Larval Exposure to Parasitic Varroa destructor Mites Triggers Specific Immune Responses in Different Honey Bee Castes and Species.

Innate immune systems are key defenses of animals and particularly important in species that lack the sophisticated adaptive immune systems as found in vertebrates. Here, we were interested to quantify variation in innate immune responses of insects in hosts that differ in their parasite susceptibility. To do this, we studied immune responses in honey bees, which can host a remarkable number of different parasites, which are major contributors of declining bee health and colony losses. The most significant parasite of honey bees is the mite Varroa destructor, which has infested the majority of global honey bee populations, and its control remains a major challenge for beekeepers. However, a number of nonmanaged honey bees seem able to control Varroa infections, for example, the Eastern honey bee Apis ceranacerana or the African honey bee Apis mellifera scutellata. These bees therefore make interesting study subjects to identify underlaying resistance traits, for example, by comparing them to more susceptible bee genotypes such as Western honey bees (A. melliferaligustica). We conducted a series of interlinked experiments and started with behavioral assays to compare the attractiveness of bee larvae to mites using different honey bee genotypes and castes. We found that 6-day-old larvae are always most attractive to mites, independently of genotype or castes. In a next step, we compared volatile profiles of the most attractive larvae to test whether they could be used by mites for host selection. We found that the abundance of volatile compounds differed between larval ages, but we also found significant differences between genotypes and castes. To further study the expected underlaying physiological differences between potentially resistant and susceptible host larvae, we compared the larval hemolymph proteomes of the three honey bee genotypes and two castes in response to mite exposure. We identified consistent upregulation of immune and stress-related genes in Varroa-exposed larvae, which differed between genotypes and castes. Tolerant honey bee castes and genotypes were characterized by stronger or more distinct immune esponses. In summary, we provide first insights into the complex involvement of the innate immune system of tolerant honey bees against mite infestations, which could be used for future breeding purposes.

Case of concurrence of bullous pemphigoid and Norwegian scabies.

Bullous pemphigoid (BP) with scabies is a condition rarely encountered in clinical practice, and when it is encountered, it is often due to the use of immunosuppressants. This paper is a report on a patient with BP and scabies, who developed scabs after taking dexamethasone. It should be noted that BP antibody is necessary, which can distinguish BP with scabies and bullous scabies, and the treatment options for the two diseases are different.

CircDUS2L (circ_0039908) promotes lung adenocarcinoma progression by upregulating PGAM1 by acting as a miR-590-5p molecular sponge.

Lung adenocarcinoma (LUAD) is usually found at the metastatic stage. Circular RNA dihydrouridine synthase 2-like (DUS2L) (circDUS2L) has been discovered to be upregulated in LUAD. Nevertheless, the function of circDUS2L in LUAD has not been verified. Levels of circDUS2L, microRNA-590-5p (miR-590-5p), and phosphoglycerate mutase 1 (PGAM1) mRNA were analyzed using quantitative real-time polymerase chain reaction (RT-qPCR). Cell proliferation, apoptosis, metastasis, and invasion were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), colony formation, 5-ethynyl-2'-deoxyuridine (Edu), flow cytometry, and transwell assays. Protein levels were detected by western blotting. Cell glycolysis was analyzed by measuring cell glucose consumption, lactate production, and extracellular acidification rate (ECAR). The regulatory mechanism of circDUS2L in LUAD cells was analyzed by bioinformatics analysis, dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays. Xenograft assay was conducted to confirm the function of circDUS2L in vivo. CircDUS2L was highly expressed in LUAD tissues and cells. CircDUS2L silencing constrained xenograft tumor growth in vivo. CircDUS2L knockdown induced apoptosis, repressed viability, colony formation, proliferation, metastasis, invasion, and glycolysis of LUAD cells in vitro by releasing miR-590-5p via functioning as a miR-590-5p sponge. MiR-590-5p was lowly expressed in LUAD tissues and cells, and miR-590-5p mimic curbed malignant behaviors and glycolysis of LUAD cells by targeting PGAM1. PGAM1 was overexpressed in LUAD tissues and cells, and circDUS2L sponged miR-590-5p to regulate PGAM1 expression. CircDUS2L elevated PGAM1 expression through functioning as a miR-590-5p sponge, thus driving malignant behaviors and glycolysis of LUAD cells.

