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Changes to the delivery of oral surgical services, the production and review of clinical guidelines, increased availability of cross-sectional imaging and the introduction of alternative techniques for surgical management of third molar disease have subtly changed the care that a patient will receive. In reviewing those changes, this article aims to promote continued discussion by the profession as to how patients can be best treated while avoiding a protectionist approach to patient care.

Cervical cancer is caused by carcinogenic human papillomavirus infection and represents one of the leading causes of cancer death worldwide. Effective means of tumour classification are required for better disease understanding. We performed an integrated multi-omic analysis of 655 cervical cancers, using epigenomic and transcriptomic signatures to discover two distinct cervical cancer subtypes we named “typical” and “atypical”. Typical tumours were largely HPV16-driven and frequently displayed an ‘immune-hot’ tumour microenvironment. Atypical tumours were associated with poor prognosis; they were more likely to be driven by HPVs from the HPV18-containing α7 clade, displayed distinct genomic aberrations, greater evidence of past immunoediting and a microenvironment associated with immune-evasion and failure of anti-PD1 checkpoint inhibition. The finding that atypical tumours encounter stronger anti-tumour immune responses during development may explain the lower frequency at which α7 HPV infected-lesions progress from pre-invasive disease. However those escaping this selection pressure evolve into aggressive tumours (independent of HPV-type) in which more intensive adjuvant treatment may be warranted.

The two European Courts (the European Court of Human Rights, ECtHR and, to a lesser degree, the European Union Court of Justice, EUCJ) have contributed greatly to the development of a legal framework for surveillance by either law enforcement agencies in the criminal law area or by secret services. Both courts put great emphasis on a system of control ex ante and post hoc by independent supervisory authorities. A complex and controversial issue remains whether the human rights to privacy, respect of communications, and to an effective remedy (enshrined in Article 8 and 13 of European Convention on Human Rights (ECHR)), requires judicial review as a necessary safeguard for secret surveillance or alternatively, at which conditions, parallel systems of non-judicial review can be accepted as adequate safeguards against illegitimate interference in citizens’ private life. The European Courts have not yet established a clear doctrine in determining suitable thresholds and parameters. In particular, the ECtHR has a flexible approach in interpreting article 8 and 13 ECHR, depending on several factors (“vital” interests at stake, political considerations, etc.). In general terms, the Court has shown a preference towards judiciary oversight, but in the European legal order there are several examples of alternative oversight systems assessed positively by the Court, such as the quasi-judiciary systems (where the independency of the supervisory body, its wide jurisdiction, its power to data access and its power to effective reactions are proved) or the system of oversight set by Data Protection Authorities in the EU member states. However, in recent judgements of the ECtHR and the EUCJ we see an increasing emphasis on declaring the necessity of a “good enough” judicial (ex ante or post hoc) control over surveillance, meaning not simply a judicial control, but a system of oversight (judicial, quasi-judicial, hybrid) which can provide an effective control over surveillance, supported by empirical checks in the national legal system at issue.

International audience; Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c(+) cells from CD11c.DTR mice induced the expansion of a variant CD64(+) Ly6C(+) monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64(+) Ly6C(+) monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64(+) Ly6C(+) monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c(+) cells induces expansion of a unique CD64(+) Ly6C(+) monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c(+) DCs in immunity.

The APOBEC3 cytidine deaminases play an important role in innate immunity but have also emerged as mediators of somatic mutations in human cancer. We recently reported a high incidence of APOBEC-mediated driver mutations in human papillomavirus-associated cancer, suggesting a key role for these enzymes in the development of such tumors.

Chordoma is a rare malignant tumour of bone, the molecular marker of which is the expression of the transcription factor, brachyury. Having recently demonstrated that silencing brachyury induces growth arrest in a chordoma cell line, we now seek to identify its downstream target genes. Here we use an integrated functional genomics approach involving shRNA-mediated brachyury knockdown, gene expression microarray, ChIP-seq experiments, and bioinformatics analysis to achieve this goal. We confirm that the T-box binding motif of human brachyury is identical to that found in mouse, Xenopus, and zebrafish development, and that brachyury acts primarily as an activator of transcription. Using human chordoma samples for validation purposes, we show that brachyury binds 99 direct targets and indirectly influences the expression of 64 other genes, thereby acting as a master regulator of an elaborate oncogenic transcriptional network encompassing diverse signalling pathways including components of the cell cycle, and extracellular matrix components. Given the wide repertoire of its active binding and the relative specific localization of brachyury to the tumour cells, we propose that an RNA interference-based gene therapy approach is a plausible therapeutic avenue worthy of investigation.

