Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.

Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic cells is often genotype specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML; explores the role of key vitamins and enzymes that regulate these processes; and provides an overview of metabolism-directed therapies currently in use or development.

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

Development and validation of a [18F]FDG PET/CT-based radiomics nomogram to predict the prognostic risk of pretreatment diffuse large B cell lymphoma patients.

OBJECTIVE: In this study, based on PET/CT radiomics features, we developed and validated a nomogram to predict progression-free survival (PFS) for cases with diffuse large B cell lymphoma (DLBCL) treated with immunochemotherapy. METHODS: This study retrospectively recruited 129 cases with DLBCL. Among them, PET/CT scans were conducted and baseline images were collected for radiomics features along with their clinicopathological features. Radiomics features related to recurrence were screened for survival analysis using univariate Cox regression analysis with p < 0.05. Next, a weighted Radiomics-score (Rad-score) was generated and independent risk factors were obtained from univariate and multivariate Cox regressions to build the nomogram. Furthermore, the nomogram was tested for their ability to predict PFS using time-dependent receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: Blood platelet, Rad-score, and gender were included in the nomogram as independent DLBCL risk factors for PFS. We found that the training cohort areas under the curve (AUCs) were 0.79, 0.84, and 0.88, and validation cohort AUCs were 0.67, 0.83, and 0.72, respectively. Further, the DCA and calibration curves confirmed the predictive nomogram's clinical relevance. CONCLUSION: Using Rad-score, blood platelet, and gender of the DLBCL patients, a PET/CT radiomics-based nomogram was developed to guide cases' recurrence risk assessment prior to treatment. The developed nomogram can help provide more appropriate treatment plans to the cases. KEY POINTS: • DLBCL cases can be classified into low- and high-risk groups using PET/CT radiomics based Rad-score. • When combined with other clinical characteristics (gender and blood platelet count), Rad-score can be used to predict the outcome of the pretreatment of DLBCL cases with a certain degree of accuracy. • A prognostic nomogram was established in this study in order to aid in assessing prognostic risk and providing more accurate treatment plans for DLBCL cases.

Prediction Model Combining Clinical and MR Data for Diagnosis of Lymph Node Metastasis in Patients With Rectal Cancer.

BACKGROUND: Determining the status of lymph node (LN) metastasis in rectal cancer patients preoperatively is crucial for the treatment option. However, the diagnostic accuracy of current imaging methods is low. PURPOSE: To develop and test a model for predicting metastatic LNs of rectal cancer patients based on clinical data and MR images to improve the diagnosis of metastatic LNs. STUDY TYPE: Retrospective. SUBJECTS: In all, 341 patients with histologically confirmed rectal cancer were divided into one training set (120 cases) and three validation sets (69, 103, 49 cases). FIELD STRENGTH/SEQUENCE: 3.0T, axial and sagittal T2 -weighted turbo spin echo and diffusion-weighted imaging (b = 0 s/mm2 , 800 s/mm2 ) ASSESSMENT: In the training dataset, univariate logistic regression was used to identify the clinical factors (age, gender, and tumor markers) and MR data that correlated with LN metastasis. Then we developed a prediction model with these factors by multiple logistic regression analysis. The accuracy of the model was verified using three validation sets and compared with the traditional MRI method. STATISTICAL TESTS: Univariate and multivariate logistic regression. The area under the curve (AUC) value was used to quantify the diagnostic accuracy of the model. RESULTS: Eight factors (CEA, CA199, ADCmean, mriT stage, mriN stage, CRM, EMVI, and differentiation degree) were significantly associated with LN metastasis in rectal cancer patients (P<0.1). In the training set (120) and the three validation sets (69, 103, 49), the AUC values of the model were much higher than the diagnosis by MR alone (training set, 0.902 vs. 0.580; first validation set, 0.789 vs. 0.743; second validation set, 0.774 vs. 0.573; third validation set, 0.761 vs. 0.524). DATA CONCLUSION: For the diagnosis of metastatic LNs in rectal cancer patients, our proposed logistic regression model, combining clinical and MR data, demonstrated higher diagnostic efficiency than MRI alone. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Advanced myocardial characterization in hypertrophic cardiomyopathy: feasibility of CMR-based feature tracking strain analysis in a case-control study.

