Kevin T. FitzGerald

Markers in normal and cancer stem cells

In an effort to better understand and address the challenges of cancer research and treatment, a new model of tumorigenesis is being developed - the cancer stem cell model. Building upon traditional concepts of cancer and stem cells, this model is intended to shed new light on the continued struggle with treatment issues such as tumor drug-resistance and recurrence. This review describes the cancer stem cell model with an emphasis on markers that represent the stemness phenotype. A thorough understanding of normal and cancer stem cells is necessary for a precise delineation of cancer stem cells. The objective of such an improved delineation is to develop targeted therapy for selective elimination of cancer stem cells with minimal toxicity to normal stem cells. Specific targeting of cancer stem cells has proved to be a significant challenge due to the commonality of many markers between normal and cancer stem cells. However, research in the area of cancer biomarkers is slowly, but steadily, progressing.

Plasma 24-metabolite Panel Predicts Preclinical Transition to Clinical Stages of Alzheimer’s Disease

We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer’s disease (LOAD). A 10 plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70–80u2009years or younger. In this report, we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (nu2009=u200928) and a matched set of cognitively normal subjects (nu2009=u200973), and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve for the discovery and internal validation cohort of 1.0 and 0.995 (95% confidence intervals of 1.0–1.0, and 0.981–1.0), respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger). Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals but may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We do anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD.

Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon

BackgroundMLL2, an epigenetic regulator in mammalian cells, mediates histone 3 lysine 4 tri-methylation (H3K4me3) through the formation of a multiprotein complex. MLL2 shares a high degree of structural similarity with MLL, which is frequently disrupted in leukemias via chromosomal translocations. However, this structural similarity is not accompanied by functional equivalence. In light of this difference, and previous reports on involvement of epigenetic regulators in malignancies, we investigated MLL2 expression in established cell lines from breast and colon tissues. We then investigated MLL2 in solid tumors of breast and colon by immunohistochemistry, and evaluated potential associations with established clinicopathologic variables.ResultsWe examined MLL2 at both transcript and protein levels in established cell lines from breast and colon cancers. Examination of these cell lines showed elevated levels of MLL2. Furthermore, we also identified incomplete proteolytic cleavage of MLL2 in the highly invasive tumor cell lines. To corroborate these results, we studied tumor tissues from patients by immunohistochemistry. Patient samples also revealed increased levels of MLL2 protein in invasive carcinomas of the breast and colon. In breast, cytoplasmic MLL2 was significantly increased in tumor tissues compared to adjacent benign epithelium (p < 0.05), and in colon, both nuclear and cytoplasmic immunostaining was significantly increased in tumor tissues compared to adjacent benign mucosa (p < 0.05).ConclusionOur study indicates that elevated levels of MLL2 in the breast and colon cells are associated with malignancy in these tissues, in contrast to MLL involvement in haematopoietic cancer. In addition, both abnormal cellular localization of MLL2 and incomplete proteolytic processing may be associated with tumor growth/progression in breast and colonic tissues. This involvement of MLL2 in malignancy may be another example of the role of epigenetic regulators in cancer.

A Mastery Rubric for the Design and Evaluation of an Institutional Curriculum in the Responsible Conduct of Research.

We describe a Mastery Rubric for the design and evaluation of an institutional curriculum in the responsible conduct of research (RCR), motivated by new federal (US) research funding requirements for documenting this training over investigators’ careers. A Mastery Rubric outlines the desired knowledge, skills and abilities (KSAs) for a course or curriculum, rather than for an assignment, together with descriptions of a learner’s performance and/or capabilities from novice to proficiency, expertise or mastery of the curricular target(s). Our MR encompasses, formalises and provides a roadmap for the institutional implementation of career-spanning training in RCR. The rubric highlights the KSAs that support learning goal articulation for the targeted content areas; it also promotes assessment that demonstrates development in the target KSAs and encourages reflection and cognitive self-monitoring throughout RCR training over the scientist’s career. It represents a flexible, criterion-referenced definition of ‘success’ for both individuals and the institution itself – concretely reflecting the institution’s norms and standards with respect to RCR and representing a flexible mechanism for self-monitoring by individuals as well as the institution. A Mastery Rubric for a curriculum in the RCR can be generated using any topical KSA framework.

Cancer stem cells and markers: New model of tumorigenesis with therapeutic implications

In an effort to improve our understanding and treatment of cancer, a new model of tumorigenesis is being developed - the cancer stem cell model. Building upon traditional concepts of cancer and stem cells, this model is intended to shed new light on the continuing struggle with treatment challenges such as tumor drug-resistance and recurrence. This review describes the cancer stem cell model with an emphasis on delineating markers that represent a stemness phenotype within certain tumor cells. The objective of this delineation is to develop targeted therapies for the selective elimination of cancer stem cells with minimal toxicity to normal stem cells and tissues. However, this specific targeting of cancer stem cells has proved to be a significant challenge due to the similarity of markers expressed by both normal and cancer stem cells. Still, research in the area of cancer biomarkers is steadily progressing.

