Citations

Abstract Prostate-specific antigen (PSA) is widely used clinically for prostate cancer diagnostics and as an indicator of therapeutic efficacy and recurrence. Several human chemoprevention trials are being conducted to validate the prostate cancer prevention efficacy of selenium and PSA is used in these trials as a biomarker of response. A better understanding of the effects of selenium metabolites on the kinetics of PSA turnover and secretion in prostate cancer cells treated with selenium at concentrations which are achievable physiologically will be important for interpreting the results of these trials. This study addresses whether the putative active anticancer selenium metabolite methylselenol or its precursor methylseleninic acid (MSeA) specifically inhibits PSA expression in the androgen-responsive LNCaP prostate cancer cell model. The results show that exposure to sub-apoptotic concentrations of MSeA and methylselenol inhibited PSA protein expression and secretion, whereas sodium selenite and selenomethionine lacked inhibitory effect. The inhibition was detectable at 3 h of exposure and required a threshold level of MSeA to sustain. Turnover experiments showed that MSeA caused rapid PSA degradation, which was partially blocked by lysosomal inhibitors, but not by a proteasomal inhibitor. Furthermore, MSeA treatment reduced PSA mRNA level, down-regulated androgen receptor protein expression, and inhibited androgen-stimulated PSA promoter transcription. In summary, methylselenol or MSeA specifically and rapidly inhibited PSA expression through two mechanisms of action: inducing PSA protein degradation and suppressing androgen-stimulated PSA transcription. These findings may have important mechanistic implications for the prostate specific cancer chemopreventive action of selenium.

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Significance Eosinophils contribute to type 2 immunity against helminths and allergens. The small intestine harbors eosinophils with incompletely understood pathophysiological roles. Here, we show that intestinal eosinophils include two subsets. One expresses the inhibitory receptor Clec4a4 and the inhibitory ligand PD-L1 and is unique to the small intestine; the other manifests a proinflammatory phenotype. Both subsets are blood derived. Remarkably, Clec4a4 + eosinophils were instructed by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that imprints many gut immune cells. Selective AHR deletion in eosinophils depleted Clec4a4 + eosinophils, augmented innate lymphocytes producing type 2 cytokines, and enhanced helminth clearance. We conclude that Clec4a4 + eosinophils have immunomodulatory functions, which could be harnessed for the therapy of food allergies and eosinophilic gastrointestinal disorders.

AbstractBackground and AimEndoscopy featured water‐aided colonoscopy (WAC) as novel in the Innovation Forum in 2011. Gastrointestinal Endoscopy published a modified Delphi consensus review (MDCR) that supports WAC for clinical practice in 2021. We tested the hypothesis that experience was an important predictor of WAC use, either as water immersion (WI), water exchange (WE), or a combination of WI and WE.MethodsA questionnaire was sent by email to the MDCR authors with an in‐depth knowledge of WAC. They responded and also invited colleagues and trainees without in‐depth knowledge to respond. Logistic regression analysis was used with the reasons for WAC use treated as the primary outcome. Reports related to WAC post MDCR were identified.ResultsOf 100 respondents, > 80% indicated willingness to adopt and modify practice to accommodate WAC. Higher adenoma detection rate (ADR) incentivized WE use. Procedure time slots ≤ 30 and > 30 min significantly predicted WI and WE use, respectively. Co‐authors of the MDCR were significantly more likely to perform WAC (odds ratio [OR] = 7.5, P = 0.037). Unfamiliarity with (OR = 0.11, P = 0.02) and absence of good experience (OR = 0.019, P = 0.002) were associated with colonoscopists less likely to perform WAC. Reports related to WAC post MDCR revealed overall and right colon WE outcomes continued to improve. Network meta‐analyses showed that WE was superior to Cap and Endocuff. On‐demand sedation with WE shortened nursing recovery time.ConclusionsAn important predictor of WAC use was experience. Superior outcomes continued to be reported with WE.

Introduction There is emerging evidence supporting the use of the radial artery (RA) as a preferred secondary conduit for coronary artery bypass grafting (CABG) as it is associated with higher rates of graft patency at 5 years when compared with saphenous vein grafts (SVG). The modified Allen’s test (MAT) is traditionally regarded as the standard of care in the assessment of ulnar artery (UA) patency prior to RA harvesting. Unfortunately, due to high false-positive rates, a substantial number of pre-CABG patients are found to have an abnormal MAT despite normal UA patency, resulting in inappropriate exclusion from RA harvesting. The SVG is generally used in its place when this occurs, resulting in potentially lower rates of long-term graft patency. Methods and analysis The CAPITAL iRADIAL-CABG trial is currently enrolling participants 18 years of age or older undergoing CABG for whom the treating physician is considering the use of an RA conduit. Eligible patients will be randomised in a 1:1 fashion to MAT or smartphone-based photoplethysmography application assessment to assess collateral palmar circulation prior to RA harvesting. The primary outcome of the trial is the use of the RA as a conduit during CABG. The primary safety outcome is postoperative palmar ischaemia as determined by clinical assessment or requirement of vascular intervention. Secondary outcomes include vascular complications, early graft failure, need for rescue percutaneous coronary intervention during the index hospitalisation and a composite cardiovascular outcome of myocardial infarction, stroke and cardiovascular death prior to discharge from hospital. A total of 236 participants are planned to be recruited. Ethics and dissemination The study was approved by the Ottawa Heart Science Network Research Ethics Board (approval number 20180865-01H). The study results will be disseminated via conference presentations and peer-reviewed publications. Trial registration number NCT03810729.

