Charlotte K. Ryan

Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer.

Purpose: Hemostatic activation is common in pancreatic cancer and may be linked to angiogenesis and venous thromboembolism. We investigated expression of tissue factor (TF), the prime initiator of coagulation, in noninvasive and invasive pancreatic neoplasia. We correlated TF expression with vascular endothelial growth factor (VEGF) expression, microvessel density, and venous thromboembolism in resected pancreatic cancer. Experimental Design: Tissue cores from a tri-institutional retrospective series of patients were used to build tissue microarrays. TF expression was graded semiquantitatively using immunohistochemistry in normal pancreas (n = 10), intraductal papillary mucinous neoplasms (n = 70), pancreatic intraepithelial neoplasia (n = 40), and resected or metastatic pancreatic adenocarcinomas (n = 130). Results: TF expression was observed in a majority of noninvasive and invasive pancreatic neoplasia, including 77% of pancreatic intraepithelial neoplasias, 91% of intraductal papillary mucinous neoplasms, and 89% of pancreatic cancers, but not in normal pancreas. Sixty-six of 122 resected pancreatic cancers (54%) were found to have high TF expression (defined as grade ≥2, the median score). Carcinomas with high TF expression were more likely to also express VEGF (80% versus 27% with low TF expression, P < 0.0001) and had a higher median MVD (8 versus 5 per tissue core with low TF expression, P = 0.01). Pancreatic cancer patients with high TF expression had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low TF expression (P = 0.04). Conclusions: TF expression occurs early in pancreatic neoplastic transformation and is associated with VEGF expression, increased microvessel density, and possibly clinical venous thromboembolism in pancreatic cancer. Prospective studies evaluating the role of TF in pancreatic cancer outcomes are warranted.

Infliximab for refractory ulcerative colitis

Eight patients with active ulcerative colitis (UC), refractory to usual combination medical therapy, were treated with a single i.v. dose of chimeric monoclonal antibody to recombinant human tumor necrosis factor α; many of these patients were scheduled for surgical colectomy because of their active disease. All patients responded extremely well to a single 5 mg/kg infusion of infliximab, with marked improvement after the infusion clinically, colonoscopically, and histologically on colonic biopsy. There were no significant complications or side effects; mean duration of remission has not been determined because none of the patients have relapsed. Infliximab appears to be a potent agent for inducing remission in refractory patients with ulcerative colitis.

Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis.

ABSTRACTFamilial adenomatous polyposis (FAP) is a rare autosomal dominant precancerous condition of the colon caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. FAP is characterized by the appearance of innumerable adenomatous polyps throughout the large bowel. Fundic gland polyps are the most common gastric lesion in FAP. It is generally believed that fundic gland polyps have little or no potential for malignant transformation in the population at large, and only a few case reports describe the development of high grade dysplasia or gastric adenocarcinoma associated with diffuse fundic gland polyposis in patients with FAP. We report the second case of gastric adenocarcinoma intimately associated with fundic gland polyposis in a family with an attenuated form of FAP. The patient had undergone routine screening per current guidelines because of his known mutation in the APC gene. This suggests that malignant transformation of fundic gland polyps in patients with FAP occur more frequently than previously believed. Current screening recommendations may not be sufficient for patients with FAP or its attenuated forms.

Androgen Receptor Promotes Hepatitis B Virus–Induced Hepatocarcinogenesis Through Modulation of Hepatitis B Virus RNA Transcription