OBJECTIVES: This study aimed to evaluate the feasibility and reproducibility of using cardiovascular magnetic resonance feature tracking (CMR-FT) for analysis of bi-ventricular strain and strain rate (SR) in hypertrophic cardiomyopathy (HCM) patients as well as to explore the correlation between right ventricular (RV) and left ventricular (LV) deformation. METHODS: A total of 60 HCM patients and 48 controls were studied. Global and segmental peak values of bi-ventricular longitudinal, circumferential, radial strain, and systolic SR were analyzed. Pearson analysis was performed to investigate the correlation of RV and LV deformation. Intra-observer and inter-observer reproducibility were also assessed. RESULTS: LV mass in the HCM group was significantly higher than that in the control group. LV end-systolic and end-diastolic volume and RV end-systolic and end-diastolic volume in the HCM group were all significantly lower than the correlated parameters in the control group (p < 0.001, respectively), whereas no statistical difference was found in ejection fraction (p > 0.05). Global longitudinal strain (GLS), global longitudinal strain rate (GLSR), global circumferential strain (GCS), global circumferential strain rate (GCSR), global radial strain (GRS), and global radial strain rate (GRSR) of the LV and RV were all significantly lower than the control group, and segmental strain and SR were also true (p < 0.001, respectively). Bi-ventricular strain and SR measurements were highly reproducible at both intra- and inter-observer levels. Additionally, Pearson analysis showed RV GCS, GLS, and GRS positively correlated with LV GCS, GLS, and GRS (r = 0.713, p < 0.001; r = 0.728, p < 0.001; r = 0.730, p < 0.001, respectively). CONCLUSIONS: CMR-FT is a promising approach to analyze impairment of global and segmental myocardium deformation in HCM patients non-invasively and quantitatively. KEY POINTS: • CMR-FT allows for advanced myocardial characterization with high reproducibility. • As compared with controls, HCM patients have significant differences in CMR-FT strain analysis while ejection fraction was similar. • CMR-FT may serve as an early biomarker of HCM in subjects at risk.

ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors.

Stem cells and progenitors in many lineages undergo self-renewing divisions, but the extracellular and intracellular proteins that regulate this process are largely unknown. Glucocorticoids stimulate red blood cell formation by promoting self-renewal of early burst-forming unit-erythroid (BFU-E) progenitors. Here we show that the RNA-binding protein ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in BFU-Es and is required for BFU-E self-renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFU-E stage, but its expression is maintained by all tested GR agonists that stimulate BFU-E self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown of ZFP36L2 in transplanted erythroid progenitors prevented expansion of erythroid lineage progenitors normally seen following induction of anaemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to messenger RNAs that are induced or maintained at high expression levels during terminal erythroid differentiation and negatively regulates their expression levels. ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated.

miR-191 regulates mouse erythroblast enucleation by down-regulating Riok3 and Mxi1.

Using RNA-seq technology, we found that the majority of microRNAs (miRNAs) present in CFU-E erythroid progenitors are down-regulated during terminal erythroid differentiation. Of the developmentally down-regulated miRNAs, ectopic overexpression of miR-191 blocks erythroid enucleation but has minor effects on proliferation and differentiation. We identified two erythroid-enriched and developmentally up-regulated genes, Riok3 and Mxi1, as direct targets of miR-191. Knockdown of either Riok3 or Mxi1 blocks enucleation, and either physiological overexpression of miR-191 or knockdown of Riok3 or Mxi1 blocks chromatin condensation. Thus, down-regulation of miR-191 is essential for erythroid chromatin condensation and enucleation by allowing up-regulation of Riok3 and Mxi1.

Schistosoma japonicum protein SjP40 inhibits TGF-ß1-induced activation of hepatic stellate cells.

