30921 research outputs found
Sort by
BCL2L13 regulates NSCLC metastasis through mechanisms dependent on mitophagy and anoikis.
No full textLung adenocarcinoma comprises about 80% of all lung cancer cases. Metastasis is the major reason for death among lung adenocarcinoma patients. Thus, understanding the determinants of metastasis is critical to improve patient outcomes. Bcl-2–like protein 13 (BCL2L13) is known as a mitophagy mediator that is linked to ceramides lipid metabolism via the inhibition of ceramide synthase 2 and 6 activity. BCL2L13 can also regulate apoptosis. Our preliminary clinical data suggested that not only the BCL2L13 gene expression was significantly downregulated in lung cancer patients with poor survival, but also the BCL2L13 protein expression was significantly reduced in metastatic sites compared to the primary lung tumor in lung cancer patients. We hypothesized that BCL2L13 regulates NSCLC metastasis through mechanisms deponent on mitophagy and detachment-dependent cell death (anoikis).
Here, for the first time, we provide evidence that BCL2L13 is involved in regulation of lung adenocarcinoma metastasis via mitophagy-dependent regulation of epithelial to mesenchymal transition (EMT) and anoikis resistance in context of CerS2 and CerS6 activity. Our investigations showed that BCL2L13 is required for the induction of mitophagy in human and mouse lung adenocarcinoma cells. Furthermore, we showed that BCL2L13 knockdown potentiates the TGFβ1- induced EMT and subsequent metastasis and induces anoikis resistance in these two lung adenocarcinoma models. Also, the oxygen consumption rate and hallmarks of mitochondrial bioenergetics (baseline respiration, maximal respiration, spare capacity, non-mitochondrial respiration, and ATP production) were reduced in BCL2L13 knockdown cells, indicating presence of the Warburg effect. Lipidomics findings showed that BCL2L13 knockdown increases levels of CerS2 and 6 related ceramides (C16, C22, and C24) under attached conditions while BCL2L13
overexpression increases levels of these ceramides under anoikis conditions. Lack of BCL2L13 increased while BCL2L13 overexpression decreased the expression of FAK, p-FAK (Tyr 576/577), and p-FAK (Tyr 925) in lung adenocarcinoma cells under anoikis conditions. Also, we showed that NIX and BNIP3 localization was increased while BAX and truncated BID localization was decreased in mitochondria in BCL2L13-KD cells under anoikis conditions. Taking our findings together, we identify BCL2L13 as an important contributor to lung adenocarcinoma metastasis through mitophagy-dependent regulation of EMT and intrinsic apoptosis-dependent anoikis resistance in context of CerS2 and CerS6 activity. Correspondingly, these effects are exerted by BCL2L13 through its role in regulation of ceramides synthesis. Targeting or mimicking BCL2L13 could be considered as a promising novel approach to enhance responses of therapy via sensitizing lung adenocarcinoma cells to undergo anoikis. This could significantly help reduce the metastasis rates in patients with lung adenocarcinoma.May 202
Resistance, reclamation, & resurgence: a history of public education and Indigenous reclamation in Manitoba, 1919 - 2009
No full textIn this dissertation I unearth the historic and present forces which inhibit Canada’s ability to remove barriers for Indigenous reclamation and resurgence as it pertains to education. My research focuses on The Manitoba Teacher, the principal publication of the Manitoba Teachers' Society, noting that it has historically excluded the voices of Indigenous learners, educators, and families over the past century. This dissertation asks, despite this historical erasure in The Manitoba Teacher, how has Indigenous resistance, reclamation, and resurgence manifested itself in Manitoba educational settings over the past century? I argue there have always been moments and movements of Indigenous resistance, resurgence, and reclamation within education throughout the past century when Indigenous communities have taken control of the educational landscape. Based on the archival documents located within the archives of the Manitoba Teachers’ Society, the Indian and Métis Friendship Centre, the Aboriginal Council of Winnipeg, and the Verna Kirkness fonds, evidence in both colonial and Indigenous archives points to critical moments and ingredients as to when Indigenous communities have resisted colonial forms of education, and have reclaimed community-led education as a means to disrupt the colonial and oppressive grip that the Canadian state has held on communities. Through the lens of Gramsci’s notion of the subaltern and Trouillot’s theory of the silencing of history and by way of juxtaposing colonial and Indigenous archival evidence, I further argue that there has always been a disconnect or a chasm between the prohibition of Indigenous-led education and the desire of white-settlers to provide this education. Despite this gap, Indigenous peoples in Manitoba have perpetually taken back control of education through language, land, culture, and community.October 202
Critical thresholds of long-pressure reactivity index and impact of intracranial pressure monitoring methods in traumatic brain injury
No full textBackground
Moderate-to-severe traumatic brain injury (TBI) has a global mortality rate of about 30%, resulting in acquired life-long disabilities in many survivors. To potentially improve outcomes in this TBI population, the management of secondary injuries, particularly the failure of cerebrovascular reactivity (assessed via the pressure reactivity index; PRx, a correlation between intracranial pressure (ICP) and mean arterial blood pressure (MAP)), has gained interest in the field. However, derivation of PRx requires high-resolution data and expensive technological solutions, as calculations use a short time-window, which has resulted in it being used in only a handful of centers worldwide. As a solution to this, low resolution (longer time-windows) PRx has been suggested, known as Long-PRx or LPRx. Though LPRx has been proposed little is known about the best methodology to derive this measure, with different thresholds and time-windows proposed. Furthermore, the impact of ICP monitoring on cerebrovascular reactivity measures is poorly understood. Hence, this observational study establishes critical thresholds of LPRx associated with long-term functional outcome, comparing different time-windows for calculating LPRx as well as evaluating LPRx determined through external ventricular drains (EVD) vs intraparenchymal pressure device (IPD) ICP monitoring.
