MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells

Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.     

Locally advanced stage IV squamous cell carcinoma of the head and neck: impact of pre-radiotherapy hemoglobin level and interruptions during radiotherapy

PURPOSE: Stage IV head and neck cancer patients carry a poor prognosis. Clear understanding of prognostic factors can help to optimize care for the individual patient. This study investigated 11 potential prognostic factors including pre-radiotherapy hemoglobin level and interruptions during radiotherapy for overall survival (OS), metastases-free survival (MFS), and locoregional control (LC) after radiochemotherapy. METHODS AND MATERIALS: Eleven factors were investigated in 153 patients receiving radiochemotherapy for Stage IV squamous cell head and neck cancer: age, gender, Karnofsky performance score (KPS), tumor site, grading, T stage, N stage, pre-radiotherapy hemoglobin level, surgery, chemotherapy type, and interruptions during radiotherapy>1 week. RESULTS: On multivariate analysis, improved OS was associated with KPS 90-100 (relative risk [RR], 2.36; 95% confidence interval [CI], 1.20-4.93; p=.012), hemoglobin>or=12 g/dL (RR, 1.88; 95% CI, 1.01-3.53; p=.048), and no radiotherapy interruptions (RR, 2.59; 95% CI, 1.15-5.78; p=.021). Improved LC was significantly associated with lower T stage (RR, 2.17; 95% CI, 1.16-4.63; p=.013), hemoglobin>or=12 g/dL (RR, 4.12; 95% CI, 1.92-9.09; p<.001), surgery (RR, 2.67; 95% CI, 1.28-5.88; p=.008), and no radiotherapy interruptions (RR, 3.32; 95% CI, 1.26-8.79; p=.015). Improved MFS was associated with KPS 90-100 (RR, 3.41; 95% CI, 1.46-8.85; p=.012). CONCLUSIONS: Significant predictors for outcome in Stage IV head and neck cancer were performance status, stage, surgery, pre-radiotherapy hemoglobin level, and interruptions during radiotherapy>1 week. It appears important to avoid anemia and radiotherapy interruptions to achieve the best treatment results.     

Cyclic AMP inhibits secretion from electroporated human neutrophils.

It has long been known that intracellular cAMP inhibits and cGMP enhances intact neutrophil function. However, these effects are modest and require relatively high concentrations of the cyclic nucleotides. We decided to re-examine the effects of cyclic nucleotides on Ca2(+)-induced secretion by electroporated cells. This system allowed us to bypass normal cell surface receptor-ligand interactions as well as to directly expose the intracellular space to native cyclic nucleotides. We found that concentrations of cAMP as low as 3 microM inhibited Ca2(+)-induced secretion; 30-300 microM cAMP was maximally inhibitory. cAMP was actually slightly more potent than dibutyryl cAMP, a membrane-permeant derivative. In contrast, cGMP was only slightly stimulatory at 3 microM and modestly inhibitory at 300 microM; dibutyryl cGMP was ineffective. A more detailed investigation of the effects of cAMP showed that inhibition was only obtained in the presence of Mg2+. Half-maximal inhibition by cAMP occurred at 10-30 microM. Inhibition by cAMP was achieved by shifting the Ca2+ dose-response curve for secretion to the right; this was observed for the release of both specific granules (vitamin B12 binding protein) and azurophil granules (B-glucuronidase). We previously showed that ATP could enhance Ca2(+)-induced secretion in the presence of Mg2+, apparently by interacting with a cell surface purine receptor. However, increasing concentrations of ATP could not overcome inhibition by cAMP; this suggested that cAMP acted at some site other than the purine receptor. Inhibition by cAMP was also less apparent in the presence of the protein kinase C agonist phorbol myristate acetate (PMA), suggesting that the cyclic nucleotide did not produce systemic desensitization of the neutrophils. In summary, these results demonstrate that low, physiologically relevant concentrations of cAMP can modulate neutrophil responsiveness.     

Chronisch fibrosierende (sklerosierende) Peritonitis als Ursache des „plötzlichen“ Todes

We report a case of a 43-year-old male who died suddenly of sclerosing encapsulating peritonitis (SEP) after a short interval of acute abdominal pain and vomiting. He was diagnosed HIV-positive 10 years prior to death. Only one case of HIV-associated SEP has been reported in the literature. The cause of death was unclear until autopsy where small bowel obstruction and mechanical ileus due to an adhesive process, encapsulating the jejunum and ileum was discovered. Histological examination led to the diagnosis of peritonitis chronica fibrosa incapsulata, or sclerosing encapsulating peritonitis. The etiology of this disease remains unknown but the occurrence is associated with abdominal operations, inflammatory processes of the peritoneum and several drugs. The causes of sclerosing mesenteritis as well as the treatment with mostly immunosuppressive drugs is discussed. Prognosis differs and in this case it is remarkable that SEP evolved despite immunological deficiency due to HIV and medical treatment. Under full retroviral therapy with a low virus count, the man died a few weeks after the first symptoms of ileus caused by sclerosing encapsulating peritonitis.     

HLA-B*4431: a new HLA-B variant with a complex ancestral history involving HLA-B*44, B*40 and B*07 alleles

We here describe the identification of the new allele HLA-B*4431, which was found in three members of a Turkish family. Sequencing of the new allele following haplotype-specific PCR amplification revealed that exon 2 is identical to HLA-B*4402, whereas exon 3 resembles a HLA-B*40 variant with the exception of position 572, where a single nucleotide transversion (C > G) leads to an amino acid exchange (Trp162Ser). The generation of the 3' part of B*4431 may be best explained by a separate recombination between B*40 and B*07. Although B*4431 consists of B44 in its alpha1 domain and of B60(40) in its alpha2 domain; the new allele only displayed B44 seroreactivity, which demonstrates that epitopes crucial for B60(40) specificity must be located in the alpha1 domain.     

Sequential acquisition of IgH and TCR rearrangements during the preleukemic phase of acute lymphoblastic leukemia in an adolescent patient

Acute lymphoblastic leukemia (ALL) can be preceded by a prodromal phase of bone marrow failure. In serial trephine biopsies in a girl with acquired bone marrow hypoplasia, we have identified a monoclonal B‐cell precursor population characterized by a clone‐specific IgH‐FR3 gene rearrangement. Progression to ALL more than 4 months later was accompanied by acquisition of an additional T‐cell receptor rearrangement. Thus, hypoplastic pre‐ and overt leukemia share a common clonal origin. Prospective biobanking and extended molecular analysis can help to better understand the nature and sequence of genetic events during progression of a covert (pre)leukemic clone. Pediatr Blood Cancer 2011;56:301–303. © 2010 Wiley‐Liss, Inc.