Search Results (85)

Fish are vital for material cycling and energy flow in aquatic ecosystems. The genus Triplophysa, with over 100 known species, is significant in the Central Asian highlands’ freshwater ecosystems. T. strauchii and T. tenuis, as representatives, occupy distinct ecological niches and face challenges from climate change and human activities. There is a lack of research on Triplophysa fishes’ digestive systems, especially comparative studies, so this research aims to fill this gap. In September 2024, 40 samples of T. strauchii were collected from Sayram Lake and 40 samples of T. tenuis were collected from the Muzat River in Xinjiang. After acclimation, morphological observations (measuring fish and digestive tract parameters) and histological analyses (paraffin sectioning, HE staining, and microscopy) were carried out. The data were sorted in Excel and analyzed with an independent samples t-test in SPSS 27.0. Morphologically, T. strauchii has an obtuse snout, terminal mouth, specific upper lip papillae, and an S-shaped intestine about (1.45 ± 0.11) times its body length, while T. tenuis has an arc-shaped subterminal mouth, fringed papillae, and a spiral-shaped intestine around (0.82 ± 0.09) times its body length. Both possess a digestive tract, glands, and a hepatopancreas attached to the mesentery. Histologically, a large number of club cells were found in the oropharyngeal cavities of both species; their secretions have an adhesive effect on food, aiding food selection. Their digestive systems vary in structure and cell composition: the oropharyngeal cavity has three layers; the esophagus has four layers with more goblet cells in T. strauchii; the stomach has three regions without goblet cells and a thicker muscular layer in T. strauchii; the intestinal wall has four layers with different villi and goblet cell distributions; the hepatopancreas has lobules; and T. strauchii has a typical portal area. In conclusion, this study systematically compared the gastrointestinal systems of T. strauchii and T. tenuis for the first time, revealing significant structural differences related to their niches and feeding patterns as adaptations to specific environments. It fills the research gap, provides a basis for exploring fish ecological adaptation and environmental impacts on digestion, offers new ideas for Triplophysa protection strategies, and guides fish evolutionary biology research and Triplophysa resource protection and utilization. Full article

The mechanisms that influence human longevity are complex and operate on cellular, tissue, and organismal levels. To better understand the tissue-level mechanisms, we compared the organization of cell proliferation, differentiation, and cytoprotective protein expression in the squamous epithelium of the esophagus between mammals with varying lifespans. Humans are the only species with a quiescent basal stem cell layer that is distinctly physically separated from parabasal transit-amplifying cells. In addition to these stark differences in the organization of proliferation, human squamous epithelial stem cells express DNA repair-related markers, such as MECP2 and XPC, which are absent or low in mouse basal cells. Furthermore, we investigated whether the transition from basal to suprabasal is different between species. In humans, the parabasal cells seem to originate from cells detaching from the basement membrane, and these can already begin to proliferate while delaminating. In most other species, delaminating cells have been rare or their proliferation rate is different from that of their human counterparts, indicating an alternative mode of how stem cells maintain the tissue. In humans, the combination of an elevated cytoprotective signature and novel tissue organization may enhance resistance to aging and prevent cancer. Our results point to enhanced cellular cytoprotection and a tissue architecture which separates stemness and proliferation. These are both potential factors contributing to the increased fitness of human squamous epithelia to support longevity by suppressing tumorigenesis. However, the organization of canine oral mucosa shows some similarities to that of human tissue and may provide a useful model to understand the relationship between tissue architecture, gene expression regulation, tumor suppression, and longevity. Full article

Background/Objectives: Isolated defects of the posterior hypopharyngeal/upper esophageal wall are rare, typically arising after cancer resection or complications following cervical spine osteosynthesis. Various local and free flaps are available for reconstruction, but we opted for a double-island anterolateral thigh (ALT) flap in this case. Methods: A scoping review was conducted (June 2024) following PRISMAScR 2018 guidelines in order to examine the coverage options available in the literature for posterior hypopharyngeal/upper esophagus wall defects while also presenting a case where such a defect was covered with a double-island anterolateral thigh (ALT) flap. Eligibility criteria: Human studies describing defect coverage of the posterior hypopharyngeal/upper esophagus wall were included. Sources of evidence: A literature search was conducted in PubMed, Cochrane Library, and Google Scholar, following PRISMAScR guidelines. Charting methods: Data on surgical techniques, outcomes, and complications were extracted and analyzed by two independent reviewers. Case report: A 57-year-old female developed a chronic posterior wall perforation following Zenker’s diverticulum treatment and C5/6 cage osteosynthesis. Reconstruction was performed using a free fasciocutaneous ALT flap with two skin paddles: one (2 × 2 cm) for the esophageal mucosa and an additional vascularized fascia layer (4 × 8 cm) to separate the cage from the hypopharyngeal defect. To enable flap monitoring in the otherwise hidden defect, a second skin island was externalized cervically. Results: Postoperative recovery was uneventful, with a continuous viable flap signal. A Gastrografin swallow test confirmed an intact esophagus without leaks or dehiscences. Oral intake resumed after 10 days. The literature review highlighted 239 cases with multiple reconstructive techniques, each with advantages and limitations. Conclusions: The double-paddle free fasciocutaneous ALT flap is a viable option for posterior hypopharyngeal/upper esophageal wall reconstruction, allowing effective postoperative monitoring. This approach offers a valuable modification for complex cases requiring enhanced structural integrity and flap assessment. Full article

The human papillomavirus (HPV) is an oncogenic DNA virus that is the most commonly transmitted sexually transmitted virus. There is substantial evidence that HPV is associated with different types of cancer. While the majority of studies have concentrated on urogenital system cancers and head and neck cancers, the relationship between HPV and gastrointestinal system cancers, particularly esophageal cancers, has also been the subject of investigation. Given that HPV is a disease that can be prevented through vaccination and treated with antiviral agents, identifying the types of cancers associated with the pathogen may inform the treatment of these cancers. This comprehensive review examines the relationship between HPV and cancers of the upper gastrointestinal tract, highlighting the oncogenic mechanisms of the virus and its reported prevalence. A deeper understanding of HPV’s association with cancer is relevant to the further development of cancer therapies. Full article

Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and immunotherapies, are less effective compared to those for other cancer types, highlighting an urgent need for novel molecular targets. NEK (NIMA related kinase) kinases are a group of serine/threonine kinases (NEK1-NEK11) that play a role in regulating cell cycle, mitosis, and various physiological processes. Recent studies suggest that several NEK members are overexpressed in human cancers, including gastrointestinal (GI) cancers, which can contribute to tumor progression and drug resistance. Among these, NEK2 stands out for its consistent overexpression in all types of GI cancer. Targeting NEK2 with specific inhibitors has shown promising results in preclinical studies, particularly for gastric and pancreatic cancers. The development and clinical evaluation of NEK2 inhibitors in human cancers have emerged as a promising therapeutic strategy. Specifically, an NEK2 inhibitor, T-1101 tosylate, is currently undergoing clinical trials. This review will focus on the gene expression and functional roles of NEKs in GI cancers, as well as the progress in developing NEK inhibitors. Full article

The endomysial antibody (EMA) immunofluorescent test is a highly specific method to detect disease-specific autoantibodies in celiac disease (CD) by their binding to natural transglutaminase-2 autoantigen in tissue sections, and it is used as a compulsory confirmatory test in the non-invasive diagnosis of CD. The classical EMA substrates are the monkey esophagus and the human umbilical cord. It is increasingly difficult to use these tissues due to ethical concerns and animal welfare regulations. In this study, we developed, in cell culture, an endomysium-type extracellular biomatrix assembled by human umbilical cord vein-derived endothelial cells which binds CD antibodies in a similar pattern as monkey esophagus and has similar macromolecular composition. Evaluating retrospectively and prospectively tested patient cohorts, including 130 CD cases and 105 non-celiac controls, IgA-class celiac antibody detection on the biomatrix was equally specific (100%) as EMA testing on tissues, and had higher sensitivity (95.6% versus 91.2%). Both EMA tests were less sensitive, but more specific than transglutaminase-based ELISA measurements. The decellularization of the biomatrix improved sensitivity, enabled the detection of IgG-class celiac antibodies, and allowed for simple reading without previous training. This easily available cell-assembled biomatrix substrate may replace substrate tissues in diagnostic EMA testing in the future. Full article

