A bioprinted sea-and-island multicellular model for dissecting human pancreatic tumor-stroma reciprocity and adaptive metabolism.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable clinical challenge due to its intricate microenvironment characterized by desmoplasia and complex tumor-stroma interactions. Conventional models hinder studying cellular crosstalk for therapeutic development. To recapitulate key features of PDAC masses, this study creates a novel sea-and-island PDAC tumor construct (s&i PTC). The s&i PTC consists of 3D-printed islands of human PDAC cells positioned within an interstitial extracellular matrix (ECM) populated by human cancer-associated fibroblasts (CAFs). This design closely mimics the in vivo desmoplastic architecture and nutrient-poor conditions. The model enables studying dynamic tumor-stroma crosstalk and signaling reciprocity, revealing both known and yet-to-be-discovered multicellular metabolic adaptations. Using the model, we discovered the orchestrated dynamic alterations of CAFs under nutrient stress, resembling critical in vivo human tumor niches, such as the secretion of pro-tumoral inflammatory factors. Additionally, nutrient scarcity induces dynamic alterations in the ECM composition and exacerbates poor cancer cell differentiation-features well-established in PDAC progression. Proteomic analysis unveiled the enrichment of proteins associated with aggressive tumor behavior and ECM remodeling in response to poor nutritional conditions, mimicking the metabolic stresses experienced by avascular pancreatic tumor cores. Importantly, the model's relevance to patient outcomes is evident through an inverse correlation between biomarker expression patterns in the s&i PTCs and PDAC patient survival rates. Key findings include upregulated MMPs and key ECM proteins (such as collagen 11 and TGFß) under nutrient-avid conditions, known to be regulated by CAFs, alongside the concomitant reduction in E-cadherin expression associated with a poorly differentiated PDAC state under nutrient deprivation. Furthermore, elevated levels of hyaluronic acid (HA) and integrins in response to nutrient deprivation underscore the model's fidelity to the PDAC microenvironment. We also observed increased IL-6 and reduced α-SMA expression under poor nutritional conditions, suggesting a transition of CAFs from myofibroblastic to inflammatory phenotypes under a nutrient stress akin to in vivo niches. In conclusion, the s&i PTC represents a significant advancement in engineering clinically relevant 3D models of PDAC masses. It offers a promising platform for elucidating tumor-stroma interactions and guiding future therapeutic strategies to improve patient outcomes.

Screening for exclusion of high-risk bleeding features of esophageal varices in cirrhosis through CT and MRI.

BACKGROUND & AIM: Esophageal varices (EV) screening guidelines have evolved with improved risk stratification to avoid unnecessary esophagogastroduodenoscopy (EGD) in individuals with low bleeding risks. However, uncertainties persist in the recommendations for certain patient groups, particularly those with hepatocellular carcinoma (HCC) and/or receiving non-selective beta-blockers (NSBB) without prior endoscopy. This study assessed the efficacy of imaging in ruling out EVs and their high-risk features associated with bleeding in patients with cirrhosis and with HCC. We also evaluated the impact of NSBB on the detection of these characteristics. METHODS: A total of 119 patients undergoing EGD with CT and/or MRI within 90 days of the procedure were included. 87 patients had HCC. A new imaging grading system was developed utilizing the size of EVs and the extent of their protrusion into the esophagus lumen. The negative predictive value (NPV) of EVimaging(-) versus EVimaging (+) (grades 1-3) in ruling out the presence of EV and/or high-risk features by EGD was calculated. The predictive performance of imaging was determined by logistic regression. RESULTS: The NPV of imaging for detecting EV and high-risk features was 81 % and 92 %, respectively. Among HCC patients, the NPV for EV and high-risk features was 80 % and 64 %, respectively. Being on NSBB didn't statistically impact the imaging detection of EV. Imaging was a better predictor of high-risk EGD findings than Child-Turcotte-Pugh scores. CONCLUSIONS: Our results suggest that imaging can effectively rule out the presence of EV and high-risk features during EGD, even in patients with HCC and/or receiving NSBB.

Predicting survival of patients with advanced hepatocellular carcinoma receiving combination targeted immunotherapy: an evaluation of volumetric imaging parameters.

PURPOSE: To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy. METHODS: Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis. RESULTS: Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis. CONCLUSION: Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy.

Utilization of Radiomics Features Extracted From Preoperative Medical Images to Detect Metastatic Lymph Nodes in Cholangiocarcinoma and Gallbladder Cancer Patients: A Systemic Review and Meta-analysis.

