This study has, for the first time, quantified global incidence patterns of CGC and NCGC providing new insights into the global burden of these cancers. Country-specific estimates are provided; however, these should be interpreted with caution. This work will support future investigations across populations.

Nerve growth factor (NGF) promotes neuronal survival and differentiation and stimulates neurite outgrowth. NGF is synthesized as a precursor, proNGF, which undergoes posttranslational processing to generate mature b-NGF. It has been assumed that, in vivo, NGF is largely processed into the mature form and that mature NGF accounts for the biological activity. However, we recently showed that proNGF is abundant in CNS tissues whereas mature NGF is undetectable, suggesting that proNGF has biological functions beyond its role as a precursor. To determine whether proNGF exhibits biological activity, we mutagenized the precursor-processing site and expressed unprocessed, cleavage-resistant proNGF protein in insect cells. Survival and neurite outgrowth assays on murine superior cervical ganglion neurons and PC12 cells indicated that proNGF exhibits neurotrophic activity similar to mature 2.5S NGF, but is approximately fivefold less active. ProNGF binds to the high-affinity receptor, TrkA, as determined by cross-linking to PC12 cells, and is also slightly less active than mature NGF in promoting phosphorylation of TrkA and its downstream signaling effectors, Erk1/2, in PC12 and NIH3T3-TrkA cells. These data, coupled with our previous report that proNGF is the major form of NGF in the CNS, suggest that proNGF could be responsible for much of the biological activity normally attributed to mature NGF in vivo.

• A trauma-informed lens is key to cervical cancer prevention in First Nations. • Colonization's disruption of family & community ties drives health disparities. • Ruptured intergenerational ties undermine community capacity for prevention. • Community-based prevention requires reconciliation with healthcare providers. • Increased uptake of HPV vaccination requires community engagement.

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The neurotrophin nerve growth factor (NGF) binds to two receptor types: the tyrosine kinase receptor TrkA and the common neurotrophin receptor p75 NTR . Although many of the biological effects of NGF (such as neuronal growth and survival) are associated with TrkA activation, p75NTR also contributes to these activities by enhancing the action of TrkA when receptors are coexpressed. The NGF antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxlic acid] interacts with NGF, preventing its binding to p75 NTR . In this study, the actions of this compound are further explored, and it is found that PD90780 is not able to inhibit the binding of either brain-derived neurotrophic factor or neurotrophin-3 to p75 NTR , consistent with the direct interactions of the antagonist with NGF. In addition, we demonstrate that the ability of PD90780 to inhibit NGF-p75 NTR interactions is lower when receptors are coexpressed, compared with when p75 NTR is the only neurotrophin receptor expressed. These results suggest that the interaction between NGF and the p75 NTR receptor is altered when TrkA is coexpressed. This alteration can be exploited in the development of antagonists that will selectively inhibit the pro-apoptotic actions of p75 NTR when expressed in the absence of TrkA, although having less effect on the pro-survival effects of p75 NTR mediated by enhanced TrkA activation.

