Summary
Background
A novel potassium‐competitive acid blocker, DWP14012, is in clinical development as a potential alternative to proton pump inhibitors for the treatment of acid‐related diseases.
...Aims
To evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of DWP14012 in humans.
Methods
A randomised, double‐blind, double‐dummy, placebo‐ and active‐controlled, single‐ and multiple‐ascending dose (SAD and MAD, respectively) study was conducted in healthy male subjects without Helicobacter pylori infection. Subjects randomly received a single oral dose of 10‐320 mg DWP14012, esomeprazole (active comparator) or placebo in the SAD study (n = 72) and once daily doses of 20‐160 mg DWP14012, esomeprazole or placebo for 7 days in the MAD study (n = 48; 8:2:2). Tolerability was evaluated using a microRNA‐122 assay. Pharmacodynamics were evaluated through 24‐hour gastric pH monitoring, and pharmacokinetics were evaluated plasma and urine DWP14012 concentrations.
Results
DWP14012 was generally well tolerated. The liver toxicity of DWP14012 was not higher than that of placebo after multiple oral administrations. DWP14012 showed rapid and sustained suppression of gastric acid secretion for 24 hours after dosing. Clear dose‐response and exposure‐response relationships were observed. Plasma concentrations of DWP14012 increased in a dose‐proportional manner in the MAD study, whereas in the SAD study, DWP14012 did not significantly accumulate in the plasma.
Conclusions
DWP14012 was well tolerated, and showed a rapid and long‐lasting gastric acid suppression effect in healthy subjects. These results justify further investigation of DWP14012 in patients with acid‐related disorders.
Linked ContentThis article is linked to Sachs et al paper. To view this article visit https://doi.org/10.1111/apt.14864.
Cylinders and rings fabricated from AerMet® 100 alloy and AISI 1018 steel have been explosively driven to fragmentation in order to determine the fracture strains for these materials under ...plane-strain and uniaxial-stress conditions. The phenomena associated with the dynamic expansion and subsequent break up of the cylinders are monitored with high-speed diagnostics. In addition, complementary experiments are performed in which fragments from the explosively driven cylinders are recovered and analyzed to determine the statistical distribution associated with the fragmentation process as well as to determine failure mechanisms. The data are used to determine relevant coefficients for the Hancock–McKenzie (Johnson–Cook) fracture model. Metallurgical analysis of the fragments provides information on damage and failure mechanisms.
Head and neck squamous cell carcinoma (HNSCC) is broadly classified into HNSCC associated with human papilloma virus (HPV) infection, and HPV negative HNSCC, which is typically smoking-related. A ...subset of HPV negative HNSCCs occur in patients without smoking history, however, and these etiologically ‘atypical’ HNSCCs disproportionately occur in the oral cavity, and in female patients, suggesting a distinct etiology.
To investigate the determinants of clinical and molecular heterogeneity, we performed unsupervised clustering to classify 528 HNSCC patients from The Cancer Genome Atlas (TCGA) into putative intrinsic subtypes based on their profiles of epigenetically (DNA methylation) deregulated genes.
HNSCCs clustered into five subtypes, including one HPV positive subtype, two smoking-related subtypes, and two atypical subtypes. One atypical subtype was particularly genomically stable, but featured widespread gene silencing associated with the ‘CpG island methylator phenotype’ (CIMP).
Further distinguishing features of this ‘CIMP-Atypical’ subtype include an antiviral gene expression profile associated with pro-inflammatory M1 macrophages and CD8+ T cell infiltration, CASP8 mutations, and a well-differentiated state corresponding to normal SOX2 copy number and SOX2OT hypermethylation. We developed a gene expression classifier for the CIMP-Atypical subtype that could classify atypical disease features in two independent patient cohorts, demonstrating the reproducibility of this subtype. Taken together, these findings provide unprecedented evidence that atypical HNSCC is molecularly distinct, and postulates the CIMP-Atypical subtype as a distinct clinical entity that may be caused by chronic inflammation.