SjP40 is a major egg antigen of Schistosoma japonicum. In the present study, the authors investigated the effect of SjP40 in vitro on transforming growth factor-ß1 (TGF-ß1)- stimulated hepatic stellate cells (HSCs). LX-2, an immortalized human HSC line, was treated with purified recombinant SjP40 (rSjP40) in the presence or absence of TGF-ß1. Quantitative real-time polymerase chain reaction and western blot analysis were performed to determine messenger ribonucleic acid and protein of fibrogenic genes and TGF-ß signaling pathway. The results showed that expression of fibrogenic genes was significantly reduced by rSjP40. Furthermore, rSjP40 also suppressed the TGF-ß1-induced upregulation of Smads and ERK proteins. We also found that the effect of rSjP40 on HSCs was similar to SB431542, an inhibitor of type I TGF-ß receptor. In conclusion, the data suggest that SjP40 attenuates HSC activation, which might be, at least in part, mediated by inhibiting the TGF-ß and ERK signaling pathways.

Numerical investigation of effect of geometric parameters on performance of rotational hydrodynamic cavitation reactor.

The objective of this paper is to discuss the influence of geometric parameters on the performance of the rotational hydrodynamic cavitation reactor (RHCR) using numerical method. The novel RHCR is implemented by modifying a centrifugal impeller into a new one using the annular slit constriction (ASC) with circumferentially distributed blind holes. The cavitation intensity and cavitation generation rate are selected to evaluate the cavitation performance, the head is used to assess conveying performance, and the entropy generation theory is used to evaluate the energy loss in the impeller. The effect of the axial width, radial length and radial position of the ASC on the cavitating flow of the RHCR is investigated by CFD method. The results indicate that three patterns of cavitation are induced in the RHCR, including separation cavitation, vortex cavitation and shear cavitation. The axial width, radial length and radial position of the ASC are the important geometric parameter that affect the performance of the RHCR. A small width is superior to a large width in terms of cavitation performance, although the conveying performance suffers as a result. The energy loss in the impeller initially increases and then decreases as the width decreases. Both a reduction in radial length and radial position leads to higher cavitation and conveying capacity, accompanying slight increase in energy loss. Compared to the original model, the RHCR with an axial width of 3 mm, a radial length of 17 mm, and a radial position of 0.541 achieves the highest performance.

From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications.

This article reviews the regulation of production of RBCs at several levels. We focus on the regulated expansion of burst-forming unit-erythroid erythroid progenitors by glucocorticoids and other factors that occur during chronic anemia, inflammation, and other conditions of stress. We also highlight the rapid production of RBCs by the coordinated regulation of terminal proliferation and differentiation of committed erythroid colony-forming unit-erythroid progenitors by external signals, such as erythropoietin and adhesion to a fibronectin matrix. We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis.

The WNT/ß-catenin system in chronic kidney disease-mineral bone disorder syndrome.

BACKGROUND: The WNT/ß-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/ß-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification. OBJECTIVE: This paper aims to comprehensively review the WNT/ß-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/ß-catenin signaling pathway in CKD-MBD therapy. METHODS: We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/ß-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/ß-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms. RESULTS: The WNT/ß-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway's components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of ß-catenin. Several regulatory molecules, including GSK-3ß, APC, and Axin, modulate ß-catenin activation. The WNT/ß-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD. CONCLUSIONS: The WNT/ß-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.

Radiomics in Gastric Cancer: First Clinical Investigation to Predict Lymph Vascular Invasion and Survival Outcome Using 18F-FDG PET/CT Images.

