search
Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
81,500 Research products, page 1 of 8,150

  • Canada
  • Publications
  • Research data
  • Research software
  • Canadian Institutes of Health Research

10
arrow_drop_down
Relevance
arrow_drop_down
  • Open Access
    Authors: 
    Adsera, Alicia; Ferrer, Ana;
    Project: SSHRC , CIHR

    This paper contributes to the analysis of the integration of immigrants in the Canadian labour market by focusing in two relatively new dimensions. We combine the large samples of the restricted version of the Canadian Census (1991-2006) with both a novel measure of linguistic proximity of the immigrant’s mother tongue to that of the destination country and with information of the occupational skills embodied in the jobs immigrants hold. This allows us to assess the role that language plays in the labour market performance of immigrants and to better study their career progression relative to the native born. Results show that linguistic proximity shapes the evolution of job-skill content of immigrant jobs over time and in some cases affects patterns of wage assimilation of immigrants.

  • Open Access
    Authors: 
    Irene Ma; Maggie Guo; Cheryl K. Lau; Zane Ramdas; Rhonda Jackson; Christopher Naugler;
    Publisher: Elsevier BV
    Project: CIHR

    Data presented in this article include the top 51 ordered laboratory tests in Calgary and surrounding area, Alberta, from January to December 2017. This data set was collected from Calgary Laboratory Service’s Laboratory Information System, and included top 51 tests ordered from community (n = 11, 224, 330), inpatient (n = 2,340,594) and emergency (n = 1,670,062) settings. Test order mnemonic that were not true laboratory tests (eg: “extra PST tube”, “extra tube”, etc.) were excluded in the analysis. The top test ordered in all 3 test encounters was the complete blood count test (community encounter, n = 921, 873; inpatient setting, n = 357, 375; and emergency setting, n = 276, 954). This data article was submitted as a companion paper to the related research article, “Estimated costs of 51 commonly ordered laboratory tests in Canada” [1]. Keywords: Laboratory medicine, Pathology informatics, Laboratory utilization management

  • Open Access
    Authors: 
    Pereira, Telma; Ferreira, Francisco; Cardoso, Sandra; Silva, Dina; Mendonça, Alexandre; Guerreiro, Manuela; Madeira, Sara;
    Publisher: figshare
    Project: FCT | PTDC/EEI-SII/1937/2014 (PTDC/EEI-SII/1937/2014), CIHR , NIH | Alzheimers Disease Neuroi... (1U01AG024904-01), FCT | SFRH/BD/118872/2016 (SFRH/BD/118872/2016), FCT | UID/CEC/00408/2013 (UID/CEC/00408/2013)

    Stability and classification performance of classification models learnt with an incremental number of (ranked) features and using NB, DT, LR, SVM Poly and SVM RBF, per time windows, using ADNI and CCC data. RPT thresholds with β set as 0.1, 1 and 10 are illustrated. (DOCX 2920 kb)

  • Open Access English
    Authors: 
    Radha MacCulloch; Joyce Nyhof-Young; David Nicholas; Sandra Donaldson; James G. Wright;
    Publisher: BMC
    Country: United Kingdom
    Project: CIHR