Study about evaluation of efficacy of methotrexate in localized scleroderma using ultrasonography.

BACKGROUND: The treatment and curative effect evaluation of localized scleroderma (LS) still perplexes many clinical workers. PURPOSE: To investigate the efficiacy of methotrexate in the treatment of LS by the evaluation of ultrasonography. METHODS: A prospective study enrolled 10 patients treated with MTX for at least 6 months was conducted. Treatment outcome was evaluated by a clinical score and 15-MHz ultrasonography. Safety assessment included the monitoring of adverse drug reactions and clinical laboratory examinations. RESULTS: Eight of the 10 patients achieved clinical remission only with MTX. One patient was relieved after MTX combined with corticosteroids, while another one does not improve after the treatment of mycophenolate mofetil and corticosteroids. The effective rate of MTX is 80%. Nine patients were significantly improved with a decrease of the Localized Scleroderma Cutaneous Assessment Tool (the mean score of the LoSCAT cutaneous activity dropped from 5.2 to 1.0, p < 0.001, the mean score of the LS cutaneous damage dropped from 4.3 to 2.3, p = 0.002). The average difference of thickness between skin lesions and normal skin evaluated by ultrasonography decreased from 0.13 cm to 0.04 cm (p = 0.009) in eight patients. No serious adverse reactions occurred. CONCLUSION: Methotrexate is a safe and effective treatment for patients with LS. Ultrasonography can be considered as an efficient assessment tool for evaluation LS.

Pomegranate peel polyphenols interaction with intestinal flora and its metabolic transformation.

1. Pomegranate peel polyphenols (PPPs) have anti-oxidation, anti-atherosclerosis, anti-obesity effects, and so on. However, few studies have been conducted on the absorption and transformation of pomegranate polyphenols in the gut and the biologically active forms that ultimately work in the body.2. In this study, PPPs (300 mg/kg/day) was given to normal rats and relatively sterile rats by gavage respectively. The relatively sterile rats were obtained by neomycin sulphate (250 mg/kg/day) gavage to rats. The purpose of this study is to elaborate on the relationship between intestinal flora and polyphenol metabolism of pomegranate peel and to quantitatively analyse the transformation process of its metabolite urolithin in rats.3. The results showed that decreased bacterial diversity could significantly reduce the abundance of PPPs metabolites in faeces and urine in relatively sterile rats. PPPs can regulate intestinal flora structure, significantly enhance the content of Clostrida Firmicutes (P < 0.05), and effectively promote acetic acid, propionic acid, butyric acid, iso-butyric acid and valeric acid production in the rat (P < 0.05 or P < 0.01 or P < 0.001). PPPs can significantly elevate the relative proportion of Ruminococcaceae (P < 0.05). Ruminococcaceae_NK4A214_group, Ruminococcaceae_UCG-014 and Ruminococcaceae_UCG-005 can promote the metabolic transformation of PPPs and make the utilisation of Urolithin A more effective.

The Neuroproteomic Basis of Enhanced Perception and Processing of Brood Signals That Trigger Increased Reproductive Investment in Honeybee (Apis mellifera) Workers.

