A chiral bipolar host for efficient solution-processed circularly polarized OLEDs via a chirality energy transfer process.

Chiral bipolar hosts of (R/S)-L-2mCPCN are synthesized, which show high singlet/triplet energy levels and clear circularly polarized luminescence. Employing racemic phosphorescent and TADF materials as emitting guest molecules, solution-processable CP-OLEDs based on such chiral hosts are obtained with an EQEmax of 10.7% and |gEL| values of 5.0 × 10-3.

Liquid-crystalline circularly polarised TADF emitters for high-efficiency, solution-processable organic light-emitting diodes.

Achieving a high emission efficiency and a large luminescence asymmetry factor (glum) in a single molecule exhibiting circularly polarised thermally activated delayed fluorescence (CP-TADF) remains a formidable challenge. In this work, a proof-of-concept, liquid-crystalline CP-TADF molecule is proposed to realise high glum by taking advantage of the order inherent in liquid crystals. Employing a chiral dinaphthol-based CP-TADF molecule as the emissive unit, a pair of liquid-crystalline CP-TADF molecules (R/S-4) is synthesised via the introduction of six mesogenic moieties. The enantiomers show intense emission at about 520 nm which has clear TADF and liquid-crystalline characteristics. Both enantiomers display symmetrical electronic circular dichroism (CD) and circular polarisation luminescence (CPL) signals as thin films. Impressively, relatively large glum values of 0.11 are realised for the films. Solution-processed devices were fabricated using R/S-4 as the dopants, with the TADF molecule CzAcSF as the sensitiser. The OLEDs so prepared show a very high maximum external quantum efficiency of 21.2%, revealing a novel strategy for realising large glum values in CP-TADF.

Fasudil promotes polyploidization of megakaryoblasts in an acute megakaryocyte leukemia model.

Acute megakaryocytic leukemia (AMKL) is a rare neoplasm caused by abnormal megakaryoblasts. Megakaryoblasts keep dividing and avoid undergoing polyploidization to escape maturation. Small-molecule probes inducing polyploidization of megakaryocytic leukemia cells accelerate the differentiation of megakaryocytes. This study aims to determine that Rho kinase (ROCK) inhibition on megakaryoblasts enhances polyploidization and the inhibition of ROCK1 by fasudil benefits AMKL mice. The study investigated fasudil on the megakaryoblast cells in vitro and in vivo. With the differentiation and apoptosis induction, fasudil was used to treat 6133/MPLW515L mice, and the differentiation level was evaluated. Fasudil could reduce proliferation and promote the polyploidization of megakaryoblasts. Meanwhile, fasudil reduced the disease burden of 6133/MPLW515L AMKL mice at a dose that is safe for healthy mice. Combination therapy of ROCK1 inhibitor fasudil and reported clinical AURKA inhibitor MLN8237 achieved a better antileukemia effect in vivo, which alleviated hepatosplenomegaly and promoted the differentiation of megakaryoblast cells. ROCK1 inhibitor fasudil is a good proliferation inhibitor and polyploidization inducer of megakaryoblast cells and might be a novel rationale for clinical AMKL treatment.

Updates in Laboratory Identification of Invasive Fungal Infection in Neonates.

Invasive fungal infection (IFI) in immunocompromised neonates is significantly associated with high morbidity and mortality and has become the third most common infection in Neonatal Intensive Care Units. The early diagnosis of IFI for neonatal patients is difficult because of the lack of specific symptoms. The traditional blood culture remains the gold standard in clinical diagnosis for neonatal patients but it requires a long duration, which delays treatment initiation. Detections of fungal cell-wall components are developed for early diagnosis but the diagnostic accuracy in neonates needs to be improved. PCR-based laboratory methods, such as real-time PCR, droplet digital PCR, and the cationic conjugated polymer fluorescence resonance energy transfer (CCP-FRET) system, distinguish the infected fungal species by their specific nucleic acids and show a high sensitivity and specificity. Particularly, the CCP-FRET system, which contains a cationic conjugated polymer (CCP) fluorescent probe and pathogen-specific DNA labeled with fluorescent dyes, could identify multiple infections simultaneously. In the CCP-FRET system, the CCP and fungal DNA fragments can self-assemble into a complex with an electrostatic interaction and the CCP triggers the FRET effect under ultraviolet light to make the infection visible. Here, we summarize the recent laboratory methods for neonatal IFI identification and provide a new perspective for early clinical fungal diagnosis.

Differentiation therapy for murine myelofibrosis model with MLN8237 loaded low-density lipoproteins.

