709 HIGH EXPRESSION OF CLASS I HISTONE DEACETYLASE IS ASSOCIATED WITH TUMOR PROGRESSION AND POOR SURVIVAL OF HEPATOCELLULAR CARCINOMA
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Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.
Crosstalk
Histone deacetylase 5
HDAC11
HDAC1
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Foreword. Preface. 1. The background to hepatocellular carcinoma and the liver. 2. Premalignant lesions of hepatocellular carcinoma. 3. Pathomorphologic characteristics of early-stage small hepatocellular carcinoma. 4. Morphologic evolution of hepatocellular carcinoma: from early to advanced. 5. Angioarchitecture of hepatocellular carcinoma. 6. Advanced hepatocellular carcinoma. 7. Multicentric occurrence of hepatocellular carcinoma. 8. Combined hepatocellular carcinoma and cholangiocarcinoma. 9. Nodular lesions mimicking hepatocellular carcinoma. 10. Biopsy diagnosis of tumorous lesions of the liver. 11. Chemoprevention of hepatocellular carcinoma. Index
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Hepatocellular carcinoma is the most common malignancy among males and the 7th among female patients in the Kingdom of Saudi Arabia. This is due to the endemicity of hepatitis B and hepatitis C. Spontaneous rupture of hepatocellular carcinoma is rare. We report 4 cases of spontaneous rupture of hepatocellular carcinoma. Initial control of bleeding was achieved surgically in 3 patients and by embolization in the 4th patient. All patients had very good hepatic reserve as reflected by Child-Pugh scoring (A & B). We found that the incidence of ruptured hepatocellular carcinoma among 85 patients was 4.7%. The prognosis of this subgroup of patients is poor as reflected by the low median survival ranging from 6-16 weeks.
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The problem and approaches to the treatment of hepatocellular carcinoma as seen in Japan are reported. Current Japanese methods for the detection of hepatocellular carcinoma and the methods used to treat hepatocellular carcinoma are described. Included in the latter discussion is a description of the untoward effects of each treatment. Finally an alogorithm for the treatment of hepatocellular carcinoma is presented based upon the Japanese experience.
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Hepatitis B
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Orthotopic liver transplant is the treatment of choice for hepatocellular carcinoma in cirrhotic patients with satisfactory oncologic and survival outcomes. Incidental hepatocellular carcinoma is frequently a reported finding in the explant pathology after orthotopic liver transplant.The present study retrospectively analyzed the tumor characteristics and outcomes of 50 incidental hepatocellular carcinomas compared with 252 transplants for known hepatocellular carcinoma.Patients with incidental hepatocellular carcinoma had lower peak alpha-fetoprotein level (P = .001), lower pretransplant alpha-fetoprotein level (P = .002), smaller total tumor size (P = .0001), fewer tumor numbers (P = .0001), lower level of microvascular invasion (P = .001), more cases within Milan criteria (P = .005), and more well-differentiated tumors (P = .017). However, no difference in survival rates was observed between the 2 groups. In 35 patients (70%) who had incidental hepatocellular carcinoma, pretransplant imaging studies were normal; ultrasonography was used as the only screening tool in 25 of 35 patients (71%) who had incidental hepatocellular carcinoma, and 15 patients (30%) who had incidental hepatocellular carcinoma had regenerative or dysplastic nodules. The accuracy of ultrasonography in our unit for diagnosing hepatocellular carcinoma was 97.5%. A quarter of hepatitis B recipients had incidental hepatocellular carcinoma with a younger median recipient age. Tumor recurrence was higher with incidental hepatocellular carcinoma in hepatitis C recipients (22%). However, the overall recurrence was similar between all hepatitis and nonhepatitis recipients who were transplanted for incidental or known hepatocellular carcinoma.Incidental hepatocellular carcinoma has similar outcome as known hepatocellular carcinoma. Early screening of hepatitis B patients is recommended, and cross-sectional imaging is not mandatory for hepatocellular carcinoma screening in patients who are on the waiting list.
