On the informative value of community-based indoor radon values in relation to lung cancer.

BACKGROUND: Radon is a radioactive gas and a major risk factor for lung cancer (LC). METHODS: We investigated the dose-response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. RESULTS: We observed a non-linear spatial-dose response relationship for sIR < 200 Bq/m3. The lowest risk was observed for areas of mean exposure of 58 Bq/m3 (95% CI: 56.1-59.2 Bq/m3). The relative risk of lung cancer increased to the same degree in areas averaging 25 Bq/m3 (OR = 1.31, 95% CI: 1.01-1.59) as in areas with a mean of 100 Bq/m3 (OR = 1.34, 95% CI: 1.20-1.45). The strongest association was observed for small cell lung cancer and the weakest for squamous cell carcinoma. A stronger association was also observed in men, but only at higher exposure levels. The non-linear association is primarily observed among the younger population (age < 69 years), but not in the older population, which can potentially represent different biological radiation responses. CONCLUSIONS: The sIR is useful as proxy of individual radon exposure in epidemiological studies on lung cancer. The usual assumption of a linear, no-threshold dose-response relationship, as can be made for individual radon exposures, may not be optimal for sIR values of less than 200 Bq/m3.

Extrahepatic Iron Loading Associates With the Propensity to Develop Advanced Hepatic Fibrosis in Hemochromatosis.

Background and Aims: Hemostatic iron regulator-hemochromatosis can result in progressive iron-loading and advanced hepatic fibrosis in some individuals. We studied total body and hepatic iron loading to determine whether the distribution of iron-loading influences the risk of advanced fibrosis. Methods: One hundred thirty-eight men and 66 women with hemochromatosis who underwent liver biopsy for staging of hepatic fibrosis had evaluation of hepatic iron concentration (HIC), hepatic iron index (HIC/age), total body iron stores (mobilizable iron), and mobilizable iron/HIC ratio (a marker of total body iron relative to hepatic iron). The potential impact of liver volume on mobilizable iron stores was assessed using magnetic resonance imaging in a separate cohort of 19 newly diagnosed individuals with hemochromatosis. Results: Of 204 biopsied subjects, 41 had advanced fibrosis and exhibited 60% greater accumulation of mobilizable iron relative to HIC (mean 0.070 ± 0.008 g Fe/[µmol Fe/g]) compared with 163 subjects with low-grade fibrosis (mean 0.044 ± 0.002 g Fe/[µmol Fe/g], P < .0001). Linear regression modeling confirmed a discrete advanced hepatic fibrosis phenotype associated with greater mobilizable iron stores relative to HIC. The ratios of the upper to lower 95% limits of the distributions of liver volumes and the mobilizable iron/HIC ratios were 2.7 (95% confidence interval 2.3-3.0) and 9.7 (95% confidence interval 8.0-11.7), respectively, indicating that the distribution of liver volumes is not sufficiently wide to explain the variability in mobilizable iron/HIC ratios, suggesting that significant extrahepatic iron loading is present in those with advanced hepatic fibrosis. Conclusion: Advanced hepatic fibrosis develops in hemostatic iron regulator-hemochromatosis individuals who also have excessive extrahepatic mobilizable iron stores.

Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.

HER2 (human epidermal growth factor receptor 2) is highly expressed in a variety of cancers, including breast, lung, gastric, and pancreatic cancers. Its amplification is linked to poor clinical outcomes. At the genetic level, HER2 is encoded by the ERBB2 gene (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), which is frequently mutated or amplified in cancers, thus spurring extensive research into HER2 modulation and inhibition as viable anti-cancer strategies. An impressive body of FDA-approved drugs, including anti-HER2 monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and HER2-tyrosine kinase inhibitors (TKIs), have demonstrated success in enhancing overall survival (OS) and disease progression-free survival (PFS). Yet, drug resistance remains a persistent challenge and raises the risks of metastatic potential and tumor relapse. Research into alternative therapeutic options for HER2+ breast cancer therefore proves critical for adapting to this ever-evolving landscape. This review highlights current HER2-targeted therapies, discusses predictive biomarkers for drug resistance, and introduces promising emergent therapies-especially combination therapies-that are aimed at overcoming drug resistance in the context of HER2+ breast cancer.

