Activation of innate immunity (natural killer [NK] cell/interferon‐γ [IFN‐γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2‐week or a 10‐week carbon tetrachloride (CCl4) challenge, respectively. Injection of polyinosinic‐polycytidylic acid (poly I:C) or IFN‐γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2‐week CCl4 model. Such activation was diminished in the 10‐week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN‐γ on liver fibrosis was markedly reduced in the 10‐week versus the 2‐week CCl4 model. In vitro coculture experiments demonstrated that 4‐day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid–induced early gene 1–dependent mechanism. Such activation was reduced when cocultured with 8‐day cultured (intermediately activated) HSCs due to the production of transforming growth factor‐β (TGF‐β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN‐γ–mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN‐γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN‐γ signaling and functioning, whereas production of TGF‐β by HSCs inhibited NK cell function and cytotoxicity against HSCs. Conclusion: The antifibrogenic effects of NK cell/IFN‐γ are suppressed during advanced liver injury, which is likely due to increased production of TGF‐β and expression of SOCS1 in intermediately activated HSCs. (HEPATOLOGY 2011;)

Clinical trials and animal models suggest that infusion of bone marrow cells (BMC) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMC. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMC showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMC and activated hepatic stellate cells (HSCs) was investigated using in vitro co-culturing system. Within 24 hours, infused BMC were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10−/−) BMC failed to reproduce these effects in the fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMC expressed more IL-10 after co-culturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMC were co-cultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMC expressed more IL-10 after co-culturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Conclusion Activated HSCs increase IL-10 expression in BMC (CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.

PurposeThe aim of this study was to investigate epidemiology, clinical characteristics and sex differences of patients with lung cancer using nationwide registry in Korea.Materials and MethodsThe Korean Association for Lung Cancer developed a registry in cooperation with the Korean Central Cancer Registry, and surveyed about 10% of lung cancer cases. For this first survey of cases diagnosed in 2014, cases were selected through a systematic sampling method.ResultsTotal 2,621 lung cancer patients were surveyed, and the median patient age was 70 years. During the study period, adenocarcinoma was the most frequent histologic type, the proportion of female patients was 28.4%, and women had a better prognosis (median survival, not reached vs. 13 months; p<0.001) than did men for non-small cell lung cancer. The proportion of never-smokers was 36.4%, and never-smoking was more prevalent in women than in men (87.5 vs. 16.0%, p<0.001). Epidermal growth factor receptor (EGFR) mutations were found in 36.8% of stage IV adenocarcinoma patients, and higher in female compared to male patients (51.2 vs. 26.6%, p<0.001). In addition, patients with EGFR mutation showed better survival (median survival, 18 vs. 8 months; p<0.001) than patients without EGFR mutation in these patients.ConclusionThis is the first survey to gather unbiased nationwide lung cancer statistics in Korea. More than one-third of lung cancer patients had no smoking history. Female had a high proportion of non-smoker, more adenocarcinoma with EGFR mutation and generally better prognosis than male.

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We investigated treatment outcomes of radiotherapy for solitary plasmacytoma (SP) and prognostic factors affecting survival. Between 1996 and 2010, a total of 38 patients were treated with radiotherapy for histologically proven plasmacytoma without evidence of multiple myeloma. Among these, 16 and 22 patients had SP originating from extramedullary soft tissue (EMP) and bone, respectively. Thirteen patients received adjuvant chemotherapy, and three patients underwent surgery prior to radiotherapy. At a median follow-up of 50 months (range, 8-142), radiotherapy demonstrated excellent local control (5- and 10-year local control rates, 81%). However, the 10-year multiple myeloma-free survival (MMFS) was 54% and the 10-year overall survival (OS) rates was 35%. Solitary bone plasmacytoma (SBP) more frequently progressed to multiple myeloma (MM) than EMP (10-year MMFS, 0% vs. 71%, p = 0.02). Radiotherapy with doses ≥40 Gy demonstrated better local control (10-year LC, 100% vs. 60%, p = 0.04) in SBP. In the multivariate analysis, elevated β₂-microglobulin was a significantly unfavorable prognostic factor affecting OS (p = 0.03). In conclusion, radiotherapy effectively treated SP without significant toxicity. However, progression to MM presents a challenging problem. Novel therapeutics are needed for patients with unfavorable prognostic factors.