OBJECTIVES: This study aimed to determine the methodological quality and evaluate the diagnostic performance of radiomics features in detecting lymph node metastasis on preoperative images in patients with cholangiocarcinoma and gallbladder cancer. METHODS: Publications between January 2005 and October 2022 were considered for inclusion. Databases such as Pubmed/Medline, Scopus, Embase, and Google Scholar were searched for relevant studies. The quality of the methodology of the manuscripts was determined using the Radiomics Quality Score and Quality Assessment of Diagnostic Accuracy Studies 2. Pooled results with corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Liard method (random-effect model). Forest plots were used to visually represent the diagnostic profile of radiomics signature in each of the data sets pertaining to each study. Fagan plot was used to determine clinical applicability. RESULTS: Overall sensitivity was 0.748 (95% CI, 0.703-0.789). Overall specificity was 0.795 (95% CI, 0.742-0.839). The combined negative likelihood ratio was 0.299 (95% CI, 0.266-0.350), and the positive likelihood ratio was 3.545 (95% CI, 2.850-4.409). The combined odds ratio of the studies was 12.184 (95% CI, 8.477-17.514). The overall summary receiver operating characteristics area under the curve was 0.83 (95% CI, 0.80-0.86). Three studies applied nomograms to 8 data sets and achieved a higher pooled sensitivity and specificity (0.85 [0.80-0.89] and 0.85 [0.71-0.93], respectively). CONCLUSIONS: The pooled analysis showed that predictive models fed with radiomics features achieve good sensitivity and specificity in detecting lymph node metastasis in computed tomography and magnetic resonance imaging images. Supplementation of the models with biological correlates increased sensitivity and specificity in all data sets.

Perceived Constraints to Pickleball Participation Among Black Older Adults.

Pickleball offers sociopsychological and physical activity benefits for older adults but lacks racial diversity. The purpose of this study was to identify constraints to pickleball participation with Black older adults (65+ years) as well as examine differences based on physical activity and sex. A Qualtrics panel included Black older adults (N = 292) who have heard of pickleball and are physically able to play but have not played. Results found Knowledge, Accessibility, Interpersonal, and Interest were the most salient constraints overall. Multivariate analysis of variance found that those who report low physical activity had significantly higher Interpersonal, Psychological, Costs, and Perceived Racism constraints. Additionally, females report significantly higher Knowledge, Psychological, and Cost constraints compared to males. The results further the theoretical application of constraints to physical activity research and provide insights into practitioner implications to grow the sport of pickleball for Black older adults.

Novel urine cell-free DNA methylation markers for hepatocellular carcinoma.

An optimized hepatocellular carcinoma (HCC)-targeted methylation next generation sequencing assay was developed to discover HCC-associated methylation markers directly from urine for HCC screening. Urine cell-free DNA (ucfDNA) isolated from a discovery cohort of 31 non-HCC and 30 HCC was used for biomarker discovery, identifying 29 genes with differentially methylated regions (DMRs). Methylation-specific qPCR (MSqPCR) assays were developed to verify the selected DMRs corresponding to 8 genes (GRASP, CCND2, HOXA9, BMP4, VIM, EMX1, SFRP1, and ECE). Using archived ucfDNA, methylation of GRASP, HOXA9, BMP4, and ECE1, were found to be significantly different (p < 0.05) between HCC and non-HCC patients. The four markers together with previously reported GSTP1 and RASSF1A markers were assessed as a 6-marker panel in an independent training cohort of 87 non-HCC and 78 HCC using logistic regression modeling. AUROC of 0.908 (95% CI, 0.8656-0.9252) was identified for the 6-marker panel with AFP, which was significantly higher than AFP-alone (AUROC 0.841 (95% CI, 0.778-0.904), p = 0.0026). Applying backward selection method, a 4-marker panel was found to exhibit similar performance to the 6-marker panel with AFP having 80% sensitivity compared to 29.5% by AFP-alone at a specificity of 85%. This study supports the potential use of methylated transrenal ucfDNA for HCC screening.

Social media consumption and depressive symptoms during the COVID-19 lockdown: the mediating effect of physical activity.