From the IASLC Early Detection and Screening Committee Terminology Issues in Screening and Early Detection of Lung Cancer - IASLC Early Detection and Screening Committee Expert Group Recommendations.

INTRODUCTION: To facilitate global implementation of lung cancer (LC) screening and early detection in a quality assured and consistent manner, common terminology is needed. Researchers and clinicians within different specialties may use the same terms but with different meanings, or different terms for the same intended meanings. METHODS: The Diagnostics Working Group of the International Association for the Study of Lung Cancer Early Detection and Screening Committee has analyzed and discussed relevant terms used on a regular basis and suggests recommendations for consensus definitions of terminology applicable in this setting. We explored how to reach consensus to define relevant and unambiguous terminology for use by health care providers, researchers, patients, screening participants and family. RESULTS: Terms and definitions for epidemiological and health-economical purposes included: Standardized incidence and mortality rates, LC specific survival, long-term survival and cure rates, and overdiagnosis, overtreatment, undertreatment. Terms and definitions for defining screening findings included: Positive, false positive, negative, false negative and indeterminate findings and additional and incidental findings. Terms and definitions for describing parameters in screening programmes included: Opportunistic vs programmatic screening, screening rounds, interval/interim diagnoses, invasive and minimally invasive procedures. Terms and definitions for shared decision making included: LC screening - possible harms and risks and LC risk and modifiers prior and posterior to a measure. CONCLUSIONS: A common set of terminology with standard definitions is recommended for describing clinical LC screening programmes, the discussion about effectiveness and outcomes, or the clinical setting. The use of the terms should be clearly defined and explained.

Improving Rice Grain Quality Through Ecotype Breeding for Enhancing Food and Nutritional Security in Asia-Pacific Region.

Rice grain is widely consumed as a staple food, providing essential nutrition for households, particularly marginalized families. It plays a crucial role in ensuring food security, promoting human nutrition, supporting good health, and contributing to global food and nutritional security. Addressing the diverse quality demands of emerging diverse and climate-risked population dietary needs requires the development of a single variety of rice grain that can meet the various dietary and nutritional requirements. However, there is a lack of concrete definition for rice grain quality, making it challenging to cater to the different demands. The lack of sufficient genetic study and development in improving rice grain quality has resulted in widespread malnutrition, hidden hunger, and micronutrient deficiencies affecting a significant portion of the global population. Therefore, it is crucial to identify genetically evolved varieties with marked qualities that can help address these issues. Various factors account for the declining quality of rice grain and requires further study to improve their quality for healthier diets. We characterized rice grain quality using Lancastrians descriptor and a multitude of intrinsic and extrinsic quality traits. Next, we examined various components of rice grain quality favored in the Asia-Pacific region. This includes preferences by different communities, rice industry stakeholders, and value chain actors. We also explored the biological aspects of rice grain quality in the region, as well as specific genetic improvements that have been made in these traits. Additionally, we evaluated the factors that can influence rice grain quality and discussed the future directions for ensuring food and nutritional security and meeting consumer demands for grain quality. We explored the diverse consumer bases and their varied preferences in Asian-Pacific countries including India, China, Nepal, Bhutan, Vietnam, Sri Lanka, Pakistan, Thailand, Cambodia, Philippines, Bangladesh, Indonesia, Korea, Myanmar and Japan. The quality preferences encompassed a range of factors, including rice head recovery, grain shape, uniform size before cooking, gelatinization, chalkiness, texture, amylose content, aroma, red-coloration of grain, soft and shine when cooked, unbroken when cooked, gelatinization, less water required for cooking, gelatinization temperature (less cooking time), aged rice, firm and dry when cooked (gel consistency), extreme white, soft when chewed, easy-to-cook rice (parboiled rice), vitamins, and minerals. These preferences were evaluated across high, low, and medium categories. A comprehensive analysis is provided on the enhancement of grain quality traits, including brown rice recovery, recovery rate of milled rice, head rice recovery, as well as morphological traits such as grain length, grain width, grain length-width ratio, and grain chalkiness. We also explored the characteristics of amylose, gel consistency, gelatinization temperature, viscosity, as well as the nutritional qualities of rice grains such as starch, protein, lipids, vitamins, minerals, phytochemicals, and bio-fortification potential. The various factors that impact the quality of rice grains, including pre-harvest, post-harvest, and genotype considerations were explored. Additionally, we discussed the future direction and genetic strategies to effectively tackle these challenges. These qualitative characteristics represent the fundamental focus of regional and national breeding strategies employed by different countries to meet consumer preference. Given the significance of rice as a staple food in Asia-Pacific countries, it is primarily consumed domestically, with only a small portion being exported internationally. All the important attributes must be clearly defined within specific parameters. It is crucial for geneticists and breeders to develop a rice variety that can meet the diverse demands of consumers worldwide by incorporating multiple desirable traits. Thus, the goal of addressing global food and nutritional security, and human healthy can be achieved.