Primary myelofibrosis (PMF) is a severe myeloproliferative neoplasm that is characterized by low-differentiation megakaryoblasts and progressive bone marrow fibrosis. Although an Aurora kinase A (AURKA) targeting small-molecule inhibitor MLN8237 has been approved in clinical trials for differentiation therapy of high-risk PMF patients, its off-target side effects lead to a partial remission and serious complications. Here, we report a dual-targeting therapy agent (rLDL-MLN) with great clinical translation potential for differentiation therapy of PMF disease. In particular, the reconstituted low-density lipoprotein (rLDL) nanocarrier and the loaded MLN8237 can actively target malignant hematopoietic stem/progenitor cells (HSPCs) via LDL receptors and intracellular AURKA, respectively. In contrast to free MLN8237, rLDL-MLN effectively prohibits the proliferation of PMF cell lines and abnormal HSPCs and significantly induces their differentiation, as well as prevents the formation of erythrocyte and megakaryocyte colonies from abnormal HSPCs. Surprisingly, even at a 1500-fold lower dosage (0.01 mg/kg) than that of free MLN8237, rLDL-MLN still exhibits a much more effective therapeutic effect, with the PMF mice almost clear of blast cells. More importantly, rLDL-MLN promotes hematological recovery without any toxic side effects at the effective dosage, holding great promise in the targeted differentiation therapy of PMF patients.

Binaphthol-based chiral host molecules for efficient solution-processed circularly polarized OLEDs.

Two kinds of chiral hosts, named (R/S)-BN-mCP and (R/S)-BN-2mCP, are prepared. Solution processable circularly polarized organic light-emitting diodes (CP-OLEDs) based on the chiral hosts and achiral emitter Ir(mypp)3 present the maximum external quantum efficiency (EQEmax) and dissymmetry factor values (gEL) of 12.7%/-1.7 × 10-3 and 17.1%/-1.3 × 10-3, respectively. Using (R)-BN-2mCP as the chiral host and Ir(mypp)3 and Ir(piq)2(acac) as the achiral emitters, the solution-processed OLED exhibits a broad emission spectrum with the EQEmax of 12.1% and gEL of -1.1 × 10-3.

Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis.

Primary myelofibrosis (PMF) is characterized by immature megakaryocytic hyperplasia, splenomegaly, extramedullary hematopoiesis and bone marrow fibrosis. Our preclinical study had demonstrated that aurora kinase A (AURKA) inhibitor MLN8237 reduced the mutation burden of PMF by inducing differentiation of immature megakaryocytes. However, it only slightly alleviated splenomegaly, reduced tissue fibrosis, and normalized megakaryocytes in PMF patients of the preliminary clinical study. So enhancing therapeutic efficacy of PMF is needed. In this study, we found that AURKA directly interacted with heat shock protein 90 (HSP90) and HSP90 inhibitors promoted the ubiquitin-dependent AURKA degradation. We demonstrated that HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), normalized peripheral blood counts, improved splenomegaly, attenuated extramedullary hematopoiesis, decreased tissue fibrosis and reduced mutant burden in a MPLW515L mouse model of PMF. Importantly, both 17-AAG and 17-DMAG treatment at effective doses in vivo did not influence on hematopoiesis in healthy mice. Collectively, the study demonstrates that HSP90 inhibitors induce cell differentiation via the ubiquitin-dependent AURKA and also are safe and effective for the treatment of a MPLW515L mouse model of PMF, which may provide a new strategy for PMF therapy. Further, we demonstrate that combined therapy shows superior activity in acute megakaryocytic leukemia mouse model than single therapy.

Combination of AURKA inhibitor and HSP90 inhibitor to treat breast cancer with AURKA overexpression and TP53 mutations.

Breast cancer is the most common cancer among women worldwide. Researches show that Aurora kinase A (AURKA) is highly expressed in approximately 73% of breast cancer patients, which induces drug resistance in breast cancer patients and decreases the median survival time. AURKA regulates spindle assembly, centrosome maturation, and chromosome alignment. AURKA overexpression affects the occurrence and development of breast cancer. Besides AURKA overexpression, heat shock protein 90 (HSP90) maintains the survival and proliferation of tumor cells by stabilizing the structure of oncoproteins, including P53 mutants (mtP53). TP53 mutations accounted for approximately 13%, 40%, 80%, 33%, 71%, and 82% of luminal A, Luminal B, Luminal C, normal basal-like, HER2-amplified, and basal-like breast cancers, respectively. TP53 mutation can aggravate cell genome instability and enhance the invasion, migration, and resistance of cancer cell. This review describes the research status of AURKA and HSP90 in breast cancer, summarizes the structure, function, and the chaperone cycle of HSP90, elaborates the interrelation between HSP90, mtP53, P53, and AURKA, and proposes the combination of HSP90 inhibitor and AURKA inhibitor to treat breast cancer. Targeting AURKA and HSP90 to treat cancer with AURKA overexpression and TP53 mutations will help improve the specificity and efficiency of breast cancer treatment and solve the problem of drug resistance.

