Citations

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Background: The study of hypertrophic cardiomyopathy (HCM) can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease. Methods: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered short hairpin ribonucleic acids and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell–derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics. Results: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio . Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell–derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil. Conclusions: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

Abstract BackgroundMany studies have evaluated bundled interventions to improve hand hygiene compliance (HHC). However, the compliance rates remain low. We aimed to use Kotter's change model (KCM) to improve HHC and conduct a complete process evaluation for HHC among medical staff in the intensive care unit (ICU). MethodsKCM was administrated in the ICU of Zhongnan Hospital of Wuhan University from March 2018 to August 2021, and 41-month longitudinal monitoring of HHC was carried out. The primary outcome was the absolute change in monthly HHC. The secondary outcomes included the characteristics of HHC in different phases, the different change trends of HHC for different HH opportunities and occupations, the quarterly incidence of the central line-associated bloodstream infection (CLABSI), and the catheter-associated urinary tract infection (CAUTI).Results. 20,222 HH actions and 24,195 HH opportunities were included in this study. The overall HHC was 83.58% (95%CI, 83.11%-84.04%). After implementing the KCM project, the HHC increased from 35.71% (95%CI, 22.99%-50.83%) to 87.75% (95%CI, 85.53%-89.67%), with an increased rate of 145.73%. The fastest-growing rate of HHC was after contact patients, which increased from 35.29% to 89.8%. Quarterly trends of the CLABSI rate (0‰-3.53‰) and CAUTI rate (0.96‰-4.26‰) remained stable at a low level under the background of the number of cases and the treatment complexities of the patients increasing year by year.ConclusionsUsing KCM can systematically change the cognition of HH in healthcare providers and create an atmosphere to promote HH to improve and maintain the stability of the HHC of healthcare providers in ICU.

Abstract Introduction Late‐onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E ( APOE ) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods Sex‐ and APOE ‐specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient‐specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine‐focused profile overriding sex‐specific differences in serum metabolites of AD patients. Discussion These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.

BackgroundThe feasibility and reproducibility of multifrequency MR elastography (MRE) for diagnosing pancreatic ductal adenocarcinoma (PDAC) have not been reported.PurposeTo determine the feasibility and reproducibility of multifrequency MRE for assessing pancreatic stiffness in healthy and diseased pancreases.Study typeProspective.SubjectsA total of 40 healthy volunteers and 10 patients with PDAC were prospectively recruited between March 2018 and October 2021.Field strength/sequenceA 3.0‐T pancreatic MRE at frequencies in the order of 30, 40, 60, 80, and 100 Hz.AssessmentBody mass index (BMI) and wave distance of the healthy pancreas and PDAC were measured. Image quality was assessed using the image quality score (IQS: 1–4, ≥3 were considered diagnostic quality). Three readers independently performed the pancreatic stiffness and IQS assessments to evaluate reproducibility.Statistical testsLogistic regression analyses were performed to determine variables that influenced IQS. Statistical significance was set at P <0.05. Levels of inter‐ and intrarater agreement were assessed using intraclass correlation coefficients (ICC) and Cohen's kappa coefficient (κ). Good reproducibility was set at ICC and κ ≥ 0.8.ResultsIn logistic regression analysis, a diagnostic IQS in healthy volunteers was independently associated with a lower BMI (odds ratio [OR] = 0.89 kg/m−2), shorter wave distance (OR = 0.70 cm−1), and lower frequency (30 and 40 Hz: OR = 170.01 and 96.02). In PDAC, frequency was the only independent factor for diagnostic IQS (30–60 Hz: OR = 46.18, 46.18, and 17.20, respectively) with 100 Hz as a reference. In healthy volunteers, good reproducibility was observed at 30 and 40 Hz. In PDAC, good reproducibility was observed at 30–60 Hz.Data conclusionMRE at 30 and 40 Hz provides diagnostic wave images and reliable measurements of pancreatic stiffness in healthy volunteers. MRE at 30–60 Hz is acceptable for PDACs (IQS ≥ 3, ICC and κ ≥ 0.80).Evidence Level1Technical EfficacyStage 2

Abstract Objective Accurate extraction of breast cancer patients’ phenotypes is important for clinical decision support and clinical research. This study developed and evaluated cancer domain pretrained CancerBERT models for extracting breast cancer phenotypes from clinical texts. We also investigated the effect of customized cancer-related vocabulary on the performance of CancerBERT models. Materials and Methods A cancer-related corpus of breast cancer patients was extracted from the electronic health records of a local hospital. We annotated named entities in 200 pathology reports and 50 clinical notes for 8 cancer phenotypes for fine-tuning and evaluation. We kept pretraining the BlueBERT model on the cancer corpus with expanded vocabularies (using both term frequency-based and manually reviewed methods) to obtain CancerBERT models. The CancerBERT models were evaluated and compared with other baseline models on the cancer phenotype extraction task. Results All CancerBERT models outperformed all other models on the cancer phenotyping NER task. Both CancerBERT models with customized vocabularies outperformed the CancerBERT with the original BERT vocabulary. The CancerBERT model with manually reviewed customized vocabulary achieved the best performance with macro F1 scores equal to 0.876 (95% CI, 0.873–0.879) and 0.904 (95% CI, 0.902–0.906) for exact match and lenient match, respectively. Conclusions The CancerBERT models were developed to extract the cancer phenotypes in clinical notes and pathology reports. The results validated that using customized vocabulary may further improve the performances of domain specific BERT models in clinical NLP tasks. The CancerBERT models developed in the study would further help clinical decision support.

In this study, we discovered 3-aminophthalic acid as a new ligand of cereblon (CRBN) E3 ubiquitin ligase and developed a phthalic acid-based O’PROTAC for ERG destruction, expanding the pool of ligands for development of PROTACs, especially O’PROTACs.

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Abstract The detection of recurrent genetic abnormalities in acute myeloid leukemia (AML), including RUNX1T1/RUNX1 gene fusion, is critical for optimal medical management. Herein, we report a 45 year old woman with newly diagnosed AML and conventional chromosome studies that revealed an apparently balanced t(8;20)(q22;p13) in all 20 metaphases analyzed. A RUNX1T1/RUNX1 dual-color dual-fusion fluorescence in situ hybridization (FISH) probe set was subsequently performed and revealed a RUNX1T1/RUNX1 gene fusion. Metaphase FISH studies performed on abnormal metaphases revealed a cryptic, complex translocation resulting in RUNX1T1/RUNX1 fusion, t(8;20;21)(q22;p13;q22). This case study shows the importance of performing FISH studies or other high-resolution genetic testing concurrently with conventional chromosome studies for the detection of cryptic recurrent gene fusions in AML, particularly a focused genetic evaluation such as RUNX1T1/RUNX1 gene fusion, when specific abnormalities involving 8q22 are identified.

Significance Repression of the large number of transposable elements in eukaryotic genomes is essential for genome stability. The Piwi-interacting RNA and short interfering RNA pathways are critical for repressing transposable elements in germlines, but the repression of transposable elements in somatic tissues involves other components. While the mammalian Hinfp has been shown to regulate Histone4 and cell-cycle progression, our manuscript provides evidence that a function of the Drosophila Hinfp is to maintain Histone1 expression to repress most transposable elements in somatic genomes. This Hinfp–Histone1 axis provides a venue to study maintenance of genome stability and progression of pathological outcomes.