Cancer immunology and canine malignant melanoma: a comparative review

Oral canine malignant melanoma (CMM) is a spontaneously occurring aggressive tumour with relatively few medical treatment options, which provides a suitable model for the disease in humans. Historically, multiple immunotherapeutic strategies aimed at provoking both innate and adaptive anti-tumour immune responses have been published with varying levels of activity against CMM. Recently, a plasmid DNA vaccine expressing human tyrosinase has been licensed for the adjunct treatment of oral CMM. This article reviews the immunological similarities between CMM and the human counterpart; mechanisms by which tumours evade the immune system; reasons why melanoma is an attractive target for immunotherapy; the premise of whole cell, dendritic cell (DC), viral and DNA vaccination strategies alongside preliminary clinical results in dogs. Current “gold standard” treatments for advanced human malignant melanoma are evolving quickly with remarkable results being achieved following the introduction of immune checkpoint blockade and adoptively transferred cell therapies. The rapidly expanding field of cancer immunology and immunotherapeutics means that rational targeting of this disease in both species should enhance treatment outcomes in veterinary and human clinics

SUMO monoclonal antibodies vary in sensitivity, specificity, and ability to detect types of SUMO conjugate

Monoclonal antibodies (MAb) to members of the Small Ubiquitin-like modifier (SUMO) family are essential tools in the study of cellular SUMOylation. However, many anti-SUMO MAbs are poorly validated, and antibody matching to detection format is without an evidence base. Here we test the specificity and sensitivity of twenty-four anti-SUMO MAbs towards monomeric and polymeric SUMO1-4 in dot-blots, immunoblots, immunofluorescence and immunoprecipitation. We find substantial variability between SUMO MAbs for different conjugation states, for detecting increased SUMOylation in response to thirteen different stress agents, and as enrichment reagents for SUMOylated RanGAP1 or KAP1. All four anti-SUMO4 monoclonal antibodies tested cross-reacted wit SUMO2/3, and several SUMO2/3 monoclonal antibodies cross-reacted with SUMO4. These data characterize the specificity of twenty-four anti-SUMO antibodies across commonly used assays, creating an enabling resource for the SUMO research community

BRCA1-BARD1: the importance of being in shape

The breast cancer type-1 susceptibility protein (BRCA1) contributes to genome integrity through homologous recombinational DNA repair and by protecting stalled replication forks from nucleolytic degradation. We recently discovered that fork protection requires a conformational change of BRCA1 unimportant to homologous recombination repair, indicating separate roles for BRCA1 in these pathways

Owner perceptions of radiotherapy treatment for veterinary patients with cancer

Veterinary clients may have trepidation about treating their pet with radiotherapy due to concerns about radiation side effects or repeated anaesthetics. The purpose of this study is to assess whether owners’ attitudes towards veterinary radiotherapy, including concerns over side effects, change during the course of treatment, and whether radiotherapy was perceived to affect pets’ quality of life. A prospective cohort study of clients from 2012-2015 was performed. Pets received palliative or definitive radiotherapy for various tumours. Clients completed questionnaires before, during and after radiotherapy. Questions assessed owner preconceptions before treatment, including side effect expectations, actual side effects experienced, and overall satisfaction with the process. In addition, at each time point the owners assessed their pet’s quality of life using a simple numerical scale. 49 patients were included. After completing treatment, owners were significantly less concerned about potential side effects of radiotherapy (P<0.001), side effects associated with repeat anaesthetics (P<0.001), and about radiotherapy in general (P<0.001). Quality of life did not show a significant change at any point during or after treatment. Following treatment, 94% reported the experience was better than expected and 100% supported the use of radiotherapy in pets. This is the first prospective study evaluating client attitudes and satisfaction before and after radiotherapy treatment in pets. The results indicate that radiotherapy is well tolerated, and the anxiety associated with radiotherapy is significantly alleviated after experiencing the process. These results will help veterinarians allay client concerns, and will hopefully lead to an increase in clients pursuing radiotherapy in pets

