Citations

Abstract Expression quantitative trait locus (eQTL) mapping is used to identify the functional link between a genomic variant and a gene’s expression. A significant eQTL association does not mean a causal relationship or mechanism, and further investigation is needed to understand how a single-nucleotide polymorphism (SNP) impacts gene expression. One of the most plausible explanations for eQTL is that a genomic variant affects transcription factor (TF) binding and thus impacts its regulation on target genes (TGs). However, the current eQTL model does not provide information on the TF and how its regulation is mediated by the SNP’s genotypes. Here, we propose a new method called differential co-expression QTL (ceQTL) among different alleles using Chow statistics to specifically detect eQTLs that are bound by a particular TF. We start with building a trio of TF, its TG, and related SNP, and then test the significant coefficient difference among different genotypes of the SNP. We applied this ceQTL model to simulated data and the lung tissue datasets from the genotype-tissue expression project. The simulated data results showed that the model was robust to detect true ceQTLs at variable sample sizes and different minor allele frequencies as measured by area under the curve. Our tool also performed a TF binding affinity analysis to add another layer of evidence for functional interpretation. In summary, ceQTL analysis provides a more interpretable and biological insight into the mechanism of eQTL and transcriptomic regulation, which would help us better understand how genomic variants affect phenotypes and diseases.

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Abstract Background: Intravenous (IV) isatuximab plus pomalidomide and dexamethasone (Isa-Pd) is approved for treatment in patients with relapsed/refractory multiple myeloma (RRMM) based on the ICARIA-MM study. Subcutaneous (SC) administration of Isa offers potential advantages such as shorter administration duration and greater patient comfort compared with IV routes. Isa SC via an on-body injector (OBI), an investigational wearable bolus injector, demonstrated safety and efficacy in a Phase 1b study in patients with RRMM. The IRAKLIA trial (NCT05405166) was the first Phase 3 trial evaluating the non-inferiority of Isa-Pd SC via an OBI vs Isa-Pd IV in patients with RRMM. Here, we report the findings of the IRAKLIA trial in the East Asian subgroup with RRMM. Methods: This global, multicenter, open-label study enrolledpatients aged ≥18 years with RRMM who had received ≥1 prior line of therapy (LOT) including lenalidomide and a proteasome inhibitor (PI). Patients were randomized 1:1 to Isa SC (1400 mg) or Isa IV (10 mg/kg) weekly in Cycle (C)1, then every 2 weeks in addition to P (4 mg orally daily, Day [D]1-21) and d (40 mg orally [20 mg if age ≥75 years] weekly). Treatment was administered in 4-week cycles and continued until disease progression, unacceptable toxicity, or patient withdrawal. Co-primary endpoints included overall response rate (ORR) and observed Isa concentration before dosing (Ctrough) at steady state (predose at C6D1). Key secondary endpoints included rate of very good partial response or better (≥VGPR), Ctroughlevel Cycle 2 Day 1 (C2D1), infusion reaction incidence, and patient satisfaction rate based on the patient experience and satisfaction questionnaire (PESQ) at C5D15. Results: The East Asian subgroup consisted of 105 patients from China (Mainland, n=82 and Taiwan, n=1) and Japan(n=22) (SC, n=50; IV, n=55). Baseline characteristics of the East Asian subgroup were generally balanced between the two arms and generally comparable to the overall global population (median age 62 years; median 2 prior LOT; 29.5% high-risk cytogenetics; 82.9% refractory to lenalidomide; 7.6% prior exposure to daratumumab). After a median of 13.0 months follow-up, ORR in the SC and IV arm was 74.0% and 70.9%, respectively (relative risk [95% CI] = 1.044 [0.815 – 1.335]). The mean (SD) of Ctroughat C6D1 was 502 (232) µg/mL for SC arm and 282 (123) µg/mL for IV arm. The geometric mean ratio (90% CI) comparing SC to IV for Ctrough at steady state was 1.756 (1.346 – 2.290). The ≥VGPR rates were 58.0% for SC and 50.9% for IV (relative risk [95% CI] = 1.139 [0.798 – 1.631]). The mean(SD) of C2D1 Ctroughlevel was 420 (161) µg/mL for the SC arm and 262 (111) µg/mL for IV arm. The geometric mean ratio (90% CI) comparing SC to IV for Ctrough at C2D1 was 1.673 (1.321 to 2.120). The infusion reaction incidence was 0% and 21.8% for SC and IV, respectively. Grade ≥3treatment-emergent adverse events were observed in 82.0% and 87.3% of patients in the SC and IV arms, respectively. Treatment discontinuation rates were 6% for the SC arm and 12.7% for the IV arm. Injection site reactions (ISRs) occurred in 4% (2/50) of patients in the SC arm and in 0.21% (2/964) of SC injections (all Grade 1), with 99.3% of SC injections completed successfully. Isa SC patients expressed higher satisfaction with their injection method, with 64.0% of patients reporting “satisfied” or “very satisfied” vs 52.7% of Isa IV patients (odds ratio [95% CI] = 1.594 [0.728 – 3.489]). Conclusions: The efficacy, safety and pharmacokinetic results between Isa SC vs IV + Pd in the East Asian population from the IRAKLIA study were consistent with the results of the overall global population, in which non-inferiority of ORR, Ctrough at C6D1, ≥VGPR and Ctrough at C2D1 was demonstrated and statistically significantly fewer infusion reactions and higher patient satisfaction were also noted for SC vs IV. These results support the potential use of Isa SC delivered via OBI in East Asian patients and demonstrate the potential of this delivery method to improve patient experience and practice efficiency.

