Citations

Abstract Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett’s esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett’s esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82–0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86–0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66–0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7–0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett’s esophagus surveillance. Prevention Relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett’s esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

Obesity is an epidemic with myriad health effects, but little is understood regarding individual obese phenotypes and how they may respond to therapy. Epigenetic changes associated with obesity have been detected in blood, liver, pancreas, and adipose tissues. Previous work using human organoids found that dietary glucose hyperabsorption is a steadfast trait in cultures derived from some obese subjects, but detailed transcriptional or epigenomic features of the intestinal epithelia associated with this persistent phenotype are unknown. This study evaluated differentially expressed genes and relative chromatin accessibility in intestinal organoids established from donors classified as non-obese, obese, or obese hyperabsorptive by body mass index and glucose transport assays. Transcriptomic analysis indicated that obese hyperabsorptive subject organoids have significantly upregulated dietary nutrient absorption transcripts and downregulated type I interferon targets. Chromatin accessibility and transcription factor footprinting predicted that enhanced HNF4G binding may promote the obese hyperabsorption phenotype. Quantitative RT-PCR assessment in organoids representing a larger subject cohort suggested that intestinal epithelial expression of CUBN, GIP, SLC5A11, and SLC2A5 were highly correlated with hyperabsorption. Thus, the obese hyperabsorption phenotype was characterized by transcriptional changes that support increased nutrient uptake by intestinal epithelia, potentially driven by differentially accessible chromatin. Recognizing unique intestinal phenotypes in obesity provides a new perspective in considering therapeutic targets and options with which to manage the disease.

Background: Mild cognitive impairment (MCI) is a precursor to dementia, with a prevalence of over 15% among community dwellers, with significant economic and social implications. Despite preserved autonomy in daily living, individuals with MCI face challenges in handling everyday technology and memory-related tasks, necessitating digital interventions, such as digital planning-based technologies to support cognitive functioning. Objective: The aim of this study is to identify and summarize available research literature on available digital planning-based technologies to support memory-related functioning in older adults with MCI. Specifically, this study seeks to (1) document the types and functions of these technologies, (2) report their effectiveness, and (3) identify gaps in the current evidence. Methods: A comprehensive literature search of four databases (Medline, Embase, APA PsycINFO, and CINAHL) was conducted in accordance with Arksey and O’Malley’s scoping review methodological framework from inception to February 6, 2024, without restrictions. Inclusion criteria focused on peer-reviewed studies involving adults aged 50 or older with diagnosed cognitive impairment, specifically using digital planning-based technologies for memory support. Results: From 1854 sources, 8 studies were included. Five categories of digital planning-based technologies were identified: (1) reminders and alarms, (2) electronic calendars, (3) digital memory notebooks, (4) digital visual mapping, and (5) smart-home integration. Several studies reported improved task performance, memory recall, and executive function, with digital memory notebooks and visual mapping software showing greatest impact on functional independence. While interventions were generally well-received, usability challenges and low adherence were common, often linked to technological familiarity and motivation. Conclusions: Digital planning-based technologies show promise in supporting memory-related functioning in older adults with MCI. While studies report positive outcomes, more research is needed to refine these tools, evaluate long-term effects, and ensure integration into daily life. Expanding the evidence base will be key to improving accessibility and effectiveness for this population.

Lacking effective therapeutics, cholangiocarcinoma (CCA) remains a deadly malignancy of the biliary tract. The Hippo pathway effector protein Yes-associated protein (YAP) is implicated in CCA pathogenesis and chemotherapeutic resistance; however, the oncogenic mechanisms underlying YAP regulation remain incompletely understood. An enhanced understanding of YAP and its role in CCA may uncover novel therapeutic targets and better define resistance pathways. Human CCA cells and murine syngeneic CCA models were utilized to explore the molecular relationship of YAP and protein tyrosine phosphatase 1B (PTP1B). Previous work in CCA has demonstrated that YAP interacts with multiple protein tyrosine phosphatases, including SHP2 and PTP1B. We observed that PTP1B pharmacologic inhibition was associated with increased cell proliferation and YAP target gene expression, while genetically enforced overexpression of PTP1B was associated with a decrease in YAP activation. Treatment of CCA cells in vitro and syngeneic, orthotopically implanted CCA murine tumors in vivo with standard cytotoxic chemotherapy, gemcitabine/cisplatin, had enhanced efficacy in the setting of PTP1B overexpression. These findings demonstrate that pYAPY357 can be modulated through protein tyrosine 1B phosphatase activity, and reducing pYAPY357 through enhanced phosphatase levels can sensitize CCA to chemotherapy.