A Survey of Prescription Errors in Paediatric Outpatients in Multi-Primary Care Settings: The Implementation of an Electronic Pre-Prescription System.

Background: Prescription errors impact the safety and efficacy of therapy and are considered to have a higher impact on paediatric populations. Nevertheless, information in paediatrics is still lacking, particularly in primary care settings. There exists a need to investigate the prevalence and characteristics of prescription errors in paediatric outpatients to prevent such errors during the prescription stage. Methods: A cross-sectional study to evaluate paediatric prescription errors in multi-primary care settings was conducted between August 2019 and July 2021. Prescriptions documented within the electronic pre-prescription system were automatically reviewed by the system and then, potentially inappropriate prescriptions would be reconciled by remote pharmacists via a regional pharmacy information exchange network. The demographics of paediatric patients, prescription details, and types/rates of errors were assessed and used to identify associated factors for prescription using logistic regression. Results: A total of 39,754 outpatient paediatric prescriptions in 13 community health care centres were reviewed, among which 1,724 prescriptions (4.3%) were enrolled in the study as they met the inclusion criteria. Dose errors were the most prevalent (27%), with the predominance of underdosing (69%). They were followed by errors in selection without specified indications (24.5%), incompatibility (12.4%), and frequency errors (9.9%). Among critical errors were drug duplication (8.7%), contraindication (.9%), and drug interaction (.8%) that directly affect the drug's safety and efficacy. Notably, error rates were highest in medications for respiratory system drugs (50.5%), antibiotics (27.3%), and Chinese traditional medicine (12.3%). Results of logistic regression revealed that specific drug classification (antitussives, expectorants and mucolytic agents, anti-infective agents), patient age (<6 years), and prescriber specialty (paediatrics) related positively to errors. Conclusion: Our study provides the prevalence and characteristics of prescription errors of paediatric outpatients in community settings based on an electronic pre-prescription system. Errors in dose calculations and medications commonly prescribed in primary care settings, such as respiratory system drugs, antibiotics, and Chinese traditional medicine, are certainly to be aware of. These results highlight an essential requirement to update the rules of prescriptions in the pre-prescription system to facilitate the delivery of excellent therapeutic outcomes.

Total Saikosaponins Attenuates Depression-Like Behaviors Induced by Chronic Unpredictable Mild Stress in Rats by Regulating the PI3K/AKT/NF-κB Signaling Axis.

Background: Depression is a major cause of disability and most antidepressant medicines are ineffective owing to their high toxicity and numerous adverse effects. As a result, there is an urgent need to find new effective treatment methods. This paper aims to investigate the effect and mechanism of total saikosaponins (TSS) on depression-like behaviors induced by chronic unpredictable mild stress (CUMS) in rats. Methods: Twenty-four male SD rats were randomly divided into 4 groups: control group, CUMS group, TSS group, and fluoxetine (Flu) group. Then, the following tests were conducted: sucrose preference test, open field test, and elevated plus maze test. Additionally, ELISA was used to detect the levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) in the serum of the rats as well as the levels of inflammatory cytokines IL-1ß, IL-6, and TNF-α in the hippocampus, and Western blot was used for measuring the expression of brain-derived neurotrophic factor (BDNF) protein and related proteins of the PI3K/AKT/NF-κB signaling pathway in the hippocampus. Results: TSS could significantly improve rat behaviors, specifically indicated by increases in sucrose preference, total movement distance, stay time in the central area, number of entries into open arms, time spent in open arms, and a decrease in stay time in the peripheral area. TSS acted to significantly reduce BDNF protein expression and increase the contents of ACTH and CORT in serum as well as the levels of IL-1ß, IL-6, and TNF-α in the hippocampal tissue in rats. In addition, it was able to raise the ratios of p-PI3K/PI3K and p-AKT/AKT and decrease the ratio of p-p65/p65 in tissues, which in turn regulated the PI3K/AKT/NF-κB signaling pathway. Conclusions: TSS, through regulating PI3K/AKT/NF-κB signaling axis, can alleviate depression-like behaviors and elevate neuroendocrine hormone levels and inflammatory factor levels.

Recent Development of LDL-Based Nanoparticles for Cancer Therapy.

Low-density lipoprotein (LDL), a natural lipoprotein transporting cholesterol in the circulatory system, has been a possible drug carrier for targeted delivery. LDL can bind to the LDL receptor (LDLR) with its outside apolipoprotein B-100 and then enter the cell via LDLR-mediated endocytosis. This targeting function inspires researchers to modify LDL to deliver different therapeutic drugs. Drugs can be loaded in the surficial phospholipids, hydrophobic core, or apolipoprotein for the structure of LDL. In addition, LDL-like synthetic nanoparticles carrying therapeutic drugs are also under investigation for the scarcity of natural LDL. In addition to being a carrier, LDL can also be a targeting molecule, decorated to the surface of synthetic nanoparticles loaded with cytotoxic compounds. This review summarizes the properties of LDL and the different kinds of LDL-based delivery nanoparticles, their loading strategies, and the achievements of the recent anti-tumor advancement.

A Rapid, Visible, and Highly Sensitive Method for Recognizing and Distinguishing Invasive Fungal Infections via CCP-FRET Technology.

Invasive fungal infection (IFI) is one of the leading causes of death in the intensive care unit (ICU) due to its high morbidity and mortality among immunocompromised patients. Early diagnosis of IFI is typically infeasible because of the lack of clinical signs and symptoms. By virtue of the cationic conjugated polymer-based fluorescence resonance energy transfer (CCP-FRET) technology, we develop a rapid, visible, simple, and sensitive method for simultaneous detection and discrimination of three types of pathogens, including Candida albicans (C. albicans), Klebsiella pneumoniae (K. pneumoniae), and Cryptococcus neoformans (C. neoformans). The CCP-FRET system contains a CCP fluorescent probe and pathogen-specific DNA labeled with fluorescent dyes. These two components spontaneously self-assemble into the complex under electrostatic attraction, resulting in an efficient FRET from CCP to fluorescent dyes when irradiated with a 380 nm ultraviolet (UV) light. The CCP-FRET method can specifically identify the DNA molecules that are extracted from culture pathogen strains or blood samples via PCR and single base extension (SBE) reactions, without any cross-reactions on the DNA of nonspecific strains. In particular, the sensitivity of this method is down to 0.03125 ng, which is ten times higher than that of real-time PCR. We further evaluate its detection efficiency by testing 15 blood samples from neonatal patients who suffer from pathogen infections, in which some of them have undergone antipathogen treatments. Using the CCP-FRET method, 33.3% (5/15) of samples tested positive for C. albicans and/or K. pneumoniae infections, whereas no pathogen DNAs are recognized with real-time PCR, despite using the same primers. Interestingly, the CCP-FRET method can output unique fluorescent color as well as RGB patterns to different types of pathogen infections, by which the infection type can be conveniently determined. Collectively, the CCP-FRET method is a sensitive and reliable detection platform for rapid identification of fungal and bacterial multiple infections, holding great promise for uses in clinical testing.

Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects.

Phosphodiesterase type 4 (PDE4) inhibitors can prevent the breakdown of the second messenger cyclic adenosine monophosphate (cAMP) and improve cognitive performances in several animal models of cognition. However, the clinical development of PDE4 inhibitors has been seriously hampered by severe side effects, such as vomiting and nausea. In this study, we investigated the effect and mechanism of roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), on learning and memory abilities in the APP/PS1 mouse model of Alzheimer's disease (AD). APP/PS1 transgenic mice received 3 intragastric doses of roflumilast (0.1, 0.2 and 0.4 mg/kg) daily for 3 weeks followed by behavioral tests. Chronic administration of roflumilast significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the novel object recognition task, Morris water maze, and the step-down passive avoidance task. In addition, roflumilast increased the cAMP, phosphorylated cAMP response-element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels, and reduced the nuclear translocation of nuclear factor-kappa B (NF-κB) p65, and proinflammatory cytokine (IL-6, TNF-a and IL-1ß) levels in the hippocampus of APP/PS1 transgenic mice. In conclusion, these findings suggest that roflumilast can enhance cognitive function in APP/PS1 transgenic mice, which may be related to its stimulation of the cAMP/CREB/BDNF pathway and anti-neuroinflammatory effects.