Abstract The interactions between transcription factors (TFs) and the target genes could provide a basis for constructing gene regulatory networks (GRNs) for mechanistic understanding of various biological complex processes. From gene expression data, particularly single-cell transcriptomic data containing rich cell-to-cell variations, it is highly desirable to infer TF–gene interactions (TGIs) using deep learning technologies. Numerous models or software including deep learning–based algorithms have been designed to identify transcriptional regulatory relationships between TFs and the downstream genes. However, these methods do not significantly improve predictions of TGIs due to some limitations regarding constructing underlying interactive structures linking regulatory components. In this study, we introduce a deep learning framework, DeepTGI, that encodes gene expression profiles from single-cell and/or bulk transcriptomic data and predicts TGIs with high accuracy. Our approach could fuse the features extracted from Auto-encoder with self-attention mechanism and other networks and could transform multihead attention modules to define representative features. By comparing it with other models or methods, DeepTGI exhibits its superiority to identify more potential TGIs and to reconstruct the GRNs and, therefore, could provide broader perspectives for discovery of more biological meaningful TGIs and for understanding transcriptional gene regulatory mechanisms.

Abstract Background Perioperative morbidity and mortality remain a point of concern for the Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS) procedure. Post-hepatectomy liver failure (PHLF) after the second step poses the most significant risk factor for futile outcome. Recovery of liver function after the first step of ALPPS is critically important to allow for sufficient liver function after this surgery. The APRI+ALBI score has been proposed as an easily assessable score to monitor liver function and its dynamic recovery. Aims We explored if the APRI+ALBI score was able to assess liver function recovery after the first step of ALPPS and allow for optimal timing of the 2nd step. Methods Based on the ALPPS registry, patients from 2012 to 2020 with available APRI+ALBI score were included. Postoperative outcomes (PHLF A – C, PHLF B + C, 90-day mortality and severe morbidity) were defined as per standard definitions. The APRI/ALBI score was monitored perioperatively. Results Overall, 464 patients from 16 international participating centers in the ALPPS registry were included. Clinically relevant PHLF (B + C) was observed in 7.5 % and of these 63 % of patients ultimately died due to liver failure. The APRI+ALBI score immediately increased after each surgical intervention and continuously decrease thereafter. Failure of the APRI+ALBI score to decrease until the 2nd step of ALPPS predicted PHLF B+C (p = 0.001; AUC 0.78). Particularly patients with high APRI+ALBI scores and short interstage intervals were at risk to develop PHLF B+C. Conclusion The APRI+ALBI score objectifies liver function recovery after the 1st step of ALPPS and failure to sufficiently decreased is associated with a higher risk for PHLF B+C. This might allow for optimized planning of the 2nd step of ALPPS to allow for sufficient liver function recovery to minimize the risk for PHLF B+C and associated futile outcome.

Abstract Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis–associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1–4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation–associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. Significance: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