The neuronal basis of complex social behavior is still poorly understood. In honeybees, reproductive investment decisions are made at the colony-level. Queens develop from female-destined larvae that receive alloparental care from nurse bees in the form of ad-libitum royal jelly (RJ) secretions. Typically, the number of raised new queens is limited but genetic breeding of "royal jelly bees" (RJBs) for enhanced RJ production over decades has led to a dramatic increase of reproductive investment in queens. Here, we compare RJBs to unselected Italian bees (ITBs) to investigate how their cognitive processing of larval signals in the mushroom bodies (MBs) and antennal lobes (ALs) may contribute to their behavioral differences. A cross-fostering experiment confirms that the RJB syndrome is mainly due to a shift in nurse bee alloparental care behavior. Using olfactory conditioning of the proboscis extension reflex, we show that the RJB nurses spontaneously respond more often to larval odors compared with ITB nurses but their subsequent learning occurs at similar rates. These phenotypic findings are corroborated by our demonstration that the proteome of the brain, particularly of the ALs differs between RJBs and ITBs. Notably, in the ALs of RJB newly emerged bees and nurses compared with ITBs, processes of energy and nutrient metabolism, signal transduction are up-regulated, priming the ALs for receiving and processing the brood signals from the antennae. Moreover, highly abundant major royal jelly proteins and hexamerins in RJBs compared with ITBs during early life when the nervous system still develops suggest crucial new neurobiological roles for these well-characterized proteins. Altogether, our findings reveal that RJBs have evolved a strong olfactory response to larvae, enabled by numerous neurophysiological adaptations that increase the nurse bees' alloparental care behavior.

A predictive model for recurrence after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC) by using preoperative clinical data and CT characteristics.

BACKGROUND: The overall survival for patients with resectable PDAC following curative surgical resection hasn't been improved significantly, as a considerable proportion of patients develop recurrence within a year. The purpose of this study was to develop and validate a predictive model to assess recurrence risk in patients with PDAC after upfront surgery by using preoperative clinical data and CT characteristics. METHODS: The predictive model was developed based on a retrospective set of 141 pancreatic cancer patients after surgery. A separate set of 77 patients was used to validate model. Between January 2017 and December 2019, all patients underwent multidetector pancreatic CT and upfront surgery. Univariable and multivariate Cox regression was used to determine the risk factors related to recurrence and then establish a nomogram to estimate the 1-year recurrence probability. The Harrell C-index was employed in evaluating the discrimination and calibration of the model. RESULTS: A total of 218 patients in this retrospective cohort. A recurrence model in nomogram form was developed with predictors including tumor size (hazard ratio [HR], 1.277; 95% CI 1.098, 1.495; P = 0.002), tumor density in the portal vein phase (HR, 0.598; 95% CI 0.424, 0.844; P = 0.003), peripancreatic infiltration (HR, 4.151; 95% CI 2.077, 8.298; P < 0.001), suspicious metastatic lymph node (HR, 2.561; 95% CI 1.653, 3.967; P < 0.001), Neutrophils/Lymphocytes ratio (HR, 1.111; 95% CI 1.016, 1.215; P = 0.020). The predictive nomogram had good discrimination capability with these predictors with an area under curve at 1 year of 0.84 (95%CI 0.77, 0.91) in the development set and 0.82 (95% CI 0.72, 0.92) and 0.84 (95% CI 0.74, 0.94) in the validation set for two radiologists reading respectively. CONCLUSIONS: The model developed based on preoperative clinical data and CT characteristics of resectable pancreatic ductal adenocarcinoma patients, which can helpfully estimate the recurrence-free survival. It may be a useful tool for clinician to select optimal candidates for upfront surgery or neoadjuvant therapy.

A Modularized IoT Monitoring System with Edge-Computing for Aquaponics.

Aquaponics is a green and efficient agricultural production model that combines aquaculture and vegetable cultivation. It is worth looking into optimizing the proportion of fish and plants to improve the quality and yield. However, there is little non-destructive monitoring of plant growth in aquaponics monitoring systems currently. In this paper, based on the Internet of Things technologies, a monitoring system is designed with miniaturization, modularization, and low-cost features for cultivation-breeding ratio research. The system can realize remote monitoring and intelligent control of parameters needed to keep fish and plants under optimal conditions. First, a 32-bit chip is used as the Microcontroller Unit to develop the intelligent sensing unit, which can realize 16 different data acquisitions as stand-alone extensible modules. Second, to achieve plant data acquisition and upload, the Raspberry Pi embedded with image processing algorithms is introduced to realize edge-computing. Finally, all the collected data is stored in the Ali-cloud through Wi-Fi and a WeChat Mini Program is designed to display data and control devices. The results show that there is no packet loss within 90 m for wireless transmission, and the error rate of environment parameters is limited to 5%. It was proven that the system is intelligent, flexible, low-cost, and stable which is suitable for small-scale aquaponics well.

