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1
Ueda, Kazuhiko, Osamu Matsui, Azusa Kitao, Satoshi Kobayashi, Jun Nakayama, Shinich Miyagawa, and Masumi Kadoya. "Tumor Hemodynamics and Hepatocarcinogenesis: Radio-Pathological Correlations and Outcomes of Carcinogenic Hepatocyte Nodules." ISRN Hepatology 2014 (March 4, 2014): 1–11. http://dx.doi.org/10.1155/2014/607628.
Повний текст джерелаАнотація:
Tumor hemodynamics of carcinogenic hepatocytes nodules, that is, low grade dysplastic nodules, high grade dysplastic nodules, early hepatocellular carcinomas (HCCs), and progressed HCCs, change during multistep dedifferentiation of the nodules. Morphometric analyses of inflow vessels of these nodules indicate that the portal veins of carcinogenic hepatocyte nodules monotonically decrease whereas the arteries bitonically change, first decrease and then increase. Findings on imaging techniques depicting these changes in tumor blood inflows, especially intra-arterial contrast-enhanced computed tomography, closely related not only to the histological differentiation of the nodules but also to the outcomes of the nodules. Histological analyses of connections between the vessels within the tumors and those in the surrounding livers and findings on imaging techniques indicate that drainage vessels of HCC change from hepatic veins to hepatic sinusoids and then to portal veins during multistep hepatocarcinogenesis. Understanding of tumor hemodynamics through radio-pathological correlations will be helpful in drawing up therapeutic strategies for carcinogenic hepatocyte nodules arising in cirrhosis.
2
Hobbie, K. R., A. B. DeAngelo, M. H. George, and J. M. Law. "Neoplastic and Nonneoplastic Liver Lesions Induced by Dimethylnitrosamine in Japanese Medaka Fish." Veterinary Pathology 49, no. 2 (July 1, 2011): 372–85. http://dx.doi.org/10.1177/0300985811409443.
Повний текст джерелаАнотація:
Small fish models have been used for decades in carcinogenicity testing. Demonstration of common morphological changes associated with specific mechanisms is a clear avenue by which data can be compared across divergent phyletic levels. Dimethylnitrosamine, used in rats to model human alcoholic cirrhosis and hepatic neoplasia, is also a potent hepatotoxin and carcinogen in fish. We recently reported some striking differences in the mutagenicity of DMN in lambda cII transgenic medaka fish vs. Big Blue® rats, but the pre-neoplastic and neoplastic commonalities between the two models are largely unknown. Here, we focus on these commonalities, with special emphasis on the TGF- β pathway and its corresponding role in DMN-induced hepatic neoplasia. Similar to mammals, hepatocellular necrosis, regeneration, and dysplasia; hepatic stellate cell and “spindle cell” proliferation; hepatocellular and biliary carcinomas; and TGF-β1 expression by dysplastic hepatocytes all occurred in DMN-exposed medaka. Positive TGF- β1 staining increased with increasing DMN exposure in bile preductular epithelial cells, intermediate cells, immature hepatocytes and fewer mature hepatocytes. Muscle specific actin identified hepatic stellate cells in DMN-exposed fish. Additional mechanistic comparisons between animal models at different phyletic levels will continue to facilitate the interspecies extrapolations that are so critical to toxicological risk assessments.
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Gligorijevic, Jasmina, Biljana Djordjevic, Aleksandar Petrovic, Aleksandra Radicevic, and Simonida Stojanovic. "Expression of CD34 in cirrhotic liver: Reliance to dedifferentiation." Vojnosanitetski pregled 67, no. 6 (2010): 459–62. http://dx.doi.org/10.2298/vsp1006459g.
Повний текст джерелаАнотація:
Background/Aim. The vascular supply of dysplastic nodules (DN) is altered compared with surrounding cirrhotic nodules. Dysplastic nodules contain unpaired arteries which are isolated arteries unaccompained by bille ducts. In adition, capillarization or neovascularization is evident on CD34 and CD31 staining. The investigation of angiogenic profile of regenerative, dysplastic and nodules of hepatocellular carcinoma aimed at assessing whether vascular profile is in reliance to the process of dedifferentiation of hepatocytes during the course of cirrhosis. Methods. Thirty four liver nodules from surgical biopsies of 12 patients previously undiagnosed to have cirrhosis, were classified as regenerative, dysplastic and small hepatocellular carcinomas (HCC). The investigation included 8 large regenerative nodules (LRN), 11 low grade dysplastic nodules (LGDN), 12 high grade dysplastic nodules (HGDN) and 3 early HCC. Serial sections of the nodules and surrounding cirrhotic liver tissue were immunostained against CD34. The vascular counting method was performed. The results were analysed using SPSS computer statistical program. Results. The number of capillary unites showed significant differences among nodular types, with the largest number of capillaries in hepatocellular carcinoma as well as strong reliance to dedifferentiation. Conclusion. There is a significant correlation of sinusoidal capillarization to dediferentiation of the liver tissue during the course of cirrhosis. From diagnostic view, capillary counting may be helpfull to distinguish dysplastic from nondysplastic nodules. The appearance of dysplastic nodules in nonselected surgical biopsies is frequent enough to challenge caution during the follow-up of cirrhotic patients.
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Guzman, Grace, Shou-Jin Wu, Andr?? Kajdacsy-Balla, and Scott J. Cotler. "??-Methylacyl-CoA Racemase (AMACR/P504S) Can Distinguish Hepatocellular Carcinoma and Dysplastic Hepatocytes From Benign Nondysplastic Hepatocytes." Applied Immunohistochemistry & Molecular Morphology 14, no. 4 (December 2006): 411–16. http://dx.doi.org/10.1097/01.pai.0000208906.66618.61.
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Pok, Sharon, Victoria Wen, Nicholas Shackel, Amber Alsop, Pawan Pyakurel, Aude Fahrer, Geoffrey C. Farrell, and Narci C. Teoh. "Cyclin E facilitates dysplastic hepatocytes to bypass G1 /S checkpoint in hepatocarcinogenesis." Journal of Gastroenterology and Hepatology 28, no. 9 (August 22, 2013): 1545–54. http://dx.doi.org/10.1111/jgh.12216.
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Thakur, Priyanka, Folami Lamoke, Joanna M. Chaffin, Manuela Bartoli, Jeffrey R. Lee, and Michael B. Duncan. "Dysplastic Hepatocytes Develop Nuclear Inclusions in a Mouse Model of Viral Hepatitis." PLoS ONE 9, no. 6 (June 16, 2014): e99872. http://dx.doi.org/10.1371/journal.pone.0099872.
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Raidl, Maria, Walter Berger, Rolf Schulte-Hermann, Daniela Kandioler-Eckersberger, Sonja Kappel, Fritz Wrba, Michael Micksche, and Bettina Grasl-Kraupp. "Expression of the lung resistance-related protein in human and rat hepatocarcinogenesis." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 5 (November 1, 2002): G1117—G1124. http://dx.doi.org/10.1152/ajpgi.00195.2002.
Повний текст джерелаАнотація:
Lung resistance-related protein (LRP) plays an important role in chemoresistance of tumor cells probably by altering nuclear-cytoplasmic transport processes. We analyzed the association between LRP expression and hepatocarcinogenesis in humans and rats by RT-PCR, immunoblotting, and immunohistochemistry. LRP was found in hepatocytes and bile epithelia of normal human and rat liver showing distinct interindividual variations. In human tissues, the LRP expression levels of dysplastic liver nodules, hepatocellular adenomas, and carcinomas were highly variable, including decreased but also distinctly increased staining intensities. Mean expression levels, however, were comparable to the surrounding tissue. Considerable levels of LRP mRNA and protein were also found in human hepatoma cell lines. To study LRP expression from the beginning of hepatocarcinogenesis onward, rats were subjected to a tumor initiation/promotion protocol leading to preneoplastic hepatocytes present as single cells or multicellular clones, followed by adenoma and carcinoma. All of the (pre)neoplastic rat liver lesions expressed, comparable to the surrounding tissue, considerable amounts of LRP. We conclude that LRP might be one mechanism involved in the intrinsically high but variable chemoresistance of normal and (pre)neoplastic hepatocytes.
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Reis, Marcio Augusto Correia Rodrigues dos, and Ronaldo Hueb Baroni. "Liver-specific magnetic resonance contrast medium in the evaluation of chronic liver disease." Einstein (São Paulo) 13, no. 2 (June 2015): 326–29. http://dx.doi.org/10.1590/s1679-45082015rw3159.
Повний текст джерелаАнотація:
ABSTRACT The hepatobiliary-specific contrast medium (gadoxetic acid – Primovist®) is primarily used to improve detection and characterization of focal hepatic lesions, such as in chronic liver disease patients with suspected hepatocellular carcinoma. Since the contrast medium is selectively taken up by functioning hepatocytes in the late hepatobiliary phase, it helps to detect typical hepatocellular carcinoma, which show low signal intensity on this phase. This imaging feature also assists in differentiating regenerative/dysplastic nodules from early hepatocellular carcinomas (with over 90% accuracy), as well as hypervascular hepatocellular carcinomas from arterial pseudo-enhancement foci. Future perspectives include its use in quantification of hepatic function and fibrosis.
