On glioblastoma and the search for a cure: where do we stand?

Although brain tumours have been documented and recorded since the nineteenth century, 2016 marked 90 years since Percival Bailey and Harvey Cushing coined the term “glioblastoma multiforme”. Since that time, although extensive developments in diagnosis and treatment have been made, relatively little improvement on prognosis has been achieved. The resilience of GBM thus makes treating this tumour one of the biggest challenges currently faced by neuro-oncology. Aggressive and robust development, coupled with difficulties of complete resection, drug delivery and therapeutic resistance to treatment are some of the main issues that this nemesis presents today. Current treatments are far from satisfactory with poor prognosis, and focus on palliative management rather than curative intervention. However, therapeutic research leading to developments in novel treatment stratagems show promise in combating this disease. Here we present a review on GBM, looking at the history and advances which have shaped neurosurgery over the last century that cumulate to the present day management of GBM, while also exploring future perspectives in treatment options that could lead to new treatments on the road to a cure.     

The eagle and the starlings: Galileo’s argument for the autonomy of science—how pertinent is it today?

After Galileo’s argument for the autonomy of science is analysed and adapted to take into account later developments of scientific practices, we conclude that, in the final analysis, it is not compelling. Nevertheless, Galileo’s argument still provides a useful point of reference, for aspects of it can be interpreted to anticipate central components of the often acclaimed ideal of science as value free, so that appraising it contributes to the larger purpose of exploring how well that ideal stands up today. Finally, we will argue that residue from Galileo’s struggle with the Church remains with us, making it difficult to identify the conditions that would need to be put into place today for any robust sense of the autonomy of science to be defensible.     

Shedding light on mitophagy in neurons: what is the evidence for PINK1/Parkin mitophagy in vivo?

Neurons are highly specialised cells with a large bioenergetic demand, and so require a healthy mitochondrial network to function effectively. This network is compromised in many neurological disorders, in which damaged mitochondria accumulate. Dysfunctional mitochondria can be removed via an organelle-specific autophagic pathway, a process known as mitophagy. The canonical mitophagy pathway is dependent on the actions of PINK1 (PTEN-induced putative kinase 1) and Parkin and has been well studied in immortalised cells and cultured neurons. However, evidence for a role of this mitophagy pathway in the brain is still limited, and studies suggest that there may be important differences in how neurons respond to mitochondrial damage in vitro and in vivo. Here, we first describe the evidence for a functional PINK1/Parkin mitophagy pathway in neurons, and review how this pathway is affected in disease models. We then critically evaluate the literature by comparing findings from in vitro models and more recent in vivo studies in flies and mice. The emerging picture implicates that alternative mitophagy pathways operate in neurons in vivo. New mouse models that employ fluorescent biosensors to monitor mitophagy in vivo will be instrumental to understand the relative role of the different clearance pathways in the brain under physiological and pathological conditions.     

What induction is (and what it should not be): A concepts-centric perspective on Norton’s radium chloride example

I argue that Norton’s reconstruction of an example inductive inference in Ch.1 of The Material Theory of Induction mischaracterizes scientific induction by treating the ampliation as separable (and separated) from that inherent in conceptualization per se—effectively severing the putative ampliation from its putative warrant. I sketch an alternative analysis in which ampliation and warrant remain closely coupled through a common root in the primary conceptualizations.     

Palmitoylation by DHHC3 is critical for the function, expression, and stability of integrin α6β4

The laminin-binding integrin α6β4 plays key roles in both normal epithelial and endothelial cells and during tumor cell progression, metastasis, and angiogenesis. Previous cysteine mutagenesis studies have suggested that palmitoylation of α6β4 protein supports a few integrin-dependent functions and molecular associations. Here we took another approach and obtained strikingly different results. We used overexpression and RNAi knockdown in multiple cell types to identify protein acyl transferase DHHC3 as the enzyme responsible for integrin β4 and α6 palmitoylation. Ablation of DHHC3 markedly diminished integrin-dependent cellular cable formation on Matrigel, integrin signaling through Src, and β4 phosphorylation on key diagnostic amino acids (S1356 and 1424). However, unexpectedly, and in sharp contrast to prior α6β4 mutagenesis results, knockdown of DHHC3 accelerated the degradation of α6β4, likely due to an increase in endosomal exposure to cathepsin D. When proteolytic degradation was inhibited (by Pepstatin A), rescued α6β4 accumulated intracellularly, but was unable to reach the cell surface. DHHC3 ablation effects were strongly selective for α6β4. Cell-surface levels of ~10 other proteins (including α3β1) were not diminished, and the appearance of hundreds of other palmitoylated proteins was not altered. Results obtained here demonstrate a new substrate for the DHHC3 enzyme and provide novel opportunities for modulating α6β4 expression, distribution, and function.     