    Background: Adolescents with idiopathic scoliosis who are considering spinal surgery face a major decision that requires access to in-depth information and support. Unfortunately, most online resources provide incomplete and inconsistent information and minimal social support. The aim of this study was to develop an online information and support resource for adolescent idiopathic scoliosis (AIS) patients considering spinal surgery. Prior to website development, a user-based needs assessment was conducted. The needs assessment involved a total of six focus groups with three stakeholder groups: (1) post-operative AIS patients or surgical candidates (10-18 years) (n = 11), (2) their parents (n = 6) and (3) health care providers (n = 11). This paper reports on the findings from focus groups with health care providers. Methods: Focus group methodology was used to invite a range of perspectives and stimulate discussion. During audio-recorded focus groups, an emergent table of website content was presented to participants for assessment of relevance, viability and comprehensiveness in targeting global domains of need. Specifically, effective presentation of content, desired aspects of information and support, and discussions about the value of peer support and the role of health professionals were addressed. Focus group transcripts were then subject to content analysis through a constant comparative review and analysis. Results: Two focus groups were held with health care providers, consisting of 5 and 6 members respectively. Clinicians provided their perceptions of the information and support needs of surgical patients and their families and how this information and support should be delivered using internet technology. Health care providers proposed four key suggestions to consider in the development of this online resource: (1) create the website with the target audience in mind; (2) clearly state the purpose of the website and organize website content to support the user; (3) offer a professionally-moderated interactive support component; and (4) ensure accessibility of website information and support by considering the age, gender, reading level and geographic location of potential users. Conclusions: Health care providers collectively identified the need for the development of an online information and support resource for adolescents considering surgery for AIS and their families and described the proposed website as a positive and needed adjunct to current clinical care.

  • Open Access English
    Authors: 
    Alanna McEneny-King; Pierre Chelle; Margaret H Goggans; Patricia J. Barker; Timothy W. Jacobs; Ellis J. Neufeld; Ulrike M. Reiss; John C. Panetta;
    Project: CIHR

    BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in hemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modeled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error 20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-hour trough from 25% to <12% in the youngest population. CONCLUSIONS: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

  • Open Access
    Authors: 
    Shea J. Andrews; Brian Fulton-Howard; Christopher Patterson; G. Peggy McFall; Alden Gross; Elias K. Michaelis; Alison Goate; Russell H. Swerdlow; Judy Pa; Alzheimer’s Disease Neuroimaging Initiative;
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Gender and APOE4 effects ... (1RF1AG054617-01A1), CIHR , NIH | Conference on Advanced Ps... (5R13AG030995-02), NIH | Administrative Core (5P30AG035982-05), NIH | Alzheimers Disease Neuroi... (1U01AG024904-01)

    AbstractWe examined the associations between mitochondrial DNA haplogroups (MT-hg) and their interactions with a polygenic risk score based on nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset of dementia (AOO). Logistic regression was used to determine the effect of MT-hgs and nMT-PRS on dementia at baseline (332 controls / 204 cases). Cox proportional hazards models were used to model dementia AOO (n=1047; 433 incident cases). Additionally, we tested for interactions between MT-hg and nMT-PRS in the logistic and Cox models. MT-hg K and a one SD larger nMT-PRS were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K and T were observed. Individual MT-hg were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T and a synergistic interaction between the nMT-PRS and MT-hg V. These results suggest that MT-hgs influence dementia risk, and that variants in the nuclear and mitochondrial genome interact to influence the age of onset of dementia.HighlightsMitochondrial dysfunction has been proposed to influence dementia riskMT-hg K and T interacted with a genetic risk score to reduce dementia riskMT-hg T and V interacted with a genetic risk score to influence dementia age of onset

  • Open Access English
    Authors: 
    Rebekah Sherburn; William D. Tolbert; Suneetha Gottumukkala; Andrew P Hederman; Guillaume Beaudoin-Bussières; Sherry Stanfield-Oakley; Marina Tuyishime; Guido Ferrari; Andrés Finzi; Margaret E. Ackerman; +1 more
    Publisher: MDPI AG
    Project: CIHR

