Search

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death (1,2). Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population (4). There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism (5), is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 A resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness., Systemic tryptophan metabolism in mammals occurs primarily via the kynurenine pathway (Fig. 1a) (5). Tryptophan metabolites contribute to acute lung injury in rats with [AP.sup.6], and the tryptophan metabolite kynurenine [...]

Context.--Lymph node status and the number of lymph node (LN) positive for cancer cells are the most important prognostic factors in breast cancer. Extranodal tumor extension (ENTE) has been used as a histopathologic feature to classify patients into high risk versus low risk for local recurrence. However, in the current era of early detection and systemic therapy, the prognostic significance of ENTE is not as well defined in patients with 1 to 3 LNs positive for cancer. Objective.--To determine whether the amount of tumor burden in an axillary dissection or the presence of ENTE provides any additional information regarding patient outcome in patents with 1 to 3 positive LN results. Design.--Clinical and pathologic factors were identified for 456 patients with breast cancer at the University of Texas MD Anderson Cancer Center, Houston, who had pT1 tumors and 1 to 3 LNs positive for cancer and were treated by mastectomy, with or without postmastectomy radiotherapy, between 1978 and 2007. Results.--Of the 456 patients, 257 (56.4%), 141 (31.6%), and 58 (12.7%) patients had 1, 2, or 3 positive LN results, respectively. Extranodal tumor extension was present in 99 patients (21.7%) and was absent in the remaining 357 cases (78.3%). Seventy-six patients (16.7%) received radiation therapy. Patients had both worse overall survival time and disease-free survival when ENTE was present, regardless of the amount, as long as the treatment era was not included in the multivariate analysis (pre-2000 versus post-2000). However, ENTE was no longer significant on multivariate analysis when the year of treatment was taken into account. Conclusions.--The number of positive LNs remains an important predictor of survival in patients with 1 to 3 positive LN results, but the prognostic significance of ENTE in this cohort of patients has diminished over time. (Arch Pathol Lab Med. 2015; 139:1288-1294; doi: 10.5858/arpa.2014-0375-0A), Lymph node (LN) status and the number of LNs positive for cancer cells are the most important prognostic factors in patients with breast cancer. Postoperative chest wall and regional LN [...]

Discusses results of a study evaluating on the prescription of dexamphetamine for injecting primary amphetamine users in South Wales. Patient demographics; Outbreak of hepatitis B and C among injection drug users; History of sharing injecting equipment; Frequency of amphetamine use for treatment group versus control group.