Mouse models of colorectal cancer as preclinical models.

In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative 'omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection.REM, SJAB, MJA and DJA are funded by Cancer Research UK.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/bies.20150003

Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability.

Oncogenes and oncosuppressors can deregulate cell replication in tumours, and recently have been shown to influence the probability of apoptosis. The effects of human c-myc and mutated (T24) Ha-ras oncogenes on susceptibility to apoptosis were investigated by introducing them into immortalised rat fibroblasts. The resulting family of transfectants showed closely similar measures of proliferation, but widely divergent rates of apoptosis, differing by up to fifteen-fold, that correlated inversely with population expansion rates in vitro. T24-ras transfectants with moderate or high p21ras expression showed reduced apoptosis, and this was reversed by pharmacological inhibition of membrane localisation of p21ras by mevinolin. In contrast, c-myc stimulated apoptosis, and this was further enhanced by serum deprivation. Inducibility of effector proteins represents one possible mechanism of genetic control of the susceptibility to apoptosis, and its investigation showed that c-myc was associated with expression by viable cells of latent calcium/magnesium sensitive endonuclease activity characteristic of apoptosis. In contrast, endonuclease activity was not detected in viable cells of a T24-ras transfectant expressing high levels of p21ras. Thus, there appeared to be differential regulation of susceptibility to apoptosis, positively by c-myc and negatively by activated ras, and this was associated with availability of endonuclease activity. Genetic modulation of apoptosis in human neoplasms is likely to influence net growth rate, retention of cells acquiring new mutations and response to certain chemotherapeutic agents

An integrated program using TAKTIC to control mange in swine

An integrated treatment program for sarcoptic mange control using TAKTIC@ (omitral.) 12.5% EC was evaluated at eight., privately owned, farrow to finish swine facilities in a four-state area. At all locations the treatment program consisted of an initial whole-herd treatment. phase followed by scheduled treatments applied in conjunction with routine ffionagement practices. Evaluations of mite scrapings taken at scheduled pretreatment and posttreatment intervals showed a 50· 100% reduction in sacroptic mange infestation levels following implementation of the TAKTIC@ treatment program which consisted of an initial treatment and a maintenllnce schedule. Comparison of pretreatment and posttreatment production records showed 10· 15 d earlier maturity in finishing pig market weight, increases of 0.1 -2.1 weaned pigs/Jitter, and decreases in piglet processing and nursing mortality following implementation of the TAKTIC@ treatment program. A theoretical example of the potential for increase return to profit based on these findings is presented

Strategies for achieving viral hepatitis C micro-elimination in the Netherlands.

The Netherlands is striving to achieve national elimination of the hepatitis C virus (HCV) as one of the first countries worldwide. The favorable HCV epidemiology with both low prevalence and incidence, together with access to care and treatment, present excellent conditions to further build on towards this objective. The Dutch national plan on viral hepatitis, introduced in 2016, defines targets in the HCV healthcare cascade and provides a structural framework for the development of elimination activities. Since many different stakeholders are involved in HCV care in the Netherlands, focus has been placed on micro-elimination initiatives as a pragmatic and efficient approach. These numerous micro-eliminations projects have brought the Netherlands closer to HCV elimination. In the near future, efforts specifically have to be made in order to optimize case-finding strategies and to successfully accomplish the nationwide implementation of the registration and monitoring system of viral hepatitis mono-infections, before this final goal can be reached. The upcoming years will then elucidate if the Dutch' hands on approach has resulted in sufficient progress against HCV and if the Netherlands will lead the way towards nationwide HCV elimination

Long-Term Treatment of Metastatic Colorectal Cancer with Panitumumab

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. More than 30% patients present with metastases at diagnoses and will require systemic chemotherapy. In recent years many anti-EGFR targets have been developed. Among them, panitumumab, a fully human IgG2 monoclonal antibody has shown important benefits in the treatment of this disease

Origin Of The Far Off-Axis GRB171205A

We show that observed properties of the low luminosity GRB171205A and its afterglow, like those of most other low-luminosity (LL) gamma ray bursts (GRBs) associate with a supernova (SN), indicate that it is an ordinary SN-GRB, which was produced by inverse Compton scattering of glory light by a highly relativistic narrowly collimated jet ejected in a supernova explosion and viewed from a far off-axis angle. As such, VLA/VLBI follow-up radio observations of a superluminal displacement of its bright radio afterglow from its parent supernova, will be able to test clearly whether it is an ordinary SN-GRB viewed from far off-axis or it belongs to a distinct class of GRBs, which are different from ordinary GRBs, and cannot be explained by standard fireball models of GRBs as ordinary GRBsComment: 5 pages, 6 figures, updated data in Fig. 3, Corrected GRB angular distance used in Fig.

Renal allograft recipients with high susceptibility to cutaneous malignancy have an increased prevalence of human papillomavirus DNA in skin tumours and a greater risk of anogenital malignancy.

