BRCA1/MAD2L1 deficiency disrupts the spindle assembly checkpoint to confer vinorelbine resistance in mesothelioma

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.Pathogenesis and treatment of chronic pulmonary disease

Long term productivity benefits of soil conservation

Many studies have documented that erosion reduces crop yields (Langdale and Shrader, 1982; Follet and Stewart, 1985; Am. Soc. Ag. Engr., 1985). Few of those studies have incorporated the effect on yield of changes in technology (Young, 1984) and only one, to our knowledge, has considered the effect of yield-enhancing agricultural technical progress on erosion damage assessment (Walker and Young, 1986). Lost yield potential is the major on-site effect of erosion. Off-site effects in the form of sedimentation and impaired water quality are also important but are not discussed here. A conservation practice that reduces erosion and yield damage produces a benefit from conservation. This potential benefit, in the form of yield damage avoided, is the objective of soil conservation research and conservation adoption. Understanding the cost of erosion damage and the benefits from erosion control are essential for developing long range policies for conserving soil resources. The tri-state STEEP multidisciplinary research program is dedicated to finding solutions to the erosion problems in the Pacific Northwest. STEEP research results concerning the long term productivity impacts of erosion are the focus of this paper. This paper describes the different types of erosion damage and presents concepts for correctly measuring that damage or the potential benefits from erosion control. STEEP research is presented to show the effect of erosion on the soil resource and on crop productivity. The potential for restoring productivity on eroded soils is discussed. The paper also describes how to separate the effects of technology and yield damage and presents empirical estimates of conservation benefits. A first classification of erosion damage distinguishes between current damage and long-term damage. Current erosion damage is due primarily to seedbed erosion, reduced tillering, and plant suffocation by sediment, all of which reduce stand density. Current damage is yield loss this year due to erosion this year. These erosional effects do not carry over into subsequent years. Long-term erosion damage occurs when erosion this year reduces yield in future years. This yield loss is due to the loss of nutrient-rich topsoil, to degradation of soil structure and to reduction of plant-available water-holding capacity of eroded soil. Long-term damage is of great concern because its effects are enduring, even irreversible in large part. Estimates of the long-term productivity benefits of soil conservation are formulated in terms of long-term erosion damage avoided by conservation

Long Term Productivity Benefits of Soil Conservation

Please contact the NWISRL if you have a copy of this publication

Long Term Productivity Benefits of Soil Conservation

Please contact the NWISRL if you have a copy of this publication