In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy ...or in combination with pembrolizumab.
Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.
Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.
Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors.•Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors.
Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.
Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors ...received an initial flat dose of quavonlimab as monotherapy 25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3) followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab 25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E) plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.
Thirty-nine patients were enrolled in DE n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3) and 134 in DC n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E). Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% 95% confidence interval (CI), 24.9-56.7; arm A, 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.
Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.
•Quavonlimab, a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a first-in-human study.•The combination therapy was safe and tolerable and showed antitumor activity in patients with advanced NSCLC.•Data from this study led to a recommended phase II dose of 25 mg Q6W for quavonlimab when used with pembrolizumab.
Intramuscular fat content (IFC) is an essential quantitative trait of meat, affecting multiple meat quality indicators. A certain amount of IFC could not only improve the sensory score of pork but ...also increase the flavour, tenderness, juiciness and shelf-life. To dissect the genetic determinants of IFC, two methods, including genome-wide efficient mixed-model analysis (GEMMA) and linkage disequilibrium adjusted kinships (LDAKs), were used to carry out genome-wide association studies for IFC in Suhuai pig population. A total of 14 and 18 significant single nucleotide polymorphisms (SNPs) were identified by GEMMA and LDAK, respectively. The results of these two methods were highly consistent and all 14 significant SNPs in GEMMA were detected by LDAK. Seven of the 18 SNPs reached the genome-wide significance level (P < 9.85E−07) while 11 cases reached the suggestive significance level (P < 1.77E−05). These significant SNPs were mainly distributed on Sus scrofa chromosome (SSC) 5, 3, and 7. Moreover, one locus resides in a 2.27 Mb (71.37–73.64 Mb) region on SSC5 harbouring 13 significant SNPs associated with IFC, and the lead SNP (rs81302978) also locates in this region. Linkage disequilibrium (LD) analysis showed that there were four pairs of complete LD (r2 = 1) among these 13 SNPs, and the remaining 9 SNPs with incomplete LD (r2 ≠ 1) were selected for subsequent analyses of IFC. Association analyses showed that 7 out of 9 SNPs were significantly associated with IFC (P < 0.05) in 330 Suhuai pigs, and the other 2 SNPs tended to reach a significant association level with IFC (P < 0.1). The phenotypic variance explained (PVE) range of these 9 SNPs was 0.92–3.55%. Meanwhile, the lead SNP was also significantly associated (rs81302978) with IFC (P < 0.05) in 378 commercial hybrid pigs (Pietrain × Duroc) × (Landrace × Yorkshire) (PDLY), and the PVE was 1.38%. Besides, two lipid metabolism-relevant candidate genes, the leucine rich repeat kinase 2 (LRRK2) and PDZ domain containing ring finger 4 (PDZRN4) were identified in the 2.27 Mb region on SSC5. In conclusion, our results may provide a set of markers useful for genetic improvement of IFC in pigs and will advance the genome selection process of IFC on pig breeding programmes.
Transformer (tra) is the key gene that turns on the sex‐determination cascade in Drosophila melanogaster and in some other insects. The honeybee Apis mellifera has two duplicates of tra, one of which ...(complementary sex determiner, csd) is the primary signal for complementary sex‐determination (CSD), regulating the other duplicate (feminizer). Two tra duplicates have been found in some other hymenopteran species, resulting in the assumption that a single ancestral duplication of tra took place in the Hymenoptera. Here, we searched for tra homologues and pseudogenes in the Hymenoptera, focusing on five newly published hymenopteran genomes. We found three tra copies in the fig wasp Ceratosolen solmsi. Further evolutionary and expression analyses also showed that the two duplicates (Csoltra‐B and Csoltra‐C) are under positive selection, and have female‐specific expression, suggesting possible sex‐related functions. Moreover, Aculeata species exhibit many pseudogenes generated by lineage‐specific duplications. We conclude that phylogenetic reconstruction and pseudogene screening provide novel evidence supporting the hypothesis of independent duplications rather an ancestral origin of multiple tra paralogues in the Hymenoptera. The case of C. solmsi is the first example of a non‐CSD species with duplicated tra, contrary to the previous assumption that derived tra paralogues function as the CSD locus.