Renal allograft recipients (RARs) have a well-documented increased incidence of viral warts and cutaneous neoplasia, particularly those with long graft life and high sun exposure. A clinicopathological survey of 69 RARs in south-east Scotland, with follow-up periods of up to 28 years after transplantation, revealed marked variation in patient susceptibility to cutaneous malignancy with concomitant variation in HPV prevalence. Skin cancers were found in 34 patients. Eight patients showed high susceptibility [defined as more than four intraepidermal carcinomas (IECs) or invasive squamous cell carcinomas (SCCs)] 42 had intermediate susceptibility (1-3 IECs or SCCs, or >3 keratoses) and 18 had low susceptibility (< or = 3 keratoses and no cancers). SCCs, IECs and keratoses from the high-susceptibility group were found to have greater prevalences of human papillomavirus (HPV) DNA (56%, 45% and 50% respectively), than SCCs (0%) and IECs (33%) from intermediate-susceptibility RARs and keratoses (36%) from the combined intermediate- and low-susceptibility groups and compared with a group of immunocompetent controls (27%, 20% and 15% respectively). No differences in p53 protein accumulation, determined immunohistochemically, were observed in tumours from the three groups. Categorization of RARs by susceptibility to cutaneous malignancy provides clinically useful information, as significantly more high-susceptibility patients (38%) developed aggressive, potentially lethal anogenital or cutaneous squamous cell cancers than did patients in the intermediate group (5%, P=0.005) or the low-susceptibility group (0%)

Accumulation of p53 is associated with tumour progression in cutaneous lesions of renal allograft recipients.

Renal allograft recipients suffer from a markedly increased susceptibility to premalignant and malignant cutaneous lesions. Although various aetiological factors have been implicated, little is known of the associated genetic events. In this study we initially employed immunocytochemical techniques to investigate the prevalence and localisation of accumulated p53 in over 200 cutaneous biopsies (including 56 squamous cell carcinomas) from renal allograft recipients and immunocompetent controls. In renal allograft recipients accumulated p53 was present in 24% of uninvolved skin samples, 14% of viral warts, 41% of premalignant keratoses, 65% of intraepidermal carcinomas and 56% of squamous cell carcinomas [squamous cell carcinoma and intraepidermal carcinoma differed significantly from uninvolved skin (P < 0.005) and viral warts (P < 0.01)]. A similar trend was revealed in immunocompetent patients (an older, chronically sun-exposed population) but with lower prevalence of p53 immunoreactivity: 25% of uninvolved skin samples, 0% of viral warts, 25% of keratoses, 53% of intraepidermal carcinomas and 53% of squamous cell carcinomas. These differences were not statistically significant. Morphologically, p53 immunoreactivity strongly associated with areas of epidermal dysplasia and the abundance of staining correlated positively with the severity of dysplasia. These data suggest that p53 plays a role in skin carcinogenesis and is associated with progression towards the invasive state. No correlation was observed between accumulated p53 and the presence of human papillomavirus (HPV) DNA in any of the lesions. Single-strand conformational polymorphism analysis (exons 5-8) was used to determine the frequency of mutated p53 in 28 malignancies with varying degrees of immunopositivity. p53 mutations were found in 5/9 (56%) malignancies with p53 staining in > 50% of cells, reducing to 1/6 (17%) where 10-50% of cells were positively stained and none where < 10% of cells were stained. These data imply that factors other than p53 gene mutation play a part in accumulation of p53 in skin cancers

Prevalence of human papillomavirus DNA in cutaneous neoplasms from renal allograft recipients supports a possible viral role in tumour promotion.

It is well established that renal allograft recipients (RARs) have an increased incidence of viral warts and premalignant and malignant cutaneous lesions, and the risk of their development increases in proportion to duration of graft survival. It has been postulated that, in addition to the effects of prolonged immunosuppression and previous sun exposure, human papillomaviruses (HPV) may also contribute to the carcinogenic process. In this study, the prevalence of HPV DNA was examined in a range of premalignant and malignant cutaneous tumours from 50 immunosuppressed patients (47 renal allograft recipients plus three cardiac allograft recipients) and 56 immunocompetent patients using Southern hybridisation as a low-stringency screening method and type-specific polymerase chain reaction (PCR) assays for eight HPV types. The combined results for renal allograft recipients show that HPV DNA was detectable in 79% of viral warts, 42% of premalignant keratoses, 33% of intraepidermal carcinomas, 43% of invasive squamous cell carcinomas and 16% of uninvolved skin specimens (squamous cell carcinomas/renal allograft recipients significantly different at P < 0.05 from uninvolved skin specimens/renal allograft recipients). In immunocompetent patients the pattern of HPV DNA prevalence was 100% for viral warts; 25% for keratoses, 23% for intraepidermal carcinomas, 22% for squamous cell carcinomas and 8% for uninvolved skin. No single HPV type predominated in tumour specimens from either group. More tumours were found to contain HPV DNA by Southern hybridisation analysis than PCR, indicating the presence of HPV types other than HPV 1, 2, 5, 6, 8, 11, 16 and 18 in some tumours. However, 'low cancer risk' HPV types 1, 2 and 6 as well as 'high cancer risk' HPV types 5 and 16 were specifically detected by PCR in a small number of neoplasms. These data suggest that multiple HPV types may contribute to cutaneous neoplasia in RARs and that they appear to act early in the process of carcinogenesis, perhaps by functioning as tumour promoters via stimulation of cell proliferation