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Ilic, Goran, Jasmina Gligorijevic, Ivica Milosavljevic, and Radovan Karadzic. "Evaluation of morphological changes of the liver caused by heroin abuse in forensic practice." Vojnosanitetski pregled 67, no. 5 (2010): 403–10. http://dx.doi.org/10.2298/vsp1005403i.
Повний текст джерелаАнотація:
Background/Aim. A study of morphological lesions in the liver of heroin addicts enables a precise overview of the type and degree of the liver damages caused by intravenous (iv) heroin abuse, additive effects of viral infections and alcohol consumption, as well as whether the expressiveness of these lesions depends on the duration of the time period of heroin application. The aim of the study was to investigate histopathological, ultrastructural and morphometric features of the liver of heroin addicts in forensic samples of the liver. Methods. The study involved the autopsy conducted on 40 bodies of iv heroin addicts and 10 control autopsies. The investigated group consisted of liver samples of 36 male subjects and 4 female subjects aged 35-40 years and the control group of 8 male and 2 female cadaveric bodies aged 15-35 years. The liver tissue samples were prepared for light microscopy. Sections of the tissue paraffin blocks 5 ? thick were stained using classical Hematoxylin and Eosin method (H&E), as well as PAS Van Gieson, Gomori, and Congo Red techniques. For investigation purposes of ultrastructural changes, liver tissue was fixed in glutaraldehyde and molded with epon. The analysis was performed using the method of transmission electron microscopy. Morphometric investigation of the liver sinusoidal macrophages was performed by using the M42 test system. Results. In the investigated group of iv heroin addicts, the liver autopsy samples showed degenerative vesicular and fat changes, chronic hepatitis, cirrhosis, sedimentation of pathologic protein amyloidosis, dysplastic changes, reduction in the amount of glycogen in hepatocytes, as well as the change in the number of Kupfer and endothelial cells. The established changes correlated with the duration of iv heroin abuse, whereas sinusoidal macrophages were activated in cases with active hepatitis, and no significant change in their number was found in hepatocytes with alcohol-related fatty changes. Conclusion. The study showed that the most present change in the hepatocytes of drug addicts was vesicular degeneration, and it is the only direct consequence of the effect of heroin. Other morphological changes were present due to viral infections and they correlated with the duration of narcotic abuse. The finding of dysplastic changes in this susceptible population of young people is particularly significant. The forensic significance of the established changes in the liver tissue is in the possibility of their practical application for determination of the immediate cause of death of iv heroin addicts, as well as the differential diagnosis of not only heroin, but also alcohol, sedative and other substances abuse, and all that on the basis of morphological damages of the liver.
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Park, Young Nyun, Young-Bae Kim, Kyung Moo Yang, and Chanil Park. "Increased Expression of Vascular Endothelial Growth Factor and Angiogenesis in the Early Stage of Multistep Hepatocarcinogenesis." Archives of Pathology & Laboratory Medicine 124, no. 7 (June 1, 2000): 1061–65. http://dx.doi.org/10.5858/2000-124-1061-ieoveg.
Повний текст джерелаАнотація:
Abstract Background.—Hepatocellular carcinoma (HCC) is known to receive its blood supply principally from the hepatic arteries. Recent studies have reported differences in the vascular supply, especially arterial supply among low- and high-grade dysplastic nodules (DNs) (also referred to as adenomatous hyperplasia and macroregenerative nodules) and HCCs. Increased expression of vascular endothelial growth factor (VEGF) has been reported in HCC. In addition, VEGF may play an important role in the early phases of hepatocarcinogenesis. Methods.—We immunohistochemically stained 7 low-grade DNs, 8 high-grade DNs, 11 early HCCs, 17 small HCCs, and 21 advanced HCCs with antibodies against VEGF, α-smooth muscle actin (to identify unpaired arteries, ie, arteries not accompanied by bile ducts, indicative of angiogenesis), CD34 (as a marker of sinusoidal capillarization), and proliferation cell nuclear antigen. Results.—Expression of VEGF was found in the hepatocytes and HCC cells. The degree of VEGF expression increased gradually according to the stepwise development of hepatocarcinogenesis. It was higher in high-grade DNs and early HCCs than in low-grade DNs. The hepatocytes and HCC cells adjacent to peliosis and fibrous septa showed stronger VEGF expression. Angiogenesis, unpaired arteries, and sinusoidal capillarization developed from low-grade DNs and gradually increased. It was highest in HCCs. The proliferation cell nuclear antigen labeling indexes of hepatocytes and HCC cells also increased gradually as hepatocarcinogenesis progressed. Small HCCs showed a higher status of neoangiogenesis and cell proliferation activity than advanced HCCs. The degree of VEGF expression was correlated with angiogenesis and cell proliferation activity. Conclusion.—We conclude that VEGF plays a significant role in angiogenesis, growth, and development of HCC.
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Guido, M., T. Roskams, P. Pontisso, M. Fassan, S. N. Thung, L. Giacomelli, A. Sergio, F. Farinati, U. Cillo, and M. Rugge. "Squamous cell carcinoma antigen in human liver carcinogenesis." Journal of Clinical Pathology 61, no. 4 (September 24, 2007): 445–47. http://dx.doi.org/10.1136/jcp.2007.051383.
Повний текст джерелаАнотація:
Background:Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor that can be overexpressed in hepatocellular carcinoma (HCC) at both molecular and protein level, but no data are available on its expression in pre-malignant stages.Aim:To assess SCCA expression by immunohistochemistry in HCC and its nodular precursors in cirrhotic livers.Methods:55 nodules from 42 explanted livers were evaluated: 7 large regenerative nodules (LRNs), 7 low-grade dysplastic nodules (LG-DNs), 10 high-grade DNs (HG-DNs), and 31 HCC. SCCA expression was semiquantitatively scored on a four-tiered scale.Results:SCCA hepatocyte immunostaining was always restricted to the cytoplasm, mainly exhibiting a granular pattern. Stain intensity varied, ranging from weak to very strong. Within the nodules, positive cells were unevenly distributed, either scattered or in irregular clusters. The prevalence of SCCA expression was 29% in LRNs, 100% in DNs and 93% in HCC. A significant difference emerged in both prevalence and score for LRNs versus LG-DNs (p<0.039), HG-DNs (p = 0.001), and HCC (p = 0.000). A barely significant difference (p = 0.49) was observed between LG-DNs and HG-DNs, while no difference in SCCA expression was detected between HG-DNs and HCC. Cirrhotic tissue adjacent to the nodules was positive in 96% of cases, with a significant difference in the score (p = 0.000) between hepatocytes adjacent to HCC and those surrounding LRNs.Discussion:This study provides the first evidence that aberrant SCCA expression is an early event in liver cell carcinomatous transformation.
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Wee, Aileen. "Fine-Needle Aspiration Biopsy of Hepatocellular Carcinoma and Related Hepatocellular Nodular Lesions in Cirrhosis: Controversies, Challenges, and Expectations." Pathology Research International 2011 (June 30, 2011): 1–17. http://dx.doi.org/10.4061/2011/587936.
Повний текст джерелаАнотація:
The role of hepatic fine-needle aspiration (FNA) biopsy has evolved. Advances in imaging modalities have obviated the need for tissue confirmation in most hepatocellular carcinomas (HCCs). There is risk of needle-tract seeding. Increasingly, small nodules are being detected on ultrasound surveillance of high-risk patients. Diagnostic challenges associated with cirrhosis include distinction of benign hepatocellular nodules, namely, large regenerative nodules and dysplastic nodules, from reactive hepatocytes; and distinction of well-differentiated HCCs from benign hepatocellular nodules. This paper will discuss (i) controversies regarding preoperative/pretransplantation FNA diagnosis of HCC, (ii) update of biological evolution, nomenclature, and histopathologic criteria for diagnosis of precancerous nodules and small HCCs, and (iii) algorithmic approach to FNA diagnosis of hepatocellular nodules. Optimal results depend on dedicated radiologist-cytopathologist team, on-site cytology service; combined cytohistologic approach, immunohistochemistry, and clinicopathologic correlation. Hepatic FNA is likely to be incorporated as a point of care as we move towards personalized medicine.
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ZHAO, ZHANG, GUANG-YONG CHEN, JIANG LONG, HAI LI, and JIAN HUANG. "Genomic losses at 5q13.2 and 8p23.1 in dysplastic hepatocytes are common events in hepatitis B virus-related hepatocellular carcinoma." Oncology Letters 9, no. 6 (April 23, 2015): 2839–46. http://dx.doi.org/10.3892/ol.2015.3140.
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Kadhom, N., C. Wolfrom, M. Gautier, J. P. Allain, and D. Frommel. "Factor VIII Procoagulant Antigen in Human Tissues." Thrombosis and Haemostasis 59, no. 02 (1988): 289–94. http://dx.doi.org/10.1055/s-0038-1642773.
Повний текст джерелаАнотація:
SummaryThe localization of factor VIII procoagulant antigen (VIII: Ag) and factor VIII von Willebrand antigen (VWF: Ag) was investigated in human liver, lung, spleen, placenta and umbilical cord, by an immunoperoxidase technique using an avidin biotin complex (ABC). Positive staining for VIII: Ag was observed in the endothelial cells of liver sinusoids, veins and arteries, as well as in the endothelial cells of placenta, lung and spleen. VWF: Ag was detected in the vascular endothelial cells of all the organs explored. The staining intensity of both VIII: Ag and VWF: Ag varied in the different tissues and showed a distinctive pattern of distribution in the liver. VIII: Ag was also observed in the cytoplasm of dysplastic, foetal-like hepatocytes which infiltrated one liver specimen. Our results agree with the view that liver endothelial cells are a major site of Factor VIII (F VIII) storage and secondary release into the circulation. However, the bright staining intensity of VIII: Ag and VWF: Ag in the lung and placenta suggests that these two tissues might also be a substantial source of F VIII.