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Direct acting antivirals stabilize or improve liver function in the majority of patients with hepatitis C virus cirrhosis. Hepatic decompensation is the main driver of death of patients with early, successfully treated hepatocellular carcinoma superimposed to cirrhosis. Treatment with direct acting antivirals could improve the prognosis of these subjects, independently from the subsequent course of hepatocellular carcinoma, if the efficacy in obtaining viral clearance is as high as in patients without a history of hepatocellular carcinoma, and if the risk of hepatocellular carcinoma recurrence is unaffected. When dealing with hepatocellular carcinoma patients, direct acting antivirals can be indicated in two different settings: (a) subjects in which hepatocellular carcinoma has been already successfully treated ("cured" hepatocellular carcinoma), or (b) subjects whose hepatocellular carcinoma is still untreated or untreatable ("active" hepatocellular carcinoma). Although there are abundant data on "cured" hepatocellular carcinoma, evidence supporting treatment decisions in patients with "active" hepatocellular carcinoma is at best scarce and controversial, since these patients as well as patients with hepatocellular carcinoma listed for liver transplantation are usually excluded from treatment.
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Hepatocellular cancer
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Overexpression of histone deacetylases (HDACs), with consequent hypoacetylation of histones, is reportedly associated with transcriptional repression of tumour suppressor genes. Thus, inhibition of HDACs has emerged as a promising strategy in cancer therapy. In order to monitor the effects of potential HDAC inhibitors, a multi-level approach consisting of preliminary screening (measurement of HDAC activity and semi-quantitative evaluation of histone H4 modification profile by MALDI-TOF MS) and detailed analysis of histone modification forms (using 2-D AUT/AU PAGE and LC-ESI-IT MS) has been used in this study. The data obtained provide a global insight into the effects of HDAC inhibitors on the histone acetylation status that participates in gene transcription control. Using two example inhibitors, valproic acid sodium salt and entinostat, we show that similar levels of HDAC inhibition induced by different agents can lead to distinct rates of histone hyperacetylation, suggesting that except for the direct inhibition of HDACs, additional molecular mechanisms amplifying the response are likely to be involved in the inhibitory process. The approach used in our study makes it possible not only to follow the dynamics of individual histone modification forms, but also of their combined occurrence in the N-terminal fragment.
HDAC11
Histone deacetylase 5
Histone deacetylase 2
HDAC10
Histone H4
Valproic Acid
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The aim of this study was to determine the characteristics of hepatocellular carcinoma at a major health center in southern Turkey. Computed tomography was compared to the combination of ultrasonography and serum alpha-fetoprotein determination in the diagnosis of hepatocellular carcinoma.Of 226 patients with liver cirrhosis, 35 were diagnosed with hepatocellular carcinoma on first admission or during follow-up in the period between 1999 and 2002. The features investigated were, age at time of hepatocellular carcinoma diagnosis, etiology of cirrhosis, severity of cirrhosis at presentation, tumor pattern, stage of hepatocellular carcinoma, serum alpha-fetoprotein level, and dynamic computed tomography findings. Results were compared to previous findings in Turkey and elsewhere.In the hepatocellular carcinoma patients, the male:female ratio was 4:1 and the mean age at presentation was 61 years. Chronic hepatitis B virus infection (65.7%) and chronic hepatitis C virus infection (28.6%) were the most frequently identified risk factors for hepatocellular carcinoma. Forty percent of the patients had Child-Pugh A cirrhosis when they were diagnosed with hepatocellular carcinoma. Sixty-seven percent of patients had fewer than three hepatocellular carcinoma nodules in the liver at the time of diagnosis. Only three of the hepatocellular carcinoma cases were Okuda stage I. The combination of ultrasonography and serum alpha-fetoprotein >20 ng/ml identified hepatocellular carcinoma in 32 of the 35 total cases.The results indicate that hepatitis B virus infection in patients with cirrhosis is still the leading risk factor for the development of hepatocellular carcinoma. Also, early-stage hepatocellular carcinoma is rarely diagnosed in cirrhosis patients from this region of Turkey. Surveillance with computed tomography for early diagnosis of hepatocellular carcinoma seems not to be mandatory.
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Objective To evaluate serum AFP levels and their influence factors in patients with hepatocellular carcinoma.Methods From January 1995 to December 1999,140 patients were subjected to hepatectomy in our hospital,AFP levels of the patients were evaluated.The data of the patients were analyzed by nonconditional logistic regression with SPSS10.0.Results The positive rate of AFP was 62.9% in patients with hepatocellular carcinoma.The positive rate of AFP of small hepatocellular carcinoma(52.0%) was significantly higher than that of large hepatocellular carcinoma (73.9%) ( P 0.05).It was showed that the AFP levels were related to tumor size and cirrhosis through logistic regression( P 0.05).Conclusion Sensitivity of AFP in hepatocellular carcinoma diagnosis,especially in small hepatocellular cancer was lower.It was notably increased when combined with other diagnostic methods.
Alpha-fetoprotein
Liver Cancer
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