Within You / Without You: Biotechnology, Ontology, and Ethics

As Implantable Cardioverter Defibrillators (ICDs) have become more common, ethical issues have arisen regarding the deactivation of these devices. Goldstein et al., have shown that both patients and cardiologists consider ICD deactivation to be different from the discontinuation of other life-sustaining treatments. It cannot be argued ethically that ICDs raise new questions about the distinction between withholding and withdrawing treatment, and neither the fact that they are used intermittently, nor the duration of therapy, nor the mere fact that they are located inside the body can be considered unique to these devices and morally decisive. However, frequent allusions to the fact that they are located inside the body might provide a clue about what bothers patients and physicians. As technology progresses, some interventions seem to become a part of the patient as a unified whole person, completely replacing body parts and lost physiological functions rather than merely substituting for impaired structure and function. If a life-sustaining intervention can be considered a “replacement”—a part of the patient as a unified whole person—then it seems that deactivation is better classified as a case of killing rather than a case of forgoing a life-sustaining treatment. ICDs are not a “replacement” therapy in this sense. The deactivation of an ICD is best classified, under the proper conditions, as the forgoing of an extraordinary means of care. As technology becomes more sophisticated, however, and new interventions come to be best classified as “replacements” (a heart transplant would be a good example), “discontinuing” these interventions should be much more morally troubling for those clinicians who oppose euthanasia and assisted suicide

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Re-examining the effect of door-to-balloon delay on STEMI outcomes in the context of unmeasured confounders: a retrospective cohort study

Literature studying the door-to-balloon time-outcome relation in coronary intervention is limited by the potential of residual biases from unobserved confounders. This study re-examines the time-outcome relation with further consideration of the unobserved factors and reports the population average effect. Adults with ST-elevation myocardial infarction admitted to one of the six registry participating hospitals in Australia were included in this study. The exposure variable was patient-level door-to-balloon time. Primary outcomes assessed included in-hospital and 30 days mortality. 4343 patients fulfilled the study criteria. 38.0% (1651) experienced a door-to-balloon delay of >90 minutes. The absolute risk differences for in-hospital and 30-day deaths between the two exposure subgroups with balanced covariates were 2.81 (95% CI 1.04, 4.58) and 3.37 (95% CI 1.49, 5.26) per 100 population. When unmeasured factors were taken into consideration, the risk difference were 20.7 (95% CI −2.6, 44.0) and 22.6 (95% CI −1.7, 47.0) per 100 population. Despite further adjustment of the observed and unobserved factors, this study suggests a directionally consistent linkage between longer door-to-balloon delay and higher risk of adverse outcomes at the population level. Greater uncertainties were observed when unmeasured factors were taken into consideration

Scientific Academies

The first Renaissance academies developed around the middle of the fifteenth century and had a primarily encyclopedic character. The main trait of the knowledge cultivated in their first phase was the revival of the classical culture. On the one hand they, fostered a renewed interest especially in Platonic philosophy, and on the other hand they cultivated the dream of a somewhat all-embracing knowledge. Vernacular literature, liberal arts, music, mathematics, and the study of nature were all parts, within the fifteenth to sixteenth-century academies, of a wider landscape of interests. It is exactly this tension and strife towards a unifying and organic picture of knowledge that threatens any attempt at formulating a classification of themes and contents that were addresses by the first renaissance academies. The question of the scientific academy in the Renaissance should thus be posed and defined considering on the one hand the relation with the wider academic phenomenology and on the other hand with the birth and rise of the \u201cnew science,\u201d in particular when it comes to the very process that science underwent in order to be autonomous from an organic and homogeneous view of knowledge, a view that was exactly the hallmark of that model in which the academies were born

Association Analysis of 94 Candidate Genes and Schizophrenia-Related Endophenotypes

While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis

The effect on survival of continuing chemotherapy to near death

<p>Abstract</p> <p>Background</p> <p>Overuse of anti-cancer therapy is an important quality-of-care issue. An aggressive approach to treatment can have negative effects on quality of life and cost, but its effect on survival is not well-defined.</p> <p>Methods</p> <p>Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 7,879 Medicare-enrolled patients aged 65 or older who died after having survived at least 3 months after diagnosis of advanced non-small cell lung cancer (NSCLC) between 1991 and 1999. We used Cox proportional hazards regression analysis, propensity scores, and instrumental variable analysis (IVA) to compare survival among patients who never received chemotherapy (n = 4,345), those who received standard chemotherapy but not within two weeks prior to death (n = 3,235), and those who were still receiving chemotherapy within 14 days of death (n = 299). Geographic variation in the application of chemotherapy was used as the instrument for IVA.</p> <p>Results</p> <p>Receipt of chemotherapy was associated with a 2-month improvement in overall survival. However, based on three different statistical approaches, no additional survival benefit was evident from continuing chemotherapy within 14 days of death. Moreover, patients receiving chemotherapy near the end of life were much less likely to enter hospice (81% versus 51% with no chemotherapy and 52% with standard chemotherapy, P < 0.001), or were more likely to be admitted within only 3 days of death.</p> <p>Conclusions</p> <p>Continuing chemotherapy for advanced NSCLC until very near death is associated with a decreased likelihood of receiving hospice care but not prolonged survival. Oncologists should strive to discontinue chemotherapy as death approaches and encourage patients to enroll in hospice for better end-of-life palliative care.</p