Targeting androgen receptor may prevent hepatitis B virus–induced liver cancer. Destroying the Source of Liver Cancer Hepatocellular carcinoma represents the majority of cases of primary liver cancer; it is the fifth most common cancer and the third leading cause of cancer death worldwide. Several risk factors for hepatocellular carcinoma have been identified, but gender and hepatitis B virus (HBV) infection have proven to be uniquely associated with the disease by undetermined mechanisms. HBV infection alone, which is endemic in many Asian countries including China, accounts for approximately 53% of hepatocellular carcinoma cases worldwide. Decades of research have examined risk factor exposures such as age, history of hepatitis, occupation, regular alcohol drinking, regular cigarette smoking, and family history of liver cancer to explain the gender disparities that are so prevalent among HBV-induced liver cancers, but none of these were fully accountable, suggesting that other unknown susceptibilities are lurking. Liver cancer arises most frequently in the setting of chronic liver inflammation. After infection by the hepatitis virus, the host’s inflammatory immune response to the viral antigens induces hepatocyte damage and is followed by the pathogenesis of liver cancer. Although it has been postulated that sex hormones may interact with HBV infection in the process and lead to a dominant sex disparity in liver cancer risk, this has never been decisively shown. Now, Wu et al. use a genetically modified mouse model of HBV-induced liver cancer to explore how sex hormones, and specifically their receptors, play a role in promoting the disease. They find that targeting of the androgen receptor—and not androgens, as is frequently done in the clinic—hampers tumor formation at the gross and mechanistic levels. These results shed new light on a previously unexplored pathway and provide an intervention modality that is translatable in the clinic, and may explain why men are more susceptible to liver cancer than women. Hepatitis B virus (HBV)–induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR−/y). HBV-L-AR−/y mice that received a low dose of the carcinogen N′-N′-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less α-fetoprotein HCC marker than do their wild-type HBV-AR+/y littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR+/y mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.

Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel—Lindau protein

Inactivation of the von Hippel—Lindau (VHL) tumor suppressor gene is linked to the hereditary VHL disease and sporadic clear cell renal cell carcinomas (CCRCC). VHL‐associated tumors are highly vascularized, a characteristic associated with overproduction of vascular endothelial growth factor (VEGF). The VHL protein (pVHL) is a component of the ubiquitin ligase E3 complex, targeting substrate proteins for ubiquitylation and subsequent proteasomic degradation. Here, we report that the pVHL can directly bind to the human RNA polymerase II seventh subunit (hsRPB7) through its β‐domain, and naturally occurring β‐domain mutations can decrease the binding of pVHL to hsRPB7. Introducing wild‐type pVHL into human kidney tumor cell lines carrying endogenous mutant non‐functional pVHL facilitates ubiquityl ation and proteasomal degradation of hsRPB7, and decreases its nuclear accumulation. pVHL can also suppress hsRPB7‐induced VEGF promoter transactivation, mRNA expression and VEGF protein secretion. Together, our results suggest that hsRPB7 is a downstream target of the VHL ubiquitylating complex and pVHL may regulate angiogenesis by targeting hsRPB7 for degradation via the ubiquitylation pathway and preventing VEGF expression.

Multiple esophageal rings: An association with eosinophilic esophagitis. Case report and review of the literature

Esophagitis may present endoscopically with erythema, edema, loss of vascular pattern, friability, and ulceration of the esophageal mucosa. Left untreated, chronic esophagitis may result in stricture formation. The presence of multiple concentric rings involving the entire esophagus has been cited as a chronic form of esophagitis. We present a case of an 8-yr-old boy with multiple concentric esophageal rings and histological evidence of eosinophilic esophagitis, who failed medical antireflux treatment and responded to an elimination diet.

Low-dose enteral feeding is beneficial during total parenteral nutrition

BACKGROUND Enteral support is the preferred feeding route for stressed patients due in part to the provision of gut-specific fuels. In those patients who must be maintained parenterally, small amounts of enteral stimulation might blunt gut atrophy and lead to improvement in host defense mechanisms decreasing macromolecular and/or bacterial translocation (BT). METHODS Forty-eight rats were infused with TPN for 9 days, and were randomized to receive 0%, 6%, 12%, or 25% of their calories as partial enteral nutrition (PEN) in an isocaloric, isonitrogenous fashion. Twenty-four hours before harvest animals were gavaged with lactulose and urinary excretion quantified. At harvest, mesenteric lymph nodes were cultured to assess BT and intestinal histology determined. RESULTS Provision of as little as 25% of total calories PEN improved nitrogen balance and reduced BT, in a dose dependent fashion. It did not alter TPN-associated increased macromolecular lactulose permeability (4.4% +/- 1.0%). CONCLUSION Concurrent small amounts of PEN, aimed to support the guts metabolic needs, are beneficial during periods of prolonged TPN.

