BACKGROUND Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)
Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining but rates of cirrhosis and hepatocellular carcinoma are projected to rise. The outcome of chronic hepatitis C is variable. It is estimated that 20–25% will develop cirrhosis over a 25–30 year period. The rate of disease progression is influenced by may host, viral and environmental factors. Unfortunately, few can be modified.
Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.Genet Med 19 2, 160-168.
Background & Aims Our previous studies showed that CD133, EpCAM and aldehyde dehydrogenase (ALDH) are useful markers to identify cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) tissues. The present study aims to evaluate chemosensitivity and invasion capability of HCC based on CSC marker profiles, and to explore underlying molecular mechanisms. Methods Hepatoma cell lines were separated into subpopulations according to CD133, EpCAM and ALDH expression profiles. Epithelial mesenchymal transition (EMT) and hedgehog (Hh) signaling were examined to identify their links with chemoresistance and aggressive invasion. Results Well-differentiated cell lines were positive for CD133+/ALDHhigh and CD133+/EpCAM+ at 1.5–15% and 2.3–8.3%; whereas, poorly-differentiated cells were almost all negative for these markers. FACS-enriched CD133+/ALDHhigh and CD133+/EpCAM+ Hep3B and Huh-7 cells formed more spheroids in vitro. CD133−/ALDHlow HLE cells were more resistant to cisplatin, doxorubicin or sorafenib than their positive counterparts. CD133−/EpCAM− Huh-7 cells or CD133−/ALDH− HLE cells exhibited a higher invasion rate than their positive counterparts. HLE and HLF cells acquired EMT in double negative subpopulations. Hh activity in Huh-7 CD133−/EpCAM− cells was higher than in their positive counterparts, and the inhibition of Hh activity by cyclopamine resulted in reduced cell proliferation. Conclusions Well-differentiated CD133+/ALDHhigh or CD133+/EpCAM+ cells appear to be a CSC/initiating subpopulation; whereas, in poorly-differentiated hepatoma cells, EMT and enhanced hedgehog signaling activity may be responsible for their chemoresistance and invasion. These findings underscore the significance of EMT and enhanced Hh signaling in liver cancer stem or initiating cells.
BACKGROUND-Cancer stem cells (CSCs) are thought to be a critical subpopulation in tumor development, progression, metastasis and recurrence, and the identification of these cells is an initial step in understanding their role in oncogenesis and in seeking valuable markers for diagnosis or development of targeting therapeutics.
The transplantation of primary hepatocytes has been shown to augment the function of damaged livers and to bridge patients to liver transplantation. However, primary hepatocytes often have low levels of engraftment and survive for only a short time after transplantation. To explore the potential benefits of using decellularized liver matrix (DLM) as a carrier for hepatocyte transplantation, DLM from whole mouse livers was generated. Human fetal hepatocytes immortalized by telomerase reconstitution (FH-hTERTs) or primary human hepatocytes were infused into the DLM, which was then implanted into the omenta of immunodeficient nonobese diabetic/severe combined immunodeficient/interleukin-2 receptor c-deficient mice or nonobese diabetic/severe combined immunodeficient/mucopolysaccharidosis type VII mice. The removal of endogenous cellular components and the preservation of the extracellular matrix proteins and vasculature were demonstrated in the resulting DLM. Bioluminescent imaging revealed that FH-hTERTs transduced with a lentiviral vector expressing firefly luciferase survived in the DLM for 8 weeks after peritoneal implantation, whereas the luciferase signal from FH-hTERTs rapidly declined in control mice 3 to 4 weeks after transplantation via splenic injection or omental implantation after Matrigel encapsulation. Furthermore, primary human hepatocytes that were reconstituted in the DLM not only survived 6 weeks after transplantation but also maintained their function, as demonstrated by messenger RNA levels of albumin and cytochrome P450 (CYP) subtypes (CYP3A4, CYP2C9, and CYP1A1) similar to the levels in freshly isolated human primary hepatocytes (hPHs). In contrast, when hPHs were transplanted into mice via splenic injection, they failed to express CYP3A4, although they expressed albumin. In conclusion, DLM provides an excellent environment for long-term survival and maintenance of the hepatocyte phenotype after transplantation.
Loss‐of‐function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity in telomere diseases, but very few studies have characterized the nature and extent of liver involvement in affected patients. We report the prevalence and characteristics of liver involvement in a large cohort of patients with telomere disease evaluated serially at the National Institutes of Health. One hundred twenty‐one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included in the current study. Median follow‐up was 2.4 years. Data were collected regarding their demographic information, laboratory analysis, imaging, and histopathology. Forty patients (40% of the cohort) with a median age of 42 years were found to have liver involvement. Liver enzyme elevation was cholestatic in pattern; 8 (21%) had drug‐related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% (9) of patients, followed by hepatomegaly in 26% (6). Biopsies were infrequent because of risk associated with thrombocytopenia, but in 6 patients, there were varying findings: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. Almost half the cohort had pulmonary diffusion abnormalities, and 25% died during the follow‐up period. Conclusion: In patients with telomere disease, hepatic involvement is common and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities. Liver disease has important implications for morbidity and mortality in patients with telomere disease.
Chronic hepatitis B (CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma (HCC). Liver transplantation (LT) is considered gold standard for treatment of hepatitis B virus (HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival. The combination of lamivudine (LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA (cccDNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.
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