BackgroundDespite the existence of human papilloma virus (HPV) vaccines with demonstrated safety and effectiveness and funded HPV vaccination programs, coverage rates are persistently lower and cervical cancer burden higher among Canadian Indigenous peoples. Barriers and supports to HPV vaccination in Indigenous peoples have not been systematically documented, nor have interventions to increase uptake in this population. This protocol aims to appraise the literature in Canadian and global Indigenous peoples, relating to documented barriers and supports to vaccination and interventions to increase acceptability/uptake or reduce hesitancy of vaccination. Although HPV vaccination is the primary focus, we anticipate only a small number of relevant studies to emerge from the search and will, therefore, employ a broad search strategy to capture literature related to both HPV vaccination and vaccination in general in global Indigenous peoples.MethodsEligible studies will include global Indigenous peoples and discuss barriers or supports and/or interventions to improve uptake or to reduce hesitancy, for the HPV vaccine and/or other vaccines. Primary outcomes are documented barriers or supports or interventions. All study designs meeting inclusion criteria will be considered, without restricting by language, location, or data type. We will use an a priori search strategy, comprised of key words and controlled vocabulary terms, developed in consultation with an academic librarian, and reviewed by a second academic librarian using the PRESS checklist. We will search several electronic databases from date of inception, without restrictions. A pre-defined group of global Indigenous websites will be reviewed for relevant gray literature. Bibliographic searches will be conducted for all included studies to identify relevant reviews. Data analysis will include an inductive, qualitative, thematic synthesis and a quantitative analysis of measured barriers and supports, as well as a descriptive synthesis and quantitative summary of measures for interventions.DiscussionTo our knowledge, this study will contribute the first systematic review of documented barriers, supports, and interventions for vaccination in general and for HPV vaccination. The results of this study are expected to inform future research, policies, programs, and community-driven initiatives to enhance acceptability and uptake of HPV vaccination among Indigenous peoples.Systematic review registrationPROSPERO Registration Number: CRD42017048844Electronic supplementary materialThe online version of this article (10.1186/s13643-018-0692-y) contains supplementary material, which is available to authorized users.

Background Indigenous communities across the circumpolar north have elevated H. pylori ( Hp ) prevalence and stomach cancer incidence. We aimed to describe the Hp -associated disease burden among western Canadian Arctic participants in community-driven projects that address concerns about health risks from Hp infection. Methods During 2008–2013, participants underwent Hp screening by urea breath test and gastroscopy with gastric biopsies. We estimated Hp prevalence and prevalence by Hp status of endoscopic and histopathologic diagnoses. Results Among 878 participants with Hp status data, Hp prevalence was: 62% overall; 66% in 740 Indigenous participants; 22% in 77 non-Indigenous participants (61 participants did not disclose ethnicity); 45% at 0–14 years old, 69% at 15–34 years old, and 61% at 35–96 years old. Among 309 participants examined endoscopically, visible mucosal lesions were more frequent in the stomach than the duodenum: the gastric to duodenal ratio was 2 for inflammation, 8 for erosions, and 3 for ulcers. Pathological examination in 308 participants with gastric biopsies revealed normal gastric mucosa in 1 of 224 Hp -positive participants and 77% (65/84) of Hp -negative participants with sharp contrasts in the prevalence of abnormalities between Hp -positive and Hp -negative participants, respectively: moderate-severe active gastritis in 50 and 0%; moderate-severe chronic gastritis in 91 and 1%; atrophic gastritis in 43 and 0%; intestinal metaplasia in 17 and 5%. Conclusions The observed pattern of disease is consistent with increased risk of stomach cancer and reflects substantial inequity in the Hp -associated disease burden in western Arctic Canadian hamlets relative to most North American settings. This research adds to evidence that demonstrates the need for interventions aimed at reducing health risks from Hp infection in Indigenous Arctic communities.

In northern Canada where there is a high prevalence of Helicobacter pylori infection, there is a paucity of information on gastric cancer by the topographical subsites cardia (CGC) and non-cardia (NCGC). Here we describe the incidence of CGC and NCGC, separately, among northern Canadian populations. We used data from the Cancer Incidence in Five Continents Volumes X (CI5X) and XI (CI5XI) to obtain CGC and NCGC incidence for Canada and for Yukon (YT), a northern Canadian territory. Using these data with those provided by the Government of the Northwest Territories (NT), we estimated standardized incidence ratios comparing northern populations to Canada as a whole. We also estimated age-standardized incidence rates to permit comparisons across populations globally. NT and YT populations were disproportionately impacted by gastric cancer, particularly NCGC. This was especially true for Indigenous populations: NCGC incidence rates among NT Indigenous men were 2.7 times the rates among all men in Canada, while rates among NT Indigenous women were 3.1 times the rates among all women in Canada. Similarly, age-standardized rates of NCGC among Indigenous NT residents were comparable to global regions where there is a high burden of NCGC. This study has, for the first time, quantified the incidence of CGC and NCGC for the NT and YT, providing new insights into the burden of these cancers among northern Canadian populations.