Emily Bell

Preparing the ethical future of deep brain stimulation

BACKGROUND Deep brain stimulation is an approved and effective neurosurgical intervention for motor disorders such as PD and ET. Deep brain stimulation may also be effective in treating a number of psychiatric disorders, including treatment refractory depression and OCD. Although DBS is a widely accepted therapy in motor disorders, it remains an invasive and expensive procedure. The ethical and social challenges of DBS need further examination, and discussion and emerging applications of DBS in psychiatry may also complicate the ethical landscape of DBS. METHODS To identify and characterize current and emerging issues in the use of DBS, we reviewed the neurosurgical literature on DBS as well as the interdisciplinary medical ethics and relevant psychological and sociological literatures. We also consulted the USPTO database, FDA regulations and report decisions, and the business reports of key DBS manufacturers. RESULTS Important ethical and social challenges exist in the current and extending practice of DBS, notably in patient selection, informed consent, resource allocation, and in public understanding. These challenges are likely to be amplified if emerging uses of DBS in psychiatry are approved. CONCLUSIONS Our review of ethical and social issues related to DBS highlights that several significant challenges, although not insurmountable, need much closer attention. A combination of approaches previously used in neuroethics, such as expert consensus workshops to establish ethical guidelines and public engagement to improve public understanding, may be fruitful to explore.

Informed consent for MRI and fMRI research: analysis of a sample of Canadian consent documents.

BackgroundResearch ethics and the measures deployed to ensure ethical oversight of research (e.g., informed consent forms, ethics review) are vested with extremely important ethical and practical goals. Accordingly, these measures need to function effectively in real-world research and to follow high level standards.MethodsWe examined approved consent forms for Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) studies approved by Canadian research ethics boards (REBs).ResultsWe found evidence of variability in consent forms in matters of physical and psychological risk reporting. Approaches used to tackle the emerging issue of incidental findings exposed extensive variability between and within research sites.ConclusionThe causes of variability in approved consent forms and studies need to be better understood. However, mounting evidence of administrative and practical hurdles within current ethics governance systems combined with potential sub-optimal provision of information to and protection of research subjects support other calls for more scrutiny of research ethics practices and applicable revisions.

Crk adaptor proteins act as key signaling integrators for breast tumorigenesis

IntroductionCT10 regulator of kinase (Crk) adaptor proteins (CrkI, CrkII and CrkL) play a role in integrating signals for migration and invasion of highly malignant breast cancer cell lines. This has important implications, as elevated CrkI/II protein levels were observed in a small cohort of breast cancer patients, which identified a potential role for Crk proteins in breast cancer progression. Numerous in vitro studies identified a role for Crk proteins in cell motility, but little is known about how Crk proteins contribute to breast cancer progression in vivo.MethodsThe clinical significance of Crk proteins in human breast cancer was assessed by analyzing published breast cancer datasets using a gene expression signature that was generated following CrkII over-expression and by examining Crk protein expression in tissue microarrays of breast tumors (n = 254). Stable knockdown of Crk (CrkI/CrkII/CrkL) proteins was accomplished using a short hairpin RNA (shRNA)-mediated approach in two basal breast cancer cell lines, MDA-231 1833TR and SUM1315, where the former have a high affinity to form bone metastases. Both in vitro assays (cell migration, invasion, soft agar growth) and in vivo experiments (intra-cardiac, tibial and mammary fat pad injections) were performed to assess the functional significance of Crk proteins in breast cancer.ResultsA gene signature derived following CrkII over-expression correlated significantly with basal breast cancers and with high grade and poor outcome in general. Moreover, elevated Crk immunostaining on tissue microarrays revealed a significant association with highly proliferative tumors within the basal subtype. RNAi-mediated knockdown of all three Crk proteins in metastatic basal breast cancer cells established a continued requirement for Crk in cell migration and invasion in vitro and metastatic growth in vivo. Furthermore, Crk ablation suppressed anchorage independent growth and in vivo orthotopic tumor growth. This was associated with diminished cell proliferation and was rescued by expression of non-shRNA targeted CrkI/II. Perturbations in tumor progression correlated with altered integrin signaling, including decreased cell spreading, diminished p130Cas phosphorylation, and Cdc42 activation.ConclusionsThese data highlight the physiological importance of Crk proteins in regulating growth of aggressive basal breast cancer cells and identify Crk-dependent signaling networks as promising therapeutic targets.