Perspectives on the incidence of Acanthamoeba Keratitis: A Systematic Review and Meta-Analysis.

TOPIC: To provide an overview on the incidence of Acanthamoeba Keratitis (AK). CLINICAL RELEVANCE: Although being a major and sight-threatening cause of infectious keratitis in the population, a comprehensive assessment of the incidence of this condition is lacking. METHODS: Incidence of AK was computed as the number of AK eyes, per healthcare center, per year (annualized-center-incidence, or ACI). Two meta-analytical ratios were also calculated: a) the ratio of AK eyes to the count of non-viral microbial keratitis (MK) eyes; b) the ratio of AK eyes to the overall population (i.e., the total number of subjects of a nation or region, as indicated by the authors in each study). Center was defined as the healthcare facility (e.g., Hospital, Private Practice, Clinic) where the study took place. Actual and projected estimates of the number of AK eyes in years were calculated multiplying the ratio of AK to the total population and the corresponding present and projected population estimates (age range: 15 to 70), sourced from the United Nations (UN) Population Prospects. RESULTS: Overall, 105 articles were included, published between 1987 and 2022. The total number of eyes identified was 91,951, with 5,660 affected by AK and 86,291 by non-viral MK. The median ACI was 1.9 new AK eyes per healthcare center per year (95%CI of the median: 1.5 to 2.6), with no statistically significant differences observed among continents. The ratio of AK eyes to the total number of MK eyes was 1.52% (95%CI: 1.02% to 2.24%), while the ratio of AK in relation to the entire population was estimated at 0.0002% (95%CI: 0.0001 to 0.0006), or 2.34 eyes per 1,000,000 subjects (95%CI: 0.98 to 5.55 per 1.000.000 subjects). The projected increase in the numbers of AK eyes indicates a rise of +18.5% (15,356 AK eyes) in 2053 and +25.5% (16,253 AK eyes) in 2073, compared to the baseline of 2023 (12,954 AK eyes) CONCLUSION: AK emerged as a relatively low-incident disorder, and no significant differences in terms of its incidence were found among different continents.

Expression patterns of immune checkpoint proteins and Plasmodium falciparum-induced cytokines in chronic hepatitis B virus-infected and uninfected individuals: A cross-sectional study.

