Surgical Repair of a Traumatic Gastrobronchial Fistula.

BACKGROUND Gastrobronchial fistulas mostly occur as a result of postoperative complications, including those of bariatric, esophageal, and spleno-pancreatic surgery. Other causes are pneumonia, neoplasm, gastric ulcer, and subphrenic abscess. Traumatic fistulous communications between the stomach and the lung tissue are rare, with only 8 cases reported in the English-language literature (PubMed search) until now. CASE REPORT We report a 49-year-old female patient with a gastrobronchial fistula secondary to diaphragm rupture 7 years prior, with intrathoracic herniation of the gastric fundus. She underwent thoracotomy for surgical repair. She presented in our Emergency Department with recurrent hemoptysis and painful cough. The diagnosis of the gastrobronchial fistula was confirmed by computed tomography and simultaneous bronchoscopy and esophagogastroscopy, with injection of toluidine blue. As a multidisciplinary team, we opted for surgical repair owing to the fistula extent and severity and the need of repair of the diaphragm hernia. The patient underwent left-sided thoracoscopy. However, owing to dense adhesions and chronic inflammation, we converted to an open procedure. The herniated gastric fundus was repaired by wedge resection. The affected lung tissue was debrided and reconstructed by suture repair. The diaphragmatic defect was closed by sutures with mesh augmentation. The patient's postoperative course was uncomplicated, and she was discharged in good clinical condition on postoperative day 7. CONCLUSIONS Owing to the scarcity of the disease, the management of a gastrobronchial fistula is not standardized. The establishment of the diagnosis of the disease is often challenging. Therapeutic options include conservative measures, endoscopic options, and surgical repair. Our case showed that a multidisciplinary workup is essential for successful treatment.

Purinergic mechanisms in breast cancer support intravasation, extravasation and angiogenesis.

Several advances have recently expanded models of tumor growth and promoted the concept of tumor homeostasis, the hypothesis that primary tumors exert an anti-proliferative effect on both themselves and subclinical secondary metastases. Recent trials indicate that the characterization of tumor growth as uncontrolled is inconsistent with animal models, clinical models, and epidemiological models. There is a growing body of evidence which lends support to an updated concept of tumor growth: tumor homeostasis. In the case of breast cancer, if not all metastasizing tumors, these advances suggest an inconvenient truth. That is, if breast tumor cells metastasize to distant sites early in the tumorigenesis process, then removal of a breast tumor may hasten the development of its metastases. We explore the heretofore unappreciated notion that nucleotides generated by tumor cells following the secretion of an ADP-kinase can promote metastasis and support angiogenesis. Evidence is presented that blockade of the actions of nucleotides in the setting of newly diagnosed breast cancer may provide a useful adjunct to current anti-angiogenesis treatment.

Histamine receptor H1 and dermatopontin: new downstream targets of the vitamin D receptor.

UNLABELLED: In this study, we used multipotential MSCs and microarray assays to follow the changing patterns of gene expression as MSCs were differentiated to osteoblasts. We analyzed co-expressed gene groups to identify new targets for known transcription factor VDR during differentiation. The roles of two genes (histamine receptor H1 and dermatopontin) as downstream targets for the VDR were confirmed by gel electromotility shift, siRNA inhibition, and chromatin immunoprecipitation assays. INTRODUCTION: Osteogenesis is stringently controlled by osteoblast-specific signaling proteins and transcription factors. Mesenchymal stem or multipotential stromal cells from bone marrow (MSCs) have been shown to differentiate into osteoblasts in the presence of vitamin D(3). MATERIALS AND METHODS: We used MSCs and microarray assays to follow the changing patterns of gene expression as MSCs were differentiated to osteoblasts. The data were analyzed with a previously developed strategy to identify new downstream targets of the vitamin D receptor (VDR), known osteogenesis transcription factor. Hierarchical clustering of the data identified 15 distinct patterns of gene expression. Three genes were selected that expressed in the same time-dependent pattern as osteocalcin, a known target for the VDR: histamine receptor H1 (HRH1), Spondin 2 (SPN), and dermatopontin (DPT). RT-PCR, electromotility shift, siRNA inhibition assays, and chromatin immunoprecipitation assays were used to analyze the role of VDR in activation of DPT and HRH1 during differentiation. RESULTS AND CONCLUSIONS: RT-PCR assays confirmed that the genes were expressed during differentiation of MSCs. The roles of two genes as downstream targets for the VDR were confirmed by gel electromotility shift and chromatin immunoprecipitation assays that showed the presence of VDR complex binding sequences. Overexpression of VDR in MG-63 osteosarcoma cells induced the expression of HRH1 and DPT. Inhibition studies with siRNA to DPT and HRH1 showed a decrease in MSC differentiation to osteogenic lineage. In addition, osteogenic differentiation of MSCs was inhibited by the HRH1 inhibitor mepyramine but not the HRH2 inhibitor ranitidine. In conclusion, we show that analysis of co-expressed gene groups is a good tool to identify new targets for known transcription factors.

Use of differentiating adult stem cells (marrow stromal cells) to identify new downstream target genes for transcription factors.

We developed a strategy for use of microarray data to rapidly identify new downstream targets of transcription factors known to drive differentiation by following the time courses of gene expression as a relatively homogeneous population of stem/progenitor cells are differentiated to multiple phenotypes. Microarray assays were used to follow the differentiation of human marrow stromal cells (MSCs) into chondrocytes or adipocytes in three different experimental conditions. The steps of the analysis were the following: (a) hierarchical clustering was used to define groups of similarly behaving genes in each experiment, (b) candidates for new downstream targets of transcription factors that drive differentiation were then identified as genes that were consistently co-expressed with known downstream target genes of the transcription factors, and (c) the list of candidate new target genes was refined by identifying genes whose signal intensities showed a highly significant linear regression with the signal intensities of the known targets in all the data sets. Analysis of the data identified multiple new candidates for downstream targets for SOX9, SOX5, CCAAT/enhancer binding protein (C/EBP)-alpha, and peroxisome proliferator-activated receptor (PPAR)-gamma. To validate the analysis, we demonstrated that PPAR-gamma protein specifically bound to the promoters of four new targets identified in the analyses. The same multistep analysis can be used to identify new downstream targets of transcription factors in other systems. Also, the same analysis should make it possible to use MSCs from bone marrow to define new mutations that alter chondogenesis or adipogenesis in patients with a variety of syndromes.