Expression of CAMK1 and its association with clinicopathologic characteristics in pancreatic cancer.

Calcium/calmodulin-dependent protein kinase (CAMKs) can control a wide range of cancer-related functions in multiple tumour types. Herein, we explore the expressions and clinical significances of calcium/calmodulin-dependent protein kinase 1 (CAMK1) in pancreatic cancer (PC). The expression of CAMK1 in PC was analysed by Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) database and the Oncomine database. For further validation, the protein level of CAMK1 in PC tissues was also detected in the Human Protein Atlas (HPA) database and the tissue microarray (TMA)-based immunohistochemistry (IHC). GEPIA 2 and Kaplan-Meier Plotter (KM Plotter) databases were used to explore the prognostic significances of CAMK1 in overall survival (OS) and disease-free survival (DFS) of PC at mRNA level. The relationship between CAMK1 expression and the clinicopathological characteristics of PC was further explored. Additionally, the Search Tool for the Retrieval of Interacting Genes (STRING) database was used to analyse protein-protein interactions (PPI). We found CAMK1 was highly expressed in PC both in bioinformatics analyses and TMA-IHC results. The prognostic analyses from the public databases also showed consistent results with follow-up data. The PPI network suggested that CALM1, CALM3, CREB1, CALM2, SYN1, NOS3, ATF1, GAPDH, PPM1F and FBXL12 were important significant genes associated with CAMK1. Our finding revealed CAMK1 has prognostic value in PC patients, suggesting that CAMK1 may has a distinct role in PC patients and can be used as a candidate marker for investigating clinical prognosis of PC.

Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators.

BACKGROUND: The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response. RESULTS: Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses. CONCLUSION: CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

In-depth Proteome of the Hypopharyngeal Glands of Honeybee Workers Reveals Highly Activated Protein and Energy Metabolism in Priming the Secretion of Royal Jelly.

Royal jelly (RJ) is a secretion of the hypopharyngeal glands (HGs) of honeybee workers. High royal jelly producing bees (RJBs), a stock of honeybees selected from Italian bees (ITBs), have developed a stronger ability to produce RJ than ITBs. However, the mechanism underpinning the high RJ-producing performance in RJBs is still poorly understood. We have comprehensively characterized and compared the proteome across the life span of worker bees between the ITBs and RJBs. Our data uncover distinct molecular landscapes that regulate the gland ontogeny and activity corresponding with age-specific tasks. Nurse bees (NBs) have a well-developed acini morphology and cytoskeleton of secretory cells in HGs to prime the gland activities of RJ secretion. In RJB NBs, pathways involved in protein synthesis and energy metabolism are functionally induced to cement the enhanced RJ secretion compared with ITBs. In behavior-manipulated RJB NBs, the strongly expressed proteins implicated in protein synthesis and energy metabolism further demonstrate their critical roles in the regulation of RJ secretion. Our findings provide a novel understanding of the mechanism consolidating the high RJ-output in RJBs.

Time to Enhance Immunity via Functional Foods and Supplements: Hope for SARS-CoV-2 Outbreak.

Coronavirus disease 2019 (COVID-19) is a recently emerged pandemic caused by a novel virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is communicable and mainly affects the respiratory tract. The outbreak of this disease has greatly influenced human health and economic activities worldwide. The absence of any medication for this infection highlights the urgent need for the development of alternative methods for managing the spread of the disease. Our immune system operates based on a complex array of cells, processes, and chemicals that continuously protect our body from invading pathogens, including viruses, toxins, and bacteria. The present study was conducted to perform a comprehensive review of all dietary treatments for boosting immunity against viral infections. No study was found to explicitly support the use of any healthy foods or supplements to protect against COVID-19. However, this study offers details on well-researched functional foods and supplements that typically improve the immune response, which could be helpful against this newly emerged pandemic.