Background and Aim: Chronic hepatitis B virus (CHB) infection remains a major public health problem. The American Association for the Study of Liver Diseases (AASLD) 2018 Hepatitis B Guidelines provide that CHB individuals not requiring antiviral therapy yet are monitored to determine the need for antiviral therapy in the future; however, these tests do not include measurement of cytokines and immune cell characterization. This case-control study compared the cytokine and immune checkpoint protein expression profiles between CHB individuals not yet on antiviral treatment and hepatitis B virus (HBV)-negative individuals. Methods: CD4 and CD8 T cells from CHB and HBV-negative individuals were characterized for immune checkpoint proteins programmed cell death-1 (PD1), T cell Immunoglobulin domain and mucin domain-containing protein 3 (TIM-3), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (CD152), and a memory marker CXCR3 (CD183) using flow cytometry. Malaria-induced cytokine expression levels were determined by stimulating their blood cells with Plasmodium falciparum 3D7 strain antigens (CSP, AMA-1, and TRAP) in whole blood assays, and cytokine levels were measured using a 13-plex Luminex kit. Results: HBV-negative and CHB individuals had comparable levels of CD4+ and CD8+ T cells. However, a proportion of the CD4+ and CD8+ populations from both groups, which were CXCR3+, expressed PD-1 and CD152. The ability to produce cytokines in response to malaria antigen stimulation was not significantly different between the groups. Conclusion: These findings support excluding CHB individuals from antiviral therapy at this stage of infection. However, CHB individuals require regular monitoring to determine the need for later antiviral treatment.

The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes.

The retinoid nuclear receptor pathway, activated by the vitamin A metabolite retinoic acid, has been extensively investigated for over a century. This study has resulted in conflicting hypotheses about how the pathway regulates health and how it should be pharmaceutically manipulated. These disagreements arise from a fundamental contradiction: retinoid agonists offer clear benefits to select patients with rare bone growth disorders, acute promyelocytic leukemia, and some dermatologic diseases, yet therapeutic retinoid pathway activation frequently causes more harm than good, both through acute metabolic dysregulation and a delayed cancer-promoting effect. In this review, we discuss controlled clinical, mechanistic, and genetic data to suggest several disease settings where inhibition of the retinoid pathway may be a compelling therapeutic strategy, such as solid cancers or metabolic syndromes, and also caution against continued testing of retinoid agonists in cancer patients. Considerable evidence suggests a central role for retinoid regulation of immunity and metabolism, with therapeutic opportunities to antagonize retinoid signaling proposed in cancer, diabetes, and obesity.

Severe radiographic artifact created by a large fenestration of the skin and labial mucosa following placement of a plate piercing: a case report.

The presence of facial jewelry and medical devices within a radiographic field of view may promote the formation of artifacts that challenge diagnostic interpretation. The objective of this article is to describe a previously unreported radiographic anomaly produced by an oral piercing site below the lower lip. This unusual artifact masqueraded as a severe resorptive defect, dental caries, or cervical abfraction and occurred following removal of an extremely large labret below the lower lip and subsequent acquisition of a radiographic image. The radiolucency was ultimately attributed to an extensive aperture below the lower lip created by a series of sequentially larger soft tissue expanders. Clinicians should seek correlation of atypical radiographic presentations with soft tissue defects secondary to injury or intentional oral piercing.

Development of an Enhanced Recovery After Surgery Program in Ventral Hernia.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) programs have spread after initial success in colorectal surgery decreasing length of stay (LOS) and decreasing opioid consumption. Adoption of ERAS specifically for ventral hernia patients remains in evolution. This study presents the development and implementation of an ERAS pathway for ventral hernia. METHODS: A multidisciplinary team met weekly over 6 months to develop an ERAS pathway specific to ventral hernia patients. 75 process components and outcome measures were included, spanning multiple phases of care: Preoperative-Clinic, Preoperative Day of Surgery (DOS), Intraoperative, and Postoperative. Preoperative components included education and physiologic optimization. Pain control across phases of care focuses on nonopioid, multimodal analgesia. Postoperatively, the pathway emphasizes early diet advancement, early mobilization, and minimization of IV fluids. We compared compliance and outcome measures between a Pre Go-Live (PGL) period (9/1/2020-8/30/2021) and After Go-live (AGL) period (5/12/2022-5/19/2023). RESULTS: There were 125 patients in the PGL group and 169 patients in the AGL group. Overall, ERAS compliance increased from 73.9% to 82.9% after implementation. Length of stay decreased from an average of 2.27 days PGL to 1.92 days AGL. Finally, the average daily postoperative opioid usage decreased from 25.4 to 13.5 MME after the implementation. DISCUSSION: Enhanced Recovery After Surgery can be successfully applied to the care of hernia patients with improvements in LOS and decreased opioid consumption. Institutional support and multidisciplinary cooperation were key for the development of such a program.

