Treatment of inclusion body myositis: is low-dose intravenous immunoglobulin the solution?

Inclusion body myositis (IBM), the most common inflammatory myopathy in the elderly, is often resistant to various forms of therapy. Placebo-controlled treatment trials with high dose intravenous immunoglobulins (IVIG) have shown disease amelioration in some but not all patients. Here, we present the informative case of a 70-year-old woman with diagnosed inclusion body myositis that showed progressive muscle weakness without treatment and following immuno-suppressive treatment with corticosteroids and azathioprine. A trial with low-dose intravenous immunoglobulins was started at that time. The patient responded rapidly to low dose IVIG treatment with amelioration of muscle strength and normalization of CK serum activities. Our results demonstrate that IBM patients may respond to low-dose IVIG treatment which has important clinical and economic consequence

Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options

Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options

The Transmembrane Adaptor Protein SIT Inhibits TCR- Mediated Signaling

Transmembrane adaptor proteins (TRAPs) organize signaling complexes at the plasma membrane, and thus function as critical linkers and integrators of signaling cascades downstream of antigen receptors. We have previously shown that the transmembrane adaptor protein SIT regulates the threshold for thymocyte selection. Moreover, T cells from SIT-deficient mice are hyperresponsive to CD3 stimulation and undergo enhanced lymphopenia-induced homeostatic proliferation, thus indicating that SIT inhibits TCR-mediated signaling. Here, we have further addressed how SIT regulates signaling cascades in T cells. We demonstrate that the loss of SIT enhances TCR-mediated Akt activation and increased phosphorylation/ inactivation of Foxo1, a transcription factor of the Forkhead family that inhibits cell cycle progression and regulates T-cell homeostasis. We have also shown that CD4 + T cells from SIT-deficient mice display increased CD69 and CD40L expression indicating an altered activation status. Additional biochemical analyses further revealed that suppression of SIT expression by RNAi in human T cells resulted in an enhanced proximal TCR signaling. In summary, the data identify SIT as an importan

Analysis of activation markers in SIT^−/− mice.

<p>A) Splenic CD4⁺ T cells from 1 year-old SIT-deficient and wild-type mice were analyzed for CD69 expression. Numbers within histograms indicate the percentage of cells. One representative profile per group is shown. B) Comparison of CD40L expression on CD4⁺ T cells isolated from SIT-deficient (empty histogram) and wild-type (filled histogram) mice. Mean fluorescent intensity (MFI) from one representative mouse per group is indicated. C) Comparison of CD5 expression on CD4⁺ T cells isolated from SIT-deficient (empty histogram) and wild-type (filled histogram) mice. Bar graphs in A), B), and C) represent statistical analyses of CD69, CD40L, and CD5 expression, respectively. Data derive from at least 5 mice per group. Statistical significance * p<0.05 and ***p<0.0001.</p

Downregulation of SIT results in an enhanced TCR-mediated signaling in primary human T cells.

<p>A) Primary human T cells were transfected with control or SIT-specific siRNA and 72 h later were stimulated with non-crosslinked CD3 (clone OKT3) mAb for the indicated times. Cell lysates were analyzed by immunoblotting using phosphospecific antibodies for ZAP-70, PLCγ-1, and Akt. Immunoblots verifying SIT downregulation are shown. B) Phosphorylated bands were quantified using the ImageQuant software and values were normalized to the corresponding β-actin signal. Graphs show the phosphorylation levels of ZAP-70, PLCγ-1, and Akt shown as of arbitrary units ± SEM of 2, 4, and 6 independent experiments, respectively. Statistical significance in B) * p<0.05 and **p<0.01.</p

T-cell subpopulations in the spleen.

<p>Number of cells in the spleen (×10⁶) ± SEM. n = number of examined mice.</p

Normal survival and steady-state proliferation of SIT-deficient CD4⁺ T cells.

<p>Lymph node cells were isolated and stained with CD4 and CD8 mAbs. A) BrdU incorporation was measured for CD4⁺ T cells. Bar graphs indicate mean values ± SEM from 3 SIT⁻/⁻ and 5 SIT⁺/⁺ mice. B) Intracellular Bcl-2 expression in CD4⁺ T cells from SIT⁻/⁻ (empty histogram) and SIT⁺/⁺ (filled histogram) mice. Isotype control is shown as a gray line. C) Annexin V expression on CD4⁺ T cells. Bar graphs indicate mean values ± SEM from 3 SIT⁻/⁻ and 3 SIT⁺/⁺ mice.</p

T-cell subsets in lymph nodes.

<p>% of lymph node cells ± SEM. n = number of examined mice.</p