Introduction Insulin resistance (IR) plays a key role in the pathogenesis and clinical course of patients with multiple metabolic diseases and diabetes. This study aimed to explore the effect of trimetazidine (TMZ) on skeletal muscle IR in mice fed a high-fat diet (HFD) and explore the possible underlying mechanism. Research design and methods In vivo, a HFD mouse IR model was adopted and TMZ and exercise were used to intervene. Postintervention the following were determined: blood levels of glucose and insulin, homeostasis model assessment of IR index, expression of skeletal muscle insulin signaling-related proteins phosphorylated insulin receptor substrate 1 (p-IRS1/IRS1) and phosphorylated protein kinase B (p-AKT/AKT), nuclear factor erythroid 2 related factor 2 (Nrf2) signaling pathway, and oxidative stress. In vitro, a palmitate-treated C2C12 myotube IR model was constructed. Cellular glucose uptake, p-IRS1/IRS1, and p-AKT/AKT were determined, and reactive oxygen species (ROS) production was analyzed based on treatments with specific small interfering RNA of Nrf2 with or without TMZ. Western blot was used to obtain the protein expression level and ROS production by functional analysis kits. Results In vivo, TMZ and exercise decreased the blood glucose and insulin levels and homeostasis model assessment of IR index, increased skeletal muscle insulin signaling-related protein ratios of p-IRS1/IRS1 and p-AKT/AKT, and both interventions activated Nrf2 signaling and reduced oxidative stress production in HFD mice. In vitro, TMZ reduced the oxidative stress reaction, increased the ratios of p-AKT/AKT and p-IRS1/IRS1, and attenuated the insulin stimulation of PA-induced glucose uptake. However, in the absence of Nrf2, TMZ failed to resist the effects of IR. Conclusions This study showed that TMZ, like exercise, brought about marked improvements to HFD-induced skeletal muscle IR through TMZ, a common pathway with exercise in the form of Nrf2, regulating oxidative stress. We provide new evidence to support the use of TMZ for diabetes treatment.

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P < 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.

BACKGROUND AND PURPOSE: Ischemic stroke is a heterogeneous complex disease that results from the interaction between numerous genetic and environmental risk factors. Stroke heritability is approximately 40% in the overall population, similar to that of cancer, although there may be important differences in the etiologies of young (<49 years old) versus older onset ischemic stroke. The goal of this study was to conduct a mechanistic genome-wide association (GWA) analysis contrasting the gene pathways involved in young- and old-onset stroke. METHODS: Our analysis included 946 young subjects (448 ischemic stroke subjects and 498 age and sex matched controls, mean age of stroke onset 41 years) and 2558 older subjects (1070 ischemic stroke subjects and 1488 controls, mean age of stroke onset 66.5 years). All subjects were of European ancestry. The young onset cases and controls were genotyped by Illumina Omni1-Quad array with imputation up to 1.8 M SNPs and the old onset cases and controls by a combination of 550 v1 and v3 as well as 610 Illumina arrays with imputation up to 5.0 M SNPs. Single SNP association testing was performed within each contributing study by logistic regression adjusting for age, sex and population structure. Numbers of genes assigned with significant SNPs (P<=0.0001) were 18 and 25 with young- and old-onset groups, respectively, which were used as an input to pathway analysis by the Pathway Studio (Ariadne Genomics, Co.) RESULTS: SNP-level analyses did not reveal any significant associations with each group that met Bonferroni adjusted thresholds for statistical significance. In analyzing the ‘suggestively associated SNPs’, protein-protein interaction pathway analysis in the young-onset group revealed a strong segregation of significant hub proteins (CAT, RUNX1, and EIF4E) with more than 100 connections, while in the old-onset group the interaction networks were dispersed without much segregation. We observed that protein-protein interaction networks have a power-law connectivity distribution in both young- and old-onset groups. We identified 3 significant and focused pathways, ROS metabolism, melanogenesis, and IGF1R->CdEBPA/FOXO1A signaling, enriched for young-onset stroke (P<0.04). In the old-onset group, 10 pathways were identified involving broader signaling pathways. CONCLUSIONS: Young-onset stroke may involve genetic predisposition characterized by a few distinct and finite pathways. Our data suggests that young onset stroke may involve a few pathways that relate to a small number of key hub proteins, including ROS metabolism, melanogenesis, and IGF1R->CEBPA/FOXO1A signaling. Our analysis is consistent with the hypothesis that different pathways may be involved in young versus old onset stroke.