Using Ethical Reasoning to Amplify the Reach and Resonance of Professional Codes of Conduct in Training Big Data Scientists

The use of Big Data—however the term is defined—involves a wide array of issues and stakeholders, thereby increasing numbers of complex decisions around issues including data acquisition, use, and sharing. Big Data is becoming a significant component of practice in an ever-increasing range of disciplines; however, since it is not a coherent “discipline” itself, specific codes of conduct for Big Data users and researchers do not exist. While many institutions have created, or will create, training opportunities (e.g., degree programs, workshops) to prepare people to work in and around Big Data, insufficient time, space, and thought have been dedicated to training these people to engage with the ethical, legal, and social issues in this new domain. Since Big Data practitioners come from, and work in, diverse contexts, neither a relevant professional code of conduct nor specific formal ethics training are likely to be readily available. This normative paper describes an approach to conceptualizing ethical reasoning and integrating it into training for Big Data use and research. Our approach is based on a published framework that emphasizes ethical reasoning rather than topical knowledge. We describe the formation of professional community norms from two key disciplines that contribute to the emergent field of Big Data: computer science and statistics. Historical analogies from these professions suggest strategies for introducing trainees and orienting practitioners both to ethical reasoning and to a code of professional conduct itself. We include two semester course syllabi to strengthen our thesis that codes of conduct (including and beyond those we describe) can be harnessed to support the development of ethical reasoning in, and a sense of professional identity among, Big Data practitioners.

Beneficence In Utero: A Framework for Restricted Prenatal Whole-Genome Sequencing to Respect and Enhance the Well-Being of Children

Peters, S. A., S. M. Laham, N. Pachter, and I. M. Winship. 2014. The future in clinical genetics: affective forecasting biases in patient and clinician decision making. Clinical Genetics 85 (4): 312–17. Pollack, A. 2012. Conflict potential seen in genetic counselors. New York Times, July 13. Available at: http://www.nytimes.com/ 2012/07/14/business/conflict-potential-seen-in-genetic-counse lors-paid-by-testing-companies.html?_rD0.

On the Viability and Potential Value of Stem Cells for Repair and Treatment of Central Neurotrauma: Overview and Speculations

Central neurotrauma, such as spinal cord injury or traumatic brain injury, can damage critical axonal pathways and neurons and lead to partial to complete loss of neural function that is difficult to address in the mature central nervous system. Improvement and innovation in the development, manufacture, and delivery of stem-cell based therapies, as well as the continued exploration of newer forms of stem cells, have allowed the professional and public spheres to resolve technical and ethical questions that previously hindered stem cell research for central nervous system injury. Recent in vitro and in vivo models have demonstrated the potential that reprogrammed autologous stem cells, in particular, have to restore functionality and induce regeneration—while potentially mitigating technical issues of immunogenicity, rejection, and ethical issues of embryonic derivation. These newer stem-cell based approaches are not, however, without concerns and problems of safety, efficacy, use and distribution. This review is an assessment of the current state of the science, the potential solutions that have been and are currently being explored, and the problems and questions that arise from what appears to be a promising way forward (i.e., autologous stem cell-based therapies)—for the purpose of advancing the research for much-needed therapeutic interventions for central neurotrauma.

How We Should Conceive of Creation: Natural Birth as an Ethical Guidepost for Neonatal Rescue

Philosophically, biologically, and colloquially, “creation” belongs properly to the act of conception. After the new human organism comes into existence, all subsequent changes in its life cycle are more accurately understood as “development,” independent of the various arguments for attribution of personhood. Our colleague rightly argues that “rescues” carry greater moral imperative than “creations.” Yet the author’s argument to establish a less binding standard for neonatal resuscitation ultimately relies on an abuse of denotation. This confusion of “creation” for “development” lacks a logical boundary and results in undesirable consequences for the healing paradigm and research at an important frontier of medical science. In our view, advances in neonatal resuscitation create ethical dilemmas at the beginning of life that parallel traditional end-of-life issues. Just as “natural death” can be a reference point for understanding the latter, we argue that “natural birth” could be a reference point for neonatal ethical deliberation that is more philosophically accurate, intuitively understandable, and practically useful in bioethics. The natural birth standard would more coherently discourage neonatal “vitalism” in cases of inappropriately aggressive resuscitation while encouraging resuscitation in cases where this would benefit the infant. Our model also avoids the arbitrary gestational age standard that is rightly criticized. Rieder’s (2017) first premise, that “human creation is a process,” is the keystone of the argument. Regrettably, the establishment and defense of this premise is abdicated, stating that it is “a simple observation that doesn’t require any defense.” However, we argue that the current established paradigm is quite different and could be summarized as: Human creation is an event and human development is a process. Seeking to replace the current paradigm, the argument for a “creation spectrum” must be supported. Failing to do so leaves the rest of the argument without basis to inform neonatal bioethics. Creation is properly defined as “the action or process of bringing something into existence.” Conception—the union of the male and female gametes into a fertilized ovum—is the process that brings a human life into existence. The substance of a new being, previously nonexistent, is created at that moment. From that point in time, changes are of degree and not kind. These changes are biologically understood as development and are not changes in substance (G omez-Lobo 2002). In this light, developmental changes from 10 weeks gestation to 20 weeks gestation are not substantively different than changes from 30 weeks gestation to 1 month postpartum. It is hard to define when a human is “fully formed.” From conception through death, the human organism is in a constant state of change and development. If the premise of “gradual human creation” is accepted, a logical boundary of the creative process does not appear to exist. One view might be that the creative process is defined as gestation, and thus ends upon physical independence from the uterus. Certainly the intimate relationship of the gestating fetus and mother informs the ethical arguments, but it remains that gestation is simply a stage of development for an already existing human organism. Indeed, humans are always in some degree of dependence on their