SUMO, a small, but powerful, regulator of double-strand break repair

The response to a DNA double-stranded break in mammalian cells is a process of sensing and signalling the lesion. It results in halting the cell cycle and local transcription and in the mediation of the DNA repair process itself. The response is launched through a series of post-translational modification signalling events coordinated by phosphorylation and ubiquitination. More recently modifications of proteins by S mall U biquitin-like MO difier (SUMO) isoforms have also been found to be key to coordination of the response (Morris et al. 2009 Nature 462 , 886–890 ( doi:10.1038/nature08593 ); Galanty et al. 2009 Nature 462 , 935–939 ( doi:10.1038/nature08657 )). However our understanding of the role of SUMOylation is slight compared with our growing knowledge of how ubiquitin drives signal amplification and key chromatin interactions. In this review we consider our current knowledge of how SUMO isoforms, SUMO conjugation machinery, SUMO proteases and SUMO-interacting proteins contribute to directing altered chromatin states and to repair-protein kinetics at a double-stranded DNA lesion in mammalian cells. We also consider the gaps in our understanding. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.</jats:p

Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer

The RUNX1 transcription factor is widely recognised for its tumour suppressor effects in leukaemia. Recently a putative link to breast cancer has started to emerge, however the function of RUNX1 in breast cancer is still unknown. To investigate if RUNX1 expression was important to clinical outcome in primary breast tumours a tissue microarray (TMA) containing biopsies from 483 patients with primary operable invasive ductal breast cancer was stained by immunohistochemistry. RUNX1 was associated with progesterone receptor (PR)-positive tumours (P&#60;0.05), more tumour CD4+(P&#60;0.05) and CD8+(P&#60;0.01) T-lymphocytic infiltrate, increased tumour CD138+plasma cell (P&#60;0.01) and more CD68+macrophage infiltrate (P&#60;0.001). RUNX1 expression did not influence outcome of oestrogen receptor (ER)-positive or HER2-positive disease, however on univariate analysis a high RUNX1 protein was significantly associated with poorer cancer-specific survival in patients with ER-negative (P&#60;0.05) and with triple negative (TN) invasive breast cancer (P&#60;0.05). Furthermore, multivariate Cox regression analysis of cancer-specific survival showed a trend towards significance in ER-negative patients (P&#60;0.1) and was significant in triple negative patients (P&#60;0.05). Of relevance, triple negative breast cancer currently lacks good biomarkers and patients with this subtype do not benefit from the option of targeted therapy unlike patients with ER-positive or HER2-positive disease. Using multivariate analysis RUNX1 was identified as an independent prognostic marker in the triple negative subgroup. Overall, our study identifies RUNX1 as a new prognostic indicator correlating with poor prognosis specifically in the triple negative subtype of human breast cancer

Spitzer Space Telescope Spectroscopy of Ices toward Low-Mass Embedded Protostars

Sensitive 5-38 μm Spitzer Space Telescope and ground-based 3-5 μm spectra of the embedded low-mass protostars B5 IRS1 and HH 46 IRS show deep ice absorption bands superposed on steeply rising mid-infrared continua. The ices likely originate in the circumstellar envelopes. The CO_2 bending mode at 15 μm is a particularly powerful tracer of the ice composition and processing history. Toward these protostars, this band shows little evidence for thermal processing at temperatures above 50 K. Signatures of lower temperature processing are present in the CO and OCN^- bands, however. The observed CO2 profile indicates an intimate mixture with H_(2)O, but not necessarily with CH_(3)OH, in contrast to some high-mass protostars. This is consistent with the low CH_(3)OH abundance derived from the ground-based L-band spectra. The CO_2 : H_(2)O column density ratios are high in both B5 IRS1 and HH 46 IRS (~35%). Clearly, the Spitzer spectra are essential for studying ice evolution in low-mass protostellar environments and for eventually determining the relation between interstellar and solar system ices