Background: Lymph vascular invasion (LVI) is an unfavorable prognostic indicator in gastric cancer (GC). However, there are no reliable clinical techniques for preoperative predictions of LVI. The aim of this study was to develop and validate PET/CT-based radiomics signatures for predicting LVI of GC preoperatively. Radiomics nomograms were also established to predict patient survival outcomes. Methods: This retrospective study registered 148 GC patients with histopathological confirmation for LVI status, who underwent pre-operative PET/CT scans (Discovery VCT 64 PET/CT system) from December 2014 to June 2019. Clinic-pathological factors (age, gender, and tumor grade, etc.) and metabolic PET data (maximum and mean standardized uptake value, total lesion glycolysis and metabolic tumor volume) were analyzed to identify independent LVI predictors. The dataset was randomly assigned to either the training set or test set in a 7:3 ratios. Three-dimensional (3D) radiomics features were extracted from each PET- and CT-volume of interests (VOI) singularly, and then a radiomics signature (RS) associated with LVI status is built by feature selection. Four models with different modalities (PET-RS: only PET radiomics features; CT-RS: only CT radiomics features; PET/CT-RS: both PET and CT radiomics features; PET/CT-RS plus clinical data) were developed to predict LVI. Patients were postoperatively followed up with PET/CT every 6-12 months for the first two years and then annually up to five years after surgery. The PET/CT radiomics score (Rad-scores) was calculated to assess survival outcome, and corresponding nomograms with radiomics (NWR) or without radiomics (NWOR) were established. Results: Tumor grade and maximum standardized uptake value (SUVmax) were the independent LVI predictor. 1037 CT and PET 3D radiomics features were extracted separately and reduced to 4 and 5 features to build CT-RS and PET-RS, respectively. PET/CT-RS and PET/CT-RS plus clinical data (tumor grade and SUVmax) were also developed. The ROC analysis demonstrated clinical usefulness of PET/CT-RS plus clinical data (AUC values for training and validation, respectively 0.936 and 0.914) and PET/CT-RS (AUC values for training and validation, respectively 0.881 and 0.854), which both are superior to CT-RS (0.838 and 0.824) and PET-RS (0.821 and 0.812). SUVmax and LVI were independent prognostic indicators of both OS and PFS. Decision curve analysis (DCA) demonstrated NWR outperformed NWOR and was established to assess survival outcomes. For estimation of OS and PFS, the C-indexes of the NWR were 0. 88 and 0.88 in the training set, respectively, while the C-indexes of the NWOR were 0. 82 and 0.85 in the training set, respectively. Conclusions: The PET/CT-based radiomics analysis might serve as a non-invasive approach to predict LVI status in GC patients and provide effective predictors of patient survival outcomes.

PET/CT Radiomic Features: A Potential Biomarker for EGFR Mutation Status and Survival Outcome Prediction in NSCLC Patients Treated With TKIs.

Backgrounds: Epidermal growth factor receptor (EGFR) mutation profiles play a vital role in treatment strategy decisions for non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the predictive efficacy of baseline 18F-FDG PET/CT-based radiomics analysis for EGFR mutation status, mutation site, and the survival benefit of targeted therapy. Methods: A sum of 313 NSCLC patients with pre-treatment 18F-FDG PET/CT scans and genetic mutations detection were retrospectively studied. Clinical and PET metabolic parameters were incorporated into independent predictors of determining mutation status and mutation site. The dataset was randomly allocated into the training and the validation sets in a 7:3 ratio. Three-dimensional (3D) radiomics features were extracted from each PET- and CT-volume of interests (VOI) singularly, and then a radiomics signature (RS) associated with EGFR mutation profiles is built by feature selection. Three different prediction models based on support vector machine (SVM), decision tree (DT), and random forest (RF) classifiers were established. Furthermore, nomograms for estimation of overall survival (OS) and progression-free survival (PFS) were established by integrating PET/CT radiomics score (Rad-score), metabolic parameters, and clinical factors. Predictive performance was assessed by the receiver operating characteristic (ROC) analysis and the calibration curve analysis. The decision curve analysis (DCA) was applied to estimate and compare the clinical usefulness of nomograms. Results: Three hundred thirteen NSCLC patients were classified into a training set (n=218) and a validation set (n=95). Multivariate analysis demonstrated that SUVmax and sex were independent indicators of EGFR mutation status and mutation site. Eight CT-derived RS, six PET-derived RS, and two clinical factors were retained to develop integrated models, which exhibited excellent ability to distinguish between EGFR wild type (EGFR-WT), EGFR 19 mutation type (EGFR-19-MT), and EGFR 21 mutation type (EGFR-21-MT). The SVM model outperformed the RF model and the DT model, yielding training area under the curves (AUC) of EGFR-WT, EGFR-19-WT, and EGFR-21-WT, with 0.881, 0.851, and 0.849, respectively, and validation AUCs of 0.926, 0.805 and 0.859, respectively. For prediction of OS, the integrated nomogram is superior to the clinical nomogram and the radiomics nomogram, with C-indexes of 0.80 in the training set and 0.83 in the validation set, respectively. Conclusions: The PET/CT-based radiomics analysis might provide a novel approach to predict EGFR mutation status and mutation site in NSCLC patients and could serve as useful predictors for the patients' survival outcome of targeted therapy in clinical practice.

Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies.

Myelodysplastic syndrome (MDS) is a group of hematopoietic disorders with limited treatment options. Anemia is a common symptom in MDS, and although erythropoiesis-stimulating agents such as erythropoietin, lenalidomide, and luspatercept are available to treat anemia, many MDS patients do not respond to these first-line therapies. Therefore, alternative drug development strategies are needed to improve therapeutic efficacy. Splicing modulators to correct splicing-related defects have shown promising results in clinical trials. Targeting differentiation of early erythroid progenitors to increase the erythroid output in MDS is another novel approach, which has shown encouraging results at the pre-clinical stage. Together, these therapeutic strategies provide new avenues to target MDS symptoms untreatable previously.

A fungal immobilization technique for efficient harvesting of oleaginous microalgae: Key parameter optimization, mechanism exploration and spent medium recycling.

To confront with energy crisis, microalgae as the promising feedstock have a great potential in exploring renewable energy field, whereas the high costs related to medium preparation and biomass harvesting are the main bottleneck to hinder the development on a large scale. Though cultivation of filamentous fungi for microalgae harvesting is an efficient, sustainable and emerging method, and the studies on specific mechanisms and spent medium recycling for efficiency improvement as well as resource saving through a co-pelletization mode are urgently needed. Hence, in this study, the harvesting process of autotrophic microalgae Chlorella vulgaris by pre-cultured Aspergillus oryzae pellets was investigated systematically. The highest efficiency (99.23%) was obtained within 5 h under the optimized conditions of 30 °C, 130 rpm and fungi:algae ratio of 1:1 on a dry weight basis without demand for pH adjustment (initial value on 9.68). Charge neutralization was not the main mechanisms involved in fungi-algae aggregations, and the functional group changes on cell surfaces as well as secreted metabolites in medium could be mainly responsible for inducing the bioflocculation process. After harvesting, separated water could also effectively support microalgae re-growth. The biomass concentration in medium with 50% recycling was higher than that in fresh medium, while lipid content was increased from 24.37% to 33.97% in fully recycled medium. These results indicated that the pellet-assisted mode for algal harvesting is a promising way to promote biofuel production and resource recycling.

Cardiac Magnetic Resonance Feature Tracking: A Novel Method to Assess Left Ventricular Three-Dimensional Strain Mechanics After Chronic Myocardial Infarction.

RATIONALE AND OBJECTIVES: This study was designed to assess left ventricular deformation after chronic myocardial infarction (CMI) using cardiac magnetic resonance feature tracking (CMR-FT) technology, and analyze its relationship with left ventricular ejection fraction (LVEF) and infarcted transmurality. MATERIALS AND METHODS: Ninety-six patients with CMI and 72 controls underwent 3.0 T CMR scanning. Strain parameters were measured by dedicated software, including global peak longitudinal strain (GPLS), global peak circumferential strain (GPCS), global peak radial strain (GPRS), segmental peak longitudinal strain (PLS), peak circumferential strain (PCS), and peak radial strain (PRS). All enhanced myocardium segments were divided into subendocardial infarction (SI) and transmural infarction (TI) group. Pearson, intraclass correlation coefficient and receiver operating characteristic analysis were performed to compare the parameters' mean values between SI and TI groups. RESULTS: GPLS, GPRS, and GPCS in CMI group were significantly decreased comparing with control group. PRS and PCS in TI group were significantly lower than those in SI group, whereas no statistical difference was observed in PLS. In Pearson correlation analysis, LVEF was strongly correlated with GPLS, GPRS, and GPCS in CMI patients. Additionally, excellent reproducibility of all strain parameters was observed. In receiver operating characteristic analysis, segmental PRS and PCS might differentiate SI from TI with higher diagnostic efficiency (p < 0.05), while PLS was less valuable (p > 0.05). CONCLUSION: CMR-FT could noninvasively and quantitatively assess global and regional myocardial strain in CMI patients with excellent reproducibility and strong correlation with LVEF. Additionally, segmental myocardial strain parameters indicate potential clinical value in differentiating myocardial infarction subtype.

Hetero-metal encapsulation induced ratiometric recognition of fluoride.

Emissive lanthanide ions are considered as luminescent species or optical probes for the analytes in ambient conditions or even cellular environment. But a variety of factors determine the stability of photo-luminescent signals due to the excitation sources, statistical errors or the selection of solvents. In this way, ratiometric assays effectively circumvent such problem and lead to more sensitive and reliable results. Herein, an organic-inorganic hybrid material has been developed with the europium complex as the core and the terbium species can be attached onto the surface of silica host. As for the evaluation of the internal structure, the terbium complex has been integrated into the hybrid network via weak forces and its sensitizing moiety will be easily attacked by Lewis acid-base interactions. In a different manner, the europium complex has been shielded from perturbation due to the protection of the outside silica shells. Such sharp difference in response to fluoride induces drastic signal changes and the conversion of binding process between fluoride and molecular receptors (boronic group) into readable optical outputs has afforded the lower detection limit for F- as 0.17 µM. In addition, the intracellular uptake and distribution of the hybrid material have been explored.

Preparation of ion-imprinted montmorillonite nanosheets/chitosan gel beads for selective recovery of Cu(â ¡) from wastewater.

The novel ion-imprinted montmorillonite nanosheets/chitosan (IIMNC) gel beads were prepared for selective adsorption of Cu2+. The IIMNC gel beads were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). The results showed that IIMNC was successfully assembled and rich in honeycombed pores, which performed well in the removal of Cu2+ through the synergistic effect of montmorillonite nanosheets and chitosan. The elimination of copper was followed by pseudo-second-order model and was enhanced by introduced montmorillonite nanosheets (MMTNS) because MMTNS attracted Cu(Ⅱ) by its negative charge and provided active adsorption sites through its high performance of cation exchange. This composite gel also showed excellent reusability, performing well in the removal of Cu2+ after undergoing adsorption-desorption in five cycles, because the adsorption sites of MMTNS can be continually reactivated by NaOH solution. More importantly, its high selectivity for Cu2+ provides a feasible way to recover Cu2+ from wastewater containing various cations.

Vitamin B6 Addiction in Acute Myeloid Leukemia.

Cancer cells rely on altered metabolism to support abnormal proliferation. We performed a CRISPR/Cas9 functional genomic screen targeting metabolic enzymes and identified PDXK-an enzyme that produces pyridoxal phosphate (PLP) from vitamin B6-as an acute myeloid leukemia (AML)-selective dependency. PDXK kinase activity is required for PLP production and AML cell proliferation, and pharmacological blockade of the vitamin B6 pathway at both PDXK and PLP levels recapitulated PDXK disruption effects. PDXK disruption reduced intracellular concentrations of key metabolites needed for cell division. Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectively inhibited AML cell proliferation and their downstream products partially rescued PDXK disruption induced proliferation blockage. Our work identifies the vitamin B6 pathway as a pharmacologically actionable dependency in AML.

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells.

BACKGROUND: Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment. METHODS: First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice. RESULTS: We demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo. CONCLUSIONS: Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.