Citations

Background— Cardiopulmonary exercise testing (CPX) with measurement of peak oxygen uptake (V o 2 ) is a powerful test for assessment and quantification of functional impairment resulting from cardiovascular disease. The safety of CPX has been established in patients with coronary artery disease and congestive heart failure, but clinical use of CPX in other cardiac diseases has been limited, in part because of a paucity of safety data. This study investigates the safety of CPX in a heterogeneous cohort of patients with a wide variety of underlying high-risk cardiac diagnoses. Methods and Results— This single-center retrospective review examined 5060 CPX studies performed in 4250 unique patients, including 1748 (35%) female subjects and 686 (14%) subjects aged ≥75 years. The primary end point was major adverse event during stress testing. The study population included patients with a variety of high-risk cardiac diseases, including congestive heart failure (n=1289, 25.5%), hypertrophic cardiomyopathy (n=598, 11.8%), pulmonary hypertension (n=194, 3.8%), and aortic stenosis (n=212, 4.2%). This patient population generally had severe functional impairment, including 1192 (24%) patients with peak V o 2 <14 mL/kg/min. Eight adverse events occurred during CPX, for an adverse event rate of 0.16%. The most common adverse event (n=6) was sustained ventricular tachycardia. There were no fatal events. Conclusions— CPX is generally a safe procedure, even in a population with underlying high-risk cardiovascular diagnoses.

Abstract Purpose: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. Experimental Design: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m2 over 72 hours (667 mg/m2/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m2/dose. Results: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m2). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m2 or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m2, consistent with unrepaired DNA damage. Conclusions: These data support a randomized phase II trial of cytarabine +/− SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m2) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517. Clin Cancer Res; 18(24); 6723–31. ©2012 AACR.

Abstract Endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) augment tissue repair but possess slightly different properties. How the cellular phenotype affects the efficacy of this approach in renovascular disease is incompletely understood. This study tested the hypothesis that EPC and MSC protect the poststenotic kidney by blunting different disease pathways. Peripheral blood EPC and adipose-derived MSC were expanded and characterized by cell surface markers (e.g., CD34/kinase insert domain receptor, or CD44/CD90). Single-kidney hemodynamics and function were assessed in pigs after 10 weeks of renal artery stenosis (RAS) treated 4 weeks earlier with an intrarenal infusion of vehicle (n = 7), EPC (RAS+EPC) or MSC (RAS+MSC) (both 10 × 106, n = 6), and normal controls (n = 7). Kidney disease mechanisms were evaluated ex vivo. The ability of EPC and MSC to attenuate endoplasmic reticulum (ER) stress was also studied in isolated ER and in tubular cells cocultured with EPC and MSC. Glomerular filtration rate in RAS was lower than controls, increased in RAS+EPC, and further improved in RAS+MSC, although both improved renal blood flow similarly. EPC prominently enhanced renal growth factor expression and decreased oxidative stress, while MSC more significantly attenuated renal inflammation, ER stress, and apoptosis. Furthermore, MSC induced a greater decrease in caspase-3 and CHOP expression in cultured tubular cells through mechanisms involving cell contact. EPC and MSC achieve a comparable decrease of kidney injury in RAS by different mechanisms, although MSC elicited slightly superior improvement of renal function. These results support development of cell-based approaches for management of renovascular disease and suggest cell selection based on the underlying pathophysiology of kidney injury.

Inhibition of the EGFR signaling pathway is one of the attractive therapeutic targets for pancreatic cancer as recent studies demonstrated that EGFR is over‐expressed in pancreatic cancer. In this article we have demonstrated the design of targeted drug delivery system containing Bovine Serum Albumin (BSA) microspheres as delivery vehicle, gemcitabine as anticancer drug and anti‐EGFR (epidermal growth factor receptor) monoclonal antibody as targeting agent. The conjugated BSA microspheres were characterized by several physico‐chemical techniques such as scanning electron microscope, optical microscopy, fluorescent microscopy etc. Administration of these BSA microspheres containing gemcitabine and anti‐EGFR (BSA‐Gem‐EGFR) shows significant inhibition of pancreatic cancer cells (AsPC1) compared to the cells treated with only BSA microspheres, BSA with gemcitabine (BSA‐Gem), and free gemcitabine. This strategy could be used as a generalized approach for the treatment of pancreatic cancer along with other cancers which overexpress EGFR on cell surface. Copyright © 2012 John Wiley & Sons, Ltd.

Background Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women. Methods The Hormones and Biomarkers Predicting Stroke Study is a case-control study of blood biomarkers assayed in 972 ischemic stroke cases and 972 controls, nested in the Women's Health Initiative Observational Study of 93 676 postmenopausal women followed for an average of eight-years. We evaluated additive predictive value of two commercially available biomarkers: C-reactive protein and lipoprotein-associated phospholipase A 2 to determine if they added to risk prediction by the Framingham Stroke Risk Score or by traditional risk factors, which included lipids and other variables not included in the Framingham Stroke Risk Score. As measures of additive predictive value, we used the C-statistic, net reclassification improvement, category-less net reclassification improvement, and integrated discrimination improvement index. Results Addition of C-reactive protein to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall net reclassification improvement of 6·3%, (case net reclassification improvement = 3·9%, control net reclassification improvement = 2·4%). In particular, high-sensitivity C-reactive protein was useful in prediction of cardioembolic strokes (net reclassification improvement = 12·0%; 95% confidence interval 4·3–19·6%) and in strokes occurring in less than three-years (net reclassification improvement = 7·9%, 95% confidence interval 0·8–14·9%). Lipoprotein-associated phospholipase A 2 was useful in risk prediction of large artery strokes (net reclassification improvement = 19·8%, 95% confidence interval 7·4–32·1%) and in early strokes (net reclassification improvement = 5·8%, 95% confidence interval 0·4–11·2%). Conclusions C-reactive protein and lipoprotein-associated phospholipase A 2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk.