The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Significant understanding ...of HSCs has been achieved using rodent models and isolated murine HSCs; as well as investigating human liver tissues and human HSCs. There is growing interest and need of translating rodent study findings to human HSCs and human liver diseases. However, species-related differences impose challenges on the translational research. In this review, we focus on the current information on human HSCs isolation methods, human HSCs markers, and established human HSC cell lines.
Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of ...mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.
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•Myeloid cell diversity in NASH is associated with distinct microanatomical niches•Reprogramming of LXR activity leads to impaired Kupffer cell identify and survival•ATF3 collaborates with LXRs to promote a scar-associated macrophage phenotype•Altered enhancer landscapes enable inference of disease mechanisms
Kupffer cells and recruited myeloid cells contribute to the pathology of nonalcoholic steatohepatitis (NASH), but molecular mechanisms specifying their distinct identities and functions are not known. Seidman and colleagues address this problem by defining cell- and disease-specific enhancer landscapes that enable inference of key transcription factors that drive myeloid cell diversity in NASH.
Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays ...important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.
Low-grade appendiceal mucinous neoplasm (LAMN) and appendiceal adenocarcinoma are known to cause the majority of pseudomyxoma peritonei (PMP, i.e. mucinous ascites); however, recognition and proper ...classification of these neoplasms can be difficult despite established diagnostic criteria.
To determine the pathological diagnostic concordance for appendix neoplasia and related lesions during patient referral to an academic medical center specialized in treating patients with PMP.
The anatomic pathology laboratory information system was searched to identify cases over a two-year period containing appendix specimens with mucinous neoplasia evaluated by an outside pathology group and by in-house slide review at a single large academic medical center during patient referral.
161 cases containing appendix specimens were identified over this period. Forty-six of 161 cases (28.6%) contained appendiceal primary neoplasia or lesions. Of these, the originating pathologist diagnosed 23 cases (50%) as adenocarcinoma and 23 cases (50%) as LAMN; however, the reference pathologist diagnosed 29 cases (63.0%) as LAMN, 13 cases (28.3%) as adenocarcinoma, and 4 cases (8.7%) as ruptured simple mucocele. Importantly, for cases in which the originating pathologist rendered a diagnosis of adenocarcinoma, the reference pathologist rendered a diagnosis of adenocarcinoma (56.5%, 13 of 23), LAMN (39.1%, 9 of 23), or simple mucocele (4.3%, 1 of 23). The overall diagnostic concordance rate for these major classifications was 71.7% (33 of 46) with an unweighted observed kappa value of 0.48 (95% CI, 0.27-0.69), consistent with moderate interobserver agreement. All of the observed discordance (28.3%) for major classifications could be attributed to over-interpretation. In addition, the majority of LAMN cases (65.5%) had potential diagnostic deficiencies including over-interpretation as adenocarcinoma and lacking or discordant risk stratification (i.e. documentation of extra-appendiceal neoplastic epithelium).
Appendiceal mucinous lesions remain a difficult area for appropriate pathological classification with substantial discordance due to over-interpretation in this study. The findings highlight the critical need for recognition and application of diagnostic criteria regarding these tumors. Recently published consensus guidelines and a checklist provided herein may help facilitate improvement of diagnostic concordance and thereby reduce over-interpretation and potential overtreatment. Further studies are needed to determine the extent of this phenomenon and its potential clinical impact.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new ...therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.
Purpose
We explore the use of intravenously delivered perfluorocarbon (PFC) nanoemulsion and
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F MRI for detecting inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD). ...Correlative studies of
1
H-based liver proton density fat fraction (PDFF) and T
1
measurements and histology are also evaluated.
Procedures
C57BL/6 mice were fed standard or high-fat diet (HFD) for 6 weeks to induce NAFLD.
1
H MRI measurements of PDFF and T
1
relaxation time were performed at baseline to assess NAFLD onset prior to administration of a PFC nanoemulsion to enable
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F MRI of liver PFC uptake.
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H and
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F MRI biomarkers were acquired at 2, 21, and 42 days post-PFC to assess changes. Histopathology of liver tissue was performed at experimental endpoint.
Results
Significant increases in liver volume, PDFF, and total PFC uptake were noted in HFD mice compared to Std diet mice. Liver fluorine density and T
1
relaxation time were significantly reduced in HFD mice.
Conclusions
We demonstrated longitudinal quantification of multiple MRI biomarkers of disease in NAFLD mice. The changes in liver PFC uptake in HFD mice were compared with healthy mice that suggests that
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F MRI may be a viable biomarker of liver pathology.