Comprehensive Understanding of the Relationship between Bioactive Compounds of Black Tea and its Angiotensin Converting Enzyme (ACE) Inhibition and Antioxidant Activity.

Long term regular intake of black tea (BT) can lower blood pressure, which is probably due to its antioxidant activity and angiotensin converting enzymes (ACE) inhibitory activity. This study achieves a comprehensive understanding of the relationship between bioactive compounds of BT and its ACE inhibitory activity and antioxidant activity. Phenolic compounds are closely related to antioxidant activity and ACE inhibitory activity. Catechin (C) exhibits stronger inhibitory activity on ACE enzyme than that of other compounds. Molecular docking demonstrates that C could directly bind to ACE active site pockets and Zn(II). Other bioactive compounds are involved in antioxidant and ACE inhibitory activity in varying degrees but no obvious trend is established. Our study proposes a conjecture that some bioactive compounds of BT regulate antioxidant defenses through mechanisms that involve ACE. The mixed mode of in vitro inhibition of ACE and oxidant of BT bioactive compounds needs to be further investigated.

Proteomics Reveals the Molecular Underpinnings of Stronger Learning and Memory in Eastern Compared to Western Bees.

The eastern (Apis cerana cerana, Acc) and western (Apis mellifera ligustica, Aml) honeybee are two major honeybee species. Surprisingly, little is known about the fundamental molecular neurobiology of brain suborgans of Acc and Aml. We characterized and compared the proteomes of mushroom bodies (MBs), antennal lobes (ALs) and optical lobes (OLs) in the brain of both species, and biologically validated the functions related to learning and memory. Acc and Aml have evolved similar proteome signatures in MBs and OLs to drive the domain-specific neural activities. In MBs of both species, commonly enriched and enhanced functional groups related to protein metabolism and Ca2+ transport relative to ALs and OLs, suggests that proteins and Ca2+ are vital for consolidating learning and memory via modulation of synaptic structure and signal transduction. Furthermore, in OLs of both species, the mainly enriched ribonucleoside metabolism suggests its vital role as second messenger in promoting phototransduction. Notably, in ALs of both species, distinct proteome settings have shaped to prime olfactory learning and memory. In ALs of Acc, this is supported by the enriched cytoskeleton organization to sustain olfactory signaling through modulation of plasticity in glomeruli and intracellular transport. In ALs of Aml, however, the enriched functional groups implicated in hydrogen ion transport are indicative of their importance in supporting olfactory processes by regulation of synaptic transmission. The biological confirmation of enhanced activities of protein metabolism and signal transduction in ALs and MBs of Acc relative to in Aml demonstrates that a stronger sense of olfactory learning and memory has evolved in Acc. The reported first in-depth proteome data of honeybee brain suborgans provide a novel insight into the molecular basis of neurobiology, and is potentially useful for further neurological studies in honeybees and other insects.

New Insights into the Biological and Pharmaceutical Properties of Royal Jelly.

Royal jelly (RJ) is a yellowish-white and acidic secretion of hypopharyngeal and mandibular glands of nurse bees used to feed young worker larvae during the first three days and the entire life of queen bees. RJ is one of the most appreciated and valued natural product which has been mainly used in traditional medicines, health foods, and cosmetics for a long time in different parts of the world. It is also the most studied bee product, aimed at unravelling its bioactivities, such as antimicrobial, antioxidant, anti-aging, immunomodulatory, and general tonic action against laboratory animals, microbial organisms, farm animals, and clinical trials. It is commonly used to supplement various diseases, including cancer, diabetes, cardiovascular, and Alzheimer's disease. Here, we highlight the recent research advances on the main bioactive compounds of RJ, such as proteins, peptides, fatty acids, and phenolics, for a comprehensive understanding of the biochemistry, biological, and pharmaceutical responses to human health promotion and life benefits. This is potentially important to gain novel insight into the biological and pharmaceutical properties of RJ.