Honokiol Arrests Cell Cycle, Induces Apoptosis, and Potentiates the Cytotoxic Effect of Gemcitabine in Human Pancreatic Cancer Cells

Survival rates for patients with pancreatic cancer are extremely poor due to its asymptomatic progression to advanced and metastatic stage for which current therapies remain largely ineffective. Therefore, novel therapeutic agents and treatment approaches are desired to improve the clinical outcome. In this study, we determined the effects of honokiol, a biologically active constituent of oriental medicinal herb Magnolia officinalis/grandiflora, on two pancreatic cancer cell lines, MiaPaCa and Panc1, alone and in combination with the standard chemotherapeutic drug, gemcitabine. Honokiol exerted growth inhibitory effects on both the pancreatic cancer cell lines by causing cell cycle arrest at G1 phase and induction of apoptosis. At the molecular level, honokiol markedly decreased the expression of cyclins (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4), and caused an increase in Cdk inhibitors, p21 and p27. Furthermore, honokiol treatment led to augmentation of Bax/Bcl-2 and Bax/Bcl-xL ratios to favor apoptosis in pancreatic cancer cells. These changes were accompanied by enhanced cytoplasmic accumulation of NF-κB with a concomitant decrease in nuclear fraction and reduced transcriptional activity of NF-κB responsive promoter. This was associated with decreased phosphorylation of inhibitor of kappa B alpha (IκB-α) causing its stabilization and thus increased cellular levels. Importantly, honokiol also potentiated the cytotoxic effects of gemcitabine, in part, by restricting the gemcitabine-induced nuclear accumulation of NF-κB in the treated pancreatic cancer cell lines. Altogether, these findings demonstrate, for the first time, the growth inhibitory effects of honokiol in pancreatic cancer and indicate its potential usefulness as a novel natural agent in prevention and therapy

Identification of Mammalian Protein Quality Control Factors by High-Throughput Cellular Imaging

Protein Quality Control (PQC) pathways are essential to maintain the equilibrium between protein folding and the clearance of misfolded proteins. In order to discover novel human PQC factors, we developed a high-content, high-throughput cell-based assay to assess PQC activity. The assay is based on a fluorescently tagged, temperature sensitive PQC substrate and measures its degradation relative to a temperature insensitive internal control. In a targeted screen of 1591 siRNA genes involved in the Ubiquitin-Proteasome System (UPS) we identified 25 of the 33 genes encoding for 26S proteasome subunits and discovered several novel PQC factors. An unbiased genome-wide siRNA screen revealed the protein translation machinery, and in particular the EIF3 translation initiation complex, as a novel key modulator of misfolded protein stability. These results represent a comprehensive unbiased survey of human PQC components and establish an experimental tool for the discovery of genes that are required for the degradation of misfolded proteins under conditions of proteotoxic stress

Pseudomonas aeruginosa Eliminates Natural Killer Cells via Phagocytosis-Induced Apoptosis

Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes the relapse of illness in immunocompromised patients, leading to prolonged hospitalization, increased medical expense, and death. In this report, we show that PA invades natural killer (NK) cells and induces phagocytosis-induced cell death (PICD) of lymphocytes. In vivo tumor metastasis was augmented by PA infection, with a significant reduction in NK cell number. Adoptive transfer of NK cells mitigated PA-induced metastasis. Internalization of PA into NK cells was observed by transmission electron microscopy. In addition, PA invaded NK cells via phosphoinositide 3-kinase (PI3K) activation, and the phagocytic event led to caspase 9-dependent apoptosis of NK cells. PA-mediated NK cell apoptosis was dependent on activation of mitogen-activated protein (MAP) kinase and the generation of reactive oxygen species (ROS). These data suggest that the phagocytosis of PA by NK cells is a critical event that affects the relapse of diseases in immunocompromised patients, such as those with cancer, and provides important insights into the interactions between PA and NK cells

Sport and Society

Despite its economic and cultural centrality, sport is a relatively neglected and undertheorized area of sociological research. In this review, we examine sports\u27 articulation with stratification issues, especially race, class, and gender. In addition, we look at how the media and processes of globalization have affected sports.We suggest that sports and cultural sociologists need to attend more closely to how leisure products and practices are produced and distributed and how they intersect with educational, political, and cultural institutions. We propose the work of Bourdieu andthe new institutionalism to undergird future research