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World Journal of Gastrointestinal... Apr 2024Blastomas, characterized by a mixture of mesenchymal, epithelial, and undifferentiated blastematous components, are rare malignant neoplasms originating from precursor... (Review)
Review
Blastomas, characterized by a mixture of mesenchymal, epithelial, and undifferentiated blastematous components, are rare malignant neoplasms originating from precursor blast cells. This review focuses on digestive system blastomas in adult patients, including gastroblastoma, hepatoblastoma, and pancreatoblastoma. Gastroblastoma is a biphasic, epitheliomesenchymal tumor, with only sixteen cases reported to date. In addition to the characteristic histology, metastasis-associated lung adenocarcinoma transcript 1 - glioma-associated oncogene homolog 1 gene fusion is typical, although recently novel ewing sarcoma breakpoint region 1 - c-terminal binding protein 1 and patched 1 - glioma-associated oncogene homolog 2 fusions have been described. Hepatoblastoma is exceptionally rare in adults and can show a variety of histologic patterns which may cause diagnostic difficulty. Pancreatoblastoma, primarily a pediatric tumor, displays acinar differentiation and squamoid nests with other lines of differentiation also present, especially neuroendocrine. Diagnostic approaches for these blastomas include a combination of imaging modalities, histopathological examination, and molecular profiling. The treatment generally involves surgical resection, which may be supplemented by chemotherapy or radiotherapy in some cases. Prognoses vary with gastroblastoma generally showing favorable outcomes post-surgery whereas hepatoblastoma and pancreatoblastoma often have poorer outcomes, particularly in the setting of metastases. This review highlights the complexity of diagnosing and managing these rare adult blastomas as well as the need for ongoing research to better understand their pathogenesis and improve treatment strategies.
PubMed: 38690053
DOI: 10.4240/wjgs.v16.i4.1030 -
Investigative Ophthalmology & Visual... Apr 2024The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively...
PURPOSE
The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq).
METHODS
Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining.
RESULTS
The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells.
CONCLUSIONS
Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.
Topics: Animals; Dry Eye Syndromes; Mice; Scopolamine; Lacrimal Apparatus; Disease Models, Animal; Mice, Inbred C57BL; Female; Cell Nucleus; Tears; Epithelial Cells
PubMed: 38687491
DOI: 10.1167/iovs.65.4.46 -
World Journal of Gastroenterology Apr 2024Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ... (Comparative Study)
Comparative Study
BACKGROUND
Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models.
AIM
To investigate the shared molecular changes underlying the development of AP across varying severity levels.
METHODS
AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using to drive the specific expression of the promoter in pancreatic acinar cells transgenic C57BL/6J- mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database.
RESULTS
Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the and -like receptor signaling pathway, TLR signaling pathway, and signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, pathway, and phagosome pathway. The significantly elevated genes in the and -like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only concurred in both mouse pancreatic tissue and human AP peripheral blood, while , , , and genes exhibited marked elevation in human AP. The genes and played significant roles in apoptosis within human AP. The transgenic mouse model successfully validated significant differential genes in the and -like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models.
CONCLUSION
The and receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the gene. Apoptosis holds a central position in the necrotic processes of AP, with and genes exhibiting prominence in human AP.
Topics: Animals; Disease Models, Animal; Ceruletide; Mice; Mice, Inbred C57BL; Pancreatitis; Gene Expression Profiling; Mice, Transgenic; Pancreas; Lipopolysaccharides; Humans; Transcriptome; Male; Signal Transduction; Acinar Cells; Transcription Factors
PubMed: 38681131
DOI: 10.3748/wjg.v30.i14.2038 -
Phytomedicine : International Journal... Jul 2024Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute...
BACKGROUND
Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute pancreatitis which is more severe with a greater incidence of persistent multiorgan failure. HLAP inflicts injury upon the organelles within the acinar cell, particularly mitochondria, the endolysosomal-autophagy system, and is accompanied by senescence-associated secretory phenotype (SASP). RAD, only two consists of Rhizoma Alismatis and Atractylodes macrocephala Rhizoma, which is best known for its ability to anti-inflammatory and lipid-lowering. Nevertheless, the mechanism by which RAD alleviates HLAP remains obscure, necessitating further investigation.
PURPOSE
The study aimed to assess the effects of the RAD on HLAP and to elucidate the underlying mechanism in vivo and in vitro, offering a potential medicine for clinical treatment for HLAP.
