Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that is overexpressed in lung cancer. The MIF receptor was recently discovered and found to be the invariant chain of the HLA class II molecule, CD74. We hypothesized that the expression of this receptor-ligand pair in lung cancer is associated with the angiogenic activity and level of CXC chemokine expression in human specimens of non-small cell lung cancer. We, therefore, performed immunolocalization of CD74 and compared it with the localization of MIF in non-small cell lung cancer to determine their respective locations, as well as the relationship between the co-expression of MIF-CD74 and angiogenic CXC chemokines with tumor angiogenesis. We found intense CD74 expression by immunohistochemistry in 57 of 70 tumors with minimal to no staining in the remaining 13 tumors. Comparing the localization of CD74 with its putative ligand, MIF, we found that CD74 and MIF were co-expressed in tumors in close proximity, and that co-expression of the MIF-CD74 pair was associated with both higher levels of tumor-associated angiogenic CXC chemokines (ie, the ELR score) and greater vascularity compared with tumors in which MIF-CD74 co-expression was not present. We also found that MIF induced angiogenic CXC chemokine expression in an autocrine manner in vitro , a function that was specifically inhibited by antibodies to CD74. (Am J Pathol

Angiogenesis is crucial for tumor biology. There are many mechanisms by which tumors induce angiogenesis. We hypothesize that each individual tumor develops a unique mechanism to induce angiogenesis, and that activation of a particular angiogenic pathway suppresses the evolution of alternative pathways. We characterized 168 human non-small cell lung cancer (NSCLC) specimens for levels of angiogenic factors (angiogenic CXC chemokines, basic fibroblast growth factor, and vascular endothelial growth factor). We also induced lung tumor formation in A/J mice by injecting the tobacco carcinogen NNK. We dissected individual lung tumors and measured expression of angiogenic factors from three distinct families using real-time PCR. Finally, we controlled the angiogenic milieu using in vivo models to determine the resultant phenotype of the angiogenic factors expressed by NSCLC cells. Human tumors displayed marked variation in the expression of angiogenic factors. Individual mouse tumors, even from within the same mouse, displayed variability in their pattern of expression of angiogenic factors. In a sponge model of angiogenesis using murine lung cancer cells, implanting LLC cells with an angiogenic factor suppressed the expression of other angiogenic factors in implanted sponges. This suppressive effect was not seen in vitro. We conclude that lung cancer tumors evolve a unique and dominant angiogenic phenotype. Once an angiogenic pathway is activated, it may allow for tumor growth to proceed in the absence of a selection pressure to activate a second pathway.

The Brg1/Brm-associated factor (BAF) chromatin remodeling complex directly binds the CD4 silencer and is essential for CD4 repression during T-cell development, because deletion of the ATPase subunit Brg1 or a dominant negative mutant of BAF57 each impairs CD4 repression in early thymocytes. Paradoxically, BAF57 is dispensable for remodeling nucleosomes in vitro or for binding of the BAF complex to the CD4 silencer in vivo. Thus, it is unclear whether BAF57-dependent CD4 repression involves chromatin remodeling and, if so, how the remodeling translates into CD4 repression. Here we show that nucleosomes at the CD4 silencer occupy multiple translational frames. BAF57 dominant negative mutant does not alter these frames, but reduces the accessibility of the entire silencer without affecting the flanking regions, concomitant with localized accumulation of linker histone H1 and eviction of Runx1, a key repressor of CD4 transcription that directly binds the CD4 silencer. Our data indicate that precise nucleosome positioning is not critical for the CD4 silencer function and that BAF57 participates in remodeling H1-containing chromatin at the CD4 silencer, which enables Runx1 to access the silencer and repress CD4. In addition to BAF57, multiple other subunits in the BAF complex are also dispensable for chromatin remodelling in vitro. Our data suggest that these subunits could also help remodel chromatin at a step after the recruitment of the BAF complex to target genes.Key words: BAF57 . CD4 . Chromatin Supporting Information available online IntroductionChromatin remodeling complexes are capable of using energy derived from ATP hydrolysis to physically disrupt DNA-histone contacts and facilitate the binding of transcription factors to nucleosomal DNA (for recent reviews, see [1,2]). There are multiple types of chromatin remodeling complexes in mammals, the best known being the Swi/Snf-like Brg1/Brm-associated factor (BAF) complexes that play diverse but tissue-specific roles in gene regulation [3][4][5]. The BAF complex consists of about 8-15 subunits including the catalytic ATPase subunit Brg1 or its homolog Brm. Surprisingly, the majority of these 15 subunits are dispensable for chromatin remodeling in vitro. The first clue came from the observation that the N-terminal HMG domain of BAF57, 580an HMG-box protein, is dispensable for the BAF complex to remodel mononucleosomes in vitro [6]. Subsequently, it was found that only four of the BAF subunits (Brg1, BAF45, BAF155 and BAF170) are sufficient to reconstitute a core complex possessing full remodeling activity on mononucleosomes and nucleosomal arrays [7]. The in vivo roles of the remaining 11 ''dispensable'' BAF subunits remain unclear, except that some of these subunits are thought to function by helping recruit the BAF complex to target genes via interactions with sequence-specific transcription factors or chromatin, thus indirectly contributing to chromatin remodeling. For example, BAF250 contains an ARID DNA-binding domain and a C-terminal domain capable of in...

Rationale: Tissue injury and repair involve highly conserved processes governed by mechanisms that can be co-opted in tumors. We hypothesized that soluble factors released during the repair response to lung injury would promote orthotopic tumor growth. Objectives: To determine whether lung injury promoted growth of orthotopic lung tumors and to study the molecular mechanisms. Methods: We initiated lung injury in C57Bl6 mice using different stimuli, then injected Lewis lung carcinoma cells during the repair phase. We assessed tumor growth 14 days later. We measured tumor angiogenesis, cytokine expression, proliferation, and apoptosis. Measurements and Main Results: Regardless of the mechanism, injured lungs contained more numerous and larger tumors than shaminjured lungs. Tumors from injured lungs were no more vascular, but had higher levels of proliferation and reduced rates of apoptosis. The cytokine macrophage migration inhibitory factor (MIF) was highly expressed in both models of tissue injury. We observed no increase in tumor growth after lung injury in MIF knockout mice. We induced lung-specific overexpression of MIF in a double-transgenic mouse, and observed that MIF overexpression by itself was sufficient to accelerate the growth of orthotopic Lewis lung carcinoma tumors. Conclusions: Lung injury leads to increased expression of the cytokine MIF, which results in protection from apoptosis and increased proliferation in orthotopic tumors injected after the acute phase of injury.

Evidence-based care of women in labor requires a thorough understanding of both "normal" and abnormal labor progress. In response to the growing cesarean delivery rate for dystocia at our institution, a multidisciplinary team of attending physicians, nurse-midwives, resident physicians, and nurses was established to review the literature and create evidence-based guidelines. This article describes the background literature and consensus guidelines reached for the diagnosis of active phase labor, active phase arrest, second-stage arrest, protraction of the active phase, and failed induction of labor. Our review illustrates that slower labor patterns than traditionally described often result in a vaginal delivery without unacceptable increases in maternal or neonatal morbidity.