    The generation of a potent vaccine for the prevention and/or control of HIV-1 has been unsuccessful to date, despite decades of research. Existing evidence from both infected individuals and clinical trials support a role for non-neutralizing or weakly neutralizing antibodies with potent Fc-effector functions in the prevention and control of HIV-1 infection. Vaccination strategies that induce such antibodies have proven partially successful in preventing HIV-1 infection. This is largely thought to be due to the polyclonal response that is induced in a vaccine setting, as opposed to the infusion of a single therapeutic antibody, which is capable of diverse Fc-effector functions and targets multiple but highly conserved epitopes. Here, we build on the success of our inner domain antigen, ID2, which incorporates conformational CD4-inducible (CD4i) epitopes of constant region 1 and 2 (C1C2 or Cluster A), in the absence of neutralizing antibody epitopes, into a minimal structural unit of gp120. ID2 has been shown to induce Cluster A-specific antibodies in a BALB/c mouse model with Fc-effector functions against CD4i targets. In order to generate an immunogen that incorporates both epitope targets implicated in the protective Fc-effector functions of antibodies from the only partially successful human vaccine trial, RV144, we incorporated the V1V2 domain into our ID2 antigen generating ID2-V1V2, which we used to immunize in combination with ID2. Immunized BALB/c mice generated both Cluster A- and V1V2-specific antibodies, which synergized to significantly improve the Fc-mediated effector functions compared to mice immunized with ID2 alone. The sera were able to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). We therefore conclude that ID2-V1V2 + ID2 represents a promising vaccine immunogen candidate for the induction of antibodies with optimal Fc-mediated effector functions against HIV-1.

  • Open Access
    Authors: 
    Balaton, Bradley P.; Fornes, Oriol; Wyeth W. Wasserman; Brown, Carolyn J.;
    Publisher: figshare
    Project: CIHR

    Additional file 1: Figure S1. The Xi/Xa expression ratio vs promoter DNAme level in individual human samples. Figure S2. The Xi/Xa expression ratio vs promoter DNAme level in individual mouse samples. Figure S3. Male vs female DNAme across species. Figure S4. A comparison of imprinted genes and genes subject to XCI. Figure S5. Comparison of DNAme data generated using WGBS and the 450 k array. Figure S6. Cross-species comparison of a primate-specific escape domain. Figure S7. Number of repeats within 15kb per TSS for genes subject or escaping XCI across species. Figure S8. Tests on mouse CTCF of our model trained on human CTCF. Figure S9. Mean female/male ATAC-seq signal across samples within 250 bp of TSSs, separated by tissue. Figure S10. Clustering of species by XCI status calls.

  • Open Access English
    Authors: 
    Jenny E. Chu; Ying Xia; Benjamin Chin-Yee; David Goodale; Alysha K. Croker; Alison L. Allan;
    Publisher: Neoplasia Press, Inc. Published by Elsevier Inc.
    Project: WT , CIHR

    Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231,MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). "Stemlike" breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDH(hi)CD44(+)) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDH(low)CD44(-) cells. Our data suggest that interactions between CD44(+) breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior.

  • Open Access English
    Authors: 
    Sean N Hatton; Khoa H Huynh; Leonardo Bonilha; Eugenio Abela; Saud Alhusaini; Andre Altmann; Marina KM Alvim; Akshara R Balachandra; Emanuele Bartolini; Benjamin Bender; +64 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Multimodal imaging of cog... (2R01NS065838-06A1), UKRI | Brain architecture and co... (MR/S00355X/1), NIH | ENIGMA-SD: Understanding ... (1R01MH116147-01), CIHR , NIH | ENIGMA Center for Worldwi... (3U54EB020403-04S1), UKRI | Translation of novel imag... (G0802012), NIH | ENIGMA World Aging Center (1R56AG058854-01), UKRI | Imaging prognostic marker... (MR/K023152/1), NSERC , NHMRC | Human Epilepsy: Understan... (1091593),...

    AbstractThe epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

search
Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
81,500 Research products, page 1 of 8,150
  • Open Access
    Authors: 
    Adsera, Alicia; Ferrer, Ana;
    Project: SSHRC , CIHR

    This paper contributes to the analysis of the integration of immigrants in the Canadian labour market by focusing in two relatively new dimensions. We combine the large samples of the restricted version of the Canadian Census (1991-2006) with both a novel measure of linguistic proximity of the immigrant’s mother tongue to that of the destination country and with information of the occupational skills embodied in the jobs immigrants hold. This allows us to assess the role that language plays in the labour market performance of immigrants and to better study their career progression relative to the native born. Results show that linguistic proximity shapes the evolution of job-skill content of immigrant jobs over time and in some cases affects patterns of wage assimilation of immigrants.