Methods
The study included a total of n = 435 TBI patients from the Karolinska University Hospital. Patients were dichotomized into alive vs. dead and favorable vs. unfavorable outcomes based on 1-year Glasgow Outcome Scale (GOS). Pearson’s chi-square values were computed for incrementally increasing LPRx or ICP thresholds against outcome. The thresholds that generated the greatest chi-squared value for each LPRx or ICP parameter had the highest outcome discriminatory capacity. This methodology was also completed for the segmentation of the population based on EVD, IPD, and time of data recorded in hospital stay.
Results
LPRx calculated with 10–120-min windows behaved similarly, with maximal chi-square values ranging at around a LPRx of 0.25–0.35, for both survival and favorable outcome. When investigating the temporal relations of LPRx derived thresholds, the first 4 days appeared to be the most associated with outcomes. The segmentation of the data based on intracranial monitoring found limited differences between EVD and IPD, with similar LPRx values around 0.3.
Conclusion
Our work suggests that the underlying prognostic factors causing impairment in cerebrovascular reactivity can, to some degree, be detected using lower resolution PRx metrics (similar found thresholding values) with LPRx found clinically using as low as 10 min-by-minute samples of MAP and ICP. Furthermore, EVD derived LPRx with intermittent cerebrospinal fluid draining, seems to present similar outcome capacity as IPD. This low-resolution low sample LPRx method appears to be an adequate substitute for the clinical prognostic value of PRx and may be implemented independent of ICP monitoring method when PRx is not feasible, though further research is warranted
The effect of interferon-lambda 3 on human T-cell polarization and activation
No full textType III interferons (IFNs) are one of the core IFNs that directly inhibit viral replication, and their function specifically acts on mucosal epithelial cells and certain immune cells. We recently showed that additional human, but not mouse, immune cell types express IFNLR1 mRNA (including T cells) and respond to IFN-λ3 stimulation. T cells are critical members of our adaptive immune system, where CD4+ T cells promote the effector functions of other immune cells, and CD8+ T cells directly kill altered cells. CD4+ T cells can differentiate into distinct T helper (Th) subtypes. We previously showed IFN-λ3 inhibited Th2 cytokine induction in influenza vaccine-stimulated peripheral blood mononuclear cells (PBMCs), but the inhibitory mechanisms were unknown. Since Th2 cytokines are associated with allergic diseases and inflammation, such as Th2-endotype allergic asthma, a better understanding of the interplay between type III IFNs and T cell polarization could aid in the development of future therapies. Little is known about the levels of IFN-λR1 on CD8+ T cells and how CD8+ T cells respond to IFN-λs with or without the presence of T cell receptor (TCR) stimulation.
To reveal the distribution of IFN-λR1 on T cells, we screened several antibodies and identified a candidate that can specifically and efficiently bind IFN-λR1. Using the newly identified antibody, we detected unique IFN-λR component IFN-λR1 at protein levels on total human CD4+ T cells and CD8+ T cells as well as different subsets. The percentage of CD8+ T cells expressing IFN-λR1 on the surface (about 10%) was higher than CD4+ T cells (about 2%) at the steady state (p < 0.05). The other component of IFN-λR, IL-10RB, was expressed on almost 100% of CD4+ and CD8+ T cells.