Background. Danlou tablet (DLT), the traditional Chinese medicine has been commonly used for dyslipidemia, atherosclerosis, and coronary heart disease. Whether it was effective against vascular injury caused by CIH has remained unknown. The aim of the current study was to observe the effects of DLT on chronic intermittent hypoxia (CIH)-induced vascular injury via regulation of blood lipids and to explore potential mechanisms. Methods. Sixteen 12-week-old male ApoE−/− mice were randomly divided into four groups. The sham group was exposed to normal room air, whereas the other three groups were exposed to CIH. Mice in the CIH + normal saline (NS) group were gavaged with NS. Mice in the CIH + Angptl4-ab group were intraperitoneally injected with Angptl4-antibody. Mice in the CIH + DLT group were gavaged with DLT. After four weeks of intervention, serum lipid concentrations, and serum lipoprotein lipase (LPL) activity were detected. The changes in atherosclerosis in vascular tissue were detected by hematoxylin and eosin (H&E) staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were applied to detect the expression levels of hypoxia-induciblefactor-1 (HIF-1), factor-inhibiting HIF-1 (FIH-1), angiopoietin-like 4 (Angptl4), and LPL in different tissues. Results. CIH exposure increases serum lipid levels, decreases serum LPL activity, and exacerbates atherosclerosis. Both Angptl4-ab and DLT treatment reversed the changes in lipid concentration, LPL activity, and atherosclerosis caused by CIH. In the epididymal fat pad, CIH exposure decreased the expression of FIH-1 and increased the expression of HIF-1, whereas DLT treatment increased the expression of FIH-1 and LPL and inhibited the expression of HIF-1 and Angptl4. In heart tissue, the expression levels of LPL and Angptl4 were not affected by modeling or treatment. Conclusions. DLT improved vascular damage by improving the increase in blood lipids induced by CIH, potentially by upregulating FIH-1 and downregulating HIF-1 and Angptl4 in adipose tissue. Therefore, DLT may be a promising agent for the prevention and treatment of CIH-induced vascular injury.

Abstract Background Chromosomal translocation has been detected in many human cancers including gliomas and is considered a driving force in tumorigenesis. Co-deletion of chromosome arms 1p and 19q is a hallmark for oligodendrogliomas. On the molecular level, 1p/19q co-deletion results from t(1;19)(q10;p10), which leads to the concomitant formation of a hybrid chromosome containing the 1q and 19p arms. A method to generate 1p/19q co-deletion is lacking, which hinders the investigation of how 1p/19q co-deletion contributes to gliomagenesis. Methods We hypothesized that chromosomal translocation, such as t(1;19)(q10;p10) resulting in the 1p/19q co-deletion, may be induced by simultaneously introducing DNA double-strand breaks (DSBs) into chromosomes 1p and 19q using CRISPR/Cas9. We developed a CRISPR/Cas9-based strategy to induce t(1;19)(q10;p10) and droplet digital PCR (ddPCR) assays to detect the hybrid 1q/19p and 1p/19q chromosomes. Results After translocation induction, we detected both 1p/19q and 1q/19p hybrid chromosomes by PCR amplification of the junction regions in HEK 293T, and U-251 and LN-229 glioblastoma cells. Sequencing analyses of the PCR products confirmed DNA sequences matching both chromosomes 1 and 19. Furthermore, the 1p/19q hybrid chromosome was rapidly lost in all tested cell lines. The 1q/19p hybrid chromosome also become undetectable over time likely due to cell survival disadvantage. Conclusion We demonstrated that t(1;19)(q10;p10) may be induced by CRISPR/Cas9-mediated genomic editing. This method represents an important step toward engineering the 1p/19q co-deletion to model oligodendrogliomas. This method may also be generalizable to engineering other cancer-relevant translocations, which may facilitate the understanding of translocation roles in cancer progression.

Objectives To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC‐P). Patients and Methods We performed targeted sequencing of plasma cell‐free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC‐P and 84 without IDC‐P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients’ survival outcomes was also explored. Results We identified that 29.8% (48/161) and 21.4% (18/84) of patients with and without IDC‐P harboured genomic alterations in DNA repair pathways, respectively ( P = 0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC‐P carriers compared to IDC‐P non‐carriers (11.8% [19/161] vs 2.4% [two of 84], P = 0.024). Germline BReast CAncer type 2 susceptibility protein ( BRCA2 ) and somatic cyclin‐dependent kinase 12 ( CDK12 ) defects were specifically identified in IDC‐P carriers relative to PAC ( BRCA2 : 8.7% [14/161] vs 0% and CDK12 : 6.8% [11/161] vs 1.2% [one of 84]). Patients with IDC‐P had a distinct androgen receptor (AR) pathway alteration, characterised by an enrichment of nuclear receptor corepressor 2 ( NCOR2 ) mutations compared with patients with pure PAC (21.1% [34/161] vs 6.0% [five of 84], P = 0.004). Increased AR alterations were detected in patients harbouring tumours with an IDC‐P proportion of ≥10% vs those with an IDC‐P proportion of <10% (6.4% [five of 78] vs 18.1% [15/83], P = 0.045). For IDC‐P carriers, tumour protein p53 ( TP53 ) mutation was associated with shorter castration‐resistant‐free survival (median 10.9 vs 28.9 months, P = 0.026), and BRCA2 alteration was related to rapid prostate‐specific antigen progression for those receiving abiraterone treatment (median 9.1 vs 11.9 months, P = 0.036). Conclusion Our findings provide genomic evidence explaining the aggressive phenotype of tumours with IDC‐P, highlighting the potential therapeutic strategies for this patient population.