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Abdel-Monem, Nehad M., Ahmed M. Abdel-Azeem, El-Sayed H. El-Ashry, Doaa A. Ghareeb, and Asmaa Nabil-adam. "Pretreatment Hepatoprotective Effect of the Marine Fungus Derived from Sponge on Hepatic Toxicity Induced by Heavy Metals in Rats." BioMed Research International 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/510879.
Повний текст джерелаАнотація:
The aim of this study was to evaluate the pretreatment hepatoprotective effect of the extract of marine-derived fungusTrichurus spiralisHasselbr (TS) isolated fromHippospongia communissponge on hepatotoxicity. Twenty-eight male Sprague-Dawley rats were divided into four groups (n=7). Group I served as −ve control, group II served as the induced group receiving subcutaneously for seven days 0.25 mg heavy metal mixtures, group III received (i.p.) TS extract of dose 40 mg for seven days, and group IV served as the protected group pretreated with TS extract for seven days as a protection dose, and then treated with the heavy metal-mixture. The main pathological changes within the liver after heavy-metal mixtures administrations marked hepatic damage evidenced by foci of lobular necrosis with neutrophilic infiltration, adjacent to dysplastic hepatocytes. ALT and AST measurements show a significant increase in group II by 46.20% and 45.12%, respectively. Total protein, elevated by about 38.9% in induction group compared to the −ve control group, in contrast to albumin, decreased as a consequence of metal administration with significant elevation on bilirubin level. The results prove that TS extract possesses a hepatoprotective property due to its proven antioxidant and free-radical scavenging properties.
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Cullen, J. M., E. P. Sandgren, R. L. Brinster, and R. R. Maronpot. "Histologic Characterization of Hepatic Carcinogenesis in Transgenic Mice Expressing SV40 T-antigens." Veterinary Pathology 30, no. 2 (March 1993): 111–18. http://dx.doi.org/10.1177/030098589303000203.
Повний текст джерелаАнотація:
The development of hepatic neoplasms was histologically characterized in transgenic mice that expressed an albumin enhancer-promotor/SV40 T-antigen fusion gene. At least five transgenic and three control mice were examined at monthly intervals over a 3-month period. At 1 month of age, five transgenic mice (two male, three female) and three controls (one male, two female) were examined. Five transgenic mice (two male, three female) and three controls (one male, two female) were examined at 2 months of age. Fourteen transgenic mice (12 male, two female) and three controls (two male, one female) were examined at 3 months of age. At 1 month of age, liver-to-body weight ratios of transgenic mice were increased nearly twofold as compared with controls. Histologically, livers from transgenic mice were characterized by dysplastic hepatocytes with marked variation in nucleus and cell size. At 2 months of age, livers from transgenic mice were 2.5 times larger than control livers and contained numerous 1–5-mm cystic spaces. Transgenic livers also contained multiple eosinophilic, basophilic, and clear foci, as well as cystic, hyperplastic bile ducts and biliary adenomas. At 3 months of age, transgenic livers were enlarged over eightfold as compared with controls and contained numerous cysts and solid masses up to 2 cm in diameter. Trabecular, glandular, and anaplastic hepatocellular carcinomas, as well as benign and malignant biliary neoplasms, were diagnosed. No metastasis was observed. Subcutaneous trabecular hepatocellular carcinomas developed in two of three syngeneic mice that had received transplants of a solid hepatic neoplasm, confirming the neoplastic behavior of these tumors. These experiments, in which viral oncogene expression is targeted to all hepatocytes, support the multistage hypothesis of tumor development and illustrate the similarities in morphologic response of liver to a variety of carcinogenic insults.
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Robinson, Prema, Leticia Hamana, Laura Beretta, Moses Kasembeli, Uddalak Bharadwaj, Yun Shin Chun, Yinghong Wang, et al. "Abstract IA004: Targeting STAT3 with TTI-101, an oral small molecule, to prevent colorectal and hepatocellular cancer." Cancer Prevention Research 15, no. 12_Supplement_2 (December 1, 2022): IA004. http://dx.doi.org/10.1158/1940-6215.tacpad22-ia004.
Повний текст джерелаАнотація:
Abstract Persistent STAT3 activation contributes to 10 of 14 hallmarks of cancer, including inflammation; successful targeting of STAT3 has the potential to prevent and/or treat cancer. However, no small molecule that directly targets STAT3 has been FDA approved. The Tweardy lab used computer-based docking of drug-like compounds into the SH2 domain of STAT3, along with hit-to-lead optimization and medicinal chemistry, to identify TTI-101; TTI-101 treatment was safe, hit its target in tumor cells, and resulted in clinical benefit in a Phase I trial of patients with advanced solid tumors. The incidence of colorectal cancer (CRC) is increased 20-30 fold in patients with inflammatory bowel disease (IBD), while 90% of hepatocellular carcinomas (HCC) arise in the setting of chronic inflammation. To assess the contribution of STAT3 to CRC secondary to IBD and to HCC, we performed immunohistochemistry (IHC) staining and computer-based scoring for activated STAT3 (phosphorylated on Y705, pY-STAT3) of epithelial and stromal cells within colonic endoscopic biopsies and surgically resected CRC from IBD patients, as well as of tumor cells and hepatocytes within surgically resected HCC tumors. Compared to epithelium of normal tissue, levels of pY-STAT3 were increased 1.9-fold in dysplastic epithelium (p=0.05) and 1.8-fold in the stroma of normal tissue (p<0.0001). In surgically resected HCC tumors, lower pY-STAT3 scores in tumor cells, but not hepatocytes, correlated with longer recurrence free survival (RFS; p=0.003). TTI-101 administration in three AOM-DSS mouse models of IBD resulted in a dose-dependent reduction in polyps, adenomas, and/or adenocarcinomas. TTI-101 administration to the HepPten- mouse model of NASH-induced HCC resulted in a dose-dependent reduction in liver pY-STAT3 levels. Thus, STAT3 may be a valid target for chemoprevention using TTI-101 in CRC arising from IBD and in HCC. We thank Tvardi Therapeutics for providing TTI-101 for these studies. Citation Format: Prema Robinson, Leticia Hamana, Laura Beretta, Moses Kasembeli, Uddalak Bharadwaj, Yun Shin Chun, Yinghong Wang, Xeumei Wang, Laura Reyes, Luisa Solis, Asif Rashid, Dipen Maru, Eduardo Vila, Apostolia Tsimberidou, Ahmed Kaseb, Scott Kopetz, David Tweardy. Targeting STAT3 with TTI-101, an oral small molecule, to prevent colorectal and hepatocellular cancer [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA004.
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Detarya, Marutpong, Kanlayanee Sawanyawisuth, Chaiwat Aphivatanasiri, Sriwipa Chuangchaiya, Paksiree Saranaruk, Lukkana Sukprasert, Atit Silsirivanit, Norie Araki, Sopit Wongkham, and Chaisiri Wongkham. "The O-GalNAcylating enzyme GALNT5 mediates carcinogenesis and progression of cholangiocarcinoma via activation of AKT/ERK signaling." Glycobiology 30, no. 5 (December 4, 2019): 312–24. http://dx.doi.org/10.1093/glycob/cwz098.
Повний текст джерелаАнотація:
Abstract Mucin type O-glycosylation is a posttranslational modification of membrane and secretory proteins. Transferring of N-acetylgalactosamine, the first sugar of O-glycosylation, is catalyzed by one of the 20 isoforms of polypeptide N-acetylgalactosaminyltransferases (GALNTs). In this study, Vicia villosa lectin (VVL), a lectin that recognizes O-GalNAcylated glycans, was used to detect VVL-binding glycans (VBGs) in cholangiocarcinoma (CCA). The elevation of VBGs in tumor tissues of the liver fluke associated with CCA from hamsters and patients was noted. VBGs were detected in hyperplastic/dysplastic bile ducts and CCA but not in normal biliary epithelia and hepatocytes, indicating the association of VBGs with CCA development and progression. GALNT5 was shown to be the major isoform found in human CCA cell lines with high VBG expression. Suppression of GALNT5 expression using siRNA significantly reduced VBG expression, signifying the connection of GALNT5 and VBGs observed. Knocked-down GALNT5 expression considerably inhibited proliferation, migration and invasion of CCA cells. Increased expression of GALNT5 using pcDNA3.1-GALNT5 expression vector induced invasive phenotypes in CCA cells with low GALNT5 expression. Increasing of claudin-1 and decreasing of slug and vimentin expression together with inactivation of Akt/Erk signaling were noted in GALNT5 knocked-down cells. These observations were reversed in GALNT5 over-expressing cells. GALNT5-modulated progression of CCA cells was shown to be, in part, via GALNT5-mediated autocrine/paracrine factors that stimulated activations of Akt/Erk signaling and the epithelial to mesenchymal transition process. GALNT5 and its O-GalNAcylated products may have important roles in promoting progression of CCA and could possibly be novel targets for treatment of metastatic CCA.
