Vitamin D-VDR signaling inhibits Wnt/beta-catenin-mediated melanoma progression and promotes anti-tumor immunity

1α,25-dihydroxyvitamin D3 signals via the Vitamin D Receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As melanoma patients commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signalling and replicated the findings in TCGA metastases. VDR expression was independently protective for melanoma death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating anti-tumor immunity and correspondingly with higher imputed immune cell scores and histologically detected tumor infiltrating lymphocytes (TILs). High VDR expressing tumors had downregulation of proliferative pathways, notably Wnt/beta-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (< 25 nmol/l ~ 10 ng/ml) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/beta-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppresive Wnt/beta-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of the causal relationship between vitamin D-VDR signaling and melanoma survival which should be explored as a therapeutic target in primary resistance to checkpoint blockade

Prognostic Significance of Promoter Hypermethylation and Diminished Gene Expression of SYNPO2 in Melanoma.

status: publishe

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Antitumour activity of a duocarmycin analogue rationalised to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder

We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was demonstrated in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells which do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed to ICT2700 in EJ138 cells expressing CYP1A2, or with exposure of EJ138 cells to CYP1B1 or CYP3A4 generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor α-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration dependent increase in γ-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice bearing CYP1A1 positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1 expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers

Adolescent self-harm and suicidal thoughts in the ALSPAC cohort: a self-report survey in England

<p>Abstract</p> <p>Background</p> <p>Substantial numbers of adolescents self-harm, but the majority of cases do not reach the attention of medical services, making community studies essential. The prevalence of suicidal thoughts and plans at this age, and the inter-relationships between suicidal thoughts, plans and self-harm remain largely unexplored.</p> <p>Method</p> <p>Cross-sectional analysis of self-reported questionnaire data collected from members of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England. Respondents (n = 4810) were aged 16–17 years old and have been followed up since birth.</p> <p>Results</p> <p>Altogether 905 (18.8%) respondents had ever self-harmed. The prevalence of lifetime self-harm was higher in females (25.6%) than males (9.1%). The most commonly used method was self-cutting: this was used alone or in combination in 73.5% of episodes, compared to 10.0% who took overdoses alone or in combination with other methods. Of those who reported self-harm, 25.3% wanted to die during the most recent episode. Concurrent depression was associated with a greatly increased risk of self-harm (OR 5.43). Only 12.4% of participants sought medical help following their most recent episode of self-harm, although this figure was higher (30.1%) where self-harm was carried out with desire to die. Of the whole sample, 15.8% had ever thought of killing themselves, and 4.3% had ever made plans to kill themselves. Compared to those who had never self-harmed, those who had self-harmed but not wanted to die during the most recent episode were at increased risk of ever having had suicidal thoughts (37.6% compared to 7.8% χ² =102.3, p < 0.001) and ever making suicidal plans (8.7% compared to 0.7%, χ² =166.9, p < 0.001). As the frequency of self-harm increased, so did the risk of suicidal thoughts and plans.</p> <p>Conclusions</p> <p>Self-harm and suicidal thoughts are common among 16/17 year olds. Although the majority of self-harm behaviour is not accompanied by a desire to die, all self-harm regardless of motivation is associated with increased risk of suicidal thoughts and plans, particularly when it is carried out repeatedly.</p