In homeostatic conditions, the basal progenitor cells of the esophagus differentiate into a stratified squamous epithelium. However, in the setting of acid exposure or inflammation, there is a marked failure of basal cell differentiation, leading to basal cell hyperplasia. We have previously shown that lysyl oxidase (LOX), a collagen crosslinking enzyme, is upregulated in the setting of allergic inflammation of the esophagus; however, its role beyond collagen crosslinking is unknown. Herein, we propose a non-canonical epithelial-specific role of LOX in the maintenance of epithelial homeostasis using 3D organoid and murine models. We performed quantitative reverse transcriptase PCR, Western blot, histologic analysis, and RNA sequencing on immortalized non-transformed human esophageal epithelial cells (EPC2-hTERT) with short-hairpin RNA (shRNA) targeting LOX mRNA in both monolayer and 3D organoid culture. A novel murine model with a tamoxifen-induced Lox knockout specific to the stratified epithelium (K5CreER; Lox^fl/fl) was utilized to further define the role of epithelial LOX in vivo. We found that LOX knockdown decreased the proliferative capacity of the esophageal epithelial cells in monolayer culture, and dramatically reduced the organoid formation rate (OFR) in the shLOX organoids. LOX knockdown was associated with decreased expression of the differentiation markers filaggrin, loricrin, and involucrin, with RNA sequencing analysis revealing 1224 differentially expressed genes demonstrating downregulation of pathways involved in cell differentiation and epithelial development. Mice with Lox knockout in their stratified epithelium demonstrated increased basaloid content of their esophageal epithelium and decreased Ki-67 staining compared to the vehicle-treated mice, suggesting reduced differentiation and proliferation in the Lox-deficient epithelium in vivo. Our results demonstrate, both in vivo and in vitro, that LOX may regulate epithelial homeostasis in the esophagus through the modulation of epithelial proliferation and differentiation. Understanding the mechanisms of perturbation in epithelial proliferation and differentiation in an inflamed esophagus could lead to the development of novel treatments that could promote epithelial healing and restore homeostasis. Full article

The esophagus, traditionally viewed as a sterile conduit, is now recognized as a dynamic habitat for diverse microbial communities. The emerging evidence suggests that the esophageal microbiota plays an important role in maintaining esophageal health and contributing to disease. The aim of this systematic review was to synthesize the current knowledge on the esophageal microbiota composition, its variation between healthy individuals and those with esophageal diseases, and the potential mechanisms through which these microorganisms influence esophageal pathology. A systematic literature search was conducted using multiple databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published up to July 2024. The inclusion criteria encompassed original research articles that used molecular techniques to characterize the esophageal microbiota in human subjects, comparing healthy individuals with patients affected by esophageal conditions such as gastroesophageal reflux disease (GERD), Barrett’s esophagus, eosinophilic esophagitis, and esophageal cancer. The primary outcomes were the composition and diversity of the esophageal microbiota, and the secondary outcomes included the correlations between microbial profiles and disease states. The esophageal microbiota of healthy individuals was dominated by Gram-positive bacteria, particularly Streptococcus. Conversely, the esophageal microbiota is considerably altered in disease states, with decreased microbial diversity and specific microbial signatures associated with these conditions, which may serve as biomarkers for disease progression and as targets for therapeutic intervention. However, the heterogeneous study designs, populations, and analytical methods underscore the need for standardized approaches in future research. Understanding the esophageal microbiota’s role in health and disease could guide microbiota-based diagnostics and treatments, offering novel avenues for managing esophageal conditions. Full article

Introduction: Esophageal inflammatory diseases are frequent diagnoses in clinical practice and have diverse etiologies, the most common being those associated with the exposure to gastric content, drugs and allergens. In diseases, the immunological component is well identified in endoscopic biopsies, which mainly contain the epithelium and the lamina propria; however, deeper layers are less studied. Moreover, the esophageal capacity of sensing luminal compounds is poorly understood. Methods: In transmural sections from proximal, middle and distal esophagus obtained from deceased patients, we performed a phenotypic analysis of the main immune cell populations and acid-sensing receptors by immunohistochemistry and immunofluorescence methods. Results: A total of nine donors were studied (absence of pathology, optimal tissue preservation and orientation). We found the following: (1) the vascular papillae and the lamina propria are the most infiltrated layers by the lymphoid lineage (T and B lymphocytes), followed by the epithelium, while the smooth muscular layers are mainly populated by the myeloid lineage (macrophages and mast cells); (2) intraepithelial macrophages are consistently found along the esophagus; and (3) eosinophils are absent in all the esophageal layers. The acid-sensing receptors ASIC-1, ASIC-2 and δENAC are expressed in the esophageal epithelium and in the lamina propria, yet only ASIC-2 is expressed in the muscularis mucosae. Conclusions: The human esophagus contains a differential distribution of immune cells and acid-sensing receptors across its layers. This study extends the esophageal histological knowledge previously described and reinforces its role as a defensive and sensing organ. Full article

