BackgroundHigh baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients.Methods and FindingsIn the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR.ConclusionsConcomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

In patients with chronic hepatitis C, low levels of intrahepatic and systemic IP-10 predict a favorable first-phase decline of HCV RNA during therapy with pegylated interferon and ribavirin for genotypes of HCV.

SUMMARY BackgroundHepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue.

The initial chemotherapy in acute myeloid leukaemia (AML) comprises a first phase of induction and a second phase of consolidation. In the majority of patients, the induction treatment leads to complete remission (CR), defined as microscopic disappearance of leukaemic disease along with the return of normal haematopoiesis. However, despite the introduction of more efficacious consolidation regimens, a worryingly large proportion of AML patients in CR will subsequently experience relapses with poor prospects of long‐term survival. A relapse is assumed to be the result of expansion of residual leukaemic cells that have escaped the initial chemotherapy. The anti‐leukaemic functions of T cells and natural killer (NK) cells has formed the background to the use of interleukin‐2 (IL‐2), a T‐ and NK cell‐activating cytokine, with the aim to eliminate residual leukaemia and hence reduce the relapse rate in AML, but the clinical trials using IL‐2 monotherapy have yielded disappointment. A recent phase III study has demonstrated that post‐consolidation treatment with the combination of histamine dihydrochloride (HDC) and IL‐2 significantly prevents relapse in AML patients. Here we account for the preclinical background to the use of HDC/IL‐2 in AML along with a review of clinical results.

LL-37 is a cationic host defense peptide that is highly expressed during acute inflammation and that kills bacteria by poorly defined mechanisms, resulting in permeabilization of microbial membranes. High concentrations of LL-37 have also been reported to have cytotoxic effects against eukaryotic cells, but the peptide is clearly capable of differentiating between membranes with different compositions (eukaryotic versus bacterial membranes). Eukaryotic cells such as leukocytes change their membrane composition during apoptotic cell death, when they are turned into nonfunctional but structurally intact entities. We tested whether LL-37 exerted specific activity on apoptotic cells and found that the peptide selectively permeabilized the membranes of apoptotic human leukocytes, leaving viable cells unaffected. This activity was seemingly analogous to the direct microbicidal effect of LL-37, in that it was rapid, independent of known surface receptors and/or active cell signaling, and inhibitable by serum components such as high-density lipoprotein. A similar selective permeabilization of apoptotic cells was recorded for both NK cells and neutrophils. In the latter cell type, LL-37 permeabilized both the plasma and granule membranes, resulting in the release of both lactate dehydrogenase and myeloperoxidase. Apoptosis is a way for inflammatory cells to die silently and minimize collateral tissue damage by retaining tissue-damaging and proinflammatory substances within intact membranes. Permeabilization of apoptotic leukocytes by LL-37, accompanied by the leakage of cytoplasmic as well as intragranular molecules, may thus shift the balance between pro-and anti-inflammatory signals and in this way be of importance for the termination of acute inflammation.