Endo180 (MRC2) antibody-drug conjugate for the treatment of sarcoma.

Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first line treatment remains high and survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From immunohistochemical staining of a large set of 625 human soft tissue sarcomas we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene expression datasets showing a significantly increased expression in both soft tissue and bone sarcomas compared to normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180 expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an Isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide pre-clinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease

Elliptic logarithms, diophantine approximation and the Birch and Swinnerton-Dyer conjecture

Most, if not all, unconditional results towards the abc-conjecture rely ultimately on classical Baker's method. In this article, we turn our attention to its elliptic analogue. Using the elliptic Baker's method, we have recently obtained a new upper bound for the height of the S-integral points on an elliptic curve. This bound depends on some parameters related to the Mordell-Weil group of the curve. We deduce here a bound relying on the conjecture of Birch and Swinnerton-Dyer, involving classical, more manageable quantities. We then study which abc-type inequality over number fields could be derived from this elliptic approach.Comment: 20 pages. Some changes, the most important being on Conjecture 3.2, three references added ([Mas75], [MB90] and [Yu94]) and one reference updated [BS12]. Accepted in Bull. Brazil. Mat. So

Childhood solid tumours in relation to population mixing around the time of birth

In a retrospective cohort study of 673 787 live births in the Northern Region of England, 1975 - 1994, we investigated whether a higher level of population mixing around birth was a risk factor for solid tumours, by diagnostic group (Hodgkin's disease, brain and spinal tumours, neuroblastoma, other solid tumours), diagnosed during 1975-2001 under age 15 years. Logistic regression was used to relate risk to population mixing, based on (i) all movers and (ii) incomers from outside the region. Both ward and county district level analyses were performed. There was a decreased risk of brain and spinal tumours with increasing population mixing based on incomers from outside the region (OR for trend across three categories = 0.79, 95% CI: 0.66-0.95, P = 0.01 in the ward level analysis). Although this may be because of chance, it is consistent with a role of exposure to infection and immunological response in the aetiology of these tumours. For other tumour groups, there was no consistent evidence of an association between risk and population mixing

An Industry Perspective on Canadian Patients\u27 Involvement in Medical Tourism: Implications for Public Health

Background: The medical tourism industry, which assists patients with accessing non-emergency medical careabroad, has grown rapidly in recent years. A lack of reliable data about medical tourism makes it difficult to createpolicy, health system, and public health responses to address the associated risks and shortcomings, such as spreadof infectious diseases, associated with this industry. This article addresses this knowledge gap by analyzinginterviews conducted with Canadian medical tourism facilitators in order to understand Canadian patients’involvement in medical tourism and the implications of this involvement for public health. Methods: Semi-structured phone interviews were conducted with 12 medical facilitators from 10 companies in2010. An exhaustive recruitment strategy was used to identify interviewees. Questions focused on businessdimensions, information exchange, medical tourists’ decision-making, and facilitators’ roles in medical tourism.Thematic analysis was undertaken following data collection.Results: Facilitators helped their Canadian clients travel to 11 different countries. Estimates of the number ofclients sent abroad annually varied due to demand factors. Facilitators commonly worked with medical touristsaged between 40 and 60 from a variety of socio-economic backgrounds who faced a number of potential barriersincluding affordability, fear of the unfamiliar, and lack of confidence. Medical tourists who chose not to usefacilitators’ services were thought to be interested in saving money or have cultural/familial connections to thedestination country. Canadian doctors were commonly identified as barriers to securing clients. Conclusions: No effective Canadian public health response to medical tourism can treat medical tourists as aunified group with similar motivations for engaging in medical tourism and choosing similar mechanisms fordoing so. This situation may be echoed in other countries with patients seeking care abroad. Therefore, a call for acomprehensive public health response to medical tourism and its effects should be coupled with a clearunderstanding that medical tourism is a highly diverse practice. This response must also acknowledge facilitators asimportant stakeholders in medical tourism