  • Open Access
    Authors: 
    Irene Ma; Maggie Guo; Cheryl K. Lau; Zane Ramdas; Rhonda Jackson; Christopher Naugler;
    Publisher: Elsevier BV
    Project: CIHR

    Data presented in this article include the top 51 ordered laboratory tests in Calgary and surrounding area, Alberta, from January to December 2017. This data set was collected from Calgary Laboratory Service’s Laboratory Information System, and included top 51 tests ordered from community (n = 11, 224, 330), inpatient (n = 2,340,594) and emergency (n = 1,670,062) settings. Test order mnemonic that were not true laboratory tests (eg: “extra PST tube”, “extra tube”, etc.) were excluded in the analysis. The top test ordered in all 3 test encounters was the complete blood count test (community encounter, n = 921, 873; inpatient setting, n = 357, 375; and emergency setting, n = 276, 954). This data article was submitted as a companion paper to the related research article, “Estimated costs of 51 commonly ordered laboratory tests in Canada” [1]. Keywords: Laboratory medicine, Pathology informatics, Laboratory utilization management

  • Open Access
    Authors: 
    Pereira, Telma; Ferreira, Francisco; Cardoso, Sandra; Silva, Dina; Mendonça, Alexandre; Guerreiro, Manuela; Madeira, Sara;
    Publisher: figshare
    Project: FCT | PTDC/EEI-SII/1937/2014 (PTDC/EEI-SII/1937/2014), CIHR , NIH | Alzheimers Disease Neuroi... (1U01AG024904-01), FCT | SFRH/BD/118872/2016 (SFRH/BD/118872/2016), FCT | UID/CEC/00408/2013 (UID/CEC/00408/2013)

    Stability and classification performance of classification models learnt with an incremental number of (ranked) features and using NB, DT, LR, SVM Poly and SVM RBF, per time windows, using ADNI and CCC data. RPT thresholds with β set as 0.1, 1 and 10 are illustrated. (DOCX 2920 kb)

  • Open Access English
    Authors: 
    Radha MacCulloch; Joyce Nyhof-Young; David Nicholas; Sandra Donaldson; James G. Wright;
    Publisher: BMC
    Country: United Kingdom
    Project: CIHR

    Background: Adolescents with idiopathic scoliosis who are considering spinal surgery face a major decision that requires access to in-depth information and support. Unfortunately, most online resources provide incomplete and inconsistent information and minimal social support. The aim of this study was to develop an online information and support resource for adolescent idiopathic scoliosis (AIS) patients considering spinal surgery. Prior to website development, a user-based needs assessment was conducted. The needs assessment involved a total of six focus groups with three stakeholder groups: (1) post-operative AIS patients or surgical candidates (10-18 years) (n = 11), (2) their parents (n = 6) and (3) health care providers (n = 11). This paper reports on the findings from focus groups with health care providers. Methods: Focus group methodology was used to invite a range of perspectives and stimulate discussion. During audio-recorded focus groups, an emergent table of website content was presented to participants for assessment of relevance, viability and comprehensiveness in targeting global domains of need. Specifically, effective presentation of content, desired aspects of information and support, and discussions about the value of peer support and the role of health professionals were addressed. Focus group transcripts were then subject to content analysis through a constant comparative review and analysis. Results: Two focus groups were held with health care providers, consisting of 5 and 6 members respectively. Clinicians provided their perceptions of the information and support needs of surgical patients and their families and how this information and support should be delivered using internet technology. Health care providers proposed four key suggestions to consider in the development of this online resource: (1) create the website with the target audience in mind; (2) clearly state the purpose of the website and organize website content to support the user; (3) offer a professionally-moderated interactive support component; and (4) ensure accessibility of website information and support by considering the age, gender, reading level and geographic location of potential users. Conclusions: Health care providers collectively identified the need for the development of an online information and support resource for adolescents considering surgery for AIS and their families and described the proposed website as a positive and needed adjunct to current clinical care.