Deep Learning-Based Electrocardiogram Analysis Predicts Biventricular Dysfunction and Dilation in Congenital Heart Disease.

BACKGROUND: Artificial intelligence-enhanced electrocardiogram (AI-ECG) analysis shows promise to detect biventricular pathophysiology. However, AI-ECG analysis remains underexplored in congenital heart disease (CHD). OBJECTIVES: The purpose of this study was to develop and externally validate an AI-ECG model to predict cardiovascular magnetic resonance (CMR)-defined biventricular dysfunction/dilation in patients with CHD. METHODS: We trained (80%) and tested (20%) a convolutional neural network on paired ECG-CMRs (≤30 days apart) from patients with and without CHD to detect left ventricular (LV) dysfunction (ejection fraction ≤40%), RV dysfunction (ejection fraction ≤35%), and LV and RV dilation (end-diastolic volume z-score ≥4). Performance was assessed during internal testing and external validation on an outside health care system using area under receiver-operating curve (AUROC) and area under precision recall curve. RESULTS: The internal and external cohorts comprised 8,584 ECG-CMR pairs (n = 4,941; median CMR age 20.7 years) and 909 ECG-CMR pairs (n = 746; median CMR age 25.4 years), respectively. Model performance was similar for internal testing (AUROC: LV dysfunction 0.87; LV dilation 0.86; RV dysfunction 0.88; RV dilation 0.81) and external validation (AUROC: LV dysfunction 0.89; LV dilation 0.83; RV dysfunction 0.82; RV dilation 0.80). Model performance was lowest in functionally single ventricle patients. Tetralogy of Fallot patients predicted to be at high risk of ventricular dysfunction had lower survival (P < 0.001). Model explainability via saliency mapping revealed that lateral precordial leads influence all outcome predictions, with high-risk features including QRS widening and T-wave inversions for RV dysfunction/dilation. CONCLUSIONS: AI-ECG shows promise to predict biventricular dysfunction/dilation, which may help inform CMR timing in CHD.

The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB.

Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) are fundamental in regulating cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce the autophagy pathway in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12 myoblast cells. ERR-dependent increases in TFEB expression result in increased expression of an array of TFEB target genes, which are critical for the stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for the treatment of many diseases where stimulation of autophagy may be therapeutic, including heart failure. Significance Statement Estrogen receptor-related receptor agonists function as exercise mimetics and also display efficacy in animal models of metabolic disease, obesity, and heart failure.

SMALL MOLECULE INDUCES TIME-DEPENDENT INHIBITION OF STAT3 DIMERIZATION AND DNA-BINDING ACTIVITY AND REGRESSES HUMAN BREAST TUMOR XENOGRAFTS.

Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through virtual library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC50 of 2.2-4.5 µM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH2 in fluorescent polarization assay with IC50 of 3.5-5.5 µM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1 activity, pErk1/2MAPK, pShc, pJAK2, pSrc induction, or cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.

Comparison of Postoperative Bleed Rates and Location of Bleed Between Vessel Sealing Devices after Laparoscopic Sleeve Gastrectomy.