STUDY DESIGN AND METHODS
C57BL/6 mice with hyperlipidemia acute pancreatitis were induced by HFD and CER, then administrated with RAD. AR42J were stimulated by cerulein or conditioned medium and then cultured with RAD. Serums were analyzed to evaluate potential pancreas and liver damage. Furthermore, tissue samples were obtained for histological, and protein investigations by H&E, Oil red staining, and Western blot. In addition, western blot and immunofluorescent staining were utilized to estimate the effect of RAD on mitochondrial function, autophagy flux, and SASP.
RESULTS
In vivo, RAD considerably alleviated systemic inflammation while attenuating TC, TG, AMY, LPS, inflammatory cytokines, histopathology changes, oxidative damage, mitochondrial fission, and autophagy markers in HLAP mice. Impaired autophagy flux and mitochondrial dysfunction resulted in a significant enhancement of NLRP3 and IL-1β in the pancreas. RAD could reverse these changes. In vitro, RAD significantly restored mitochondrial membrane potential and oxidative phosphorylation levels. RAD decreased Beclin-1 and LC3-II expression and increased LAMP-1 and Parkin-Pink expression, which showed that RAD significantly ameliorated HLAP-induced damage to the mitochondria function by suppressing mitochondrial oxidative damage and enhancing autophagy flux and mitophagy to remove the damaged mitochondria. In addition, we found that RAD could up-regulate the expression of BAX, and Bad and down-regulate the expression of p16, and p21, indicating that RAD could promote damaged cell apoptosis and alleviate SASP.
CONCLUSIONS
This study revealed that RAD ameliorates mitochondrial function to alleviate SASP through enhancing autophagy flux, mitophagy, and apoptosis which provided a molecular basis for the advancement and development of protection strategies against HLAP.
Topics: Animals; Pancreatitis; Autophagy; Apoptosis; Hyperlipidemias; Mitochondria; Mice, Inbred C57BL; Mice; Male; Atractylodes; Drugs, Chinese Herbal; Pancreas; Rhizome; Disease Models, Animal; Alisma
PubMed: 38677271
DOI: 10.1016/j.phymed.2024.155629 -
Cancer Treatment and Research... 2024Large amino acid transporter type 1 (LAT1) provides cancer cells with essential amino acids for both protein synthesis and cell growth and may predict patient prognosis....
BACKGROUND
Large amino acid transporter type 1 (LAT1) provides cancer cells with essential amino acids for both protein synthesis and cell growth and may predict patient prognosis. Additionally, LAT1 inhibition can be a therapeutic target. This study aimed to examine the prognostic significance of LAT1 expression in lung cancer, paying special attention to adenocarcinoma subtypes.
METHODS
Tissue microarrays (TMA) of 1,560 total cores obtained from surgically resected lung cancer specimens between 1995 and 2008 at our hospital were used. Overall, 795 cases of adenocarcinoma were identified, and 717 underwent further evaluation. Immunohistochemical staining of whole slides and TMA cores were assessed to set H-score cutoff value.. Immunohistochemical expression of LAT1 was examined based on the subtypes of adenocarcinoma. Statistical analyses explored the prognostic significance of LAT1.
RESULTS
Adenocarcinoma accounted for 71.8% of all cases (n = 795), and 216 cases (27.1%) expressed LAT1. The 795 cases were categorized into five subtypes: lepidic (n = 29, 3.6%), papillary (n = 601, 75.6%), acinar (n = 58, 7.3%), and solid (n = 9, 1.1%); 717 of the 795 cases were further assessed according to the exclusion criteria. The LAT1-positive ratio increased as the architectural grade increased. Notably, in papillary adenocarcinoma, the LAT1-positive group had significantly lower overall survival compared to the negative group (10-year survival: 45.6% vs. 60.8%, p < 0.001).
CONCLUSION
LAT1 expression was higher in high-grade subtypes of pulmonary adenocarcinoma. Moreover, LAT1 expression is useful for predicting prognosis, particularly in papillary adenocarcinoma, facilitating prognostic stratification of papillary adenocarcinoma.
Topics: Humans; Large Neutral Amino Acid-Transporter 1; Female; Male; Prognosis; Adenocarcinoma of Lung; Tissue Array Analysis; Middle Aged; Lung Neoplasms; Aged; Biomarkers, Tumor; Adult
PubMed: 38677033
DOI: 10.1016/j.ctarc.2024.100814 -
Cancers Apr 2024Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain...
Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography-tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFβ, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar-ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial-mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved.
PubMed: 38672675
DOI: 10.3390/cancers16081593 -
Cancer Science Apr 2024N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their...
N6-methyladenosine (m6A) is an RNA modification involved in RNA processing and widely found in transcripts. In cancer cells, m6A is upregulated, contributing to their malignant transformation. In this study, we analyzed gene expression and m6A modification in cancer tissues, ducts, and acinar cells derived from pancreatic cancer patients using MeRIP-seq. We found that dozens of RNAs highly modified by m6A were detected in cancer tissues compared with ducts and acinar cells. Among them, the m6A-activated mRNA TCEAL8 was observed, for the first time, as a potential marker gene in pancreatic cancer. Spatially resolved transcriptomic analysis showed that TCEAL8 was highly expressed in specific cells, and activation of cancer-related signaling pathways was observed relative to TCEAL8-negative cells. Furthermore, among TCEAL8-positive cells, the cells expressing the m6A-modifying enzyme gene METTL3 showed co-activation of Notch and mTOR signaling, also known to be involved in cancer metastasis. Overall, these results suggest that m6A-activated TCEAL8 is a novel marker gene involved in the malignant transformation of pancreatic cancer.
PubMed: 38659235
DOI: 10.1111/cas.16152 -
Scientific Reports Apr 2024Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in...
Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCre™; LSL-Kras) and functional WT Ptf1aCre™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.
Topics: Animals; Activins; Mice; Humans; Macrophages; Pancreatitis; Signal Transduction; Cell Movement; Neutrophil Activation; Neutrophils; Disease Models, Animal; RAW 264.7 Cells; Macrophage Activation; HL-60 Cells; Pancreatitis, Chronic; Male
PubMed: 38654064
DOI: 10.1038/s41598-024-60065-y -
Investigative Ophthalmology & Visual... Apr 2024This study aims to elucidate the calcitonin gene-related peptide (CGRP) mediation and primary mechanism of corneal sensory nerves on tear production of the lacrimal...
PURPOSE
This study aims to elucidate the calcitonin gene-related peptide (CGRP) mediation and primary mechanism of corneal sensory nerves on tear production of the lacrimal gland.
METHODS
Mouse corneal denervation models were constructed through surgical axotomy, pharmacologic treatment with capsaicin or resiniferatoxin, and Trpv1-Cre/DTR mice with diphtheria toxin injection. The capsaicin-treated mice received subconjunctival injection of CGRP or substance P, while the normal C57BL/6J mice were administered with CGRP receptor antagonist BIBN-4096. Furthermore, double immunostaining of c-FOS+ and choline acetyltransferase was used to evaluate the activation of the superior salivatory nucleus (SSN). Mouse lacrimal glands were collected for transcriptomic sequencing and subsequent RNA and protein expression analysis.
RESULTS
The corneal denervated mice exhibited a significant reduction in corneal sensitivity and tear secretion. In capsaicin-treated mice, tear secretion decreased to 2.5 ± 0.5 mm compared to 6.3 ± 0.9 mm in control mice (P < 0.0001). However, exogenous administration of CGRP in capsaicin-treated mice increased tear secretion from 2.6 ± 0.5 mm to 4.5 ± 0.5 mm (P = 0.0009), while BIBN-4096 treatment reduced tear secretion to 3.4 ± 0.5 mm when compared to 7.3 ± 0.7 mm in control mice (P = 0.0022). Furthermore, c-FOS+ cell number in the SSN increased by twofold (P = 0.0168) after CGRP administration compared with capsaicin-treated mice. In addition, the expressions of CCNA2, Ki67, PCNA, and CDK1 in acinar cells of the lacrimal gland were impaired by corneal denervation and alleviated by CGRP administration.
CONCLUSIONS
CGRP released by corneal sensory nerves mediates tear secretion of the lacrimal gland, providing a new strategy for improving tear secretion in patients with neurotrophic keratitis.
Topics: Animals; Mice; Calcitonin Gene-Related Peptide; Capsaicin; Genes, fos; Lacrimal Apparatus; Mice, Inbred C57BL; Proto-Oncogene Proteins c-fos
PubMed: 38635244
DOI: 10.1167/iovs.65.4.30 -
The American Journal of Pathology Jul 2024Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic...
Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse Kras;Trp53;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-μm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)-overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.
Topics: Animals; Pancreatic Neoplasms; Mice; Disease Progression; Chromosomal Instability; Humans; Carcinoma in Situ; Stromal Cells; Tumor Microenvironment; Mechanotransduction, Cellular; Focal Adhesion Kinase 1
PubMed: 38631549
DOI: 10.1016/j.ajpath.2024.02.023