SHEAR WAVE DISPERSION MEASURES LIVER STEATOSIS

Crawling waves, which are interfering shear wave patterns, can be generated in liver tissue over a range of frequencies. Some important biomechanical properties of the liver can be determined by imaging the crawling waves using Doppler techniques and analyzing the patterns. We report that the dispersion of shear wave velocity and attenuation, that is, the frequency dependence of these parameters, are strongly correlated with the degree of steatosis in a mouse liver model, ex vivo. The results demonstrate the possibility of assessing liver steatosis using noninvasive imaging methods that are compatible with color Doppler scanners and, furthermore, suggest that liver steatosis can be separated from fibrosis by assessing the dispersion or frequency dependence of shear wave propagations.

Evaluation of a carboxymethylcellulose sponge for prevention of postoperative adhesions

BACKGROUND A novel lyophilized carboxy-methylcellulose (CMC) sponge has been developed for prevention of surgical wound adhesions. One potential mechanism for preventing abdominal adhesion is suppression of the cytokine transforming growth factor beta (TGF-beta) and other macrophage derived fibroblast stimulating factors that partially mediate adhesion formation. METHODS To study the efficacy and mechanisms of action of the CMC sponge, we performed standard cecal denudation and abdominal wall apposition on rats. A CMC sponge or a commercially available adhesion preventive barrier (Interceed) was placed on the denuded surface. After 14 days, adhesion severity was graded blindly on a scale ranging from 0 (no adhesion) to 5 (severe adhesion). TGF-beta expression was determined by immunocytochemical staining. To assess the secretion of macrophage derived fibrogenic factors in control and CMC rats, labeled thymidine and proline uptake and hydroxyproline production were measured in NRK rat fibroblasts cultured with conditioned medium of peritoneal macrophages. RESULTS The severity of adhesions in the CMC sponge group (0.7 +/- 0.3) was significantly lower than in the Interceed or control groups (2.2 +/- 0.3; 4.6 +/- 0.1). In control animals TGF-beta expression in endothelium and fibroblasts was maximal on day 3. Neither CMC nor Interceed reduced this expression. Conditioned media derived from sponge-exposed postsurgical peritoneal macrophages did not inhibit fibroblast growth or collagen formation. CONCLUSIONS In this model the CMC sponge was more effective than Interceed in preventing postoperative adhesions. Its action was not due to inhibition of TGF-beta expression or macrophage derived fibrogenic factors. These data highlight the primary importance of local barrier effect in adhesion prevention.

Epidermal growth factor and human growth hormone accelerate adaptation after massive enterectomy in an additive, nutrient-dependent, and site-specific fashion

BACKGROUND After massive enterectomy (ME), remnant intestine undergoes compensatory adaptation. Epidermal growth factor (EGF) and human growth hormone (hGH) have each been shown to enhance total length small intestine nutrient transport after ME. This study aims to determine the differential effects of EGF and hGH on proximal and distal small intestinal remnants after ME. METHODS New Zealand white rabbits underwent 70% mid-jejunoileal resection. After 1 week, animals received hGH (0.2 mg/kg/day), EGF (1.5 micrograms/kg/hr), hGH + EGF, or vehicle (equal volume) for 7 days. Sodium-dependent uptake of glucose, glutamine, alanine, leucine, and arginine into brush border membrane vesicles was quantitated. Serum insulin-like growth factor-I concentrations as well as proximal and distal villus and microvillus heights were measured. IGF binding protein-3 and -4 mRNA expression was determined in full-thickness proximal and distal gut remnants. RESULTS Concomitant hGH and EGF treatment up-regulates glucose (100%), glutamine (80%), and leucine (60%) transport in the proximal remnant; alanine (150%) and arginine (400%) transport in the distal remnant; and microvillus height (25% to 35%) both proximally and distally. Serum IGF-I levels and gross villus heights were not different among groups. CONCLUSIONS Co-infusion of hGH and EGF accelerates intestinal adaptation after ME in an additive, nutrient-dependent, and site-specific fashion via enhanced nutrient transport as well as microvillus hypertrophy.