Inducing differentiation of premalignant hepatic cells as a novel therapeutic strategy in hepatocarcinoma.

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells be found in 28-50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In the present research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human Interleukin 8, a chemokine which correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiationof premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1-mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy

Higher-order Matching for Program Transformation

We present a simple, practical algorithm for higher order matching in the context of automatic program transformation. Our algorithm finds more matches than the standard second order matching algorithm of Huet and Lang, but it has an equally simple specification, and it is better suited to the transformation of programs in modern programming languages such as Haskell or ML. The algorithm has been implemented as part of the MAG system for transforming functional programs. 1 Background and motivation 1.1 Program transformation Many program transformations are conveniently expressed as higher order rewrite rules. For example, consider the well-known transformation that turns a tail recursive function into an imperative loop. The pattern f x = if p x then g x else f (h x ) is rewritten to the term f x = j[ var r ; r := x ; while :(p r) do r := h r ; r := g r ; return r ]j Carefully consider the pattern in this rule: it involves two bound variables, namely f and x , and ..