•We identified five etiologically distinct DNA methylation subtypes of head and neck squamous cell carcinoma.•One subtype appears not to be associated with smoking or HPV, and may represent a distinct etiological entity.•Distinctive molecularly features of this subtype include CIMP, CASP8 mutations, and antiviral immune response.
To identify factors that define clinical and biological variability in head and neck squamous cell carcinoma (HNSCC), we clustered patients into subtypes based on their epigenetic profiles, revealing five subtypes, including previously identified subtypes. We focus on discovery of a subtype that matches the clinical characteristics previously ascribed to ‘atypical’ HNSCC, i.e., HNSCC that is not caused by the classic HNSCC risk factors of smoking or HPV. This subtype is biologically distinct across multiple molecular data types, and was reproducible in independent patient populations. We postulate that this ‘CIMP-Atypical’ subtype represents a clinically distinct HNSCC subtype of unknown cause.
In the era of personalized cancer medicine, identifying techniques for effectively matching patients to efficacious treatments is a critical step in the treatment process. The advent of anti-cancer ...immunotherapies necessitates novel approaches to biomarker identification beyond traditional genomic profiling. One promising approach is incorporation of nomograms into treatment decisions. Nomograms are prediction tools, based on statistical modeling, designed to predict treatment outcomes. As a first step toward developing a nomogram, we conducted analyses to predict CD137 expression of natural killer cells after monoclonal antibody (mAb) treatment.
Patient, tumor and immune characteristics were collected from 199 patients with breast cancer (N=62), head/neck cancers (N=46) and non-Hodgkin’s lymphoma (NHL) (N=91), who were receiving mAb therapy as part of clinical trials. The difference in CD137 expression before and after mAb therapy was assessed by flow cytometry. To evaluate those who respond to mAb therapy via increased CD137 expression, we applied classification and regression trees (CART), multivariable lasso regression tools and Random Forest.
The CD137 expression was significantly different for each cancer type mean (SD): Breast: 6.6 (6.5); Head/Neck: 11.0 (7.0); NHL: 7.5 (7.1), P<0.0001. For breast cancer and NHL, FcR polymorphism and baseline CD137 expression were significant predictors of increased CD137 expression; for head/neck cancer, FcR polymorphism and age were significant predictors of increased expression.
Our preliminary results suggest that FcR polymorphism, pre-treatment CD137 expression and age are significant predictors of CD137 upregulation in patients. This study demonstrates that the development of a nomogram for therapy response is feasible. Further work validating our models in an independent cohort will provide the next steps in developing a nomogram that may be used to individualize this therapeutic approach for patients (NCT01114256).
Objective: To identify emotional and environmental factors that aggravate dream enactment behaviors (DEBs) in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Methods: In this ...cross-sectional study, a total of 96 polysomnography-confirmed iRBD patients (mean age, 68.5 years; men, 68%) and their caregivers completed questionnaires regarding potential aggravating factors related to DEBs, including emotion/feelings (stress, anger, anxiety, depressive mood, fatigue, pain), food (alcohol, caffeine, overeating in the evening, fasting/hunger), activities and sleep patterns (strenuous exercise, sex before bed, conflict/fighting, sleep deprivation, oversleeping, sleeping away from home, watching TV before bed), weather/environmental factors (cloudy or rainy weather, heat, cold, noise) and medication (skipping medication, taking hypnotics). Results: The patients reported that stress (61%) was the most aggravating factor for DEBs, followed by anxiety (56%), anger (51%), fatigue (49%), and watching TV before bed (46%). Similarly, the caregivers reported that these factors were most relevant to the aggravation of DEBs in the patients, although some factors were ranked differently. In the subgroup analyses, aggravating factors for DEBs did not differ by RBD symptom severity. Interestingly, the proportion of patients experiencing DEB aggravation by stress, anxiety and depressive mood was significantly higher in women than in men. Furthermore, depressed patients reported that stress and cloudy or rainy weather made DEBs worse than nondepressed patients. Conclusion: Our results suggest that DEBs in iRBD patients may be mainly aggravated by emotional factors. These negative effects appeared to be more prominent in female and depressed patients. Keywords: REM sleep behavior disorder, dream enactment behavior, precipitating factors
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