Introduction: Social media platforms played a critical role during the COVID-19 pandemic. This study aimed to explore: (1) the changes in social media consumption patterns, physical activity levels/sedentary behavior, and depressive symptoms, and (2) how the changes in social media consumption patterns predict the changes in depressive symptoms while investigating the mediating role of changes in physical activity levels/sedentary behavior between before, and after the COVID-19 lockdown among U.S. adults with different age clusters. Methods: A total of 695 U.S. participants completed an online questionnaire via MTurk, and participants were asked to recall their social media consumption patterns, physical activity/sedentary behavior, depressive symptoms in January and May of 2020 while covariates included non-physical activity health behavior including diet quality, alcohol consumption, smoking, and sleep quality. Results: The results of Bayesian significance testing of changes showed that the older participants tended to spend more time with content-focused social media platforms during the lockdown. While significantly increased sitting time was reported by all age clusters, no significant changes were found in activity levels. Additionally, the middle-aged and older participants reported significantly higher depressive symptoms. The findings of a multigroup structural analysis showed the significant mediating effect of moderate-to-vigorous physical activity on the relationship between changes in social media consumption and depressive symptoms. Discussion: This study highlights the need for targeting specific social media platforms for older adults and the importance of moderate-to-vigorous physical activity to alleviate the mental health issues resulting from social media consumption. The result of this study also highlights the need for sport-based intervention programs in the future and the need for more social media campaigns at the institution/organization levels established by public health stakeholders and policy makers to promote physical activity and maximize population perception and reach during the pandemic.

Temporal collections to study invasion biology.

Biological invasions represent an extraordinary opportunity to study evolution. This is because accidental or deliberate species introductions have taken place for centuries across large geographical scales, frequently prompting rapid evolutionary transitions in invasive populations. Until recently, however, the utility of invasions as evolutionary experiments has been hampered by limited information on the makeup of populations that were part of earlier invasion stages. Now, developments in ancient and historical DNA technologies, as well as the quickening pace of digitization for millions of specimens that are housed in herbaria and museums globally, promise to help overcome this obstacle. In this review, we first introduce the types of temporal data that can be used to study invasions, highlighting the timescale captured by each approach and their respective limitations. We then discuss how ancient and historical specimens as well as data available from prior invasion studies can be used to answer questions on mechanisms of (mal)adaptation, rates of evolution, or community-level changes during invasions. By bridging the gap between contemporary and historical invasive populations, temporal data can help us connect pattern to process in invasion science. These data will become increasingly important if invasions are to achieve their full potential as experiments of evolution in nature.

Impact of Cell-Debris and Room-Temperature Storage on Urine Circulating Tumor DNA from Hepatocellular Carcinoma.

This study evaluated the impact of cell debris and 7-day room temperature storage on the quality and yield of transrenal DNA. Archived urine specimens collected from five hepatocellular carcinoma (HCC) patients and two pregnant women carrying male fetuses were used to assess the impact of cell debris on urine cell-free DNA (ucfDNA) isolation as measured by quantitative PCR for Y-chromosome DNA, or HCC-associated mutation and methylation markers, and by capillary electrophoresis. Prospectively collected urine from 21 HCC patients was aliquoted after collection for paired immediate freezing versus 7-day room temperature storage followed by freezing for further analysis. Cell debris contained more Y-chromosome DNA than supernatant in three of the six urine specimens tested from pregnant women, suggesting that cell debris can be associated with 20.6% to 84.9% of transrenal ucfDNA. Ninety-five percent (20 of 21) of frozen and room temperature urine pairs had overlapping DNA size distribution. ucfDNA quantity determined by quantitative PCR for TP53, CTNNB1, TERT, and HCC-associated urine circulating tumor DNA markers were statistically similar between room temperature and frozen samples. This suggests no significant difference in DNA degradation between the groups. The association of transrenal ucfDNA with cell debris and HCC circulating DNA stability at room temperature is significant to further the understanding of transrenal circulating tumor DNA pre-analytical handling for HCC screening.

Relationship of Hepatocellular Carcinoma Stage and Hepatic Function to Health-Related Quality of Life: A Single Center Analysis.

Health-related quality of life (HRQoL) is known to be an important prognostic indicator and clinical endpoint for patients with hepatocellular carcinoma (HCC). However, the correlation of the Barcelona Clinic Liver Cancer (BCLC) stage with HRQoL in HCC has not been previously studied. We examined the relationship between BCLC stage, Child-Pugh (CP) score, and Eastern Cooperative Oncology Group (ECOG) performance status on HRQoL for patients who presented at a multidisciplinary liver cancer clinic. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Fifty-one patients met our inclusion criteria. The FACT-Hep total and subscales showed no significant association with BCLC stages (p = 0.224). Patients with CP B had significantly more impairment in FACT-Hep than patients with CP A. These data indicate that in patients with HCC, impaired liver function is associated with reduced quality of life, whereas the BCLC stage poorly correlates with quality of life metrics. Impairment of quality of life is common in HCC patients and further studies are warranted to determine the impact of early supportive interventions on HRQoL and survival outcomes.

Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer.

Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.

"You Just Have to Keep It Movin':" Perceptions of Physical Function Limitations in an African American Health Ministry.

Physical function (PF) limitations are common in aging. However, there is a dearth of interventions focused on addressing PF limitations in community-based settings, particularly in minoritized communities. To guide intervention development, we conducted focus groups to understand perceptions of PF limitations, gauge intervention interest, and identify potential intervention strategies as part of a large health partnership of African American churches in Chicago, IL. Participants were age 40+ years with self-reported PF limitations. Focus groups (N=6 focus groups; N=40 participants) were audio recorded, transcribed, and analyzed using thematic analysis methods.Six themes were identified: (1) causes of PF limitations, (2) impact of PF limitations, (3) terminology and communication, (4) adaptations and treatments, (5) faith and resilience, and (6) prior program experiences. Participants described how PF limitations affected their ability to live a full life and play an active role in their family, church, and community. Faith and prayer aided in coping with limitations and pain. Participants expressed that it is important to keep moving, both from an emotional (not giving up) and physical (to prevent further exacerbation of limitations) standpoint. Some participants shared adaptation and modification strategies, but there were overall frustrations with communicating regarding PF limitations and obtaining medical care for them. Participants expressed that they would like to have programs in their church focused on improving PF (including physical activity), particularly as their communities often lacked resources conducive to being active. Community-based programs focusing on reducing PF limitations are needed, and the church is a potentially receptive setting.

Genomics of plant speciation.

Studies of plants have been instrumental for revealing how new species originate. For several decades, botanical research has complemented and, in some cases, challenged concepts on speciation developed via the study of other organisms while also revealing additional ways in which species can form. Now, the ability to sequence genomes at an unprecedented pace and scale has allowed biologists to settle decades-long debates and tackle other emerging challenges in speciation research. Here, we review these recent genome-enabled developments in plant speciation. We discuss complications related to identification of reproductive isolation (RI) loci using analyses of the landscape of genomic divergence and highlight the important role that structural variants have in speciation, as increasingly revealed by new sequencing technologies. Further, we review how genomics has advanced what we know of some routes to new species formation, like hybridization or whole-genome duplication, while casting doubt on others, like population bottlenecks and genetic drift. While genomics can fast-track identification of genes and mutations that confer RI, we emphasize that follow-up molecular and field experiments remain critical. Nonetheless, genomics has clarified the outsized role of ancient variants rather than new mutations, particularly early during speciation. We conclude by highlighting promising avenues of future study. These include expanding what we know so far about the role of epigenetic and structural changes during speciation, broadening the scope and taxonomic breadth of plant speciation genomics studies, and synthesizing information from extensive genomic data that have already been generated by the plant speciation community.

Changes in children's dental fear after restorative treatment under different sedation types: Associations with parents' experiences and dental health.

BACKGROUND: Dentists often use sedative medications such as nitrous oxide inhaled sedation and general anesthesia (GA) to help decrease patient fear and manage paediatric patients' behavior during treatment. AIM: The goal of this study was to examine factors associated with dental fear changes after restorative dental treatment under nitrous oxide or GA in children 4-12 years old. DESIGN: A prospective cohort study of 124 children examined changes in dental fear, number of treatment visits, and parental factors among children receiving restorative dental treatment under nitrous oxide (n = 68) or GA (n = 56) sedation. Data were collected at pretreatment (T1), 16 weeks post-treatment (T2), and at 29-month follow-up (T3). RESULTS: Dental fear increased slightly, but not significantly, under both forms of sedation between T1 and T3. Children's dental fear was associated with parents' poor dental experiences and oral health, but not with number of treatment visits. CONCLUSIONS: Progression of children's dental fear seems not dependent solely on the type of sedation used but is likely predicted by factors including pretreatment dental fear and dental needs. Dentists recommending sedation for children's dental care may consider pretreatment dental need, fear levels, and parental factors when determining which type of sedation to use.

Sport participation, acculturative stress, and depressive symptoms among international college students in the United States.

