The mRNA expression of SETD2 in human breast cancer: Correlation with clinico-athological parameters

BACKGROUND: SET domain containing protein 2 (SETD2) is a histone methyltransferase that is involved in transcriptional elongation. There is evidence that SETD2 interacts with p53 and selectively regulates its downstream genes. Therefore, it could be implicated in the process of carcinogenesis. Furthermore, this gene is located on the short arm of chromosome 3p and we previously demonstrated that the 3p21.31 region of chromosome 3 was associated with permanent growth arrest of breast cancer cells. This region includes closely related genes namely: MYL3, CCDC12, KIF9, KLHL18 and SETD2. Based on the biological function of these genes, SETD2 is the most likely gene to play a tumour suppressor role and explain our previous findings. Our objective was to determine, using quantitative PCR, whether the mRNA expression levels of SETD2 were consistent with a tumour suppressive function in breast cancer. This is the first study in the literature to examine the direct relationship between SETD2 and breast cancer. METHODS: A total of 153 samples were analysed. The levels of transcription of SETD2 were determined using quantitative PCR and normalized against (CK19). Transcript levels within breast cancer specimens were compared to normal background tissues and analyzed against conventional pathological parameters and clinical outcome over a 10 year follow-up period. RESULTS: The levels of SETD2 mRNA were significantly lower in malignant samples (p = 0.0345) and decreased with increasing tumour stage. SETD2 expression levels were significantly lower in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for > 10 years (p = 0.041). CONCLUSION: This study demonstrates a compelling trend for SETD2 transcription levels to be lower in cancerous tissues and in patients who developed progressive disease. These findings are consistent with a possible tumour suppressor function of this gene in breast cancer

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University

The prognosis of allocentric and egocentric neglect : evidence from clinical scans

We contrasted the neuroanatomical substrates of sub-acute and chronic visuospatial deficits associated with different aspects of unilateral neglect using computed tomography scans acquired as part of routine clinical diagnosis. Voxel-wise statistical analyses were conducted on a group of 160 stroke patients scanned at a sub-acute stage. Lesion-deficit relationships were assessed across the whole brain, separately for grey and white matter. We assessed lesions that were associated with behavioural performance (i) at a sub-acute stage (within 3 months of the stroke) and (ii) at a chronic stage (after 9 months post stroke). Allocentric and egocentric neglect symptoms at the sub-acute stage were associated with lesions to dissociated regions within the frontal lobe, amongst other regions. However the frontal lesions were not associated with neglect at the chronic stage. On the other hand, lesions in the angular gyrus were associated with persistent allocentric neglect. In contrast, lesions within the superior temporal gyrus extending into the supramarginal gyrus, as well as lesions within the basal ganglia and insula, were associated with persistent egocentric neglect. Damage within the temporo-parietal junction was associated with both types of neglect at the sub-acute stage and 9 months later. Furthermore, white matter disconnections resulting from damage along the superior longitudinal fasciculus were associated with both types of neglect and critically related to both sub-acute and chronic deficits. Finally, there was a significant difference in the lesion volume between patients who recovered from neglect and patients with chronic deficits. The findings presented provide evidence that (i) the lesion location and lesion size can be used to successfully predict the outcome of neglect based on clinical CT scans, (ii) lesion location alone can serve as a critical predictor for persistent neglect symptoms, (iii) wide spread lesions are associated with neglect symptoms at the sub-acute stage but only some of these are critical for predicting whether neglect will become a chronic disorder and (iv) the severity of behavioural symptoms can be a useful predictor of recovery in the absence of neuroimaging findings on clinical scans. We discuss the implications for understanding the symptoms of the neglect syndrome, the recovery of function and the use of clinical scans to predict outcome

Psychosocial functioning and intelligence both partly explain socioeconomic inequalities in premature death. A population-based male cohort study

The possible contributions of psychosocial functioning and intelligence differences to socioeconomic status (SES)-related inequalities in premature death were investigated. None of the previous studies focusing on inequalities in mortality has included measures of both psychosocial functioning and intelligence.The study was based on a cohort of 49 321 men born 1949-1951 from the general community in Sweden. Data on psychosocial functioning and intelligence from military conscription at ∼18 years of age were linked with register data on education, occupational class, and income at 35-39 years of age. Psychosocial functioning was rated by psychologists as a summary measure of differences in level of activity, power of initiative, independence, and emotional stability. Intelligence was measured through a multidimensional test. Causes of death between 40 and 57 years of age were followed in registers.The estimated inequalities in all-cause mortality by education and occupational class were attenuated with 32% (95% confidence interval: 20-45%) and 41% (29-52%) after adjustments for individual psychological differences; both psychosocial functioning and intelligence contributed to account for the inequalities. The inequalities in cardiovascular and injury mortality were attenuated by as much as 51% (24-76%) and 52% (35-68%) after the same adjustments, and the inequalities in alcohol-related mortality were attenuated by up to 33% (8-59%). Less of the inequalities were accounted for when those were measured by level of income, with which intelligence had a weaker correlation. The small SES-related inequalities in cancer mortality were not attenuated by adjustment for intelligence.Differences in psychosocial functioning and intelligence might both contribute to the explanation of observed SES-related inequalities in premature death, but the magnitude of their contributions likely varies with measure of socioeconomic status and cause of death. Both psychosocial functioning and intelligence should be considered in future studies

On the magnetic fields generated by experimental dynamos

We review the results obtained by three successful fluid dynamo experiments and discuss what has been learnt from them about the effect of turbulence on the dynamo threshold and saturation. We then discuss several questions that are still open and propose experiments that could be performed to answer some of them.Comment: 40 pages, 13 figure

Using shared needles for subcutaneous inoculation can transmit bluetongue virus mechanically between ruminant hosts

Bluetongue virus (BTV) is an economically important arbovirus of ruminants that is transmitted by Culicoides spp. biting midges. BTV infection of ruminants results in a high viraemia, suggesting that repeated sharing of needles between animals could result in its iatrogenic transmission. Studies defining the risk of iatrogenic transmission of blood-borne pathogens by less invasive routes, such as subcutaneous or intradermal inoculations are rare, even though the sharing of needles is common practice for these inoculation routes in the veterinary sector. Here we demonstrate that BTV can be transmitted by needle sharing during subcutaneous inoculation, despite the absence of visible blood contamination of the needles. The incubation period, measured from sharing of needles, to detection of BTV in the recipient sheep or cattle, was substantially longer than has previously been reported after experimental infection of ruminants by either direct inoculation of virus, or through blood feeding by infected Culicoides. Although such mechanical transmission is most likely rare under field condition, these results are likely to influence future advice given in relation to sharing needles during veterinary vaccination campaigns and will also be of interest for the public health sector considering the risk of pathogen transmission during subcutaneous inoculations with re-used needles

Explosive Nucleosynthesis: What we learned and what we still do not understand

This review touches on historical aspects, going back to the early days of nuclear astrophysics, initiated by B$^2$FH and Cameron, discusses (i) the required nuclear input from reaction rates and decay properties up to the nuclear equation of state, continues (ii) with the tools to perform nucleosynthesis calculations and (iii) early parametrized nucleosynthesis studies, before (iv) reliable stellar models became available for the late stages of stellar evolution. It passes then through (v) explosive environments from core-collapse supernovae to explosive events in binary systems (including type Ia supernovae and compact binary mergers), and finally (vi) discusses the role of all these nucleosynthesis production sites in the evolution of galaxies. The focus is put on the comparison of early ideas and present, very recent, understanding.Comment: 11 pages, to appear in Springer Proceedings in Physics (Proc. of Intl. Conf. "Nuclei in the Cosmos XV", LNGS Assergi, Italy, June 2018

Epistemic and Ontic Quantum Realities

Quantum theory has provoked intense discussions about its interpretation since its pioneer days. One of the few scientists who have been continuously engaged in this development from both physical and philosophical perspectives is Carl Friedrich von Weizsaecker. The questions he posed were and are inspiring for many, including the authors of this contribution. Weizsaecker developed Bohr's view of quantum theory as a theory of knowledge. We show that such an epistemic perspective can be consistently complemented by Einstein's ontically oriented position

Theoretical study of the insulating oxides and nitrides: SiO2, GeO2, Al2O3, Si3N4, and Ge3N4

An extensive theoretical study is performed for wide bandgap crystalline oxides and nitrides, namely, SiO_{2}, GeO_{2}, Al_{2}O_{3}, Si_{3}N_{4}, and Ge_{3}N_{4}. Their important polymorphs are considered which are for SiO_{2}: $\alpha$-quartz, $\alpha$- and $\beta$-cristobalite and stishovite, for GeO_{2}: $\alpha$-quartz, and rutile, for Al_{2}O_{3}: $\alpha$-phase, for Si_{3}N_{4} and Ge_{3}N_{4}: $\alpha$- and $\beta$-phases. This work constitutes a comprehensive account of both electronic structure and the elastic properties of these important insulating oxides and nitrides obtained with high accuracy based on density functional theory within the local density approximation. Two different norm-conserving \textit{ab initio} pseudopotentials have been tested which agree in all respects with the only exception arising for the elastic properties of rutile GeO_{2}. The agreement with experimental values, when available, are seen to be highly satisfactory. The uniformity and the well convergence of this approach enables an unbiased assessment of important physical parameters within each material and among different insulating oxide and nitrides. The computed static electric susceptibilities are observed to display a strong correlation with their mass densities. There is a marked discrepancy between the considered oxides and nitrides with the latter having sudden increase of density of states away from the respective band edges. This is expected to give rise to excessive carrier scattering which can practically preclude bulk impact ionization process in Si_{3}N_{4} and Ge_{3}N_{4}.Comment: Published version, 10 pages, 8 figure