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Wee, Aileen. "Fine needle aspiration biopsy of the liver : Algorithmic approach and current issues in the diagnosis of hepatocellular carcinoma." CytoJournal 2 (June 8, 2005): 7. http://dx.doi.org/10.1186/1742-6413-2-7.
Повний текст джерелаАнотація:
The role of fine needle aspiration biopsy (FNAB) in the evaluation of focal liver lesions has evolved. Guided FNAB is still useful to procure a tissue diagnosis if clinical, biochemical and radiologic findings are inconclusive. Major diagnostic issues include: (i) Distinction of benign hepatocellular nodular lesions from reactive hepatocytes, (ii) Distinction of well-differentiated hepatocellular carcinoma (WD-HCC) from benign hepatocellular nodular lesions, (iii) Distinction of poorly differentiated HCC from cholangiocarcinoma and metastatic carcinomas, (iv) Determination of histogenesis of malignant tumor, and (v) Determination of primary site of origin of malignant tumor. This review gives a general overview of hepatic FNAB; outlines an algorithmic approach to cytodiagnosis with emphasis on HCC, its variants and their mimics; and addresses current diagnostic issues. Close radiologic surveillance of high-risk cirrhotic patients has resulted in the increasing detection of smaller lesions with many subjected to biopsy for tissue characterization. The need for tissue confirmation in clinically obvious HCC is questioned due to risk of malignant seeding. When a biopsy is indicated, core needle biopsy is favored over FNAB. The inherent difficulty of distinguishing small/early HCC from benign hepatocellular nodular lesions has resulted in indeterminate reports. Changing concepts in the understanding of the biological behavior and morphologic evolution of HCC and its precursors; and the current lack of agreement on the morphologic criteria for distinguishing high-grade dysplastic lesions (with small cell change) from WD-HCC, have profound impact on nomenclature, cytohistologic interpretation and management. Optimization of hepatic FNAB to enhance the yield and accuracy of diagnoses requires close clinicopathologic correlation; combined cytohistologic approach; judicious use of ancillary tests; and skilled healthcare teams.
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Freynd, Genrietta G., and Elena V. Zhivaeva. "THE MORPHOGENESIS OF NONPARASITIC LIVER CYSTS." Morphological newsletter 28, no. 3 (August 26, 2020): 51–57. http://dx.doi.org/10.20340/mv-mn.2020.28(3):51-57.
Повний текст джерелаАнотація:
As a result of the introduction of imaging research methods into clinical practice, the frequency of detection of cavities in the liver has significantly increased, among which nonparasitic cysts have not been sufficiently studied. The paper provides an overview of the most commonly used classifications of this pathology. Clinical and radiological manifestations of cysts were investigated based on the analysis of the results of computed tomography, magnetic resonance imaging and ultrasound sonography of 175 patients (109 with solitary cysts and 66 with polycystic liver). The tissues of the resected areas of 81 cysts and adjacent liver tissue were studied by histological and immune-histochemical methods. Various variants of liver cysts were identified: polycystic cysts, solitary cysts and the rarest variant - ciliated anterior-intestinal hepatic cysts. The morphological and histogenetic features of solitary and ciliated anterior-intestinal hepatic cysts, as well as changes in the liver tissue adjacent to the cavities, are described. Polycystic is characterized by the presence of cavities of various sizes, with thin connective tissue partitions and a lining of cubic or flattened epithelium. The lining of solitary cysts is represented by cubic, cylindrical, sometimes multi-row epithelium. Immature biliary structures in the form of von Meijenburg complexes, islets of hepatocytes, conglomerates of dysplastic vessels are revealed in their wall among the cells of connective tissue. Ciliated anterior-intestinal hepatic cysts contain components of the primary intestine wall - a lining of a cylindrical ciliated epithelium, a layer of loose connective tissue, a muscle layer, a connective tissue capsule. Morphological studies made it possible to establish violations of embryogenesis in various types of cysts. Ciliated anterior intestinal hepatic cysts develop from the anterior section of the primary intestine, while solitary cysts are derived from its middle section. Migration of the developing buds of bronchioles from the cranial part of the primary midgut into the hepatic diverticulum determines the presence of all components of the wall of the hollow organ - cylindrical ciliated epithelium, loose connective tissue, bundles of smooth muscle fibers. Simple solitary cysts are the result of abnormal remodeling of the embryonic ductal lamina, thus being a developmental abnormality of the middle section of the primary midgut. Morphological examination of the liver tissue adjacent to the walls of the cysts reveals hypoplasia of lobules, persistence of elements of the embryonic ductal plate in the form of cords and complexes of the biliary epithelium, foci of ductopenia, von Meijenburg complexes, and various variants of vascular dysplasia.
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Jundt, Franziska, Rudolf A. Rupec, Bernd Rebholz, Bernd Doerken, Irmgard Foerster, Ralf Huss та Klaus Pfeffer. "The Notch Ligand Jagged1 Causes a Myeloproliferative Disorder in Mice Lacking IκBα." Blood 106, № 11 (16 листопада 2005): 1226. http://dx.doi.org/10.1182/blood.v106.11.1226.1226.
Повний текст джерелаАнотація:
Abstract Hematopoiesis occurs in the liver and the bone marrow during murine development. Newborn mice with a ubiquitous deletion of IκBα develop a severe hematological disorder characterized by an increase of granulocyte/erythroid/monocyte/macrophage colony-forming units (CFU-GEMM) and hypergranulopoiesis. Here, we provide evidence that this particular myeloproliferative disturbance is mediated by continuously deregulated perinatal expression of the Notch ligand Jagged1 in IκBα-deficient hepatocytes. Signaling through Notch-family cell surface receptors and their ligands has been shown to be involved in cell fate decisions of stem cells during hematopoietic/mesenchymal differentiation. However, the role of Notch signaling in myelopoiesis is still under discussion as results gained using different experimental conditions are contradictory. Due to embryonic lethality of Notch1- and Jagged1-deficient mice, alterations of myelopoiesis are difficult to be adressed. In this study, we investigated the function of IκBα and its role within the Jagged/Notch signaling pathway during myelopoiesis. Therefore, a novel mouse line with a conditional (floxed) allele of ikba was established. Ubiquitous deletion of IκBα after cross-breeding with Deleter-Cre mice results in hypergranulopoiesis comparable to the conventional deletion of the allele. A detailed analysis revealed a myeloproliferative syndrome with increased numbers of cycling progenitor cells. The morphological analysis of liver and bone marrow of IκBα-deficient mice showed hypercellularity. The cellular components were dominated by myeloid lineages and represented mostly granulocyts with dysplastic features, characterized by pseudo-Pelger-Huet formation. Myelodysplasia could also be detected in megakaryopoiesis by the presence of micromegakaryocytes. Alterations in erythropoiesis were detectable by condensed chromatin and an asychrony of the nucleocytoplasmic ratio in the red cell precursor population. Together, our results indicate that ubiquitous loss of IκBα results in hypergranulopoiesis progressing to a myelodysplastic syndrome. Systematic analysis of transcription factors, growth factor receptors and NF-κB-regulated cell-survival genes was performed to determine molecular mechanisms underlying hypergranulopoiesis. Our data suggested that Notch1-dependent signals were responsible for the myeloproliferative disorder as Notch1 was upregulated in neutrophils and the Notch ligand Jagged1 in non-hematopoietic cells, namly hepatocytes. Myeloproliferation could be inhibited by blocking the Notch1 ligand Jagged1. Interestingly, deletion of IκBα in neutrophils and macrophages or hematopoietic stem cells did not result in dysregulation of myelopoiesis despite constitutive NF-κB activation in these cells. This establishes the relevance of non-hematopoietic expression of Jagged1 for the control and regulation of myelopoiesis. In summary, we show that cell-fate decisions leading to a premalignant hematopoietic disorder can be initiated by non-hematopoietic cells with inactive IκBα.
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Mukherjee, Devoshree, and Riaz Ahmad. "Dose-dependent effect of N′-Nitrosodiethylamine on hepatic architecture, RBC rheology and polypeptide repertoire in Wistar rats." Interdisciplinary Toxicology 8, no. 1 (March 1, 2015): 1–7. http://dx.doi.org/10.1515/intox-2015-0001.
Повний текст джерелаАнотація:
Abstract N′-Nitrosodiethylamine (NDEA) is an effective hepatotoxicant, carcinogen and mutagen. NDEA-induced hepatic necrosis, through metabolic activation by CYP2E1, is an extensively used experimental model. In the present study, we analysed the dose- and time-dependent effect of NDEA on hepatic damage, RBC rheology and proteomic profile in male Wistar rats. The rats, 5–6 weeks old, were divided into four groups: Group-1 served as control and received normal saline, Group-2 received a single dose of 200 mg/kg body weight NDEA intraperitoneally (i.p.) and the animals were sacrificed after one week; the rats of Group-3 received a single dose of 100 mg/kg body weight NDEA and were sacrificed after one week; Group-4 received 100 mg/kg body weight/wk NDEA for two weeks and were then sacrificed. Various biochemical parameters such as ALT, AST, ALP and bilirubin were determined. Further, RBC rheology, histopathology (H&E staining) of liver biopsies and polypeptide profiling (SDS-PAGE) in sera and liver sections were also carried out both in control and NDEA treated groups. Our results showed a significant increase in all the biochemical parameters of the liver function test (p<0.05). In NDEA treated categories dacryocytes (tear drop cells), schistocytes (fragmented cells), codocytes (target cells), acanthocytes (spur cells) and ovalocytes (oval cells) were observed. H & E stained liver biopsies treated with NDEA showed abnormal liver architecture with severe haemorrhage, neutrophilic infiltration and dysplastic hepatocytes manifested in a dose-dependent manner. Software analysis of SDS-PAGE of control and NDEA treated rat sera and liver revealed qualitative and quantitative differences in polypeptide composition. Based on the presence/absence, polypeptides were classified in three different categories: (1) house-keeping, present in all the groups investigated; (2) novel, present in either control or NDEA treated group at any given time; (3) differential expression, showing quantitative differences. Our study indicates a dose and time-dependent hepatocellular damage and proteome profile which is likely due to NDEA-mediated oxidative stress in rats.