Models of Crk Adaptor Proteins in Cancer

The Crk family of adaptor proteins (CrkI, CrkII, and CrkL), originally discovered as the oncogene fusion product, v-Crk, of the CT10 chicken retrovirus, lacks catalytic activity but engages with multiple signaling pathways through their SH2 and SH3 domains. Crk proteins link upstream tyrosine kinase and integrin-dependent signals to downstream effectors, acting as adaptors in diverse signaling pathways and cellular processes. Crk proteins are now recognized to play a role in the malignancy of many human cancers, stimulating renewed interest in their mechanism of action in cancer progression. The contribution of Crk signaling to malignancy has been predominantly studied in fibroblasts and in hematopoietic models and more recently in epithelial models. A mechanistic understanding of Crk proteins in cancer progression in vivo is still poorly understood in part due to the highly pleiotropic nature of Crk signaling. Recent advances in the structural organization of Crk domains, new roles in kinase regulation, and increased knowledge of the mechanisms and frequency of Crk overexpression in human cancers have provided an incentive for further study in in vivo models. An understanding of the mechanisms through which Crk proteins act as oncogenic drivers could have important implications in therapeutic targeting.

Perspectives of Canadian Researchers on Ethics Review of Neuroimaging Research

The current and potential uses of neuroimaging in healthcare and beyond have spurred discussion about the ethical issues related to neuroimaging and neuroimaging research. This study examined the perspectives of neuroimagers on ethical issues in their research and on the ethics review process. One hundred neuroimagers from 13 Canadian neuroscience centers completed an online survey and 35 semi-structured interviews were conducted. Neuroimagers felt that most ethical and social issues identified in the literature were dealt with adequately, well, and even very well by research ethics boards (REBs), but some issues such as incidental findings and transfer of knowledge were problematic. Neuroimagers reported a range of practical problems in the ethics review process. We aimed to gather perspectives from REB on the ethics review process, but insufficient participation by REBs prevented us from reporting their perspectives. Given shortcomings identified by neuroimagers as well as longstanding issues in Canadian ethics governance, we believe that substantial challenges exist in Canadian research ethics governance that jeopardize trust, communication, and the overall soundness of research ethics governance. Neuroimagers and REBs should consider their shared responsibilities in developing guidance to handle issues such as incidental findings, risk assessment, and knowledge transfer.

DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior

The small guanosine triphosphatase Rab13 functions in exocytic vesicle trafficking in epithelial cells. Alterations in Rab13 activity have been observed in human cancers, yet the mechanism of Rab13 activation and its role in cancer progression remain unclear. In this paper, we identify the DENN domain protein DENND2B as the guanine nucleotide exchange factor for Rab13 and develop a novel Förster resonance energy transfer-based Rab biosensor to reveal activation of Rab13 by DENND2B at the leading edge of migrating cells. DENND2B interacts with the Rab13 effector MICAL-L2 at the cell periphery, and this interaction is required for the dynamic remodeling of the cells leading edge. Disruption of Rab13-mediated trafficking dramatically limits the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo. Thus, blocking Rab13 activation by DENND2B may provide a novel target to limit the spread of epithelial cancers.

Deep brain stimulation and ethics: perspectives from a multisite qualitative study of Canadian neurosurgical centers.

