Pluripotent human embryonic stem cell derived neural lineages for in vitro modelling of enterovirus 71 infection and therapy

The incidence of neurological complications and fatalities associated with Hand, Foot & Mouth disease has increased over recent years, due to emergence of newly-evolved strains of Enterovirus 71 (EV71). In the search for new antiviral therapeutics against EV71, accurate and sensitive in vitro cellular models for preliminary studies of EV71 pathogenesis is an essential prerequisite, before progressing to expensive and time-consuming live animal studies and clinical trials. This study thus investigated whether neural lineages derived from pluripotent human embryonic stem cells (hESC) can fulfil this purpose. EV71 infection of hESC-derived neural stem cells (NSC) and mature neurons (MN) was carried out in vitro, in comparison with RD and SH-SY5Y cell lines. Results: Upon assessment of post-infection survivability and EV71 production by the various types, it was observed that NSC were significantly more susceptible to EV71 infection compared to MN, RD (rhabdomyosarcoma) and SHSY5Y cells, which was consistent with previous studies on mice. The SP81 peptide had significantly greater inhibitory effect on EV71 production by NSC and MN compared to the cancer-derived RD and SH-SY5Y cell lines. Hence, this study demonstrates that hESC-derived neural lineages can be utilized as in vitro models for studying EV71 pathogenesis and for screening of antiviral therapeutics

Molecular detection and characterization of pathogenic leptospira species in environmental samples of selected districts in Perak, Malaysia

Leptospirosis is an endemic zoonotic disease in Malaysia caused by pathogenic species of genus Leptospira. Most cases of human leptospirosis are resulted from environmental exposure to water and soils contaminated with bacteria shed in urine of infected carrier animals. Epidemiological information about leptospirosis and Leptospira in the Perak state is scarce despite high disease incidence and mortality rate. To assess public health risk for leptospirosis, this study aims to determine the cross-sectional prevalence of pathogenic Leptospira in recreational and residential public places, as well as to characterize the genetic diversity of pathogenic Leptospira isolated from environmental samples. A total of 228 environmental water and shore soils samples were collected from 20 amenity forests and wet markets, filtered, and subjected to cultivation of leptospires in enriched EMJH medium. Presence of pathogenic Leptospira was confirmed by specific amplification of lipL32 gene by polymerase chain reaction (PCR). Results showed a high prevalence of pathogens (11 %, n = 25) throughout Perak, with highly varied localised prevalence among 13 positive sampling sites (6.7 - 41.7 %). Further distribution analysis implies a higher exposure risk in amenity forests than wet markets, through soil than water, as well as in the districts Kampar and Kinta than Batang Padang, Kuala Kangsar, Kerian, Larut, Matang & Selama. Unexpectedly the localised prevalence was not significantly associated with provision of waste management and site cleanliness. In addition to that, the total absence of pathogen at sites BF, GF, KW, LI, MM, PF, and SS in this present study has no relation to environmental parameters of samples, including temperature, pH, and water salinity. On another hand, seeking a sensitive molecular detection tool for accurate surveillance has driven this study to compare performance of other pathogen-specific diagnostic PCR assays on the positive samples. Unexpectedly a notably low and varied detection sensitivity (12 - 83 %) was determined among environmental isolates in relation to reference Leptospira strains sourced from human or animal hosts. ii Among genetic markers studied, lipL32 and flaB have been most prevalent, followed by gyrB and lfb1, whereas PCRs targeting secY and ligB showed high false-negativity. The absence of amplification was most likely attributed to mismatch in primer-annealing sites owing to high sequence polymorphisms. Phylogenetic analysis of partial 16S rRNA gene sequences revealed a subclade formed by all environmental isolates (except intermediate KF4) within the ‘pathogens’ clade, suggesting a fair distance from described host- associated Leptospira strains despite the low bootstrap values. A noticeable clustering of isolates sourced from similar sampling site, district, nor ecological niches was not observed. Through comparative polymorphic nucleotide analysis, ten pathogenic isolates were found closest to L. kmetyi and L. alstonii which have been prevailing in Malaysia, while the others probably represent novel species. In conclusion, genetically diverse pathogenic Leptospira spp. was widely distributed in Perak. Determining the virulence potential and whole- genome sequence for these atypical pathogenic isolates is important to validate the risk of leptospirosis, evolutionary relationship and reclassification of genus Leptospira

Advancing access and equity : the vision of a new generation in cancer control

We must dramatically alter the current trajectory of cancer care to ensure that improvements are accessible by all in the global community. We must bridge the gap between what is achievable and what is accessible. We must act with urgency and precision, recognising the tremendous social and economic costs of inaction. The first priority should be to reframe cancer care. Second, we need to identify different measures of cancer outcomes. Third, we need to challenge extant priorities

Collagen induces a more proliferative, migratory and chemoresistant phenotype in head and neck cancer via DDR1

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and includes squamous cell carcinomas of the oropharynx and oral cavity. Patient prognosis has remained poor for decades and molecular targeted therapies are not in routine use. Here we showed that the overall expression of collagen subunit genes was higher in cancer-associated fibroblasts (CAFs) than normal fibroblasts. Focusing on collagen8A1 and collagen11A1, we showed that collagen is produced by both CAFs and tumour cells, indicating that HNSCCs are collagen-rich environments. We then focused on discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, and showed that it is over-expressed in HNSCC tissues. Further, we demonstrated that collagen promoted the proliferation and migration of HNSCC cells and attenuated the apoptotic response to cisplatin. Knockdown of DDR1 in HNSCC cells demonstrated that these tumour-promoting effects of collagen are mediated by DDR1. Our data suggest that specific inhibitors of DDR1 might provide novel therapeutic opportunities to treat HNSCC

Enhancing career paths for tomorrow's radiation oncologists

The purpose for this manuscript is to enhance career opportunities for radiation oncologists (ROs) by expanding the scope of work as a prelude to redefining the scope of our contributions at this critical inflection point in our history. The direct stimulus is the speculation and debate over the ROs' future, a logical issue in today's rapidly changing world of health care economics, cancer biology, artificial intelligence, and global resource disparities. 123456 To be proactive and effective in adapting to—and with—these external factors, the data upon which decisions are based should be well understood. Yet accuracy of workforce forecasts for ROs are notoriously inconsistent, partly because of the imperfect assumptions inherent in such complex models. 1234 Nonetheless, over 50% of ROs are concerned about a future oversupply, 56 and the downstream effects already appear to have negatively affected specialty choice among highly talented and pragmatic medical students. Discussions of practitioner supply and demand imbalance often focus on the numerator—are there too many? Better solutions may reside in a broadening of the denominator—the talent and contributions that ROs bring to cancer care and greater society. 78 Regardless of how one views these complex issues, this is a critical juncture for exploring how to evolve ROs' skills and ensure that our contributions continue to help solve the challenges facing health care and patients

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. &amp; Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.</p