The modernity of Dedekind’s anticipations contained in What are numbers and what are they good for?

Archive for History of Exact Sciences - We show that Dedekind, in his proof of the principle of definition by mathematical recursion, used implicitly both the concept of an inductive cone from an...     

Correction to: The modernity of Dedekind’s anticipations contained in What are numbers and what are they good for?

Archive for History of Exact Sciences - The original version of this article unfortunately contained a mistake: The equation on page 34 was incorrect. The corrected equation is given below.     

Nelson–Siegel,Affine and Quadratic Yield Curve Specifications: Which One is Better at Forecasting?

In this paper we compare the in‐sample fit and out‐of‐sample forecasting performance of no‐arbitrage quadratic, essentially affine and dynamic Nelson–Siegel term structure models. In total, 11 model variants are evaluated, comprising five quadratic, four affine and two Nelson–Siegel models. Recursive re‐estimation and out‐of‐sample 1‐, 6‐ and 12‐month‐ahead forecasts are generated and evaluated using monthly US data for yields observed at maturities of 1, 6, 12, 24, 60 and 120 months. Our results indicate that quadratic models provide the best in‐sample fit, while the best out‐of‐sample performance is generated by three‐factor affine models and the dynamic Nelson–Siegel model variants. Statistical tests fail to identify one single best forecasting model class. Copyright © 2011 John Wiley & Sons, Ltd.     

Are more data always better for factor analysis? Results for the euro area,the six largest euro area countries and the UK

Factor‐based forecasting has been at the forefront of developments in the macroeconometric forecasting literature in the recent past. Despite the flurry of activity in the area, a number of specification issues such as the choice of the number of factors in the forecasting regression, the benefits of combining factor‐based forecasts and the choice of the dataset from which to extract the factors remain partly unaddressed. This paper provides a comprehensive empirical investigation of these issues using data for the euro area, the six largest euro area countries, and the UK. Copyright © 2011 John Wiley & Sons, Ltd.     

Food for thought?: the relations between the Royal Society Food Committee and government, 1915-19

This paper traces the relationship between the food committees of the Royal Society and government during the First World War, concentrating on the period up to the resignation of Lord Devonport as first Food Controller. It argues that, in the context of a radical public science discourse emanating from some sections of the scientific community and greatly increased contacts between scientists and the government, the food scientists of the committees were moved to press for a formalization of the committees' role in food policy. The members constantly manoeuvered to achieve this aim, but also used a network of alternative channels into the heart of the policy process to get their findings translated into hard policy. In doing so, they explicitly rehearsed characteristic 'public science' arguments. In the institutional blur of wartime state-science relations, scientists often got close to the policy-making process. Post-War, the state swiftly moved to clarify the position: science was to be given more money, but was to be specifically blocked by new administrative arrangements embodied in the Haldane Report on the Machinery of Government from having any say in the core areas of general policy, the expert domain of the generalist policy-maker.     

Plasma enteroglucagon,peptide YY and gastrin in rats deprived of luminal nutrition,and after urogastrone-EGF administration. A proliferative role for PYY in the intestinal epithelium?

Intestinal tissue mass was significantly reduced throughout the gastrointestinal tract (p<0.001) of=" intravenously=" fed=" (tpn)=" rats.=" urogastrone-epidermal=" growth=" factor,=" (uro-egf),=" reversed=" these=" changes.=" although=" plasma=" enteroglucagon=" and=" gastrin=" levels=" showed=" a=" small=" increase=" with=" uro-egf,=" this=" was=" far=" less=" than=" the=" gut=" tissue=" weight=" change,=" suggesting=" that=" it=" was=" unlikely=" that=" they=" were=" involved=" in=" modulating=" the=" proliferative=" response=" of=" the=" intestine=" to=" uro-egf.=" peptide=" tyrosine=" tyrosine=" (pyy)=" levels=" were=" however=" significantly=" increased=" by=" uro-egf,=" indicating=" that=" pyy=" may=" possibly=" have=" a=" role=" in=" the=" modulation=" of=" intestinal=" cell=">We thank the Cancer Research Campaign for their financial assistance and acknowledge the technical assistance of Mr W. Lenton.