Regulation mechanism of silkworm pupa oil PUFAs on cholesterol metabolism in hepatic cell L-02.

BACKGROUND: Silkworm pupa oil polyunsaturated fatty acid (SPO PUFA) has been confirmed to have a cholesterol-lowering function. METHODS AND RESULTS: The effect of SPO PUFA and its main component, α-linolenic acid (ALA), on the metabolism of cholesterol and its regulation was investigated. The model of lipid denatured cells were constructed to carry out lipid accumulation, cholesterol metabolism and transformation. Real-time PCR and western blots were also used to analyze the expression levels of related genes and proteins to investigate the cholesterol efflux regulation mechanism. The data indicated that SPO PUFA and ALA dose-dependently decreased intracellular total cholesterol (TC) and enhanced total bile acid (TBA). They could also promote cholesterol removal by enhancing bile acid secretion and by upregulating genes LXRα, PPARγ, ABCA1, ABCG1, and CYP7A1, which were regulated by LXRα/PPARγ-ABCA1/ABCG1-CYP7A1 nuclear receptor signal pathways. CONCLUSIONS: This study is of great significance in maintaining the balance of cholesterol and lipid metabolism, and in reducing the risk of steatohepatitis. © 2019 Society of Chemical Industry.

Behavioural, physiological and molecular changes in alloparental caregivers may be responsible for selection response for female reproductive investment in honey bees.

Reproductive investment is a central life history variable that influences all aspects of life. Hormones coordinate reproduction in multicellular organisms, but the mechanisms controlling the collective reproductive investment of social insects are largely unexplored. One important aspect of honey bee (Apis mellifera) reproductive investment consists of raising female-destined larvae into new queens by alloparental care of nurse bees in form of royal jelly provisioning. Artificial selection for commercial royal jelly production over 40 years has increased this reproductive investment by an order of magnitude. In a cross-fostering experiment, we establish that this shift in social phenotype is caused by nurse bees. We find no evidence for changes in larval signalling. Instead, the antennae of the nurse bees of the selected stock are more responsive to brood pheromones than control bees. Correspondingly, the selected royal jelly bee nurses are more attracted to brood pheromones than unselected control nurses. Comparative proteomics of the antennae from the selected and unselected stocks indicate putative molecular mechanisms, primarily changes in chemosensation and energy metabolism. We report expression differences of several candidate genes that correlate with the differences in reproductive investment. The functional relevance of these genes is supported by demonstrating that the corresponding proteins can competitively bind one previously described and one newly discovered brood pheromone. Thus, we suggest several chemosensory genes, most prominently OBP16 and CSP4, as candidate mechanisms controlling queen rearing, a key reproductive investment, in honey bees. These findings reveal novel aspects of pheromonal communication in honey bees and explain how sensory changes affect communication and lead to a drastic shift in colony-level resource allocation to sexual reproduction. Thus, pheromonal and hormonal communication may play similar roles for reproductive investment in superorganisms and multicellular organisms, respectively.

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite.

AIMS: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors. METHODS: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed. RESULTS: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred. CONCLUSIONS: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.

The Emerging Proteomic Research Facilitates in-Depth Understanding of the Biology of Honeybees.

Advances in instrumentation and computational analysis in proteomics have opened new doors for honeybee biological research at the molecular and biochemical levels. Proteomics has greatly expanded the understanding of honeybee biology since its introduction in 2005, through which key signaling pathways and proteins that drive honeybee development and behavioral physiology have been identified. This is critical for downstream mechanistic investigation by knocking a gene down/out or overexpressing it and being able to attribute a specific phenotype/biochemical change to that gene. Here, we review how emerging proteome research has contributed to the new understanding of honeybee biology. A systematic and comprehensive analysis of global scientific progress in honeybee proteome research is essential for a better understanding of research topics and trends, and is potentially useful for future research directions.