Search

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 μg PBR was 1.70 (±0.56); the mean 50 μg PBR was 2.64 (±0.97); the mean 100 μg PBR was 3.32 (±1.33); and the mean 150 μg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 μg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy.

Summary: Here, we present a protocol for isolating human hepatocytes and neural progenitor cells from normal and nonalcoholic steatohepatitis livers. We describe steps for perfusion for scaled-up liver cell isolation and optimization of chemical digestion to achieve maximal yield and cell viability. We then detail a liver cell cryopreservation and potential applications, such as the use of human liver cells as a tool to link experimental and translational research. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Gastric cancer is the third leading cause of cancer-related deaths, with more than one million new cases and approximately 841,000 deaths annually worldwide. We report a case of a young patient (25 years old) with an aggressive form of gastric cancer. The patient had previously been treated for Helicobacter pylori (H. pylori), which is a main risk factor for developing gastric cancer. Genetic testing showed an E-cadherin (CDH1) germline mutation of unknown significance. After eight cycles of chemotherapy, a positron emission tomography (PET) scan showed disease progression with an enlarging hypermetabolic right adnexal mass suspicious for metastatic disease. Tumor pathology demonstrated invasive and poorly differentiated gastric carcinoma. The analysis of the tumor biopsy indicated the very high expression of a chemokine, C-X-C motif chemokine 5 (CXCL5). The combination of H. pylori infection with an existence of a rare CDH1 mutation could have contributed to this aggressive gastric cancer.

CRIg is expressed on liver macrophages and binds Gram-positive bacteria to mediate phagocytosis, but it is not clear how its phagocytic functions contribute to liver homeostasis or disease. Here the authors report that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of alcoholic liver disease.

Background & Aims: How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH–HCC progression, as well as regression. Methods: Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. Results: Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. Conclusions: The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.

Abstract Background Numerous investigations have previously evaluated the association of interleukin (IL) 4 gene polymorphisms and the risk of asthma, conferring inconsistent results. To resolve the incongruent outcomes yielded from different single studies, we conducted the most up-to-date meta-analysis of IL4 gene −589C/T (rs2243250) polymorphism and susceptibility to asthma. Methods A systematic literature search was performed in ISI web of science, Scopus, Medline/PubMed databases prior to September 2020, and the pooled odds ratio (OR) and their corresponding 95% CI were calculated to determine the association strength. Results Literature search led to retrieving of 49 publications (55 case-control studies) containing 9572 cases and 9881 controls. It was revealed that IL4 gene −589C/T polymorphism increased the risk of asthma across all genetic models, including dominant model (OR = 1.22), recessive model (OR = 1.17), allelic model (OR = 1.21), and TT vs. CC model (OR = 1.34), but not the CT vs. TT model. The subgroup analysis by age indicated that IL4 gene -589C/T polymorphism was significantly associated with asthma risk in both pediatrics and adults. Additionally, the subgroup analysis by ethnicity revealed significant association in Asian, American, and Europeans. Finally, subgroup analysis by East Asian and non-East Asian populations indicated significant associations. Conclusions The current meta-analysis revealed that IL4 gene -589C/T polymorphism was a susceptibility risk in both pediatrics and adults in the whole and different ethnic groups.

Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins and formation of a fibrous scar. Hepatic stellate cells (HSCs) are the major source of collagen type 1 producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol‐induced activation of human and mouse HSCs is not fully understood. We compared the gene‐expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n = 3) or without underlying liver disease (n = 4) using RNA‐sequencing analysis. Furthermore, the gene‐expression profile of ALD hHSCs was compared with that of alcohol‐activated mHSCs (isolated from intragastric alcohol‐fed mice) or CCl4‐activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, in addition to alcohol‐activated and CCl4‐activated mHSCs, share the expression of common HSC activation (Col1a1 [collagen type I alpha 1 chain], Acta1 [actin alpha 1, skeletal muscle], PAI1 [plasminogen activator inhibitor‐1], TIMP1 [tissue inhibitor of metalloproteinase 1], and LOXL2 [lysyl oxidase homolog 2]), indicating that a common mechanism underlies the activation of human and mouse HSCs. Furthermore, alcohol‐activated mHSCs most closely recapitulate the gene‐expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely up‐regulated in primary cultured alcohol‐activated hHSCs and freshly isolated mHSCs, which include CSF1R (macrophage colony‐stimulating factor 1 receptor), PLEK (pleckstrin), LAPTM5 (lysosmal‐associated transmembrane protein 5), CD74 (class I transactivator, the invariant chain), CD53, MMP9 (matrix metallopeptidase 9), CD14, CTSS (cathepsin S), TYROBP (TYRO protein tyrosine kinase‐binding protein), and ITGB2 (integrin beta‐2), and other genes (compared with CCl4‐activated mHSCs). Conclusion: We identified genes in alcohol‐activated mHSCs from intragastric alcohol‐fed mice that are largely consistent with the gene‐expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol‐induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD.

