oxidative stress ͉ PARK7 ͉ NQO1 ͉ Keap1 ͉ neurodegeneration

Heightened DJ-1 (Park7) expression is associated with a reduction in chemotherapeutic-induced cell death and poor prognosis in several cancers, whereas the loss of DJ-1 function is found in a subgroup of Parkinson disease associated with neuronal death. This study describes a novel pathway by which DJ-1 modulates cell survival. Mass spectrometry shows that DJ-1 interacts with BBS1, CLCF1, MTREF, and Cezanne/ OTUD7B/Za20d1. Among these, Cezanne is a known deubiquitination enzyme that inhibits NF-B activity. DJ-1/Cezanne interaction is confirmed by co-immunoprecipitation of overexpressed and endogenous proteins, maps to the amino-terminal 70 residues of DJ-1, and leads to the inhibition of the deubiquitinating activity of Cezanne. Microarray profiling of shRNA-transduced cells shows that DJ-1 and Cezanne regulate IL-8 and ICAM-1 expression in opposing directions. Similarly, DJ-1 enhances NF-B nuclear translocation and cell survival, whereas Cezanne reduces these outcomes. Analysis of mouse Park7 ؊/؊ primary cells confirms the regulation of ICAM-1 by DJ-1 and Cezanne. As NF-B is important in cellular survival and transformation, IL-8 functions as an angiogenic factor and pro-survival signal, and ICAM-1 has been implicated in tumor progression, invasion, and metastasis; these data provide an additional modality by which DJ-1 controls cell survival and possibly tumor progression via interaction with Cezanne.Lung cancer is the leading cause of cancer-related mortality in the world. It is estimated that over 215,000 new cases were diagnosed in the United States in 2008 alone (1). Of the two major types of lung cancer, 85% are non-small cell lung carcinomas (NSCLC) 2 (2). With NSCLC, the best chance for a long term cure is surgery. Unfortunately, 70% of NSCLC patients are initially contraindicated for surgery due to locally invasive or metastatic disease (3). For these patients, the current treatment options are a combination of chemotherapy and radiation. With treatment, NSCLC patients have a 5-year survival rate of 15%. It is therefore imperative to investigate new pathways to target in NSCLC. Our work in the H157 NSCLC squamous cell line has focused on the role of DJ-1.DJ-1 is associated with a spectrum of human disease. Loss of DJ-1 activity, due to inactivation by mutation or genetic deletion, causes early onset Parkinson disease with high penetrance (4). Due to the protective effects of DJ-1 against toxic insults, this association is hypothesized to be due to a protective role of DJ-1 in dopaminergic neurons of the substantia nigra (5-7). As loss of DJ-1 activity leads to neuronal cell death, increased DJ-1 activity can promote cell survival, leading to its association with human malignancies. Initial research on the role of DJ-1 in cancer showed that although DJ-1 can weakly transform cells alone, it can act synergistically in combination with Ras (8). DJ-1 is highly expressed in a number of cancer types including acute leukemia, breast, prostate, ovarian, and thyroid cancer, and NSCLC and is associated with tumo...

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Objectives Communication between medical oncologists (MO) and plastic surgeons (PS) is important to optimize outcomes for breast cancer patients seeking breast reconstruction. We sought to evaluate knowledge MO and PS have of each other’s fields, roles expected of each other, and frequency of communication. Methods A cross-sectional survey was conducted in a convenience sample of MO and PS. The survey included knowledge questions about reconstruction and chemotherapy, questions about provider and patient responsibilities for timely chemotherapy initiation, and questions about communication with other specialties. Results MO and PS had similar knowledge scores (MO 59%, PS 56%, p=0.5), but both lacked knowledge about aspects of the other specialty’s field related to breast reconstruction. The MO and PS agreed on the MO’s degree of responsibility for timely chemotherapy initiation (MO mean 4.6, PS mean 4.4 out of 5, p =0.2). However, they disagreed about the PS’s responsibility for timely chemotherapy initiation (MO mean 3.8, PS mean 3.0, p=0.01). Communication occurred about 2.5 times more often for patients with complications than uncomplicated patients (p<0.0001). Conclusion MO and PS have deficits in knowledge about each other fields and differ in their opinion regarding the burden of responsibility in ensuring timely chemotherapy initiation suggesting room for improvement in communication and understanding.

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