Breast cancer (BC) is one of the most common causes of death among women, and second in Iran. The objectives of this study were to determine the frequency of methyltetrahydrofolate-homocysteine ...methyltransferase (MTR) 2756 gene polymorphism in patients with breast cancer. For the first time, we evaluated these polymorphisms and effects on the breast cancer risk association in an Iranian sporadic population-based case-control study of 282 breast cancer cases and 310 controls using a PCR-RFLP-based assay. Analyses of affected and controls show that homozygote genotype MTR 2756 AA has the highest frequency in both groups (33.3 in patients). Genotype MTR 2756 GG was the highest risk factor in our population AG/GG odds ratio, 0.329 (95% CI: 0.146-0.741) p = 0.006, AA/AG, OR, 2.316, 95% CI: 1.509-3.555, p = 0.001, AA/GG odds ratio, 0.761 (95% CI: 0.363-1.595) p = 0.297. There was a significant association of breast cancer risk with MTR 2756 GG and AA polymorphism.
Chick embryos are a great historical research model in basic and applied sciences. Along with other animal models, avian and specifically chicken embryo has been attended, as well. Avian fertilized ...eggs as a natural bioreactor are an efficient tool for producing recombinant proteins and vaccines manufacturing. Due to the limitations of birdschr('39') eggs for viral replication, avian stem cells culture technologies access to safe methods as well as large-scale production of a variety of human and animal vaccines. Chicken pluripotent stem cells present the unique property of self-renewal and the ability to generate differentiated progeny in all embryonic lineages such as ectoderm, mesoderm, and endoderm in vitro. For the first time, chicken embryonic stem cells (cESCs) derived from the blastodermal cells of stage X embryos in vitro. Chicken ESC provides a great model of early embryo and they are useful for gene manipulation, virus proliferation, and the generation of transgenic birds. In addition to blastodermal cells, pluripotent cell lines can be produced by reprogramming of chicken fibroblasts into induced pluripotent stem cells (iPSCs) with transcription factors such as OCT4, NANOG, SOX2, KLF4, LIN28, and C-MYC that are well known to contribute to the reprogramming of somatic cells into an iPSCs. Similar to chicken ESCs, iPSCs have properties of unlimited self-renewal in vitro and the capacity for differentiation to all three embryonic germ layers. Chicken iPSCs have been a useful tool for the production of transgenic birds and viral vaccines. Despite the benefits and multiple applications of chicken pluripotent stem cells, the propagation of these cells is limited and some important challenges should be eliminated before their use in vaccine manufacturing. It is necessary to define the appropriate culture conditions for chicken pluripotent stem cells. For example, the presence of endogenous viruses in the avian species should be evaluated for human vaccine production. Currently, primary chicken fibroblast cells are still mainly used for vaccine production. This review covers the resources to achieve chicken derived cell lines for vaccine manufacturing.
Summary Acquired cystic disease (ACD) is common in patients with end-stage renal disease. Given the significant increased risk of renal cell carcinoma (RCC) in these patients, we characterized the ...pathologic spectrum of cysts in end-stage kidneys to determine the possible relationship with coincidental neoplasms. Twenty-one native end-stage kidneys contained multiple cysts (0.1-4 cm), which could be categorized into 3 groups based on the cytoplasm of the predominant cell type: clear, eosinophilic, or foamy. Clear cell cysts showed strong staining with carbonic anhydrase IX (CA9) in a cup-shaped manner. Of 7 kidneys with CA9-positive clear cell cysts, 3 had at least 2 foci of RCC (0.5-8 cm), which all demonstrated the morphologic features and immunoprofile of clear cell papillary RCC. Eight kidneys contained foamy cysts, and 4 of these contained ACD-associated RCC, but 1 papillary RCC was also encountered. Six kidneys had eosinophilic cysts, which were negative for CA9, and 3 of these were associated with papillary RCC. Clear cell cysts, although few in number, are common in end-stage nephrectomy specimens. These cysts were present in all kidneys with clear cell papillary RCC and a few kidneys without an obvious mass. In specimens with ACD-associated RCC or papillary RCC, cysts lined by epithelial cells with predominantly eosinophilic or foamy cytoplasm were identified. These data support the idea that the cysts in end-stage kidneys could represent the earliest precursor lesion of renal neoplasia.
Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this ...study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm
). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm
and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm
. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm
. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm
, and two were >5.0 cm with a mitotic rate <5/5 mm
. All but one appendiceal GIST measured <2.0 cm. These tumors were composed of spindle cells with low mitotic rates (<5/5 mm
), and none progressed. Our results suggest that progression risk among esophageal and colonic GISTs is associated with increased mitotic activity (>5/5 mm
) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.
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