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El-Sayed, Sayed S., Mohamed El-Sadany, Ashraf A. Tabll, Ahmad Soltan, Ibrahim El-Dosoky, and Abdelfattah M. Attallah. "DNA Ploidy and Liver Cell Dysplasia in Liver Biopsies from Patients with Liver Cirrhosis." Canadian Journal of Gastroenterology 18, no. 2 (2004): 87–91. http://dx.doi.org/10.1155/2004/638136.
Повний текст джерелаАнотація:
There is controversy among pathologists when assessing the presence or absence of liver cell dysplasia in liver biopsies taken from cirrhotic patients. The objective of the present study was to determine the DNA ploidy pattern of hepatocytes of patients with liver cirrhosis and its relationship to liver cell dysplasia. A total of 48 male patients diagnosed with liver cirrhosis based on clinical, laboratory and histopathological criteria were included in the study. A liver biopsy was taken from each patient; one part of the biopsy was subjected to histopathology, and the other to flow cytometry. The histopathological examination revealed liver cell dysplasia in 60% of patients with liver cirrhosis (62% of them had large cell dysplasia [LCD] and 38% had small cell dysplasia [SCD]). Abnormal DNA content (aneuploidy) was found in 81.5% of positive liver cell dysplasia specimens and found only in 11.1% of negative liver cell dysplasia specimens, with a statistically significant difference (P<0.001). Aneuploidy was found more commonly in LCD but without significant difference (P>0.05) in comparison with SCD. In conclusion, SCD (similar to LCD) is also associated with aneuploidy and elevated DNA index, and may carry the same risk for progression to hepatocellular carcinoma.
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Fong, Sylvia, Bridget Yates, Choong-Ryoul Sihn, Aras N. Mattis, Nina Mitchell, Su Liu, Chris B. Russell, et al. "Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A." Nature Medicine 28, no. 4 (April 2022): 789–97. http://dx.doi.org/10.1038/s41591-022-01751-0.
Повний текст джерелаАнотація:
AbstractFactor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial (NCT02576795), liver biopsy samples were collected 2.6–4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.
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NITA, Marcelo Eidi, Venâncio Avancini Ferreira ALVES, Flair José CARRILHO, Suzane Kioko ONO-NITA, Evandro Sobroza de MELLO, and Joaquim J. GAMA-RODRIGUES. "Molecular aspects of hepatic carcinogenesis." Revista do Instituto de Medicina Tropical de São Paulo 44, no. 1 (February 2002): 39–48. http://dx.doi.org/10.1590/s0036-46652002000100007.
Повний текст джерелаАнотація:
Exogenous agents correlated with hepatocellular carcinoma (HCC) have been identified and well characterized. These agents, including the different viruses that cause chronic hepatitis and cirrhosis, can lead to regenerative nodules and dysplastic nodules/adenomatous hyperplasia. These conditions associated with several molecular alterations of hepatocyte ultimately culminate in hepatocellular carcinoma. Recently, there has been a great progress in the identification of somatic and germinative mutations that may be correlated with the development of HCC, justifying a review on the subject. Hence, the factors involved in the process of hepatic carcinogenesis, such as infection by the hepatitis B and C viruses, with a special focus in the molecular alterations described in recent years are discussed herein, pointing out areas potentially relevant for clinical development.
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Berman, Jules J., and G. William Moore. "Liver Dysplasia and the Interpretation of Image and Flow Cytometric Data of Hepatocytes." American Journal of Clinical Pathology 100, no. 6 (December 1, 1993): 706.1–706. http://dx.doi.org/10.1093/ajcp/100.6.706.
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Choi, Katherine M., Lily Mei, Frederick Behm, and Grace Guzman. "Sa1691 Hepatocyte Cytometry Employing FOXM1 Immunohistochemistry Can Distinguish Normal, Non-Dysplastic Cirrhosis, and Dysplasia (Small Cell Change and Large Cell Change) by Vectra® Automated Multispectral Imaging System." Gastroenterology 146, no. 5 (May 2014): S—952. http://dx.doi.org/10.1016/s0016-5085(14)63463-6.
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Guzman, Grace, Rohini Chennuri, Alexander Chan, Bryan Rea, Ada Quintana, Roshan Patel, Pei-Zhang Xu, Hui Xie, and Nissim Hay. "Evidence for Heightened Hexokinase II Immunoexpression in Hepatocyte Dysplasia and Hepatocellular Carcinoma." Digestive Diseases and Sciences 60, no. 2 (November 8, 2014): 420–26. http://dx.doi.org/10.1007/s10620-014-3364-3.
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Ohki, Yasushi, Hiroo Mayuzumi, Kenichi Tokuyama, Yukihiro Yoshizawa, Hirokazu Arakawa, Hiroyuki Mochizuki, and Akihiro Morikawa. "Hepatocyte Growth Factor Treatment Improves Alveolarization in a Newborn Murine Model of Bronchopulmonary Dysplasia." Neonatology 95, no. 4 (2009): 332–38. http://dx.doi.org/10.1159/000187651.
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Enomoto, A., E. P. Sandgren та R. R. Maronpot. "Interactive Effects of c-myc and Transforming Growth Factor α Transgenes on Liver Tumor Development in Simian Virus 40 T Antigen Transgenic Mice". Veterinary Pathology 35, № 4 (липень 1998): 283–91. http://dx.doi.org/10.1177/030098589803500407.
Повний текст джерелаАнотація:
To analyze the effects of c- myc and transforming growth factor α (TGFα) on hepatocarcinogenesis induced by simian virus 40 T antigen (TAg), livers from single and bitransgenic mice, 3 to 11 mice per line, were examined morphologically 1 to 8 weeks after birth. Mice carrying c- myc or TGFα alone exhibited centrilobular hypertrophy and increased apoptosis (c- myc mice only) of hepatocytes after 3 or 4 weeks of age, but no detectable changes in cell proliferation or proliferative lesions were observed in either line during the 8 weeks. Mice carrying TAg alone exhibited increased cell proliferation, apoptosis, and dysplasia of hepatocytes with notably high mitotic and apoptotic indices as major changes before development of putative preneoplastic lesions after 4 weeks of age and neoplastic lesions after 6 weeks. In bitransgenic mice coexpressing c- myc or TGFα with TAg, nonproliferative lesions and mitotic and apoptotic indices were similar to those in mice carrying TAg alone. In TAg X c- myc bitransgenic mice, however, both preneoplastic and neoplastic lesions developed sooner and grew more rapidly than those in TAg mice, whereas in TAg X TGFα bitransgenic mice, rapid tumor growth was the principle observation. Because of the effects of transgene coexpression, livers from TAg X c- myc and TAg X TGFα mice had multiple tumors as early as 3 and 6 weeks of age, respectively. The results indicate cooperative functions of c- myc and TGFα with TAg during development and/or growth of liver tumors in vivo.
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KOLATSI-JOANNOU, MARIA, CORALIE BINGHAM, SIAN ELLARD, MICHAEL P. BULMAN, LISA I. S. ALLEN, ANDREW T. HATTERSLEY та ADRIAN S. WOOLF. "Hepatocyte Nuclear Factor-1β: A New Kindred with Renal Cysts and Diabetes and Gene Expression in Normal Human Development". Journal of the American Society of Nephrology 12, № 10 (жовтень 2001): 2175–80. http://dx.doi.org/10.1681/asn.v12102175.
Повний текст джерелаАнотація:
Abstract. The hepatocyte nuclear factor—1β (HNF-1β) transcription factor controls endoderm development. Human mutations cause early-onset diabetes mellitus and have recently been associated with dysplastic, hypoplastic, and glomerulocystic kidneys. A new kindred with this “renal cysts and diabetes” syndrome is described, and nephrogenic HNF-1β expression is defined. The proband had congenital cystic kidneys: over the next 12 yr, his renal function was impaired, but he was normoglycemic. His mother developed diabetes during pregnancy: renal ultrasonography at age 24 yr was normal, but she subsequently developed cysts. Both subjects have a heterozygous frameshift mutation inHNF-1β that results from a 1-bp insertion in exon 5 (Y352fsinsA). When reverse-transcription PCR andin situhybridization were used, HNF-1β mRNA was detected in normal human metanephroi, with the highest levels of transcripts localized to fetal medullary and cortical collecting ducts and low levels of expression in nephrogenic cortex mesenchyme, primitive nephron tubules, and immature glomeruli. These results constitute the first demonstration of HNF-1β expression during human nephrogenesis and emphasize a disease spectrum associated withHNF-1β mutation.
