Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation.

In the present study, we show that transforming growth factor beta1 (TGF-beta1) was frequently overexpressed in human head and neck squamous cell carcinomas (HNSCCs) and adjacent tissues in comparison with normal head and neck tissues. To determine the role of TGF-beta1 overexpression in HNSCC carcinogenesis, we generated transgenic mice in which TGF-beta1 transgene expression can be induced in head and neck epithelia. TGF-beta1 transgene induction in head and neck epithelia, at levels similar to those in human HNSCCs, caused severe inflammation and angiogenesis.

KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications.

The diagnosis of gastrointestinal stromal tumor (GIST) is currently based on morphologic features and immunohistochemical demonstration of KIT (CD117). However, some tumors (in our estimation approximately 4%) have clinicopathologic features of GIST but do not express KIT. To determine if these lesions are truly GISTs, we evaluated 25 tumors with clinical and histologic features typical of GIST, but with negative KIT immunohistochemistry, for KIT and PDGFRA mutations using DNA extracted from paraffin-embedded tissue.

The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status.

We recently characterized gene expression patterns in gastrointestinal stromal tumors (GISTs) using cDNA microarrays, and found that the gene FLJ10261 (DOG1, discovered on GIST-1), encoding a hypothetical protein, was specifically expressed in GISTs. The immunoreactivity of a rabbit antiserum to synthetic DOG1 peptides was assessed on two soft tissue tumor microarrays. The tissue microarrays included 587 soft tissue tumors, with 149 GISTs, including 127 GIST cases for which the KIT and PDGFRA mutation status was known.

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas.

CDX2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestines. Based on recent studies, CDX2 expression is immunohistochemically detectable in normal colonic enterocytes and is retained in most, but not all, colorectal adenocarcinomas. CDX2 expression has also been documented in a subset of adenocarcinomas arising in the stomach, esophagus and ovary.

NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)--expansion and update of NCCN clinical practice guidelines.

NCCN's Sarcoma Clinical Practice Guidelines in Oncology include a subsection regarding treatment recommendations on gastrointestinal stromal tumors (GISTs). GIST is one area of medicine where the standard of practice has been affected rapidly and dramatically by the introduction of effective molecularly targeted therapy for this disease. There are few examples in modern medicine in which the implementation of new technologies into practice has so radically and rapidly affected clinical diagnostic strategies and treatments with significant implications for the care of patients.

Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation.

Small intestinal submucosa aneurysm sac embolization for endoleak prevention after abdominal aortic aneurysm endografting: a pilot study in sheep.

Purpose: To percutaneously create an improved abdominal aortic aneurysm model of endoleak after endograft placement and to explore efficacy of small intestinal submucosal embolization of the residual aneurysmal sac for prevention of endoleaks.

Materials And Methods: Abdominal aortic aneurysm was created transluminally by over-dilation of a Palmaz stent in 12 sheep. Approximately 20% undersized endografts suspended between two stent-graft adapters were used to bridge the aneurysm in a manner that two lumbar pairs remained patent within the residual aneurysm sac.

KIT mutations are common in testicular seminomas.

Expression of KIT tyrosine kinase is critical for normal germ cell development and is observed in the majority of seminomas. Activating mutations in KIT are common in gastrointestinal stromal tumors and mastocytosis. In this study we examined the frequency and spectrum of KIT mutations in 54 testicular seminomas, 1 ovarian dysgerminoma and 37 non-seminomatous germ cell tumors (NSGCT).

c-CBL is not required for leukemia induction by Bcr-Abl in mice.

Bcr-Abl tyrosine kinase activity is essential for the pathogenesis of chronic myeloid leukemia (CML). A number of Bcr-Abl substrates have been identified, but it is not clear which of these substrates are required for Bcr-Abl to transform cells. The multifunctional protein c-Cbl is one of the most prominently tyrosine-phosphorylated proteins in Bcr-Abl-expressing cells.

Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.

Purpose: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST.

Patients And Methods: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA.

A canine model for studying endoleak after endovascular aneurysm repair.

Purpose: The aim of this study was to create an animal model of endoleak after stent-graft placement for abdominal aortic aneurysm (AAA) in which a large aneurysmal sac would be preserved for the testing of techniques for its percutaneous occlusion.

Materials And Methods: Infrarenal AAAs were created in nine dogs by anastomosis of an isolated segment of the inferior vena cava to the right side of the abdominal aorta in combination with a large anterior patch from the external jugular vein. One hour later, animals underwent percutaneous implantation of polytetrafluoroethylene-covered Z stent endografts with three 3-mm-diameter holes through the fabric.

Absence of BRAF and NRAS mutations in uveal melanoma.

Uveal melanoma (UM) and cutaneous melanoma (CM) differ significantly in their epidemiological, clinical, immunophenotypical, and cytogenetic features, but the molecular basis for these differences has not been delineated. CMs frequently harbor an activating mutation in either NRAS or the RAS-regulated kinase BRAF, suggesting that either of these oncogenes may increase signaling through the mitogen-activated protein (MAP) kinase pathway and promote melanoma development. The aim of this study was to examine BRAF and NRAS gene mutations in UM.

Graft failure from severe recurrent primary sclerosing cholangitis following orthotopic liver transplantation.