Background: Breast cancer is the most common cause of cancer-related death in women worldwide. Novel genetic markers for breast cancer susceptibility have been identified in population-based studies. The aim of this study was to examine the association of two single-nucleotide polymorphisms (SNPs) of FGFR2 (rs1219648) and TOX3 (rs8051542) with the risk of breast cancer in Iranian women. Methods: Breast cancer patients (n?=?126) and healthy controls (n?=?160) were genotyped for SNPs in FGFR2 (rs1219648) and TOX3 (rs8051542) using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Also, immunohistochemical tests for human epidermal growth factor receptor-2, estrogen receptor, and progesterone receptor were carried out on breast tumor tissues. Results: TOX3 (rs8051542) CC (OR?=?1.24; 95% CI, 0.72-0.214; P?0.001) and FGFR2 (rs1219648) GG (OR?=?62.0; 95% CI, 23.63-162.66; ?2?=132.775?; P?

Background: Genetic factors associated with cancer have been widely investigated and several polymorphisms have been connected with breast cancer. Breast cancer (BC) can be considered one of the most popular reasons of death among women. BC, likewise, is the second cause of death in Iran. The present research aims at determining the frequency of the ?broblast growth factor receptor (FGFR) gene polymorphism in patients with breast cancer. Methods: The FGFR family is one of the tyrosine kinase receptors containing 4 members, whose pathway is activated in many tumors. We assessed, for the first time, these polymorphisms and their consequences on the breast cancer risk association in an Iranian sporadic population-based case-control study including 126 patients with breast cancer and 160 controls using a PCR-RFLP-based assay. Results: The analyses of the experimental and control groups indicated that homozygote genotype FGFR4 Gly/Gly has the highest frequency in experimental and control groups (30.4% and 18.9%). The main genotype FGFR4 Gly/Gly risk factors in our population were: ArgGly /GlyGly, OR = 2.359, 95% CI = 0.208 - 4.621, P = 0.001; ArgArg /ArgGly, OR = 0.412, 95% CI = 0.082 - 0.547, P = 0.078, ArgArg /GlyGly, OR = 0.076, 95% CI = 0.030 - 0.189, P = 0.26. Conclusions: A significant association was observed between breast cancer risk and FGFR4 GlyGly and ArgGly polymorphism.

Linear porokeratosis is a rare variant of porokeratosis that most often presents in newborns and children; development of this porokeratosis variant in adulthood is far less common. We report the case of a 25-year-old female who presented with a progressive eruption on the proximal upper extremity of 6-year duration, which was ultimately diagnosed as adult-onset linear porokeratosis and safely treated with oral isotretinoin. We propose that a sporadic mutation resulting in mosaicism after birth may explain the development of linear porokeratosis in adulthood, although the exact trigger of such a somatic mutation is not known. This case also describes a unique clinical presentation, with linear porokeratosis lesions originating on the proximal extremity rather than on the more common distal extremity. This demonstrates a distinctive clinical presentation not seen in the pediatric forms of disease.

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.

Introduction: There are numerous studies addressing associations of polymorphisms in DNA repair genes and cancer risks because accurate and efficient DNA repair is crucial to genomic integrity and fidelity. ERCC1 is important in DNA nucleotide excision repair., Material and Methods: We genotyped constitutive variants of ERCC1 in approximately 300 adults with breast adenocarcinoma and 126 controls of Iranian women. In total, 426 Iranian sporadic breast cancer affected women compared to the control group were studied by PCR-RFLP for ERCC1 variant., Results: The genotype ERCC1 TT has the highest frequency in both groups (36.6 in patients and 8.5 in controls). The genotype ERCC1 was the most important risk factor in our population [GG/AA odds ratio: 0.692, 95% confidence interval (CI): 0.4-1.199, p = 0.188; GG/AG odds ratio: 3.333, 95% CI: 1.917-5.795, p = 0.001; AA/AG odds ratio: 0.208, 95% CI: 0.124-0.348, p = 0.342]., Conclusions: Our patients was associated with breast cancer risk.