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Griffing, Emily, and Sarah J. L. Tsai. "LBODP032 Case Report Of A 13 Years Old Female With A Novel Pathogenic Variant In The Hnf1b Gene." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A264. http://dx.doi.org/10.1210/jendso/bvac150.542.
Повний текст джерелаАнотація:
Abstract Background MODY5 results from mutations in the gene encoding hepatocyte nuclear factor 1 homeobox B (HNF1B), a transcription factor critical in development of the pancreas, liver, intestines, and the urogenital tract (1). We report the case of a pediatric patient with a novel frameshift variant (p. Phe309SerfsTer18) in the HNF1B gene accounting for the co-occurrence of diabetes mellitus and structural renal abnormalities. Clinical case: A 13-years-old female with chronic kidney disease stage 3 (eGFR = 48 ml/min/1.73m2) secondary to congenital dysplastic-appearing left kidney and surgical removal of a cystic dysplastic right kidney was referred to our diabetes clinic for hyperglycemia. She reported long-standing polyuria and polydipsia previously attributed to her kidney disease. She required laparoscopic right nephrectomy at age 5 years due to increasing cyst size. Her left kidney also has small renal parenchymal cysts which have been monitored over time. There is no known family history of kidney disease, and grandparents have a history of diabetes. Laboratory investigation revealed a random blood glucose of 478 mg/dL and a hemoglobin A1c of 12.2%. She was not in diabetic ketoacidosis. She had a detectable insulin level of 5.1 mcIU/mL and C-peptide was 3.4 ng/mL. She was initially presumed to have Type 1 diabetes based on a relatively low insulin level and started on basal-bolus insulin (up to 0.59 units/kg of weight/day). Glycosylated hemoglobin was 8.7% one month after diagnosis. Glutamic acid decarboxylase, zinc transporter, islet cell, and insulin autoantibodies were not detected, however, and she was then suspected to have either Type 2 diabetes or MODY. Approximately one year later, she was taken off insulin due to hypoglycemia and managed only with metformin 500 mg twice daily. Next-generation sequencing revealed a de novo pathogenic variant in HNF1B causing a frameshift deletion (p. Phe309SerfsTer18). Genetic testing of parents was negative. Once her diagnosis of MODY5 was made, she was started on glipizide 2.5 mg once daily which has been titrated up to a dose of 5 mg with some success. However, she has since been re-started on insulin (up to 0.2 units/kg/day) due to hyperglycemia keeping in line with the MODY5 phenotype likely causing destruction of beta cells over time (1). Conclusion We report a case of MODY5 with a novel frameshift mutation (p. Phe309SerfsTer18) in the HNF1B gene. This case highlights the importance of screening for HNF-1B mutations in those patients with structural renal abnormalities and hyperglycemia, as diagnosis can guide management decisions and provide prognostic information. Reference Bellanné-Chantelot C, Chauveau D, Gautier JF, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7): 510-517. doi: 10.7326/0003-4819-140-7-200404060-0000 Presentation: No date and time listed
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Pani, Giovambattista, Salvatore Fusco, Renata Colavitti, Silvia Borrello, Nicola Maggiano, Amerys A. M. Cravero, Stella M. Farré, Tommaso Galeotti, and Osvaldo R. Koch. "Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice." Biochemical and Biophysical Research Communications 325, no. 1 (December 2004): 97–100. http://dx.doi.org/10.1016/j.bbrc.2004.09.213.
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Yang, Ruihan, Yilan Mei, Yuhan Jiang, Huiling Li, Ruixi Zhao, Jian Sima, and Yuyuan Yao. "Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases." International Journal of Molecular Sciences 23, no. 16 (August 10, 2022): 8911. http://dx.doi.org/10.3390/ijms23168911.
Повний текст джерелаАнотація:
Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention.
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Ridder, Dirk Andreas, Lana Louisa Urbansky, Hagen Roland Witzel, Mario Schindeldecker, Arndt Weinmann, Kristina Berndt, Tiemo Sven Gerber та ін. "Transforming Growth Factor-β Activated Kinase 1 (Tak1) Is Activated in Hepatocellular Carcinoma, Mediates Tumor Progression, and Predicts Unfavorable Outcome". Cancers 14, № 2 (15 січня 2022): 430. http://dx.doi.org/10.3390/cancers14020430.
Повний текст джерелаАнотація:
Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.
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Yorifuji, Tohru, Keiji Kurokawa, Mitsukazu Mamada, Tsuyoshi Imai, Masahiko Kawai, Yoshikazu Nishi, Seiichiro Shishido, Yukihiro Hasegawa та Tatsutoshi Nakahata. "Neonatal Diabetes Mellitus and Neonatal Polycystic, Dysplastic Kidneys: Phenotypically Discordant Recurrence of a Mutation in the Hepatocyte Nuclear Factor-1β Gene Due to Germline Mosaicism". Journal of Clinical Endocrinology & Metabolism 89, № 6 (1 червня 2004): 2905–8. http://dx.doi.org/10.1210/jc.2003-031828.
Повний текст джерелаАнотація:
Abstract Mutations in the gene coding for hepatocyte nuclear factor-1β (HNF-1β) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1β gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1β, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1β gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1β mutations.
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Ohki, Y., H. Mayuzumi, K. Tokuyama, Y. Yoshizawa, H. Arakawa, H. Mochizuki, and A. Morikawa. "D4/163 – Hepatocyte growth factor attenuates functional and pathological abnormalities in newborn mouse model of bronchopulmonary dysplasia." Paediatric Respiratory Reviews 7 (January 2006): S299—S300. http://dx.doi.org/10.1016/j.prrv.2006.04.079.
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Stahlman, Mildred T., Mary E. Gray та Jeffrey A. Whitsett. "Temporal-Spatial Distribution of Hepatocyte Nuclear Factor-3β in Developing Human Lung and Other Foregut Derivatives". Journal of Histochemistry & Cytochemistry 46, № 8 (серпень 1998): 955–62. http://dx.doi.org/10.1177/002215549804600809.
Повний текст джерелаАнотація:
SUMMARY We assessed the temporal-spatial distribution of hepatocyte nuclear factor-3β (HNF-3β) in developing human lung and other foregut derivatives. Tissue from 31 fetuses (10-40 weeks) and 24 infants with hyaline membrane disease (HMD) or bronchopulmonary dysplasia (BPD) (2 days to 7 months) was studied. HNF-3β was detected in nuclei of epithelial cells of trachea and of conducting and terminal airways at 10 weeks. Thereafter, epithelial nuclei were immunolabeled more widely in peripheral than proximal airways. HNF-3β was confined to bronchiolo-alveolar portals and Type II cells in nonfetal lung. In infants with BPD, HNF-3 β was expressed abundantly in regenerating epithelial cells at the periphery of lung lobules. HNF-3 β was also detected in fetal esophagus, pancreas, duodenum, stomach, and gallbladder, suggesting that it is a marker for progenitor cells in foregut derivatives. The pattern of expression of HNF-3 β in the lung was similar to that of thyroid transcription factor-1 (TTF-1) at all ages. The temporal-spatial patterns of HNF-3 β and TTF-1 in the developing and regenerating lung are consistent with their proposed role in epithelial cell differentiation, regeneration, and surfactant protein gene expression.
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Papizh, S. V., та O. R. Piruzieva. "THE NUCLEAR FACTOR OF HEPATOCYTES 1β (HNF1β)–ASSOCIATED DISEASE. CLINIC, DIAGNOSTIC, TREATMENT (LITERATURE REVIEW AND CLINICAL OBSERVATION)". Nephrology (Saint-Petersburg) 23, № 2 (21 лютого 2019): 100–108. http://dx.doi.org/10.24884/1561-6274-2019-23-2-100-108.
Повний текст джерелаАнотація:
Hepatocyte nuclear factor 1β (HNF1β)-associated disease is a rare autosomal dominant disease caused by various mutations in the HNF1β gene coding the hepatocyte nuclear factor 1β. HNF1β is a transcription factor that is critical for the development of kidney urogenital tract, pancreas, liver, brain, and parathyroid gland. Renal phenotype or HNF1β- nephropathy appeared to be extremely heterogenic: multicystic renal dysplasia, renal hypoplasia, unilateral renal agenesis, horseshoe kidney, atypical familial juvenile hyperuricemic nephropathy, urinary tract malformations and tubular dysfunction. Extrarenal phenotype of HNF1β-associated disease could be maturity-onset diabetes of the young (MODY), pancreatic atrophy and exocrine pancreatic dysfunction, elevated liver enzymes, neonatal cholestasis, congenital abnormalities of the genital tract, hyperparathyroidism, neurological symptoms. The multisystem phenotype makes clinical verification of the diagnosis extremely difficult. In this article, we present a clinical observation of a child with HNF1β – associated disease. The first clinical presentation of HNF1β-associated disease was ultrasound changes in the kidneys (hyperechogenic kidneys?), which were detected by prenatal ultrasonography in pregnancy. Renal ultrasound revealed polycystic kidney disease in the first days of life and bilateral medullary nephrocalcinosis by the age of three. The clinical examination showed a reduced renal function and developed Fanconi syndrome (glycosuria, low molecular proteinuria, hypophosphatemia, aminoaciduria, hyperuricosuria) in the first year of life. Also the child had a non-constant asymptomatic elevation of liver enzymes, hyperparathyroidism, osteoporosis. The diagnosis was confirmed by the results of next generation sequencing which revealed novel heterozygous mutation in exon 4 of the HNF1b gene (chr17: 36091813C>T), p.Cys273Tyr (c.818G>A). The identified mutation was validated by Sanger sequencing. Validation by Sanger sequencing did not reveal a chr17: 36091813C>T mutation in parents, which suggested the appearance of a mutation in the child de novo.