OBJECTIVE Deep brain stimulation (DBS) is an approved neurosurgical intervention for motor disorders such as Parkinson disease. The emergence of psychiatric uses for DBS combined with the fact that it is an invasive and expensive procedure creates important ethical and social challenges in the delivery of care that need further examination. We endeavored to examine health care provider perspectives on ethical and social challenges encountered in DBS. METHODS Health care providers working in Canadian DBS surgery programs participated in a semistructured interview to identify and characterize ethical and social challenges of DBS. A content analysis of the interviews was conducted. RESULTS Several key ethical issues, such as patient screening and resource allocation, were identified by members of neurosurgical teams. Providers described challenges in selecting patients for DBS on the basis of unclear evidence-based guidance regarding behavioral issues or cognitive criteria. Varied contexts of resource allocation, including some very challenging schemas, were also reported. In addition, the management of patients in the community was highlighted as a source of ethical and clinical complexity, given the need for coordinated long-term care. CONCLUSIONS This study provides insights into the complexity of ethical challenges that providers face in the use of DBS across different neurosurgical centers. We propose actions for health care providers for the long-term care and postoperative monitoring of patients with DBS. More data on patient perspectives in DBS would complement the understanding of key challenges, as well as contribute to best practices, for patient selection, management, and resource allocation.

Comments and Reflections on Ethics in Screening for Biomarkers of Prenatal Alcohol Exposure

Early identification of and intervention for fetal alcohol spectrum disorder (FASD) has been shown to optimize outcomes for affected individuals. Detecting biomarkers of prenatal alcohol exposure (PAE) in neonates may assist in the identification of children at risk of FASD enabling targeted early interventions. Despite these potential benefits, complicated ethical issues arise in screening for biomarkers of PAE and these must be addressed prior to the implementation of screening programs. Here, we identify and comment, based on a North American perspective, on concerns raised in the current ethical, social, and legal literature related to meconium screening for PAE. Major ethical concerns revolve around the targeting of populations for PAE screening, consent and respect for persons, stigma and participation rates, the cost-benefit analysis of a screening program, consequences of false-positive and false-negative test results, confidentiality and appropriate follow-up to positive screen results, and the use of screen results for criminal prosecution. We identify gaps in the literature on screening for PAE, most notably related to a lack of stakeholder perspectives (e.g., parents, healthcare providers) about screening and the ethical challenges it presents.

Dynamic Reprogramming of Signaling Upon Met Inhibition Reveals a Mechanism of Drug Resistance in Gastric Cancer

Understanding how inhibitors rewire the Met receptor pathway points to a strategy for more effective gastric cancer treatment. Met with Resistance in Gastric Cancer The hepatocyte growth factor receptor Met is associated with poor prognosis in various cancers, but the efficacy of Met inhibitors is often impeded by resistance. By comparing transcriptional changes at multiple time points after stimulation or inhibition of Met, Lai et al. identified critical mediators of Met-induced proliferation and Met inhibitor resistance in gastric cancer cell lines. Cancer cells or tumors exposed to Met inhibitors had decreased abundance of phosphatases, and this correlated with reactivation of the pro-proliferative MEK-ERK pathway and the emergence of drug resistance. Combining Met and MEK inhibitors was more cytotoxic to gastric cancer cells in culture than was either inhibitor alone, suggesting that this combination strategy may be effective in gastric cancer. The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle–related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal–regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)–ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.

Beyond consent in research. Revisiting vulnerability in deep brain stimulation for psychiatric disorders.

Vulnerability is an important criterion to assess the ethical justification of the inclusion of participants in research trials. Currently, vulnerability is often understood as an attribute inherent to a participant by nature of a diagnosed condition. Accordingly, a common ethical concern relates to the participants decisionmaking capacity and ability to provide free and informed consent. We propose an expanded view of vulnerability that moves beyond a focus on consent and the intrinsic attributes of participants. We offer specific suggestions for how relational aspects and the dynamic features of vulnerability could be more fully captured in current discussions and research practices.