Quantitation of EGFR and TGF-alpha protein levels in primary head and neck squamous cell carcinomas may be useful in identifying subgroups of patients at high risk of tumor recurrence and in guiding therapy.

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SummaryResuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N 6 -(iminoethyl)-l -lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor B and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions. H emorrhagic shock initiates an inflammatory response characterized by the upregulation of cytokine expression (1) and accumulation of neutrophils (2) in a variety of tissues. These changes are prominent in the lungs and liver and are likely to contribute to end organ damage and resultant dysfunction after shock. The mechanisms by which hemorrhage triggers this inflammatory response remain poorly understood. Heightened adrenergic activity (3) and systemic release of proinflammatory agents from the gut (4, 5) have been hypothesized to contribute to acute lung injury after hemorrhage. In addition, reactive radicals are produced after ischemia/reperfusion and resuscitation from hemorrhagic shock, and have been implicated in a number of signal transduction pathways (6).Among the important radicals produced during hemorrhagic shock is the bioregulatory molecule nitric oxide (NO) 1 generated catalytically by three enzymes collectively termed NO synthases. We (7) and others (8) have shown that the inflammatory or inducible NO synthase (iNOS or NOS2) is upregulated in both the lungs and liver during shock. Therefore, this isoform may be capable of catalyzing the sustained production of NO after the tissue reperfusion associated with fluid resuscitation. NO can have both direct effects on cell signaling as well as indirect actions mediated by the reaction products formed when NO interacts with other molecules such as oxygen or superoxide (9). We hypothesized that enhanced NO production resulting from iNOS expression would contribute to proinflammatory signaling in hemorrhagic shock. Hemorrhagic shock experiments were therefore carried out in rats treated with the iNOS-selective inhibitor N 6 -(iminoethyl)-l -lysine (L-NIL; reference 10) and mice genetically deficient in iNOS. We report here that iNOS inhibition or deficiency prevents t...

SUMMARY Catabolic conditions like chronic kidney disease (CKD) cause loss of muscle mass by unclear mechanisms. In muscle biopsies from CKD patients, we found activated Stat3 (p-Stat3) and hypothesized that p-Stat3 initiates muscle wasting. We created mice with muscle-specific knockout (KO) that prevents activation of Stat3. In these mice, losses of body and muscle weights were suppressed in models of CKD or acute diabetes. A small molecule that inhibits Stat3 activation produced similar responses suggesting a potential for translation strategies. Using C/EBPδ KO mice and C2C12 myotubes with knockdown of C/EBPδ or myostatin, we determined that p-Stat3 initiates muscle wasting via C/EBPδ, stimulating myostatin, a negative muscle growth regulator. C/EBPδ KO also improved survival of CKD mice. We verified that p-Stat3, C/EBPδ and myostatin were increased in muscles of CKD patients. The pathway from p-Stat3 to C/EBPδ to myostatin and muscle wasting could identify therapeutic targets that prevent muscle wasting.

Background:No reliable treatment exists for cancer-related muscle loss. Results: In muscles of mice with cancer, p-Stat3 stimulates proteolysis by activating caspase-3 and the ubiquitin-proteasome system through a C/EBP␦ and myostatin pathway. Conclusion: Inhibition of Stat3 suppresses cancer-induced muscle losses.Significance: A small-molecule Stat3 inhibitor could be integrated into therapeutic strategies for preventing cancer-induced muscle losses.