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Martinez Barbera, J. P., M. Clements, P. Thomas, T. Rodriguez, D. Meloy, D. Kioussis, and R. S. Beddington. "The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation." Development 127, no. 11 (June 1, 2000): 2433–45. http://dx.doi.org/10.1242/dev.127.11.2433.
Повний текст джерелаАнотація:
The homeobox gene Hex is expressed in the anterior visceral endoderm (AVE) and rostral definitive endoderm of early mouse embryos. Later, Hex transcripts are detected in liver, thyroid and endothelial precursor cells. A null mutation was introduced into the Hex locus by homologous recombination in embryonic stem cells. Hex mutant embryos exhibit varying degrees of anterior truncation as well as liver and thyroid dysplasia. The liver diverticulum is formed but migration of hepatocytes into the septum transversum fails to occur. Development of the thyroid is arrested at the thyroid bud stage at 9.5 dpc. Brain defects are restricted to the rostral forebrain and have a caudal limit at the zona limitans intrathalamica, the boundary between dorsal and ventral thalamus. Analysis of Hex(−/−) mutants at early stages shows that the prospective forebrain ectoderm is correctly induced and patterned at 7.5 days post coitum (dpc), but subsequently fails to develop. AVE markers are expressed and correctly positioned but development of rostral definitive endoderm is greatly disturbed in Hex(−/−) embryos. Chimeric embryos composed of Hex(−/−) cells developing within a wild-type visceral endoderm show forebrain defects indicating that Hex is required in the definitive endoderm. All together, these results demonstrate that Hex function is essential in definitive endoderm for normal development of the forebrain, liver and thyroid gland.
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Su, Q., Axel Benner, Walter J. Hofmann, Gerd Otto, Rudolf Pichlmayr, and P. Bannasch. "Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia." Virchows Archiv 431, no. 6 (November 28, 1997): 391–406. http://dx.doi.org/10.1007/s004280050116.
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Warburton, David, Jingsong Zhao, Mary Anne Berberich, and Merton Bernfield. "Molecular embryology of the lung: then, now, and in the future." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 5 (May 1, 1999): L697—L704. http://dx.doi.org/10.1152/ajplung.1999.276.5.l697.
Повний текст джерелаАнотація:
Complementary molecular and genetic approaches are yielding information about gain- versus loss-of-function phenotypes of specific genes and gene families in the embryonic, fetal, neonatal, and adult lungs. New insights are being derived from the conservation of function between genes regulating branching morphogenesis of the respiratory organs in Drosophila and in the mammalian lung. The function of specific morphogenetic genes in the lung are now placed in context with pattern-forming functions in other, better understood morphogenetic fields such as the limb bud. Initiation of lung morphogenesis from the floor of the primitive foregut requires coordinated transcriptional activation and repression involving hepatocyte nuclear factor-3β, Sonic hedgehog, patched, Gli2, and Gli3 as well as Nkx2.1. Subsequent inductive events require epithelial-mesenchymal interaction mediated by specific fibroblast growth factor ligand-receptor signaling as well as modulation by other peptide growth factors including epidermal growth factor, platelet-derived growth factor-A and transforming growth factor-β and by extracellular matrix components. A scientific rationale for developing new therapeutic approaches to urgent questions of human pulmonary health such as bronchopulmonary dysplasia is beginning to emerge from work in this field.
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Arjaans, Sanne, Brandie D. Wagner, Peter M. Mourani, Erica W. Mandell, Brenda B. Poindexter, Rolf M. F. Berger, and Steven H. Abman. "Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 4 (April 1, 2020): L644—L654. http://dx.doi.org/10.1152/ajplung.00131.2019.
Повний текст джерелаАнотація:
Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH); however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signaling pathways with the risk for BPD or PH. We prospectively enrolled infants with gestational age <34 wk and collected blood samples during their first week of life. BPD and PH were assessed at 36 wk postmenstrual age. Samples were assayed for each of the 1,121 peptides included in the SOMAscan scan technology, with subsequent pathway analysis. Of 102 infants in the study, 82 had BPD, and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, bone morphogenetic protein 10 [BMP10], hepatocyte growth factor (HGF), ANG-2) were associated with the subsequent diagnosis of BPD; and FGF-19, PF-4, connective tissue activating peptide (CTAP)-III, and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research.
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Seedorf, Gregory, Alexander J. Metoxen, Robert Rock, Neil Markham, Sharon Ryan, Thiennu Vu, and Steven H. Abman. "Hepatocyte growth factor as a downstream mediator of vascular endothelial growth factor-dependent preservation of growth in the developing lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 11 (June 1, 2016): L1098—L1110. http://dx.doi.org/10.1152/ajplung.00423.2015.
Повний текст джерелаАнотація:
Impaired vascular endothelial growth factor (VEGF) signaling contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesized that the effects of VEGF on lung structure during development may be mediated through its downstream effects on both endothelial nitric oxide synthase (eNOS) and hepatocyte growth factor (HGF) activity, and that, in the absence of eNOS, trophic effects of VEGF would be mediated through HGF signaling. To test this hypothesis, we performed an integrative series of in vitro (fetal rat lung explants and isolated fetal alveolar and endothelial cells) and in vivo studies with normal rat pups and eNOS−/−mice. Compared with controls, fetal lung explants from eNOS−/−mice had decreased terminal lung bud formation, which was restored with recombinant human VEGF (rhVEGF) treatment. Neonatal eNOS−/−mice were more susceptible to hyperoxia-induced inhibition of lung growth than controls, which was prevented with rhVEGF treatment. Fetal alveolar type II (AT2) cell proliferation was increased with rhVEGF treatment only with mesenchymal cell (MC) coculture, and these effects were attenuated with anti-HGF antibody treatment. Unlike VEGF, HGF directly stimulated isolated AT2 cells even without MC coculture. HGF directly stimulates fetal pulmonary artery endothelial cell growth and tube formation, which is attenuated by treatment with JNJ-38877605, a c-Met inhibitor. rHGF treatment preserves alveolar and vascular growth after postnatal exposure to SU-5416, a VEGF receptor inhibitor. We conclude that the effects of VEGF on AT2 and endothelial cells during lung development are partly mediated through HGF-c-Met signaling and speculate that reciprocal VEGF-HGF signaling between epithelia and endothelia is disrupted in infants who develop BPD.
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SOBCZAK-FILIPIAK, MAŁGORZATA, JÓZEF SZAREK, MICHAŁ CZOPOWICZ, MAREK GALANTY, IZABELLA DOLKA, PIOTR TRĘBACZ, JAN FRYMUS, and ROMAN LECHOWSKI. "Stellate cells in livers of dogs with portal vein hypoperfusion." Medycyna Weterynaryjna 74, no. 1 (2018): 6017–2018. http://dx.doi.org/10.21521/mw.6017.
Повний текст джерелаАнотація:
Hepatic stellate cells play a crucial role in the development of liver fibrosis. In a damaged liver, stellate cells undergo activation, which is manifested as a change of their phenotype: differentiation of stellate cells to myofibroblast-type cells, expression of alpha-Smooth Muscle Actin, their proliferation and a reduction in the size of cytoplasmic lipid droplets. The aim of this study was to determine the number and morphology of stellate cells in the canine liver affected by congenital portosystemic shunt (PSS) and portal vein hypoplasia – hepatic microvascular dysplasia (PVH-HMD). The material for investigation were archived paraffin blocks with liver samples collected supravitally from six dogs with PSS, six dogs with PVH-HMD and six healthy dogs. On the HE-stained sections, the number of stellate cells per 100 hepatocytes was counted (Sztark method) and the diameter of veins in the hepatic triads was measured (light microscope Olympus BX 43, SC30 camera, CellSens Entry 2011 Olympus). In addition, the diameter of lipid droplets in stellate cells was measured (computed image analysis system LUCIA 4.21). The results were analysed statistically (the Kruskal-Wallis test followed by Dunn’s post-hoc procedure; significance level (α) at 0.05; Statistica 12 StatSoft Inc.). The degree of liver fibrosis was determined (Masson’s method of slide stain; Scheuer scale). The liver samples from the dogs with PSS and PVH-HMD were stained immunohistochemically with Monoclonal Mouse Anti-Human Smooth Muscle Actin (α-SMA), clone 1A4, antibodies (DAKO). Portosystemic shunt and primary portal vein hypoplasia in the dog results in a reduction in the diameter of portal vein branches and in insufficient portal blood flow through the liver. In the material investigated, this was particularly evident in the animals affected by PSS: such dogs had a significantly smaller diameter of the veins than did the healthy dogs (p<0.001) or the dogs with PVH-HMD (p=0.023). Fibrosis and the expression of α-SMA were stronger in the dogs with PSS than in those with PVH-HMD. Moreover, the dogs with PSS had a significantly higher average number of stellate cells than the healthy animals (p=0.007) did. However, the examination of the material revealed an enlargement of cytoplasmic lipid droplets: the dogs with PSS had a significantly larger diameter of lipid vacuoles in the cytoplasm of stellate cells than did the healthy animals (p<0.001) or the dogs with PVH-HMD (p=0.043); the dogs with PVH-HMD had lipid droplets with a significantly larger diameter than the healthy animals (p<0.001) did. Hypoperfusion of the liver and the accompanying regressive lesions in hepatocytes result mainly in an increased number of stellate cells and stronger expression of α-SMA, while cytoplasmic lipid droplets in the stellate cells are not reduced in size. The present study indicates the need for detailed analyses of clinical cases and warrants further comprehensive studies of comparative hepatopathology because it demonstrates differences between humans and dogs in the morphological indicators of hepatic stellate cell activation in chronic liver damage.