Background: Optimized surgical fixation and meniscal stabilization during rehabilitation increase healing success. However, the latest generation of all-inside devices has not yet been biomechanically compared with inside-out suture tape (IO-ST) repair. Hypothesis: (1) The contact area of a suture anchor (SA) would compensate for a meniscal defect better than polyether ether ketone anchors (PA); (2) adjustable tensioning for all-inside meniscal repair fixation would result in higher initial load than IO-ST repair; and (3) stiffer constructs would decrease secondary displacement. Study Design: Controlled laboratory study. Methods: This study investigates human menisci (N = 39) via microscopic imaging and a biomechanical testing protocol. For the imaging protocol, needles of an all-inside SA or PA device and an IO-ST device were inserted after staining to measure the iatrogenic defect created by the needle insertion (n = 20) and the length, width, and meniscus contact area of deployed all-inside anchors (n = 6). For biomechanical testing, menisci with longitudinal bucket handle tears were prepared, and single stitches were repaired (each n = 9). After suture tensioning (50 N) and fixation, initial load, initial stiffness, and relief displacement were measured. Constructs underwent cyclic loading between 2 and 20 N, with 10,000 cycles (0.75 Hz), and stiffness and displacement were measured. Ultimate stiffness and load-to-failure were analyzed at 3.15 mm/sec. Results: All-inside needles created greater iatrogenic meniscal defects ( P < .001) than IO-ST repair. While PAs were longer ( P < .001), SAs were wider with a greater meniscal contact area (both P < .001). IO-ST repair resulted in the lowest initial load ( P < .001) and relief displacement ( P < .001), whereas SA repair resulted in a higher initial load ( P < .007) and stiffness ( P < .023) than PA repair. The overall stiffer SA fixation ( P < 001) significantly reduced cyclic displacement compared with other repairs ( P < .044). The PA group failed due to an anchor fracture at a significantly lower load (84.3 ± 10.7 N; P < .001) than the IO-ST (136.4 ± 10.5 N) and the SA repair (122.1 ± 17.5 N), with a suture-based failure mode. The ultimate stiffness of SA constructs was higher ( P < .045) than that of other repairs. Conclusion: While all-inside devices showed improved primary stability, the IO-ST construct demonstrated the highest load-to-failure. In a human cadaveric model, meniscal repair with a more compact and conforming SA was stiffer and reduced cyclic displacement compared with PA and IO-ST repair. Clinical Relevance: All-inside SA repair improved primary stability. Future clinical series will define the overall significance of healing rates.

Abstract INTRODUCTION Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European‐ancestry (EA) individuals. METHODS We generated transcriptome‐wide bulk pre‐frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls. RESULTS Transcriptome‐wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2 , showed 1.52 times higher expression in AD cases ( p = 2.96x10 −8 ). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2 . Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS‐implicated variants identified several expression quantitative trait loci. CONCLUSION This first large‐scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2 , and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants. Highlights We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2 , were study‐wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD‐associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.

ABSTRACT Anesthetic technique affects surgical outcomes and oncological prognosis. Recognizing the critical role of surgery in cancer treatment, this narrative review aims to improve anesthesiology practices for cancer patients by evaluating actions that positively influence outcomes. Anesthesiologist experience helps guide technique choice in complex cases. Decisions should be customized based on the type of surgery and patient condition, as different techniques can significantly impact results. The expertise of the entire team at specialized centers further enhances outcomes.