Chemical modification of extracellular matrix by cold atmospheric plasma-generated reactive species affects chondrogenesis and bone formation.

The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (μsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or power (~1 W). Recombinant human bone morphogenetic protein-2 was added and the mixture subcutaneously injected into mice to simulate ectopic endochondral ossification. Two weeks later, the masses were extracted and analysed by microcomputed tomography. A significant increase in bone formation was observed in Matrigel treated with μsp DBD compared with control, while a significant decrease in bone formation was observed for both nsp treatments. Histological and immunohistochemical analysis showed Matrigel treated with μsp plasma increased the number of invading cells, the amount of vascular endothelial growth factor and chondrogenesis while the opposite was true for Matrigel treated with nsp plasma. In support of the in vivo Matrigel study, 10 T1/2 cells cultured in vitro on μsp DBD-treated type I collagen showed increased expression of adhesion proteins and activation of survival pathways, which decreased with nsp plasma treatments. These results indicate DBD modification of ECM can influence cellular behaviours to accelerate or inhibit chondrogenesis and endochondral ossification. Copyright © 2016 John Wiley & Sons, Ltd

The Cultural Project : Formal Chronological Modelling of the Early and Middle Neolithic Sequence in Lower Alsace

Starting from questions about the nature of cultural diversity, this paper examines the pace and tempo of change and the relative importance of continuity and discontinuity. To unravel the cultural project of the past, we apply chronological modelling of radiocarbon dates within a Bayesian statistical framework, to interrogate the Neolithic cultural sequence in Lower Alsace, in the upper Rhine valley, in broad terms from the later sixth to the end of the fifth millennium cal BC. Detailed formal estimates are provided for the long succession of cultural groups, from the early Neolithic Linear Pottery culture (LBK) to the Bischheim Occidental du Rhin Supérieur (BORS) groups at the end of the Middle Neolithic, using seriation and typology of pottery as the starting point in modelling. The rate of ceramic change, as well as frequent shifts in the nature, location and density of settlements, are documented in detail, down to lifetime and generational timescales. This reveals a Neolithic world in Lower Alsace busy with comings and goings, tinkerings and adjustments, and relocations and realignments. A significant hiatus is identified between the end of the LBK and the start of the Hinkelstein group, in the early part of the fifth millennium cal BC. On the basis of modelling of existing dates for other parts of the Rhineland, this appears to be a wider phenomenon, and possible explanations are discussed; full reoccupation of the landscape is only seen in the Grossgartach phase. Radical shifts are also proposed at the end of the Middle Neolithic

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users

Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer

PURPOSE: The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. PATIENTS AND METHODS: We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14days q21days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints (e.g., efficacy [response] per RECIST and toxicity), adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25% response rate from null response rate of 10% using a Simon two-stage design. RESULTS: Twenty six patients were enrolled in the first-stage and 21 were evaluable after a median of 4 cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m(2) BSA-dosing schedule. Eight patients had stable disease but progressed after a median of 7 cycles. Despite a clinical benefit rate of 19%, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28%) and vomiting (5%). Adherence was similar when using both patient-reported and Medication Event Monitoring System (MEMS) methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. CONCLUSION: Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing