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The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.

Background The cell-surface attachment protein (Env) of the HERV-K(HML-2) lineage of endogenous retroviruses is a potentially attractive tumour-associated antigen for anti-cancer immunotherapy. The human genome contains around 100 integrated copies (called proviruses or loci) of the HERV-K(HML-2) virus and we argue that it is important for therapy development to know which and how many of these contribute to protein expression, and how this varies across tissues. We measured relative provirus expression in HERV-K(HML-2), using enriched RNA-Seq analysis with both short- and long-read sequencing, in three Mantle Cell Lymphoma cell lines (JVM2, Granta519 and REC1). We also confirmed expression of the Env protein in two of our cell lines using Western blotting, and analysed provirus expression data from all other relevant published studies. Results Firstly, in both our and other reanalysed studies, approximately 10% of the transcripts mapping to HERV-K(HML-2) came from Env-encoding proviruses. Secondly, in one cell line the majority of the protein expression appears to come from one provirus (12q14.1). Thirdly, we find a strong tissue-specific pattern of provirus expression. Conclusions A possible dependency of Env expression on a single provirus, combined with the earlier observation that this provirus is not present in all individuals and a general pattern of tissue-specific expression among proviruses, has serious implications for future HERV-K(HML-2)-targeted immunotherapy. Further research into HERV-K(HML-2) as a possible tumour-associated antigen in blood cancers requires a more targeted, proteome-based, screening protocol that will consider these polymorphisms within HERV-K(HML-2). We include a plan (and necessary alignments) for such work.

Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines. Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines [RAW_REF_TEXT] Witold Tatkiewicz1 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] James Dickie2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Franchesca Bedford2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Alexander Jones2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Mark Atkin2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Michele Kiernan2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Emmanuel Atangana Maze2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Bora Agit1 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Garry Farnham2 na1, [/RAW_REF_TEXT] [RAW_REF_TEXT] Alexander Kanapin3,4 & [/RAW_REF_TEXT] [RAW_REF_TEXT] Robert Belshaw 2 [/RAW_REF_TEXT] Mobile DNA volume 11, Article number: 31 (2020) Cite this article [RAW_REF_TEXT] 225 Accesses [/RAW_REF_TEXT] [RAW_REF_TEXT] 2 Altmetric [/RAW_REF_TEXT] [RAW_REF_TEXT] Metrics details [/RAW_REF_TEXT] [RAW_REF_TEXT] The original article was published in Mobile DNA 2020 11:9 [/RAW_REF_TEXT] Correction to: Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines [RAW_REF_TEXT] Witold Tatkiewicz1 na1, James Dickie2 na1, Franchesca Bedford2 na1, Alexander Jones2 na1, Mark Atkin2 na1, Michele Kiernan2 na1, Emmanuel Atangana Maze2 na1, Bora Agit1 na1, Garry Farnham2 na1, Alexander Kanapin3,4 & Robert Belshaw 2 [/RAW_REF_TEXT] Mobile DNA volume 11, Article number: 31 (2020) Cite this article [RAW_REF_TEXT] 225 Accesses 2 Altmetric Metrics details The original article was published in Mobile DNA 2020 11:9

Background: The susceptibility of plasma lipids to oxidation is thought to be a factor contributing to atherogenic risk. Various groups have studied the in vitro oxidizability of isolated LDL and examined the effects of conventional antioxidants. The drawbacks associated with the isolation of LDL for evaluation of in vitro oxidizability, however, have limited the application of this measurement in large-scale studies. Methods: We developed and evaluated an assay that can be used to directly assess the oxidative susceptibility of unfractionated serum or plasma lipids, obviating the need for isolation of lipoprotein fractions. Oxidative conditions were initiated in vitro with cuprous chloride and 2,2′-azobis(2-amidinopropane) hydrochloride. The effects of antioxidants added in vitro, and as an oral supplement, were monitored by conjugated diene formation. Results: The addition of ascorbic acid (0–50 μmol/L) in vitro elicited a dose-dependent protective effect, increasing the lag time to oxidation (P <0.001). In contrast, α-tocopherol demonstrated prooxidant behavior at increasing concentrations (0–50 μmol/L), although we observed a decrease in the maximum rate of oxidation. Our findings are supported by the results from plasma samples of participants in a randomized antioxidant (vitamins C and E) intervention study after acute ischemic stroke. The group receiving vitamins C and E for 14 days showed an increased lag time to plasma lipid oxidation in vitro compared with the nonsupplemented group (P <0.05). Conclusion: The susceptibility of unfractionated plasma or serum lipids to oxidation in vitro offers an alternative to LDL for evaluating the efficacy of antioxidant regimens.