Air pollution and general practitioner access and utilization: a population based study in Sarnia, 'Chemical Valley,' Ontario

<p>Abstract</p> <p>Background</p> <p>Health impacts of poor environmental quality have been identified in studies around the world and in Canada. While many of the studies have identified associations between air pollution and mortality or morbidity, few have focused on the role of health care as a potential moderator of impacts. This study assessed the determinants of health care access and utilization in the context of ambient air pollution in Sarnia, Ontario, Canada.</p> <p>Methods</p> <p>Residents of Sarnia participated in a Community Health Study administered by phone, while several ambient air pollutants including nitrogen dioxide (NO₂), sulphur dioxide (SO₂) and the volatile organic compounds benzene, toluene, ethylbenzene, mp- and o-xylene (BTEX) were monitored across the city. Land Use Regression models were used to estimate individual exposures to the measured pollutants and logistic regression models were utilized to assess the relative influence of environmental, socioeconomic and health related covariates on general practitioner access and utilization outcomes.</p> <p>Results</p> <p>The results show that general practitioner use increased with levels of exposure to nitrogen dioxide (NO₂- Odds Ratio [OR]: 1.16, <it>p </it>< 0.05) and sulphur dioxide (SO₂- OR: 1.61, <it>p </it>< 0.05). Low household income was a stronger predictor of having no family doctor in areas exposed to high concentrations of NO₂and SO₂. Respondents without regular care living in high pollution areas were also more likely to report travelling or waiting for care in excess of 20 minutes (OR: 3.28, <it>p </it>< 0.05) than their low exposure counterparts (OR: 1.11, <it>p </it>> 0.05).</p> <p>Conclusions</p> <p>This study provides evidence for inequitable health care access and utilization in Sarnia, with particular relevance to its situation as a sentinel high exposure environment. Levels of exposure to pollution appears to influence utilization of health care services, but poor access to primary health care services additionally burden certain groups in Sarnia, Ontario, Canada.</p

Genome-Wide Identification of HrpL-Regulated Genes in the Necrotrophic Phytopathogen Dickeya dadantii 3937

BACKGROUND: Dickeya dadantii is a necrotrophic pathogen causing disease in many plants. Previous studies have demonstrated that the type III secretion system (T3SS) of D. dadantii is required for full virulence. HrpL is an alternative sigma factor that binds to the hrp box promoter sequence of T3SS genes to up-regulate their expression. METHODOLOGY/PRINCIPAL FINDINGS: To explore the inventory of HrpL-regulated genes of D. dadantii 3937 (3937), transcriptome profiles of wild-type 3937 and a hrpL mutant grown in a T3SS-inducing medium were examined. Using a cut-off value of 1.5, significant differential expression was observed in sixty-three genes, which are involved in various cellular functions such as type III secretion, chemotaxis, metabolism, regulation, and stress response. A hidden Markov model (HMM) was used to predict candidate hrp box binding sites in the intergenic regions of 3937, including the promoter regions of HrpL-regulated genes identified in the microarray assay. In contrast to biotrophic phytopathgens such as Pseudomonas syringae, among the HrpL up-regulated genes in 3937 only those within the T3SS were found to contain a hrp box sequence. Moreover, direct binding of purified HrpL protein to the hrp box was demonstrated for hrp box-containing DNA fragments of hrpA and hrpN using the electrophoretic mobility shift assay (EMSA). In this study, a putative T3SS effector DspA/E was also identified as a HrpL-upregulated gene, and shown to be translocated into plant cells in a T3SS-dependent manner. CONCLUSION/SIGNIFICANCES: We provide the genome-wide study of HrpL-regulated genes in a necrotrophic phytopathogen (D. dadantii 3937) through a combination of transcriptomics and bioinformatics, which led to identification of several effectors. Our study indicates the extent of differences for T3SS effector protein inventory requirements between necrotrophic and biotrophic pathogens, and may allow the development of different strategies for disease control for these different groups of pathogens