Unlabelled: Speculation that primary sclerosing cholangitis (PSC) may recur in the transplanted liver is based on the relative increase in frequency of biliary abnormalities and histologic evidence of periportal fibrosis without other causes. A recent study demonstrated almost 9% of patients undergoing liver transplantation (OLT) for primary sclerosing cholangitis (PSC) develop recurrent sclerosing cholangitis although the patient and graft survival is not different from those in whom recurrence does not develop. Most reports of PSC recurrence post-OLT estimate rates of 1% to 14%, but to date, no center has reported rapidly progressive fibro-obliterative cholangitis leading to graft failure.

High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.

Hypothesis: The use of potentially hepatotoxic herbal and dietary supplements is highly prevalent in the fulminant hepatic failure (FHF) patient population at our institution, and this subgroup of patients has a worse prognosis.

Design: Retrospective case series. Settings An adult tertiary care university hospital and a Veterans Affairs hospital in Oregon.

Generation of anti-insulin-like growth factor-binding protein-related protein 1 (IGFBP-rP1/MAC25) monoclonal antibodies and immunoassay: quantification of IGFBP-rP1 in human serum and distribution in human fluids and tissues.

The IGF-binding protein (IGFBP)-related proteins (rPs) are a group of recently described cysteine-rich proteins that share significant amino-terminal structural similarity with the conventional IGFBPs. IGFBP-rP1 (also known as MAC25/angiomodulin/prostacyclin-stimulating factor and T1A12), regulates cellular proliferation, adhesion, and angiogenesis and stimulates prostacyclin synthesis. We characterized new monoclonal antibodies generated against IGFBP-rP1 and have used them to study the distribution of IGFBP-rP1 in human biological fluids and tissues.

Expression of KIT and epidermal growth factor receptor in chemotherapy refractory non-seminomatous germ-cell tumors.

Background: The majority of patients with germ-cell tumors (GCTs) are curable with standard therapy. The molecular differences between curable and incurable disease are unknown. We have studied the expression of KIT and the epidermal growth factor receptor (EGFR) to determine their incidence in chemorefractory disease.

Tumor necrosis factor-alpha promoter polymorphisms and the risk of rejection after liver transplantation: a case control analysis of 210 donor-recipient pairs.

After orthotopic liver transplantation (OLT), allograft rejection remains an important problem and is the major reason that immunosuppressive therapy must be administered. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that is central to the immune response, and intragraft expression of this cytokine is increased during acute cellular rejection (ACR). Polymorphisms within the TNF promoter have been identified and correlated with alterations in production.

Response to imatinib mesylate of a gastrointestinal stromal tumor with very low expression of KIT.

More than 90% of gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT, and activating mutations of the KIT gene are detectable in the vast majority of these tumors. Imatinib mesylate (formerly STI571) is a potent inhibitor of KIT kinase activity and has been proven to be highly active in patients with unresectable or metastatic GIST expressing immunohistochemically detectable KIT protein. Here we report a patient with metastatic GIST who responded well to imatinib mesylate treatment despite the near absence of KIT expression in two different samples of his tumor.

Remodeling of suspended small intestinal submucosa venous valve: an experimental study in sheep to assess the host cells' origin.

Purpose: To investigate the origin of host cells during remodeling of small intestinal submucosa (SIS) square stent-based bicuspid venous valves (VVs).

Materials And Methods: Suspended VVs (SVVs) were developed by suspending VVs within bare square stents so the valve elements would not contact the vein wall after deployment. Eight SVVs were placed within the intrahepatic and infrahepatic inferior venae cavae (IVCs) of four adult female sheep.

Cytomegalovirus-mediated upregulation of chemokine expression correlates with the acceleration of chronic rejection in rat heart transplants.

Cytomegalovirus (CMV) infections have been shown to dramatically affect solid organ transplant graft survival in both human and animal models. Recently, it was demonstrated that rat CMV (RCMV) infection accelerates the development of transplant vascular sclerosis (TVS) in both rat heart and small bowel graft transplants. However, the mechanisms involved in this process are still unclear.

PDGFRA activating mutations in gastrointestinal stromal tumors.

Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression.

The epidemic of prostate cancer and the medical literature: a causal association?

The diagnosis of prostate cancer has undergone an unprecedented recent increase, while mortality has increased much more slowly. We examined new prostate cancer diagnoses from 1987-1992 in a nationwide prospective cohort study of 51 529 men enrolled in the Health Professionals Follow-up Study, a population likely to be medically sophisticated and thus early to adopt medical innovations. The age-adjusted incidence of prostate cancer rose approximately 2(1/2) fold during the study period.

ANG II AT(1) and AT(2) receptors in developing kidney of normal microswine.

To identify an appropriate model of human renin-angiotensin system (RAS) involvement in fetal origins of adult disease, we quantitated renal ANG II AT(1) and AT(2) receptors (AT1R and AT2R, respectively) in fetal (90-day gestation, n = 14), neonatal (3-wk, n = 5), and adult (6-mo, n = 8) microswine by autoradiography ((125)I-labeled [Sar(1)Ile(8)]ANG II+cold CGP-42112 for AT1R, (125)I-CGP-42112 for AT2R) and by whole kidney radioligand binding. The developmental pattern of renal AT1R in microswine, like many species, exhibited a 10-fold increase postnatally (P < 0.001), with maximal postnatal density in glomeruli and lower density AT1R in extraglomerular cortical and outer medullary sites.