Human tumors progress in part by accumulating epigenetic alterations, which include gains and losses of DNA methylation in different parts of the cancer cell genome. Recent work has revealed a link between these two opposite alterations by showing that DNA hypomethylation in tumors can induce the expression of transcripts that overlap downstream gene promoters and thereby induce their hypermethylation. Preliminary in silico evidence prompted us to investigate if this mechanism applies to the locus harboring AGO1, a gene that plays a central role in miRNA biogenesis and RNA interference. Inspection of public RNA-Seq datasets and RT-qPCR experiments show that an alternative transcript starting 13.4 kb upstream of AGO1 (AGO1-V2) is expressed specifically in testicular germ cells, and becomes aberrantly activated in different types of tumors, particularly in tumors of the esophagus, stomach, and lung. This expression pattern classifies AGO1-V2 into the group of “Cancer-Germline” (CG) genes. Analysis of transcriptomic and methylomic datasets provided evidence that transcriptional activation of AGO1-V2 depends on DNA demethylation of its promoter region. Western blot experiments revealed that AGO1-V2 encodes a shortened isoform of AGO1, corresponding to a truncation of 75 aa in the N-terminal domain, and which we therefore referred to as “∆NAGO1”. Interestingly, significant correlations between hypomethylation/activation of AGO1-V2 and hypermethylation/repression of AGO1 were observed upon examination of tumor cell lines and tissue datasets. Overall, our study reveals the existence of a process of interdependent epigenetic alterations in the AGO1 locus, which promotes swapping between two AGO1 protein-coding mRNA isoforms in tumors. Full article

The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. The predictive significance of PHLDA genes in cancer remains unclear. To determine the role of pleckstrin as a prognostic biomarker in human cancers, we conducted a systematic multiomics investigation. Through various survival analyses, pleckstrin expression was evaluated, and their predictive significance in human tumors was discovered using a variety of online platforms. By analyzing the protein–protein interactions, we also chose a collection of well-known functional protein partners for pleckstrin. Investigations were also carried out on the relationship between pleckstrins and other cancers regarding mutations and copy number alterations. The cumulative impact of pleckstrin and their associated genes on various cancers, Gene Ontology (GO), and pathway analyses were used for their evaluation. Thus, the expression profiles of PHLDA family members and their prognosis in various cancers may be revealed by this study. During this multiomics analysis, we found that among the PHLDA family, PHLDA1 may be a therapeutic target for several cancers, including kidney, colon, and brain cancer, while PHLDA2 can be a therapeutic target for cancers of the colon, esophagus, and pancreas. Additionally, PHLDA3 may be a useful therapeutic target for ovarian, renal, and gastric cancer. Full article

Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics. Full article

The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3′ terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome. Full article

Electroporation is used in medicine for drug and gene delivery, and as a nonthermal ablation method in tumor treatment and cardiac ablation. Electroporation involves delivering high-voltage electric pulses to target tissue; however, this can cause effects beyond the intended target tissue like nerve stimulation, muscle contractions and pain, requiring use of sedatives or anesthetics. It was previously shown that adjusting pulse parameters may mitigate some of these effects, but not how these adjustments would affect electroporation’s efficacy. We investigated the effect of varying pulse parameters such as interphase and interpulse delay while keeping the duration and number of pulses constant on nerve stimulation, muscle contraction and assessing pain and electroporation efficacy, conducting experiments on human volunteers, tissue samples and cell lines in vitro. Our results show that using specific pulse parameters, particularly short high-frequency biphasic pulses with short interphase and long interpulse delays, reduces muscle contractions and pain sensations in healthy individuals. Higher stimulation thresholds were also observed in experiments on isolated swine phrenic nerves and human esophagus tissues. However, changes in the interphase and interpulse delays did not affect the cell permeability and survival, suggesting that modifying the pulse parameters could minimize adverse effects while preserving therapeutic goals in electroporation. Full article

The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in EAC and its precancerous condition (Barrett’s esophagus, BE) has not been investigated. In the present study, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which 8 contain EAC and 6 contain BE) using bioinformatic approaches for NEKs expression in EAC and BE. We identified that several NEK members, such as NEK2 (7/8), NEK3 (6/8), and NEK6 (6/8), were significantly upregulated in EAC as compared to normal esophagus samples. Alternatively, NEK1 was downregulated in EAC as compared to the normal esophagus. On the contrary, genomic alterations of these NEKs are not frequent in EAC. We validated the above findings using qRT-PCR and the protein expression of NEKs in EAC cell lines using Western blotting and in primary EAC tissues using immunohistochemistry and immunofluorescence. Our data suggest that frequent upregulation of NEK2, NEK3, and NEK7 may be important in EAC. Full article