Since the end of 2019, China and other regions around the world have been facing a pandemic of novel coronavirus pneumonia (COVID-19). The virus is highly transmissible, and the human population is ...generally susceptible. Most patients with osteoporosis are postmenopausal women or elderly people with hypoimmunity, so the osteoporosis clinic has become a new hotspot for corona virus infection. During the COVID-19 pandemic, it is necessary to establish standardized out-patient protocols to provide safe and effective treatment for osteoporosis patients and medical staff. In an osteoporosis clinic, we advocate the following suggestions to prevent and control osteoporosis during the pandemic period: (1) specialized diagnosis and treatment techniques for osteoporosis patients in the outpatient care, including enhancing the prevention for outpatient medical staff, strengthening awareness of COVID-19 prevention, strictly screening outpatients with COVID-19 infection, and insistent administration of anti-osteoporosis drugs during outbreaks; (2) home prevention for osteoporosis patients including keeping windows open, exposing them to sunlight, supplementing them with enough protein, exercising regularly, and administrating calcium supplements; and (3) simplifying the follow-up and evaluation of osteoporosis using online platforms.
The interaction between figs and their pollinating wasps is regarded as a model system for studying specialized co‐evolved mutualism. Chemoreception of fig wasps plays an important role in this ...interaction, and odorant‐binding proteins (OBP) function in the first step of odorant detection. The OBP repertoire of the fig wasp Ceratosolen solmsi is reported to be one of the smallest among insects; however, it is unknown how these OBPs are related to the complicated mating process occurring within the fig cavity and the extreme host specificity of the species. In the present study, we combined a structural analysis of the conserved cysteine pattern and motif order, a phylogenetic analysis, and previous studies on ligand‐binding assays to deduce the function of OBPs. We also quantified the expression of OBP genes in different life stages of female and male fig wasps by using real‐time quantitative PCR, which can help to predict the function of these genes. The results indicated that CsolOBP1 and CsolOBP2 (or CsolOBP5) in males may bind to pheromones and play important roles in mate choice, whereas CsolOBP4 and CsolOBP5 may primarily function in host localization by females through binding of volatile compounds emitted by receptive figs.
Objectives
Cases of sporadic Alzheimer’s disease (SAD) are the predominant form of the age-related dementia. New evidence suggests that metabolic syndrome (MS), a metabolic disorder, is an initiating ...factor of some SAD cases. A high-sugar high-fat diet could cause MS, we aimed to investigate whether it could directly lead to SAD.
Measurements
The characteristic molecules of AD (hippocampus Aβ and Tau) were tested by using ELISA and western blotting to confirm the happening hallmarks of AD in brain. MS and inflammation related biochemical indicators were measured using immunological method. Proteins associated with the insulin resistance signal pathway (JNK, PI-3K, AKT, GSK-3β, GLUT3) were evaluated using western blotting method. The levels of reactive oxygen species (ROS) were measured by immunofluorescence method.
Results
Expressions of hippocampus Aβ, phosphorylation-Tau (p-Tau), inflammatory factors and p-JNK, Gsk-3βwere higher in the model rats than those in the control rats and expressions of p-PI3K, p-AKT and GLUT3 were reversed.
Conclusions
The MS model animals, which can induce the characteristics symptoms of AD, and therefore it may be preliminarily considered that the AD pertains to the MS-related diseases.
•Effective distribution of airflow for indoor built environments is research focus.•Theory and practical applications of air distribution methods are reviewed.•Measuring and evaluating methods of air ...distribution are discussed.
Ventilation and air distribution methods are important for indoor thermal environments and air quality. Effective distribution of airflow for indoor built environments with the aim of simultaneously offsetting thermal and ventilation loads in an energy efficient manner has been the research focus in the past several decades. Based on airflow characteristics, ventilation methods can be categorized as fully mixed or non-uniform. Non-uniform methods can be further divided into piston, stratified and task zone ventilation. In this paper, the theory, performance, practical applications, limitations and solutions pertaining to ventilation and air distribution methods are critically reviewed. Since many ventilation methods are buoyancy driving that confines their use for heating mode, some methods suitable for heating are discussed. Furthermore, measuring and evaluating methods for ventilation and air distribution are also discussed to give a comprehensive framework of the review.
Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off‐target ...effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg−1), Beta (0.1 mg kg−1), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO‐dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin‐1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system.
Antenatal glucocorticoids trigger adverse effects on the developing cardiovascular system, but mechanisms are unknown. We investigated effects of Dexamethasone (Dex) and Betamethasone (Beta) using the chicken embryo, an established model to isolate effects of therapy, independent of the mother and placenta. While Dex triggered cardiomyocyte hypertrophy, Beta reduced cardiomyocyte number. Dex activated oxidative stress, p38 and caspase 3. In contrast, impaired GR downregulation, p53 activation and CDK2 repression linked the effects of Beta on cardiomyocyte senescence and greater cardiac dysfunction.
Retraction of 'Cell orientation, proliferation, and differentiation on poly(
l
-lactide) spherulites' by F. Zou
et al.
,
RSC Adv.
, 2016,
6
, 57396-57402.
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