  • Open Access English
    Authors: 
    Alanna McEneny-King; Pierre Chelle; Margaret H Goggans; Patricia J. Barker; Timothy W. Jacobs; Ellis J. Neufeld; Ulrike M. Reiss; John C. Panetta;
    Project: CIHR

    BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in hemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modeled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error 20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-hour trough from 25% to <12% in the youngest population. CONCLUSIONS: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

  • Open Access
    Authors: 
    Shea J. Andrews; Brian Fulton-Howard; Christopher Patterson; G. Peggy McFall; Alden Gross; Elias K. Michaelis; Alison Goate; Russell H. Swerdlow; Judy Pa; Alzheimer’s Disease Neuroimaging Initiative;
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Gender and APOE4 effects ... (1RF1AG054617-01A1), CIHR , NIH | Conference on Advanced Ps... (5R13AG030995-02), NIH | Administrative Core (5P30AG035982-05), NIH | Alzheimers Disease Neuroi... (1U01AG024904-01)

    AbstractWe examined the associations between mitochondrial DNA haplogroups (MT-hg) and their interactions with a polygenic risk score based on nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset of dementia (AOO). Logistic regression was used to determine the effect of MT-hgs and nMT-PRS on dementia at baseline (332 controls / 204 cases). Cox proportional hazards models were used to model dementia AOO (n=1047; 433 incident cases). Additionally, we tested for interactions between MT-hg and nMT-PRS in the logistic and Cox models. MT-hg K and a one SD larger nMT-PRS were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K and T were observed. Individual MT-hg were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T and a synergistic interaction between the nMT-PRS and MT-hg V. These results suggest that MT-hgs influence dementia risk, and that variants in the nuclear and mitochondrial genome interact to influence the age of onset of dementia.HighlightsMitochondrial dysfunction has been proposed to influence dementia riskMT-hg K and T interacted with a genetic risk score to reduce dementia riskMT-hg T and V interacted with a genetic risk score to influence dementia age of onset

  • Open Access English
    Authors: 
    Rebekah Sherburn; William D. Tolbert; Suneetha Gottumukkala; Andrew P Hederman; Guillaume Beaudoin-Bussières; Sherry Stanfield-Oakley; Marina Tuyishime; Guido Ferrari; Andrés Finzi; Margaret E. Ackerman; +1 more
    Publisher: MDPI AG
    Project: CIHR

    The generation of a potent vaccine for the prevention and/or control of HIV-1 has been unsuccessful to date, despite decades of research. Existing evidence from both infected individuals and clinical trials support a role for non-neutralizing or weakly neutralizing antibodies with potent Fc-effector functions in the prevention and control of HIV-1 infection. Vaccination strategies that induce such antibodies have proven partially successful in preventing HIV-1 infection. This is largely thought to be due to the polyclonal response that is induced in a vaccine setting, as opposed to the infusion of a single therapeutic antibody, which is capable of diverse Fc-effector functions and targets multiple but highly conserved epitopes. Here, we build on the success of our inner domain antigen, ID2, which incorporates conformational CD4-inducible (CD4i) epitopes of constant region 1 and 2 (C1C2 or Cluster A), in the absence of neutralizing antibody epitopes, into a minimal structural unit of gp120. ID2 has been shown to induce Cluster A-specific antibodies in a BALB/c mouse model with Fc-effector functions against CD4i targets. In order to generate an immunogen that incorporates both epitope targets implicated in the protective Fc-effector functions of antibodies from the only partially successful human vaccine trial, RV144, we incorporated the V1V2 domain into our ID2 antigen generating ID2-V1V2, which we used to immunize in combination with ID2. Immunized BALB/c mice generated both Cluster A- and V1V2-specific antibodies, which synergized to significantly improve the Fc-mediated effector functions compared to mice immunized with ID2 alone. The sera were able to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). We therefore conclude that ID2-V1V2 + ID2 represents a promising vaccine immunogen candidate for the induction of antibodies with optimal Fc-mediated effector functions against HIV-1.

