Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

Single-layer continuous suture for gastrojejunostomy.

A variety of techniques are available for the construction of a gastrojejunostomy. Little information is available regarding the influence of anastomotic technique on functional outcome, particularly delayed gastric emptying and other postgastrectomy syndromes. Twenty-seven cases were reviewed in which single-layer continuous suture was used for gastrojejunostomy. Most patients underwent pancreatoduodenectomy, subtotal gastrectomy, or gastrojejunal bypass for malignant obstruction. There were no anastomotic leaks. A regular diet was tolerated at a median of 6 days. There were no cases of delayed gastric emptying, and follow-up to date demonstrates a low incidence of postgastrectomy morbidity

Pylorus Preserving Pancreaticoduodenectomy After Prior Esophagogastrectomy.

Background: As treatment of esophageal carcinomas continues to improve, we have seen an increasing population of long-term survivors giving rise to the observation of additional primary malignancies not previously seen. Esophagogastrectomy for previously treated esophageal carcinoma presents unique anatomic changes providing further technical difficulties for surgical management of new primary malignancies. Presentation: A 65-year-old male with a history of esophagogastrectomy for esophageal adenocarcinoma presents with a pancreatic head mass consistent with pancreatic adenocarcinoma. Our case report describes a pylorus sparing pancreaticoduodenectomy with preservation of the right gastric and right gastroepiploic vessels in order to preserve blood supply to the gastric conduit. Conclusion: Here we demonstrate that in select cases where location of the pancreatic head tumor is favorable, pancreaticoduodenectomy can be performed in the context of prior esophagogastrectomy with preservation of the native blood supply to the gastric conduit. Pancreaticoduodenectomy may have yet been possible if the tumor involved the gastroduodenal artery via vascular reconstruction to the right gastroepiploic artery or sacrifice of the gastric conduit with reconstruction using small or large intestine

Peritoneal seeding following potentially curative resection of colonic carcinoma: implications for adjuvant therapy.

Adjuvant therapeutic strategies for colon cancer are based on the knowledge of tumor recurrence patterns following potentially curative resection. Innovative methods for regional delivery of chemotherapy to the liver and peritoneal surfaces are now available to complement systemic treatment. We reviewed clinical, reoperation, and autopsy series to determine the incidence of peritoneal seeding following colon cancer resection. The data suggest a 25-35 percent peritoneal failure rate among patients that recur, indicating that intraperitoneal chemotherapy is a sensible adjuvant approach. The theory behind intraperitoneal chemotherapy and potential complications is discussed. We suggest initiation of clinical trials combining systemic and intraperitoneal chemotherapy