Introduction: The distinctive social nature of sport in its capacity to promote immigrants' adaptation to the new society has been regarded as a vehicle to cope with adverse mental health outcomes derived from acculturative stress (AS) and feelings of marginalization. However, the evidence on the relationship between sport participation (SP), AS, and mental health have been lacking and fragmented. Recognizing this challenge, we examined the mediating effect of AS on the relationship between SP and depressive symptoms (DS) among international college students in the USA. Methods: A total of 203 international college students in the USA were recruited via Prolific. The instrumentation included previously validated measures: SP (SLIM-18), AS (ASSIS), DS (CES-D-10), sense of coherence (SOC-13), and demographic characteristics. Results: Mediation analysis showed a significant association between (1) SP and DS (ß = -0.030, p < 0.05) and (2) AS and DS (ß = 0.053, p < 0.001), while (3) no significant indirect effect of AS was found [ß = -0.001, SE = 0.0003, 95% CI (-0.008, 0.004)]. Discussion: Even though several previous scholars have argued that SP is an effective tool to cope with AS among international students, the present study implies this may not be applied to all international students. Specifically, AS and DS among European participants were lower than those from non-European countries, including Asia. Future studies using meta-analysis could be beneficial to examine the external validity of the previous studies on the relationship between SP, acculturation, and mental health to address this potential heterogeneity on the level of AS based on their origin countries or continents. The current study provides meaningful implications for adopting the transformative marketing perspective, which is a marketing approach that pursues positive social outcomes by promoting positive behavior of the target population.

Role of MEF2C in the Endothelial Cells Derived from Human Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (hiPSCs) not only provide an abundant source of vascular cells for potential therapeutic applications in vascular disease but also constitute an excellent model for understanding the mechanisms that regulate the differentiation and the functionality of vascular cells. Here, we reported that myocyte enhancer factor 2C (MEF2C) transcription factor, but not any other members of the MEF2 family, was robustly upregulated during the differentiation of vascular progenitors and endothelial cells (ECs) from hiPSCs. Vascular endothelial growth factors (VEGF) strongly induced MEF2C expression in endothelial lineage cells. The specific upregulation of MEF2C during the commitment of endothelial lineage was dependent on the extracellular signal regulated kinase (ERK). Moreover, knockdown of MEF2C with shRNA in hiPSCs did not affect the differentiation of ECs from these hiPSCs, but greatly reduced the migration and tube formation capacity of the hiPSC-derived ECs. Through a chromatin immunoprecipitation-sequencing, genome-wide RNA-sequencing, quantitative RT-PCR, and immunostaining analyses of the hiPSC-derived endothelial lineage cells with MEF2C inhibition or knockdown compared to control hiPSC-derived ECs, we identified TNF-related apoptosis inducing ligand (TRAIL) and transmembrane protein 100 (TMEM100) as novel targets of MEF2C. This study demonstrates an important role for MEF2C in regulating human EC functions and highlights MEF2C and its downstream effectors as potential targets to treat vascular malfunction-associated diseases.

Outcomes of immunotherapy-related hepatotoxicity from a multi-disciplinary toxicity team.

BACKGROUND: Despite the efficacy of immune checkpoint inhibitors (ICIs), adverse events including hepatotoxicity limit their ongoing use. We investigated the outcomes and management of patients with immune-mediated hepatitis (IMH) and clinical predictors of toxicity resolution. METHODS: Patients referred to our multidisciplinary immunotherapy-related toxicity group from August 2017 to December 2020 for IMH were evaluated. Toxicity was defined according to CTCAEv4.0. IMH resolution was defined as liver enzyme normalization after steroid initiation. RESULTS: Thirty-three patients were included in the study, 62% female, and 71% Caucasian. The most common ICI used was PD-1/PD-L1 (76%). Peak IMH occurred at a median of 89 [45,193] days, for which most patients received 1-2 mg/kg/day prednisone equivalent with 35% requiring MMF. Median follow-up was 123 [33,472] days with IMH resolution seen in 48% of patients at a median of 111 [41,214] days. While high-dose steroid use was not associated with IMH resolution, liver enzyme improvement one week after steroids predicted resolution in univariate analysis (p = 0.041). All 11 patients without IMH resolution died from cancer progression or complications with three patients having acute liver failure. Available liver biopsies showed bile duct injury, with varying degrees of portal and lobular inflammation. CONCLUSION: IMH improvement one week after steroid initiation may predict ultimate IMH resolution.

Detecting Liver Cancer Using Cell-Free DNA Fragmentomes.

Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection. SIGNIFICANCE: There is a great need for accessible and sensitive screening approaches for HCC worldwide. We have developed an approach for examining genome-wide cfDNA fragmentation features to provide a high-performing and cost-effective approach for liver cancer detection. See related commentary Rolfo and Russo, p. 532. This article is highlighted in the In This Issue feature, p. 517.