Problems with Using Evolutionary Theory in Philosophy

Does science move toward truths? Are present scientific theories (approximately) true? Should we invoke truths to explain the success of science? Do our cognitive faculties track truths? Some philosophers say yes, while others say no, to these questions. Interestingly, both groups use the same scientific theory, viz., evolutionary theory, to defend their positions. I argue that it begs the question for the former group to do so because their positive answers imply that evolutionary theory is warranted, whereas it is self-defeating for the latter group to do so because their negative answers imply that evolutionary theory is unwarranted

Reactions to treatment debriefing among the participants of a placebo controlled trial

BACKGROUND: A significant proportion of trial participants respond to placebos for a variety of conditions. Despite the common conduct of these trials and the strong emphasis placed on informed consent, very little is known about informing participants about their individual treatment allocation at trial closure. This study aims to address this gap in the literature by exploring treatment beliefs and reactions to feedback about treatment allocation in the participants of a placebo-controlled randomized clinical trial (RCT). METHODS: Survey of trial participants using a semi-structured questionnaire including close and open-ended questions administered as telephone interviews and postal questionnaires. Trial participants were enrolled in a double-blind placebo-controlled RCT evaluating the effectiveness of corticosteroid for heel pain (ISRCTN36539116). The trial had closed and participants remained blind to treatment allocation. We assessed treatment expectations, the percentage of participants who wanted to be informed about their treatment allocation, their ability to guess and reactions to debriefing. RESULTS: Forty-six (73%) contactable participants responded to our survey. Forty-two were eligible (four participants with bilateral disease were excluded as they had received both treatments). Most (79%) participants did not have any expectations prior to receiving treatment, but many 'hoped' that something would help. Reasons for not having high expectations included the experimental nature of their care and possibility that they may get a placebo. Participants were hopeful because their pain was so severe and because they trusted the staff and services. Most (83%) wanted to be informed about their treatment allocation and study results. Over half (55%) said they could not guess which treatment they had been randomized to, and many of those who attempted a guess were incorrect. Reactions to treatment debriefing were generally positive, including in placebo responders. CONCLUSION: Our study suggests that most trial participants want to be informed about their treatment allocation and trial results. Further research is required to develop measure of hope and expectancy and to rigorously evaluate the effects of debriefing prospectively

Stock price reaction to profit warnings: The role of time-varying betas

This study investigates the role of time-varying betas, event-induced variance and conditional heteroskedasticity in the estimation of abnormal returns around important news announcements. Our analysis is based on the stock price reaction to profit warnings issued by a sample of firms listed on the Hong Kong Stock Exchange. The standard event study methodology indicates the presence of price reversal patterns following both positive and negative warnings. However, incorporating time-varying betas, event-induced variance and conditional heteroskedasticity in the modelling process results in post-negative-warning price patterns that are consistent with the predictions of the efficient market hypothesis. These adjustments also cause the statistical significance of some post-positive-warning cumulative abnormal returns to disappear and their magnitude to drop to an extent that minor transaction costs would eliminate the profitability of the contrarian strategy

Influence of slag composition on the stability of steel in alkali-activated cementitious materials

Among the minor elements found in metallurgical slags, sulfur and manganese can potentially influence the corrosion process of steel embedded in alkali-activated slag cements, as both are redox-sensitive. Particularly, it is possible that these could significantly influence the corrosion process of the steel. Two types of alkali-activated slag mortars were prepared in this study: 100% blast furnace slag and a modified slag blend (90% blast furnace slag? 10% silicomanganese slag), both activated with sodium silicate. These mortars were designed with the aim of determining the influence of varying the redox potential on the stability of steel passivation under exposure to alkaline and alkaline chloride-rich solutions. Both types of mortars presented highly negative corrosion potentials and high current density values in the presence of chloride. The steel bars extracted from mortar samples after exposure do not show evident pits or corrosion product layers, indicating that the presence of sulfides reduces the redox potential of the pore solution of slag mortars, but enables the steel to remain in an apparently passive state. The presence of a high amount of MnO in the slag does not significantly affect the corrosion process of steel under the conditions tested. Mass transport through the mortar to the metal is impeded with increasing exposure time; this is associated with refinement of the pore network as the slag continued to react while the samples were immersed

Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

BACKGROUND: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. METHODOLOGY/PRINCIPAL FINDINGS: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. CONCLUSIONS/SIGNIFICANCE: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF

An ancient family of SelB elongation factor-like proteins with a broad but disjunct distribution across archaea

<p>Abstract</p> <p>Background</p> <p>SelB is the dedicated elongation factor for delivery of selenocysteinyl-tRNA to the ribosome. In archaea, only a subset of methanogens utilizes selenocysteine and encodes archaeal SelB (aSelB). A SelB-like (aSelBL) homolog has previously been identified in an archaeon that does not encode selenosysteine, and has been proposed to be a pyrrolysyl-tRNA-specific elongation factor (EF-Pyl). However, elongation factor EF-Tu is capable of binding archaeal Pyl-tRNA in bacteria, suggesting the archaeal ortholog EF1A may also be capable of delivering Pyl-tRNA to the ribosome without the need of a specialized factor.</p> <p>Results</p> <p>We have phylogenetically characterized the aSelB and aSelBL families in archaea. We find the distribution of aSelBL to be wider than both selenocysteine and pyrrolysine usage. The aSelBLs also lack the carboxy terminal domain usually involved in recognition of the selenocysteine insertion sequence in the target mRNA. While most aSelBL-encoding archaea are methanogenic Euryarchaea, we also find aSelBL representatives in Sulfolobales and Thermoproteales of Crenarchaea, and in the recently identified phylum Thaumarchaea, suggesting that aSelBL evolution has involved horizontal gene transfer and/or parallel loss. Severe disruption of the GTPase domain suggests that some family members may employ a hitherto unknown mechanism of nucleotide hydrolysis, or have lost their GTPase ability altogether. However, patterns of sequence conservation indicate that aSelBL is still capable of binding the ribosome and aminoacyl-tRNA.</p> <p>Conclusions</p> <p>Although it is closely related to SelB, aSelBL appears unlikely to either bind selenocysteinyl-tRNA or function as a classical GTP hydrolyzing elongation factor. We propose that following duplication of aSelB, the resultant aSelBL was recruited for binding another aminoacyl-tRNA. In bacteria, aminoacylation with selenocysteine is essential for efficient thermodynamic coupling of SelB binding to tRNA and GTP. Therefore, change in tRNA specificity of aSelBL could have disrupted its GTPase cycle, leading to relaxation of selective pressure on the GTPase domain and explaining its apparent degradation. While the specific role of aSelBL is yet to be experimentally tested, its broad phylogenetic distribution, surpassing that of aSelB, indicates its importance.</p

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

Background: VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings: Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion: Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise

Bacillus anthracis TIR Domain-Containing Protein Localises to Cellular Microtubule Structures and Induces Autophagy

Toll-like receptors (TLRs) recognise invading pathogens and mediate downstream immune signalling via Toll/IL-1 receptor (TIR) domains. TIR domain proteins (Tdps) have been identified in multiple pathogenic bacteria and have recently been implicated as negative regulators of host innate immune activation. A Tdp has been identified in Bacillus anthracis, the causative agent of anthrax. Here we present the first study of this protein, designated BaTdp. Recombinantly expressed and purified BaTdp TIR domain interacted with several human TIR domains, including that of the key TLR adaptor MyD88, although BaTdp expression in cultured HEK293 cells had no effect on TLR4- or TLR2- mediated immune activation. During expression in mammalian cells, BaTdp localised to microtubular networks and caused an increase in lipidated cytosolic microtubule-associated protein 1A/1B-light chain 3 (LC3), indicative of autophagosome formation. In vivo intra-nasal infection experiments in mice showed that a BaTdp knockout strain colonised host tissue faster with higher bacterial load within 4 days post-infection compared to the wild type B. anthracis. Taken together, these findings indicate that BaTdp does not play an immune suppressive role, but rather, its absence increases virulence. BaTdp present in wild type B. anthracis plausibly interact with the infected host cell, which undergoes autophagy in self-defence