75 years ago, the bombing of Hiroshima showed the appalling destructive power of the atomic bomb. Mark Cousins’ bold new documentary looks at death in the atomic age, but life too. Using only archive film and a new musical score by the band Mogwai, Atomic shows us an impressionistic kaleidoscope of our nuclear times: protest marches, Cold War sabre rattling, Chernobyl and Fukishima, but also the sublime beauty of the atomic world, and how X Rays and MRI scans have improved human lives. The nuclear age has been a nightmare, but dreamlike too.

An amendment to this paper has been published and can be accessed via the original article.

Background The cell-surface attachment protein (Env) of the HERV-K(HML-2) lineage of endogenous retroviruses is a potentially attractive tumour-associated antigen for anti-cancer immunotherapy. The human genome contains around 100 integrated copies (called proviruses or loci) of the HERV-K(HML-2) virus and we argue that it is important for therapy development to know which and how many of these contribute to protein expression, and how this varies across tissues. We measured relative provirus expression in HERV-K(HML-2), using enriched RNA-Seq analysis with both short- and long-read sequencing, in three Mantle Cell Lymphoma cell lines (JVM2, Granta519 and REC1). We also confirmed expression of the Env protein in two of our cell lines using Western blotting, and analysed provirus expression data from all other relevant published studies. Results Firstly, in both our and other reanalysed studies, approximately 10% of the transcripts mapping to HERV-K(HML-2) came from Env-encoding proviruses. Secondly, in one cell line the majority of the protein expression appears to come from one provirus (12q14.1). Thirdly, we find a strong tissue-specific pattern of provirus expression. Conclusions A possible dependency of Env expression on a single provirus, combined with the earlier observation that this provirus is not present in all individuals and a general pattern of tissue-specific expression among proviruses, has serious implications for future HERV-K(HML-2)-targeted immunotherapy. Further research into HERV-K(HML-2) as a possible tumour-associated antigen in blood cancers requires a more targeted, proteome-based, screening protocol that will consider these polymorphisms within HERV-K(HML-2). We include a plan (and necessary alignments) for such work. Keywords: HERV-K(HML-2), HERV-K, Transposable element, Cancer immunotherapy, Leukemia, NGS, minION, Transcriptomics, RNA-Seq

In this thesis we consider the properties of waveguide modes in photonic crystal planar waveguides. These are waveguides that have been etched with multi-dimensional gratings to create new wavelength dispersive and spatially dispersive behaviours. Analytical models have been developed for the modes in one and two-dimensional photonic crystal waveguides. These describe many of the rich phenomena that may be observed. Weak two-dimensional photonic crystal planar waveguides have been fabricated and their properties have been measured with a specially developed conical prism coupling technique.This thesis demonstrates the advantages of combining photonic crystals with planar waveguides. While future lithographic systems will have sufficient resolution to incorporate photonic crystal regions in integrated optical devices, we have shown that the waveguide geometry increases the actual grating period required for optical and gaps and so lessens technological difficulties. We also show that there are stationary modes which could act as microresonators and that ranges of modes can be suppressed in multimode waveguides. Prism coupling has demonstrated the strong dispersive and frequency selective behaviour of weak photonic crystal waveguides.The future application of this work to efficient, broadband, nonlinear wavelength conversion is proposed.

Disassembly of apoptotic cells into smaller fragments (a form of extracellular vesicle called apoptotic bodies) can facilitate removal of apoptotic debris and intercellular communication. However, the mechanism underpinning this process is unclear. While observing monocytes undergoing apoptosis by time-lapse microscopy, we discovered a new type of membrane protrusion that resembles a ‘beads-on-a-string’ structure. Strikingly, the ‘beads’ are frequently sheared off the ‘string’ to form apoptotic bodies. Generation of apoptotic bodies via this mechanism can facilitate a sorting process and results in the exclusion of nuclear contents from apoptotic bodies. Mechanistically, generation of ‘beads-on-a-string’ protrusion is controlled by the level of actomyosin contraction and apoptopodia formation. Furthermore, in an unbiased drug screen, we identified the ability of sertraline (an antidepressant) to block the formation of ‘beads-on-a-string’ protrusions and apoptotic bodies. These data uncover a new mechanism of apoptotic body formation in monocytes and also compounds that can modulate this process. During apoptosis, cells break up into smaller fragments to facilitate removal. Here the authors characterize a beads-on-a-string structure formed by monocytes undergoing apoptosis in vitro , which shears into apoptotic bodies lacking nuclear contents, and is blocked by the antidepressant sertraline.