A strategic analysis was completed to determine the feasibility of initiating a factory-built home manufacturing facility in Western Canada. We completed an industry analysis, internal analysis, an opportunity analysis and provide a recommendation on how to proceed. The results indicate a factory built facility is economically feasible if a market of 60 houses per year can be established. The competitive advantages of factory built homes over on-site homes indicate a better quality home can be produced for thirty to forty percent less cost. The value-chain analysis indicates the margin can be most significantly increased during the marketing, sales and engineering phase. The profitability of a firm improves as the size of the factory increases and if it continues to operate at capacity. The factory built home construction opportunity is very promising. A recommendation to pursue this opportunity is suggested.

The two European Courts (the European Court of Human Rights, ECtHR and, to a lesser degree, the European Union Court of Justice, EUCJ) have contributed greatly to the development of a legal framework for surveillance by either law enforcement agencies in the criminal law area or by secret services. Both courts put great emphasis on a system of control ex ante and post hoc by independent supervisory authorities. A complex and controver- sial issue remains whether the human rights to privacy, respect of communications, and to an effective remedy (enshrined in Article 8 and 13 of European Convention on Human Rights (ECHR)), requires judicial review as a necessary safeguard for secret surveillance or alternatively, at which conditions, parallel systems of non-judicial review can be accepted as adequate safeguards against illegitimate interference in citizens’ private life. The European Courts have not yet established a clear doctrine in determining suitable thresholds and parameters. In particular, the ECtHR has a flexible approach in interpreting article 8 and 13 ECHR, depending on several factors (“vital” interests at stake, political considerations, etc.). In general terms, the Court has shown a preference towards judiciary oversight, but in the European legal order there are several examples of alternative oversight systems assessed positively by the Court, such as the quasi-judiciary systems (where the independency of the supervisory body, its wide jurisdiction, its power to data access and its power to effective reactions are proved) or the system of oversight set by Data Protection Authorities in the EU member states. However, in recent judgements of the ECtHR and the EUCJ we see an increasing emphasis on declaring the necessity of a “good enough” judicial (ex ante or post hoc) control over surveillance, meaning not simply a judicial control, but a system of oversight (judicial, quasi-judicial, hybrid) which can provide an effective control over surveillance, supported by empirical checks in the national legalsystem at issue.

Purpose: The G-protein–coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) and its ligand peptide adrenomedullin (encoded by ADM gene) are implicated in tumor angiogenesis in mouse models but poorly defined in human cancers. We therefore investigated the diagnostic/prognostic use for CLR in human tumor types that may rely on adrenomedullin signaling and in clear cell renal cell carcinoma (RCC), a highly vascular tumor, in particular. Experimental Design: In silico gene expression mRNA profiling microarray study (n = 168 tumors) and cancer profiling cDNA array hybridization (n = 241 pairs of patient-matched tumor/normal tissue samples) were carried out to analyze ADM mRNA expression in 13 tumor types. Immunohistochemistry on tissue microarrays containing patient-matched renal tumor/normal tissues (n = 87 pairs) was conducted to study CLR expression and its association with clinicopathologic parameters and disease outcome. Results: ADM expression was significantly upregulated only in RCC and endometrial adenocarcinoma compared with normal tissue counterparts (P < 0.01). CLR was localized in tumor cells and vessels in RCC and upregulated as compared with patient-matched normal control kidney (P < 0.001). Higher CLR expression was found in advanced stages (P < 0.05), correlated with high tumor grade (P < 0.01) and conferred shorter overall survival (P < 0.01). Conclusions: In human tissues ADM expression is upregulated in cancer type–specific manner, implicating potential role for adrenomedullin signaling in particular in RCC, where CLR localization suggests autocrine/paracrine mode for adrenomedullin action within the tumor microenvironment. Our findings reveal previously unrecognized CLR upregulation in an autocrine loop with adrenomedullin in RCC with potential application for this GPCR as a target for future functional studies and drug development. Clin Cancer Res; 19(20); 5740–8. ©2013 AACR.