Facial Curvature Detects and Explicates Ethnic Differences in Effects of Prenatal Alcohol Exposure

Background Our objective is to help clinicians detect the facial effects of prenatal alcohol exposure by developing computer-based tools for screening facial form. Methods All 415 individuals considered were evaluated by expert dysmorphologists and categorized as (i) healthy control (HC), (ii) fetal alcohol syndrome (FAS), or (iii) heavily prenatally alcohol exposed (HE) but not clinically diagnosable as FAS; 3D facial photographs were used to build models of facial form to support discrimination studies. Surface curvature-based delineations of facial form were introduced. Results (i) Facial growth in FAS, HE, and control subgroups is similar in both cohorts. (ii) Cohort consistency of agreement between clinical diagnosis and HC-FAS facial form classification is lower for midline facial regions and higher for nonmidline regions. (iii) Specific HC-FAS differences within and between the cohorts include: for HC, a smoother philtrum in Cape Coloured individuals; for FAS, a smoother philtrum in Caucasians; for control-FAS philtrum difference, greater homogeneity in Caucasians; for control-FAS face difference, greater homogeneity in Cape Coloured individuals. (iv) Curvature changes in facial profile induced by prenatal alcohol exposure are more homogeneous and greater in Cape Coloureds than in Caucasians. (v) The Caucasian HE subset divides into clusters with control-like and FAS-like facial dysmorphism. The Cape Coloured HE subset is similarly divided for nonmidline facial regions but not clearly for midline structures. (vi) The Cape Coloured HE subset with control-like facial dysmorphism shows orbital hypertelorism. Conclusions Facial curvature assists the recognition of the effects of prenatal alcohol exposure and helps explain why different facial regions result in inconsistent control-FAS discrimination rates in disparate ethnic groups. Heavy prenatal alcohol exposure can give rise to orbital hypertelorism, supporting a long-standing suggestion that prenatal alcohol exposure at a particular time causes increased separation of the brain hemispheres with a concomitant increase in orbital separation

Mobilisation of Public Support for Policy Actions to Prevent Obesity

Public mobilisation is needed to enact obesity prevention policies and to mitigate backlash against their implementation. However, current approaches in public health focus primarily on dialogue between public health professionals and political leaders. Strategies to increase popular demand for obesity prevention policies include refining and streamlining public information, identifying effective frames for each population, enhancing media advocacy, building citizen protest and engagement, and developing a receptive political environment with change agents embedded across organisations and sectors. Long-term support and investment in collaboration among diverse stakeholders to create shared value is also important. Each actor in an expanded coalition for obesity prevention can make specific contributions to engaging, mobilising and coalescing the public. Shifting from a top-down to an integrated bottom-up and top-down approach would require an overhaul of current strategies and re-prioritisation of resources

