method to further select and verify the positive selection sites (PSSs) in the Mollusca c-Jun AP-1 genes, and we detected four PSSs located in the Jun transcription factor domain. In addition, a spatial expression analysis showed that the Csc-Jun cDNA transcript was ubiquitously expressed in all of the tested tissues and was strongly expressed in the hepatopancreas and weakly expressed in the tissues of the hemocytes, gill filaments, mantle and adductor muscle. Quantitative real-time PCR showed that the expression profiles of Csc-Jun were significantly upregulated at different times in all of the tested tissues when challenged with lipopolysaccharide (LPS). Furthermore, knockdown of Csc-Jun by RNA interference resulted in a higher mortality of C. sinensis following LPS exposure. Finally, we explored the function of the TLR13-MyD88 signaling pathway in the innate immunity of C. sinensis by RNA interference and immune challenges. The results revealed that the mRNA expression levels of Csc-Jun were all decreased (P < 0.01) in normal and stimulated C. sinensis hemocytes. These data collectively indicated that the c-Jun AP-1 gene might play vital roles in innate immunity and provide new evidence for the evolutionary patterns of innate immune genes in Mollusca.

Inactivation of FoxM1 transcription factor contributes to curcumin-induced inhibition of survival, angiogenesis, and chemosensitivity in acute myeloid leukemia cells.

UNLABELLED: Aberrant expression of forkhead box protein M1 (FoxM1) contributes to carcinogenesis in human cancers, including acute myeloid leukemia (AML), suggesting that the discovery of specific agents targeting FoxM1 would be extremely valuable for the treatment of AML. Curcumin, a naturally occurring phenolic compound, is suggested to possess anti-leukemic activity; however, the underlying mechanism has not been well elucidated. In this study, we found that curcumin inhibited cell survival accompanied by induction of G2/M cell cycle arrest and apoptosis in HL60, Kasumi, NB4, and KG1 cells. This was associated with concomitant attenuation of FoxM1 and its downstream genes, such as cyclin B1, cyclin-dependent kinase (CDK) 2, S-phase kinase-associated protein 2, Cdc25B, survivin, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF), as well as the reduction of the angiogenic effect of AML cells. We also found that specific downregulation of FoxM1 by siRNA prior to curcumin treatment resulted in enhanced cell survival inhibition and induction of apoptosis. Accordingly, FoxM1 siRNA increased the susceptibility of AML cells to doxorubicin-induced apoptosis. More importantly, curcumin suppressed FoxM1 expression, selectively inhibited cell survival as well as the combination of curcumin and doxorubicin exhibited a more inhibitory effect in primary CD34(+) AML cells, while showing limited lethality in normal CD34(+) hematopoietic progenitors. These results identify a novel role for FoxM1 in mediating the biological effects of curcumin in human AML cells. Our data provide the first evidence that curcumin together with chemotherapy or FoxM1 targeting agents may be effective strategies for the treatment of AML. KEY MESSAGE: Curcumin inhibited AML cell survival and angiogenesis and induced chemosensitivity. Aberrant expression of FoxM1 induces AML cell survival and chemoresistance. Inactivation of FoxM1 contributes to curcumin-induced anti-leukemic effects. Curcumin together with FoxM1 targeting agents may be effective for AML therapy.

Development and immunological evaluation of HLA-specific chronic myeloid leukemia polyepitope vaccine in Chinese population.

BACKGROUND: BCR/ABL and Wilms' tumor 1 (WT1) are an ideal tumor associated antigens which can be used to develop a potential chronic myeloid leukemia (CML) dentritic cell (DC) vaccine. Here, we constructed a novel polyepitope vaccine which used recombinant lentiviral vector carrying BCR/ABL and WT1 genes, and determined the immunological effects of this vaccine in vitro. METHODS: The DC vaccine was constructed using lentiviral vector transduced DCs. T lymphocytes were stimulated with DC vaccine and then co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) from CML or ALL patients, respectively. The cytotoxicity of proliferous cytotoxic T lymphocytes (CTLs) was determined by the LDH assay. The IFN-γ production of CTLs was detected using ELISPOT assay. RESULTS: We constructed an lentiviral vector encoding 50 different epitopes from BCR/ABL and WT1 antigens, and transferred it into DCs to prepare the DC vaccine successfully. The in vivo stimulation of CTLs with this DC vaccine were proved to show strong cytotoxicity and produce high level of IFN-γ. CONCLUSIONS: The novel recombinant lentiviral polyepitope DC vaccine is a promising candidate for clinical trials and may be an effective approach for CML immunotherapy.

Gene expression profiling of the DNMT3A R882 mutation in acute leukemia.

DNA methyltransferase 3A (DNMT3A) is one of two human de novo DNA methyltransferases essential for the regulation of gene expression. DNMT3A mutations and deletions have been previously observed in acute myeloid leukemia (AML), myelodysplastic sydromes and myeloproliferative neoplasms. However, the involvement of DNMT3A in acute lymphoblastic leukemia (ALL) has rarely been reported. In the present study, PCR and direct sequencing was performed to analyze mutations of DNMT3A amino acid residue 882 in 99 acute leukemia patients, including 57 AML patients, 41 ALL patients and a single biphenotypic acute leukemia (BAL) patient. DNMT3A expression was detected in mono-nuclear cells of the bone marrow in these patients and in normal individuals using real-time quantitative polymerase chain reaction, and 17.5% (10/57) of AML patients were found to exhibit DNMT3A mutations. Four missense mutations were observed in the DNMT3A-mutated AML patients, including R882 mutations and a novel single nucleotide polymorphism resulting in the M880V amino acid substitution. However, the ALL and BAL patients were not found to exhibit DNMT3A mutations. The DNMT3A expression levels in the AML patients were significantly higher compared with those of the ALL patients or normal controls. The reduced expression levels of DNMT3A were associated with a significantly lower complete remission rate in the AML patients. However, in the ALL patients, no statistical significance was identified. The results of the present study indicate that DNMT3A may play varying roles in the regulation of DNA methylation in AML and ALL.

Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30-mediated PKC pathway.

Resveratrol (REV) is a naturally occurring phytoalexin that inhibits neuronal K⁺ channels; however, the molecular mechanisms behind the effects of REV and the relevant α-subunit are not well defined. With the use of patch-clamp technique, cultured cerebellar granule cells, and HEK-293 cells transfected with the K(v)2.1 and K(v)2.2 α-subunits, we investigated the effect of REV on K(v)2.1 and K(v)2.2 α-subunits. Our data demonstrated that REV significantly suppressed Kv2.2 but not Kv2.1 currents with a fast, reversible, and mildly concentration-dependent manner and shifted the activation or inactivation curve of Kv2.2 channels. Activating or inhibiting the cAMP/PKA pathway did not abolish the inhibition of K(v)2.2 current by REV. In contrast, activation of PKC with phorbol 12-myristate 13-acetate mimicked the inhibitory effect of REV on K(v)2.2 by modifying the activation or inactivation properties of Kv2.2 channels and eliminated any further inhibition by REV. PKC and PKC-α inhibitor completely eliminated the REV-induced inhibition of K(v)2.2. Moreover, the effect of REV on K(v)2.2 was reduced by preincubation with antagonists of GPR30 receptor and shRNA for GPR30 receptor. Western blotting results indicated that the levels of PKC-α and PKC-ß were significantly increased in response to REV application. Our data reveal, for the first time, that REV inhibited K(v)2.2 currents through PKC-dependent pathways and a nongenomic action of the oestrogen receptor GPR30.