Hypertension is an independent predictor of survival disparity between African‐American and white breast cancer patients

The objective of this study was to determine whether comorbidity, or pre‐existing conditions, can account for some of the disparity in survival between African‐American and white breast cancer patients. A historical cohort study was conducted of 416 African‐American and 838 white women diagnosed with breast cancer between 1973 and 1986, and followed through 1999 in the Kaiser Permanente Northern California Medical Care Program. Information on comorbidity, tumor characteristics and breast cancer treatment was obtained from medical records, and Surveillance, Epidemiology and End Results, Northern California Cancer Center Registry. Associations between comorbidity and survival were analyzed with multiple Cox proportional hazards regression. Over a mean follow‐up of 9 years, African Americans had higher overall crude mortality than whites: 165 (39.7%) versus 279 (33.3%), respectively. When age, race, tumor characteristics and breast cancer treatment were controlled, the presence of hypertension was associated with all cause survival [hazard ratio (HR) = 1.33, 95% confidence intervals (CI) 1.07–1.67] and it accounted for 30% of racial disparity in this outcome. Hypertension‐augmented Charlson Comorbidity Index was a significant predictor of survival from all causes (HR = 1.32, 95%CI 1.18–1.49), competing causes (HR = 1.52, 95%CI 1.32–1.76) and breast cancer specific causes (HR = 1.18, 95%CI 1.03–1.35). In conclusion, hypertension has prognostic significance in relation to survival disparity between African‐American and white breast cancer patients. If our findings are replicated in contemporary cohorts, it may be necessary to include hypertension in the Charlson Comorbidity Index and other comorbidity measures. © 2008 Wiley‐Liss, Inc.     

Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile.

The aim of this study was to determine the role of pregnane X receptor (PXR) in the induction of UDP-glucuronosyltransferases (UGTs) by pregnenolone-16 alpha-carbonitrile (PCN). Four- to six-month-old male wild-type and PXR-null mice received control or PCN-treated (1500 ppm) diet for 21 days. On day 22, livers were taken to prepare microsomes and total RNA to determine UGT activity and mRNA levels, respectively. In wild-type mice, PCN treatment significantly increased UGT activities toward bilirubin, 1-naphthol, chloramphenicol, thyroxine, and triiodothyronine. On control diet, the UGT activities toward the above substrates (except for 1-naphthol) in the PXR-null mice were significantly higher than those of wild-type mice. However, UGT activities in PXR-null mice were not increased by PCN. In agreement with the above findings, mRNA levels of mouse Ugt1a1 and Ugt1a9, which are involved in the glucuronidation of bilirubin and phenolic compounds, were increased about 100% in wild-type mice following PCN treatment, whereas the expression of Ugt1a2, 1a6, and 2b5 was not affected. In contrast, PCN treatment had no effect on the mRNA levels of these UGTs in PXR-null mice. Taken together, these results indicate that PCN treatment induces glucuronidation in mouse liver, and that PXR regulates constitutive and PCN-inducible expression of some UGTs.     

Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation

A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs—with varying length, polarity, and rigidity—were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure–activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design–make–test cycles.     

Argatroban for suspected heparin-induced thrombocytopenia: contemporary experience at a large teaching hospital

Heparin-induced thrombocytopenia requires immediate alternative anticoagulation to prevent or treat thromboembolic complications. Argatroban was approved based on multiple-center studies from the 1990s, but subsequent changes in prevailing awareness, diagnostic testing and therapeutic strategies for heparin-induced thrombocytopenia might affect results of argatroban therapy. Charts were retrospectively reviewed from patients administered argatroban for suspected heparin-induced thrombocytopenia over 22 months at a single large university hospital. Twenty-seven patients, most in intensive care units, received a median 0.5 microg/kg/min argatroban over a median 5.5 days. Patients had isolated heparin-induced thrombocytopenia (n = 10), had heparin-induced thrombocytopenia with thrombosis (n = 9), or lacked active heparin-induced thrombocytopenia (n = 8) on final analysis. New thromboses (14.8%), progression of preexisting thromboses (0%), amputation secondary to heparin-induced thrombocytopenia (0%), death (22.2%), bleeding requiring transfusion (3.7%), and any bleeding (22.2%) compared favorably with older multiple-center reports. Deaths occurred mainly with preexisting multiple-organ failure. In contemporary "real world" use, argatroban provides safe and effective anticoagulation, strengthening the mandate to initiate alternative anticoagulation whenever heparin-induced thrombocytopenia appears likely.