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

DNA repair in kidney development and Wilms tumor

DNA repair is of particular importance in the rapidly-dividing progenitor cells of developing organs. Unrepaired damage in these cells may disrupt embryonic development and be propagated throughout an entire cell lineage of the adult organ. We hypothesize that specific DNA repair programs are activated during embryogenesis to protect the genome in this critical phase and that, in the developing kidney, a panel of DNA repair genes are activated to accompany the burst of cell division during nephrogenesis. Furthermore, we hypothesize that activation of a subset of the DNA repair genes in nephron progenitor cells (NPCs) is elicited by Wilms Tumor 1 (WT1) and therefore loss of WT1 might compromise DNA repair in the developing kidney. Loss of WT1 from NPCs is known to cause clones of developmentally-arrested cells that carry a high risk of acquiring activating mutations of the CTNNB1 gene. Constitutive CTNNB1 activation is associated with malignant transformation into a Wilms tumor. However, the mechanism underlying this apparent genomic instability of NPCs, following loss of WT1, is unknown. In this project, we quantified the expression of 84 DNA repair genes in embryonic versus adult mouse kidney. We identified 7 genes with a 20-fold or greater upregulation in the embryo compared to the adult. To isolate NPCs from the embryonic mouse kidney, we used a transgenic mouse model consisting of Cited1-driven Cre recombinase crossed with a tdTomato reporter strain. Using Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR), we showed that expression of the DNA repair gene Neil3 was 15-fold higher in NPCs compared to total kidney. When we examined Neil3 expression in another rapidly-dividing embryonic kidney lineage, the Hoxb7/GFP-tagged ureteric bud lineage, we saw no enrichment relative to total kidney. We adapted our Cited1-driven Cre recombinase system to allow isolation of NPCs carrying an inducible Wt1 knockout mutation. Using RT-qPCR, we confirmed that enrichment of Neil3 in NPCs with conditional ablation of Wt1 was reduced by 60% compared to NPCs with wildtype Wt1. We propose that WT1-mediated activation of a DNA repair program that may include Neil3 is critical for maintaining genomic stability in rapidly-proliferating NPCs. Loss of this DNA repair activity could contribute to development of the activating mutations driving Wilms tumor.La réparation de l'ADN est particulièrement importante pour les cellules progénitrices qui se divisent rapidement pour former les organes. Les dommages qui n'ont pas été réparées dans ces cellules peuvent perturber le développement embryonnaire et être propagées à travers tout l'organe. Notre hypothèse est que des programmes de réparation d'ADN sont activés durant l'embryogénèse afin de protéger le génome durant cette phase cruciale. Lors du développement rénal, une panoplie de gènes de réparation de l'ADN est activée pendant la période de division rapide de la néphrogénèse. De plus, nous proposons qu'il y a un sous-ensemble des gènes responsables de la réparation de l'ADN qui est activé dans les cellules rénales progénitrices (NPCs) et que celui-ci dépend du gène suppresseur de tumeur de Wilms, WT1. Nous formulons l'hypothèse que la perte de WT1 compromet l'activation du système de réparation de l'ADN qui protège normalement les NPCs. La perte de WT1 dans les NPCs génère des clones de cellules dont le développement a été interrompu. Ces clones ont un risque élevé d'incorporation des mutations activantes du gène CTNNB1. L'activation constante de ce dernier est associée à la transformation maligne en tumeur de Wilms. Le mécanisme qui sous-tend cette apparente instabilité génomique des NPCs, suivant la perte de WT1, est inconnu. Dans cette étude, nous quantifions l'expression de 84 gènes de réparation de l'ADN dans les reins embryonnaires et adultes, chez la souris. Nous avons identifié 7 gènes dont l'expression était au moins 20 fois plus élevée dans embryon que dans adulte. Pour isoler les NPCs, nous avons utilisé un modèle de souris transgénique dont la Cre recombinase est contrôlée par le promoteur de Cited1 croisé avec une lignée de souris qui possèdent le gène rapporteur tdTomato. En utilisant la réaction en chaîne de la polymérase de transcription inverse quantitative (RT-qPCR), nous avons observé que l'expression du gêne de réparation Neil3 était 15 fois plus élevé dans les NPCs par rapport au rein dans son ensemble. Lorsque nous avons examiné l'expression de Neil3 dans une autre lignée cellulaire de reins embryonnaires dérivée du bourgeon urétéral marquée par Hoxb7/GFP, nous n'avons pas observé une telle augmentation. Nous avons adapté notre système Cited-1/Cre recombinase afin de permettre l'isolation de NPCs qui possèdent une mutation knock-out inductible de Wt1. En utilisant la RT-qPCR, nous avons confirmé que l'enrichissement de Neil3 dans NPCs avec l'ablation conditionnelle de Wt1 est réduit de 60% par rapport aux NPCs sans l'ablation. Nous proposons que l'activation du programme de réparation de l'ADN dépendant de WT1, qui peut inclure Neil3, est critique pour maintenir une stabilité génomique dans les NPCs en prolifération rapide. La perte de cette activité de réparation de l'ADN peut contribuer au développement des mutations activantes qui causent les tumeurs de Wilms

Minding the data-gap trap : exploring dynamics of abundant dolphin populations under uncertainty

This work was supported by Save Our Coast, Sitka Foundation, and McLean Foundation.Preventing declines in common species is key to sustaining the structure and function of marine ecosystems. Yet for many common marine mammals, including oceanic dolphins, statistical power to detect declines remains low due to patchy distribution and large variability in group sizes. In this study, population viability analyses (PVA) were used to model the dynamics of four oceanic dolphin populations off the United States West Coast: eastern North Pacific long-beaked common dolphins (Delphinus delphis capensis), short-beaked common dolphins (D. delphis delphis), Pacific white-sided dolphins (Lagenorhynchus obliquidens), and “offshore” common bottlenose dolphins (Tursiops truncatus). We calibrated the PVA with life-history tables, studies on proxy species, and stock assessment reports. We explored the sensitivity of populations to demographic variation and projected how they may respond to changes in three sublethal threats (prey limitation, ocean noise, and chemical pollution) and one lethal threat (fisheries bycatch). We found the most serious projected declines in long-beaked common dolphins, which showed the lowest birth rate. Most threat scenarios resulted in declines that would not be detected by existing monitoring programs in the United States, which are among the most data-rich surveys of their kind. The cumulative effects of the three sublethal stressors exceeded the effect of the one lethal stressor (fisheries bycatch). To implement pro-active management and monitoring programs, anticipating which cetaceans are more at risk and which anthropogenic threats could cause declines is paramount. Our study highlights the value of model testing with PVA when monitoring data are poor, thereby identifying priorities for future research, monitoring, and management.Publisher PDFPeer reviewe

Harnessing Stakeholder Perspectives and Experience to Address Nutrition Risk in Community-Dwelling Older Adults

Community-dwelling, older adults have a high prevalence of nutrition risk but strategies to mitigate this risk are not routinely implemented. Our objective was to identify opportunities for the healthcare system and community organizations to combat nutrition risk in this population in the jurisdiction of Alberta, Canada. An intersectoral stakeholder group that included patient representatives was convened to share perspectives and experiences and to identify problems in need of solutions using a design thinking approach. Results: Two main themes emerged from the workshop: (1) lack of awareness and poor communication of the importance of nutrition risk between healthcare providers and from healthcare providers to patients and (2) the necessity to work in partnerships comprised of patients, community organizations, healthcare providers and the health system. Conclusion: Improving awareness, prevention and treatment of malnutrition in community-dwelling older adults requires intersectoral cooperation between patients, healthcare providers and community-based organizations