Background: Laparoscopic sleeve gastrectomy (SG) is a commonly performed bariatric procedure. At our institution, two vessel sealing devices, Thunderbeat® (Olympus) and Maryland LigaSure™ (Covidien) are utilized for intraoperative dissection. Methods: A retrospective review of all patients who underwent primary SG from July 2013 through August 2022 was performed to evaluate postoperative bleeding (POB) rates between the two devices. The primary outcome measured was POB as defined by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP), with secondary outcomes including reoperation, source of bleed, and overall safety. Results: A total of 8157 underwent SG. Average BMI and age were 43.2 kg/m2 and 37.1 years, respectively. A total of 6600 (80.9%) were female. Thunderbeat® was utilized in 5143 (63%) cases and Maryland LigaSure™ was used in 3014 (37%) cases. There was no significant difference in overall bleeding between the Thunderbeat® (18/5143, .35%) and the Maryland LigaSure™ (19/3014, .63%; P = .0689). However, there was a difference noted when comparing reoperation for bleeding between Thunderbeat® (9/5143, .17%) and Maryland LigaSure™ (13/3014, .43%; P = .0291). Furthermore, the location of bleeding in the reoperations was more common from the cut edge of the mesentery compared to the staple line with the Maryland LigaSure™ versus the Thunderbeat® (P = .038). Conclusions: The Thunderbeat® device is comparatively more hemostatic than the Maryland LigaSure™ for SG. The location of postoperative bleed may be related to vessel sealing devices used.

Cell-Free DNA Analysis of Fetal Aneuploidies in Early Pregnancy Loss.

Background: Products of conception samples are often collected and analyzed to try to determine the cause of an early pregnancy loss. However, sample collection may not always be possible, and maternal cell contamination and culture failure can affect the analysis. Cell-free DNA-based analysis of a blood sample could be used as an alternative method in early pregnancy loss cases to detect if aneuploidies were present in the fetus. Methods: In this prospective study, blood samples from early pregnancy loss patients were analyzed for the presence of fetal aneuploidies using a modified version of a noninvasive prenatal testing assay for cell-free DNA analysis. Results from cell-free DNA analysis were compared against the gold standard, microarray analysis of products of conception samples. This study was registered with ClinicalTrials.gov, identifier: NCT04935138. Results: Of the 76 patient samples included in the final study cohort, 11 were excluded from performance calculations. The 65 patient samples included in the final analysis included 49 with an abnormal microarray result and 16 with a normal microarray result. Based on results from these 65 samples, the study found that genome-wide cell-free DNA analysis had a sensitivity of 73.5% with a specificity of 100% for the detection of fetal aneuploidies in early pregnancy loss cases. Conclusions: This prospective study provides further support for the utility of cell-free DNA analysis in detecting fetal aneuploidies in early pregnancy loss cases. This approach could allow for a noninvasive method of investigating the etiology of miscarriages to be made available clinically.

Investigating iRHOM2-Associated Transcriptional Changes in Tylosis With Esophageal Cancer.

Background and Aims: Survival rates for esophageal squamous cell carcinoma (ESCC) are extremely low due to the late diagnosis of most cases. An understanding of the early molecular processes that lead to ESCC may facilitate opportunities for early diagnosis; however, these remain poorly defined. Tylosis with esophageal cancer (TOC) is a rare syndrome associated with a high lifetime risk of ESCC and germline mutations in RHBDF2, encoding iRhom2. Using TOC as a model of ESCC predisposition, this study aimed to identify early-stage transcriptional changes in ESCC development. Methods: Esophageal biopsies were obtained from control and TOC individuals, the latter undergoing surveillance endoscopy, and adjacent diagnostic biopsies were graded as having no dysplasia or malignancy. Bulk RNA-Seq was performed, and findings were compared with sporadic ESCC vs normal RNA-Seq datasets. Results: Multiple transcriptional changes were identified in TOC samples, relative to controls, and many were detected in ESCC. Accordingly, pathway analyses predicted an enrichment of cancer-associated processes linked to cellular proliferation and metastasis, and several transcription factors were predicted to be associated with TOC and ESCC, including negative enrichment of GRHL2. Subsequently, a filtering strategy revealed 22 genes that were significantly dysregulated in both TOC and ESCC. Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in 'normal' TOC esophagus tissue. Conclusion: Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC. These findings support the utility of TOC to help reveal the early molecular processes that lead to sporadic ESCC.