TCF1 expression marks self-renewing human CD8+ T cells.

Expression of the transcription factor T-cell factor 1 (TCF1) identifies antigen-experienced murine CD8+ T cells that retain potential for lymphoid recirculation and the ability to self-renew while producing more differentiated effector cells. We found that CD8+ T cells in the blood of both healthy and chronically infected humans expressed TCF1 at 3 distinct levels: high (TCF1-hi), intermediate (TCF1-int), and low (TCF1-lo). TCF1-hi cells could be found within both the naive and memory compartments and were characterized by relative quiescence and lack of immediate effector function. A substantial fraction of TCF1-int cells were found among memory cells, and TCF1-int cells exhibited robust immediate effector functions. TCF1-lo cells were most enriched in effector memory cells that expressed the senescence marker CD57. Following reactivation, TCF1-hi cells gave rise to TCF1-lo descendants while self-renewing the TCF1-hi progenitor. By contrast, reactivation of TCF1-lo cells produced more TCF1-lo cells without evidence of de-differentiating into TCF1-hi cells. Flow cytometric analyses of TCF1 expression from patient specimens may become a useful biomarker for adaptive immune function in response to vaccination, infection, autoimmunity, and cancer.

Sorafenib: where do we go from here?

The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.

Interferon-alpha-2b and ribavirin for retreatment of chronic hepatitis C.

BACKGROUND/AIMS: Subjects with chronic hepatitis C who fail treatment with interferon-alpha are generally divided into two groups: "relapsers" who normalized serum aminotransferase activity and have undetectable viral RNA during treatment and "non-responders" who do not achieve these results. The aim of this study was to examine retreatment of such subjects. METHODOLOGY: We studied 117 subjects with chronic hepatitis C who failed treatment with interferon-alpha, 87 of whom were "non-responders" and 30 "relapsers." Retreatment was with either interferon-alpha-2b plus ribavirin for 48 weeks or with interferon-alpha-2b plus placebo for 24 weeks followed by 24 weeks of combined therapy. RESULTS: Sustained response rates, defined as undetectable viral RNA in serum 6 months after retreatment, were 53% in "relapsers" and 10% in "non-responders" (P < 0.005). There was no significant difference if ribavirin was given for 24 or 48 weeks. In "non-responders" infected with genotypes other than type 1, 42% achieved a sustained response compared to 5% infected with genotype 1 (P = 0.027; odds ratio 7.09). CONCLUSIONS: Treatment with interferon-alpha-2b plus ribavirin is effective in approximately 50% of "relapsers" and "non-responders" infected with non-type 1 genotypes of hepatitis C virus. This therapy is only marginally effective in "non-responders" infected with genotype 1a or 1b.