Portal Vein Thrombosis After a Right Hemicolectomy: A Case Report.

The patient, a 43-year-old male, underwent uneventful laparoscopic right-sided hemicolectomy for a benign polyp, too large to be removed by colonoscopy. His postoperative course was uneventful; however, he returned 16 days after discharge with vague abdominal pain. A CT scan of his abdomen and pelvis showed extensive acute thrombus in portal, superior mesenteric, and splenic veins. After initial intravenous anticoagu- lation, follow-up imaging showed a persistent clot. The patient then underwent catheter-guided portal vein thrombolysis with tissue plasminogen activator (tPA), on postoperative day 29. He was doing well on 12-month follow-up. Portomesenteric thrombosis is a rare complication of laparoscopic surgery. It can occur even in the absence of any direct vascular trauma, as well as in delayed fashion after an initially uneventful procedure. Gold standard for treatment has not been developed and remains individualized based on the extent ofthe thrombus, the patient's clinical status, and condition of the affected bowel.

FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents.

Fibroblast growth factor 21 (FGF21) mitigates many of the pathogenic features of type 2 diabetes, despite a short circulating half-life. PEGylation is a proven approach to prolonging the duration of action while enhancing biophysical solubility and stability. However, in the absence of a specific protein PEGylation site, chemical conjugation is inherently heterogeneous and commonly leads to dramatic loss in bioactivity. This work illustrates a novel means of specific PEGylation, producing FGF21 analogs with high specific activity and salutary biological activities. Using homology modeling and structure-based design, specific sites were chosen in human FGF21 for site-specific PEGylation to ensure that receptor binding regions were preserved. The in vitro activity of the PEGylated FGF21 ana-logs corresponded with the site of PEG placement within the binding model. Site-specific PEGylated analogs demonstrated dramatically increased circulating half-life and enhanced efficacy in db/db mice. Twice-weekly dosing of an optimal FGF21 analog reduced blood glucose, plasma lipids, liver triglycerides, and plasma glucagon and enhanced pancreatic insulin content, islet number, and glucose-dependent insulin secretion. Restoration of insulin sensitivity was demonstrated by the enhanced ability of insulin to induce Akt/protein kinase B phosphorylation in liver, muscle, and adipose tissues. PEGylation of human FGF21 at a specific and preferred site confers superior metabolic pharmacology.

Optimized clinical performance of growth hormone with an expanded genetic code.

The ribosomal incorporation of nonnative amino acids into polypeptides in living cells provides the opportunity to endow therapeutic proteins with unique pharmacological properties. We report here the first clinical study of a biosynthetic protein produced using an expanded genetic code. Incorporation of p-acetylphenylalanine (pAcF) at distinct locations in human growth hormone (hGH) allowed site-specific conjugation with polyethylene glycol (PEG) to produce homogeneous hGH variants. A mono-PEGylated mutant hGH modified at residue 35 demonstrated favorable pharmacodynamic properties in GH-deficient rats. Clinical studies in GH-deficient adults demonstrated efficacy and safety comparable to native human growth hormone therapy but with increased potency and reduced injection frequency. This example illustrates the utility of nonnative amino acids to optimize protein therapeutics in an analogous fashion to the use of medicinal chemistry to optimize conventional natural products, low molecular weight drugs, and peptides.