An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF-and PV-like disease.

No abstract

The overall mortality of hepatitis C virus (HCV)-infected patients has not been fully elucidated. The aim of this study was to analyze mortality in subjects positive for antibody to HCV (anti-HCV) in a community-based, prospective cohort study conducted in an HCV hyperendemic area of Japan. During a 10-year period beginning in 1995, 1,125 anti-HCV seropositive residents of Town C were enrolled into the study and followed for mortality through 2005. Cause of death was assessed by death certificates. Subjects with detectable HCV core antigen (HCVcAg) or HCV RNA were considered as having hepatitis C viremia and were classified as HCV carriers; subjects who were negative for both HCVcAg and HCV RNA (i.e., viremia-negative) were considered as having had a prior HCV infection and were classified as HCV noncarriers. Among the anti-HCV-positive subjects included in the analysis, 758 (67.4%) were HCV carriers, and 367 were noncarriers. A total of 231 deaths occurred in these subjects over a mean follow-up of 8.2 years: 176 deaths in the HCV carrier group and 55 in the noncarrier group. The overall mortality rate was higher in HCV carriers than in noncarriers, adjusted for age and gender (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.13–2.07). Although liver-related deaths occurred more frequently among the HCV carriers (HR, 5.94; 95% CI, 2.58–13.7), the rates of other causes of death did not differ between HCV carriers and noncarriers. Among HCV carriers, a higher level of HCVcAg (≥100 pg/ml) and persistently elevated alanine aminotransferase levels were important predictors of liver-related mortality. Conclusions The presence of viremia increases the rate of mortality, primarily due to liver-related death, among anti-HCV seropositive persons in Japan.

No abstract

Early detection of HCC increases the potential for curative treatment and improves survival. To facilitate early detection of HCC, this study sought to identify novel diagnostic markers of HCC using surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS) ProteinChip technology. Serum samples were obtained from 153 patients with or without HCC, all of whom had been diagnosed with HCV-associated chronic liver disease. To identify proteins associated with HCC, serum samples were analyzed using SELDI-TOF/MS. We constructed an initial decision tree for the correct diagnosis of HCC using serum samples from patients with (n ‫؍‬ 35) and without (n ‫؍‬ 44) HCC. Six protein peaks were selected to construct a decision tree using this first group. The efficacy of the decision tree was then assessed using a second group of patients with (n ‫؍‬ 29) and without (n ‫؍‬ 33) HCC. The sensitivity and specificity of this decision tree for the diagnosis of HCC were 83% and 76%, respectively. For a third group, we analyzed sera from seven patients with HCC obtained before the diagnosis of HCC by ultrasonography (US) and from five patients free of HCC for the past 3 years. Use of these diagnostic markers predicted the diagnosis of HCC in six of these seven patients before HCC was clinically apparent without any false positives. Conclusion: Serum profiling using the SELDI ProteinChip system is useful for the early detection and prediction of HCC in patients with chronic HCV infection. (HEPATOLOGY 2007;45:948-956.) A pproximately 170 million people worldwide are infected with HCV, which when persistent can progress to HCC. The incidence of HCC is rising; in the United States over the past 2 decades, age-specific incidence has shifted toward younger people. 1 IFN or combined IFN and ribavirin, which are currently the only effective treatments for chronic hepatitis C, reduce the occurrence of HCC. 2,3 Some patients, however, do not receive IFN treatment or fail to clear HCV even with IFN treatment. In addition, a subset of individuals remain unaware that they are infected with HCV; in these patients, HCC may present only in the advanced stage. The prognosis of patients presenting with symptoms related to HCC is extremely poor. In contrast, early detection of HCC before the onset of clinical symptoms can lead to curative treatment, significantly improving prognosis.Several methods developed for the diagnosis of HCC, including evaluation of serum markers, ultrasonography (US), computed tomography (CT), and magnetic resonance imaging, have been tested clinically. Alpha-fetoprotein (AFP) and des-gamma carboxy prothrombin (DCP), serum proteins that are elevated in HCC, have been the most widely used markers. Although routine screening offers the best chance for early tumor detection and improved survival, the reported sensitivities and specificities of elevated serum AFP and DCP levels vary significantly. [4][5][6][7][8][9] In addition, AFP levels are elevated in only 30% to 40% of patients with HCC, par...