HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers

The search for novel tumour antigens that are either uniquely expressed or over-expressed in a wide variety of tumours is still ongoing. Because of their expression in a broad spectrum of cancers and limited expression in normal tissues, cancer/testis antigens are considered to be potentially reliable targets for immunotherapy of cancer in general. The helicase antigen HAGE has been identified as a cancer/testis antigen. However, little is known about its expression in normal and cancer tissues. Using a newly developed antibody against HAGE, specific staining of its expression by immunohistochemistry was validated and optimised on murine tumours transfected to express the HAGE protein. The antibody was subsequently used to determine HAGE expression in normal human and cancer tissue microarrays. HAGE protein expression was confirmed in 75% (12/16) of carcinomas as compared to normal tissues, which either did not express HAGE at all or expressed HAGE at very low levels with the exception of testis. Interestingly, discrepancies were also found between mRNA analysis by real time quantitative PCR (RT-qPCR) and protein analysis by immunohistochemistry, emphasising the need to validate the expression of cancer/testis antigens at the protein level prior to the development of new vaccine strategies. HAGE is therefore proposed to be a valid candidate for designing a broad spectrum vaccine against cancer

Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the 'silent' cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of 'silent' cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.Significance StatementPregabalin is an analgesic drug in the clinic, that is supposed to act by blocking neurotransmitter release. Here we show that silent nociceptors that are activated by chemotherapeutic insults like oxaliplatin are silenced by pregabalin, which blocks the associated pain. This mode of action suggests that peripheral acting pregabalin-like drugs could be very useful for pain during chemotherapy, as they would have no CNS side effects - a problem for many patients with pregabalin. This novel effect of pregabalin is mediated by its interaction with the α2δ1 calcium channel subunit, but how this works is not yet understood

Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity.

yesAncient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions

Fishes of the hadal zone including new species, in situ observations and depth records of Liparidae

AbstractObservations and records for fish exceeding 6000m deep are few and often spurious. Recent developments in accessing and sampling the hadal zone 6000–11,000m) have led to an acceleration in new findings in the deep subduction trenches, particularly in the Pacific Ocean. This study describes the discovery of two new species of snailfish (Liparidae) from the Mariana Trench; the ‘Mariana snailfish’ (6198–8076m) and the ‘Ethereal snailfish’ (7939–8145m). These new findings represent respectively the deepest known specimen caught with corroborating depth data, and the deepest fish seen alive. Further specimens and observations of the Kermadec Trench snailfish, Notoliparis kermadecensis, are also presented, as well as the first hadal records of Synaphobranchidae and Zoarcidae (6068 and 6145m respectively) and a depth extension for the Macrouridae (maximum depth now 7012m). Details of these new snailfish specimens caught by baited trap and behaviour observations filmed by baited cameras are presented. An updated assessment of fishes from hadal depths is also reported

Distribution, composition and functions of gelatinous tissues in deep-sea fishes

Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion. © 2017 The Authors

The development of the Meaning in Life Index (MILI) and its relationship with personality and religious behaviours and beliefs among UK undergraduate students

The scales available for assessing meaning in life appear to be confounded with several related constructs, including purpose in life, satisfaction with life, and goal-directed behaviour. The Meaning in Life Index (MILI), a new instrument devised as a specific measure of meaning in life, was developed from responses to a pool of 22 items rated by a sample of 501 undergraduate students in Wales. The nine-item scale demonstrated sufficient face validity, internal consistency, and scale reliability to commend the instrument for future use. With respect to personality, the MILI scores were most strongly predicted by neuroticism (negatively), and less strongly by extraversion (positively) and psychoticism (negatively). With respect to several religious behavioural variables, those who attended church at least weekly returned significantly higher MILI scores than those who attended church less frequently. Intrinsic religiosity was the only orientation to be significantly associated with the MILI scale scores, although the magnitude of the association was smaller than anticipated. These results suggest that meaning in life is associated more strongly with individual differences in personality than with specific religious behaviours and attitudes. The implications of these results are discussed in terms of individual's personal values and attitudes that might underlie their experience of a meaning in life

Evaluating the taxa that provide shared pollination services across multiple crops and regions

Many pollinator species visit multiple crops in multiple regions, yet we know little about their pollination service provisioning at local and regional scales. We investigated the floral visitors (n = 13,200), their effectiveness (n = 1718 single visits) and response to landscape composition across three crops avocado, mango and macadamia within a single growing region (1 year), a single crop (3 years) and across different growing regions in multiple years. In total, eight wild visitor groups were shared across all three crops. The network was dominated by three pollinators, two bees (Apis mellifera and Tetragonula spp.) and a fly, Stomorhina discolor. The visitation network for the three crops was relatively generalised but with the addition of pollen deposition data, specialisation increased. Sixteen managed and wild taxa were consistently present across three years in avocado, yet their contribution to annual network structure varied. Node specialisation (d’) analyses indicated many individual orchard sites across each of the networks were significantly more specialised compared to that predicted by null models, suggesting the presence of site-specific factors driving these patterns. Identifying the taxa shared across multiple crops, regions and years will facilitate the development of specific pollinator management strategies to optimize crop pollination services in horticultural systems

A proteomic study of human Merkel Cell Carcinoma

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin. The incidence has been quadrupled with a 5-year mortality rate of 46%, presently there is no cure for metastatic disease. Despite the contribution of Merkel cell polyomavirus, the molecular events of MCC carcinogenesis are poorly defined. To better understand MCC carcinogensis, we have performed the first quantitative proteomic comparison of formalin-fixed, paraffin-embedded (FFPE) MCC tissues using another neuroendocrine tumor (carcinoid tumor of the lung) as controls. Bioinformatic analysis of the proteomic data has revealed that MCCs carry distinct protein expression patterns. Further analysis of significantly over-expressed proteins suggested the involvement of MAPK, PI3K/Akt/mTOR, wnt, and apoptosis signaling pathways. Our previous study and that from others have shown mTOR activation in MCCs. Therefore, we have focused on two downstream molecules of the mTOR pathway, lactate dehydrogenase B (LDHB) and heterogeneous ribonucleoprotein F (hnRNPF). We confirm over-expression of LDHB and hnRNPF in two primary human MCC cell lines, 16 fresh tumors, and in the majority of 80 tissue microarray samples. Moreover, mTOR inhibition suppresses LDHB and hnRNPF expression in MCC cells. The results of the current study provide insight into MCC carcinogenesis and provide rationale for mTOR inhibition in pre-clinical studies