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Not Available, Not Available. "Splice site mutation in the hepatocyte nuclear factor-1β Gene, IVS2nt + 1G > A, associated with maturity-onset diabetes of the young, renal dysplasia and bicornuate uterus". Diabetologia 44, № 3 (9 березня 2001): 387–88. http://dx.doi.org/10.1007/s001250051631.
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Elsonbaty, Sawsan M., Walid E. Zahran та Fatma SM Moawed. "Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats". Tumor Biology 39, № 8 (серпень 2017): 101042831770870. http://dx.doi.org/10.1177/1010428317708703.
Повний текст джерелаАнотація:
β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host’s biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan–treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal–regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both β-glucan therapeutic and preventive treatments. In conclusion, irradiated β-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal–regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis.
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Morrow, Matthew, Rajendra P. Mulpuri, Kevin Dowlatshahi, Katherine Mia Choi, Michael J. Walsh, Ming Jin, Frederick Behm, Pradip Raychaudhuri, and Grace Guzman. "Sa1849 Hepatocyte Nuclear FoxM1 Immunoexpression by Vectra® Automated Multispectral Imaging System Rises in the Large Cell Change Variant of Liver Cell Dysplasia Prior to the Development of Hepatocellular Carcinoma." Gastroenterology 148, no. 4 (April 2015): S—1023—S—1024. http://dx.doi.org/10.1016/s0016-5085(15)33501-0.
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Dowlatshahi, Kevin, Matthew Morrow, Rajendra Mulpuri, Katherine Mia Choi, Ming Jin, Michael J. Walsh, Frederick Behm, Pradip Raychaudhuri, and Grace Guzman. "Sa1846 Hepatocyte FoxMl Nuclear and Cytoplasmic Immunoexpression Range Was Highest in Hepatocellular Carcinoma, and Sequentially Decreased in Large Cell Change, Small Cell Change/Non-Dysplastic Cirrhosis, and Normal Liver Cells As Quantified by Vectra® Automated Multispectral Imaging System." Gastroenterology 148, no. 4 (April 2015): S—1023. http://dx.doi.org/10.1016/s0016-5085(15)33498-3.
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Feng, Xingmin, Phillip Scheinberg, Colin O. Wu, Leigh Samsel, Olga Nunez, Courtney Prince, Barbara Weinstein, et al. "Circulating Cytokine Profiles of Patients with Acquired Aplastic Anemia and Myelodysplastic Syndrome." Blood 112, no. 11 (November 16, 2008): 1038. http://dx.doi.org/10.1182/blood.v112.11.1038.1038.
Повний текст джерелаАнотація:
Abstract Aplastic anemia (AA) and myelodysplastic syndrome (MDS) are acquired hematologic diseases in which bone marrow failure predominates, leading to life-threatening anemia, neutropenia, and thrombocytopenia. Clinically, it may be difficult to distinguish AA from MDS, especially when blood count depression is moderate or marrow hypocellularity is variable. Many studies have focused on immune destruction of hematopoietic stem and progenitor cells in AA and cytogenetic abnormalities in MDS, but comprehensive studies on circulating cytokine profiles of patients with these disorders are scarce. Here, we used multiplex bead array assays (Luminex) to detect 31 cytokines in the plasma of 25 untreated AA patients, 35 MDS patients (including 6 RCMD [refractory cytopenia with multilineage dysplasia], 6 RA-RS [refractory anemia with ringed sideroblasts], 6 MDS-U [MDS, unclassified], 8 RAEB [refractory anemia with excess blasts], 5 MDS 5q- [MDS associated with isolated del(5q)], and 4 RA [refractory anemia]) and 36 healthy controls in order to understand the potential contributions of these cytokines to the pathophysiology of AA and MDS and to provide a possible assistance in differential diagnosis. The measurements were transformed using a natural log-transformation to reduce the skewness of the distributions, and pairwise t-tests were used to compare the means among AA, MDS and healthy controls. The results are summarized in Table 1. AA patients showed significantly higher levels of thrombopoietin (Tpo) and granulocyte colony-stimulating factor (G-CSF) but much lower levels of CD40 ligand (CD40L), Eotaxin, C-X-C chemokine 5 (CXCL5), chemokine (C-C motif) ligand 5 (CCL5), and CXCL11 than MDS patients or healthy controls. Both AA and MDS patients showed higher levels of IL-6 and CCL-3, but lower levels of epidermal growth factor (EGF) than controls. However, levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-a (TNF-a), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ra, hepatocyte growth factor (HGF), CCL4, interferon (INF)-g inducible protein-10 (IP-10), and IL-8 were higher in MDS only and not elevated in AA. There was no difference in Leptin among AA, MDS patients, and controls. INF-g, IL-1b, IL-2, IL-10, IL-4, IL-5, IL-12p70, IL-13, IL-17, fibroblast growth factor (FGF) basic, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-1a were undetectable in most samples. We investigated alterations in CD40L, Eotaxin, CXCL5, and CCL5 in 9 AA patients retrospectively as their clinical status changed: levels of these cytokines positively correlated with hematologic recovery, indicating that they might be useful as prognostic markers of clinical outcome. In summary, we found both similarities and distinctions in cytokine profiles between AA and MDS. High concentrations of Tpo and G-CSF, in combination with low levels of CD40L, Eotaxin, CXCL5, CCL5 and CXCL11 may represent a cytokine signature for AA, while elevated MCP-1, IL-1ra, VEGF and TNF-a may be the cytokine signature for MDS. VEGF may reflect the tumor-associated angiogenic properties described in some cases of MDS. Our results suggest that plasma cytokine screening may be practically useful to distinguish between AA and MDS and also allow inferences concerning pathophysiology in marrow failure. Table 1. Cytokine levels (log-transformed [pg/mL]) in the plasma of patients with AA, MDS and HC cytokine (Mean ± SE) p values cytokine (Mean ± SE) p values AA MDS HC AA vs HC MDS vs HC AA vs MDS AA: aplastic anemia; MDS: myelodysplastic syndrome; HC: healthy controls; SE: standard error; NS: not significant, p > 0.05. G-CSF 4.63 ± 0.42 2.28 ± 0.25 0.89 ± 0.16 <0.0001 <0.0001 <0.0001 Tpo 7.61 ± 0.07 6.36 ± 0.13 5.69 ± 0.05 <0.0001 <0.0001 <0.0001 CD40L 5.80 ± 0.19 7.61 ± 0.18 7.60 ± 0.11 <0.0001 NS <0.0001 Eotaxin 5.32 ± 0.16 6.49 ± 0.09 6.34 ± 0.14 <0.0001 NS <0.0001 CXCL5 4.27 ± 0.23 5.91 ± 0.23 7.01 ± 0.13 <0.0001 0.0001 <0.0001 CCL5 7.34 ± 0.21 9.19 ± 0.17 9.71 ± 0.06 <0.0001 0.0062 <0.0001 CXCL11 4.64 ± 0.26 6.80 ± 0.12 5.55 ± 0.23 0.0132 <0.0001 <0.0001 CCL3 1.67 ± 0.48 4.56 ± 0.16 0.45 ± 0.21 0.0273 <0.0001 <0.0001 IL-6 1.47 ± 0.30 1.85 ± 0.14 0.52 ± 0.07 0.0044 <0.0001 NS EGF 2.35 ± 0.21 2.52 ± 0.31 3.53 ± 0.28 0.0013 0.0184 NS MCP-1 5.34 ± 0.14 5.70 ± 0.11 5.05 ± 0.08 NS <0.0001 0.0388 IL-1ra 6.15 ± 0.12 7.12 ± 0.12 6.36 ± 0.08 NS <0.0001 <0.0001 VEGF 2.10 ± 0.30 3.24 ± 0.17 2.50 ± 0.24 NS 0.0172 0.0033 TNF-a 0.81 ± 0.29 2.26 ± 0.13 0.80 ± 0.14 NS <0.0001 0.0001 IL-8 3.34 ± 0.38 3.21 ± 0.20 2.64 ± 0.16 NS 0.0307 NS CCL4 4.50 ± 0.40 4.31 ± 0.17 3.78 ± 0.13 NS 0.0154 NS HGF 5.18 ± 0.15 5.55 ± 0.12 4.99 ± 0.10 NS 0.0006 NS IP-10 4.50 ± 0.22 4.89 ± 0.15 4.15 ± 0.12 NS 0.0002 NS Leptin 9.12 ± 0.25 8.99 ± 0.20 9.46 ± 0.22 NS NS NS