  • Open Access
    Authors: 
    Balaton, Bradley P.; Fornes, Oriol; Wyeth W. Wasserman; Brown, Carolyn J.;
    Publisher: figshare
    Project: CIHR

    Additional file 1: Figure S1. The Xi/Xa expression ratio vs promoter DNAme level in individual human samples. Figure S2. The Xi/Xa expression ratio vs promoter DNAme level in individual mouse samples. Figure S3. Male vs female DNAme across species. Figure S4. A comparison of imprinted genes and genes subject to XCI. Figure S5. Comparison of DNAme data generated using WGBS and the 450 k array. Figure S6. Cross-species comparison of a primate-specific escape domain. Figure S7. Number of repeats within 15kb per TSS for genes subject or escaping XCI across species. Figure S8. Tests on mouse CTCF of our model trained on human CTCF. Figure S9. Mean female/male ATAC-seq signal across samples within 250 bp of TSSs, separated by tissue. Figure S10. Clustering of species by XCI status calls.

  • Open Access English
    Authors: 
    Jenny E. Chu; Ying Xia; Benjamin Chin-Yee; David Goodale; Alysha K. Croker; Alison L. Allan;
    Publisher: Neoplasia Press, Inc. Published by Elsevier Inc.
    Project: WT , CIHR

    Breast cancer preferentially metastasizes to lung, lymph node, liver, bone, and brain. However, it is unclear whether properties of cancer cells, properties of organ microenvironments, or a combination of both is responsible for this observed organ tropism. We hypothesized that breast cancer cells exhibit distinctive migration/growth patterns in organ microenvironments that mirror common clinical sites of breast cancer metastasis and that receptor-ligand interactions between breast cancer cells and soluble organ-derived factors mediate this behavior. Using an ex vivo model system composed of organ-conditioned media (CM), human breast cancer cells (MDA-MB-231,MDA-MB-468, SUM149, and SUM159) displayed cell line-specific and organ-specific patterns of migration/proliferation that corresponded to their in vivo metastatic behavior. Notably, exposure to lung-CM increased migration of all cell lines and increased proliferation in two of four lines (P < .05). Several cluster of differentiation (CD) 44 ligands including osteopontin (OPN) and L-selectin (SELL) were identified in lung-CM by protein arrays. Immunodepletion of SELL decreased migration of MDA-MB-231 cells, whereas depletion of OPN decreased both migration and proliferation. Pretreatment of cells with a CD44-blocking antibody abrogated migration effects (P < .05). "Stemlike" breast cancer cells with high aldehyde dehydrogenase and CD44 (ALDH(hi)CD44(+)) responded in a distinct chemotactic manner toward organ-CM, preferentially migrating toward lung-CM through CD44 receptor-ligand interactions (P < .05). In contrast, organ-specific changes in migration were not observed for ALDH(low)CD44(-) cells. Our data suggest that interactions between CD44(+) breast cancer cells and soluble factors present in the lung microenvironment may play an important role in determining organotropic metastatic behavior.

  • Open Access English
    Authors: 
    Sean N Hatton; Khoa H Huynh; Leonardo Bonilha; Eugenio Abela; Saud Alhusaini; Andre Altmann; Marina KM Alvim; Akshara R Balachandra; Emanuele Bartolini; Benjamin Bender; +64 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Multimodal imaging of cog... (2R01NS065838-06A1), UKRI | Brain architecture and co... (MR/S00355X/1), NIH | ENIGMA-SD: Understanding ... (1R01MH116147-01), CIHR , NIH | ENIGMA Center for Worldwi... (3U54EB020403-04S1), UKRI | Translation of novel imag... (G0802012), NIH | ENIGMA World Aging Center (1R56AG058854-01), UKRI | Imaging prognostic marker... (MR/K023152/1), NSERC , NHMRC | Human Epilepsy: Understan... (1091593),...

    AbstractThe epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.