In the context of TCR stimulation, IFN-λR1 levels on human T cells were significantly increased over 1-3 days within whole PBMC as well as purified CD4+ and CD8+ T cell cultures in vitro. Through testing multiple TCR signalling inhibitors, we identified multiple signalling intermediates that likely contribute to IFN-λR1 upregulation on T cells after TCR stimulation.
Lastly, we demonstrated that IFN-λ3 downregulated IL-13 production in whole PBMCs during TCR stimulation and also during longer-term naïve CD4+ T cell Th2 polarization. For CD8+ T cells, using RNA sequencing transcriptome analyses, we showed that without TCR stimulation, IFN-λ3 inhibited protein synthesis and activated antiviral genes. When comparing transcriptome changes after TCR stimulation, with or without IFN-λ3, we found multiple pathways altered upon IFN-λ3 addition with some overlap to when IFN-λ3 was added alone to CD8+ T cells.
Overall, this body of work has demonstrated that human T cells can directly respond to IFN-λ3, although the subset of T cell and activation state dramatically alter the magnitude of IFN-λ responsiveness due to the different surface levels of IFN-λR1. This means that although some T cells (e.g. naïve CD4+ T cells) are poor responders at rest, IFN-λ can directly influence Th2 and CD8+ T cell responses during an infection or periods of chronic inflammation that we wouldn’t have expected if we only studied T cells at steady state. Through the greater understanding of IFN-λ immunoregulatory pathways, IFN-λ3 could be an ideal future immunotherapy going beyond just promoting antiviral pathways and instead targeting specific immune cell types, including T cells, with fewer side effects compared to other IFNs.Rady Faculty of Health Sciences Graduate Studentship, Research Manitoba New Investigator Operating Grant, University of Manitoba new investigator start-up funds and University Research Grants ProgramOctober 202
Structure-activity relationships of niclosamide to overcome colistin resistance
No full textAntibacterial resistance poses a significant threat to global healthcare systems, particularly against Gram-negative bacteria (GNB). Addressing this challenge requires urgent development of new therapies, especially given the emergence of resistance even to last-resort antibiotics like colistin. However, rising rates of colistin resistance highlight the need for alternative strategies. One promising approach involves repurposing existing drugs, such as the anthelmintic niclosamide, known to enhance colistin activity in combination therapy. Despite its potential, niclosamide faces limitations due to poor solubility, bioavailability, and off-target toxicity. Thus, repurposing it as an antibacterial agent necessitates the synthesis of new derivatives capable of overcoming these challenges. Additionally, a comprehensive exploration of niclosamide's structure–activity relationship (SAR) against GNB remains unexplored. We synthesized a series of niclosamide analogs to address these gaps, focusing on three main objectives: mitigating toxicity by replacing the nitro group, modifying the central amide moiety, and designing niclosamide-based hybrid antibiotics. Our SAR investigation led to the discovery of several lead compounds with comparable colistin-potentiating activity to niclosamide but with reduced cytotoxicity. Notably, we also identified synergy with antibiotics beyond colistin, including cefiderocol and bacitracin. Overall, our work provides critical insights into synthetic strategies for developing new niclosamide derivatives. We also demonstrate that toxicity to mammalian cells can be minimized while maintaining colistin potentiation and reveal promising avenues for repurposing niclosamide in combating antibacterial resistance.October 202
Taxonomic studies of western North American Lasioglossum (Hemihalictus) and a problematic L. (Sphecodogastra) species complex
No full textSweat bees in the cosmopolitan genus Lasioglossum are some of the most diverse and commonly collected bees in terrestrial ecosystems. Lasioglossum is made up of several difficult to define subgenera including L. (Hemihalictus) and L. (Sphecodogastra). These two subgenera have never been completely revised in western North America. Taxonomic studies of western Lasioglossum were conducted to clarify subgeneric and species limits. A problematic species complex within L. (Sphecodogastra) was described, which created challenges for subgeneric diagnostics. An improved subgeneric diagnosis was developed for L. (Sphecodogastra) along with a revised key to Lasioglossum subgenera in North America. Then, a review of western Lasioglossum (Hemihalictus) was conducted. The species delimitation process employed an integrated approach, following morphological and geographical data to delineate species boundaries. Morphometric analysis was used for species in the L. (Sphecodogastra) iridescens and L. (Hemihalictus) arizonense groups, using linear discriminant analysis and partitioning around medioids. Three new L. (Sphecodogastra) were described: L. iridescens, L. dilisena, and L. silveirai. Twenty five species of L. (Hemihalictus) were treated, five of which are described as new: L. angustoides sp. nov., L. engleri sp. nov., L. pathiranae sp. nov., L. opata sp. nov., and L. tomentosum sp. nov. Two Palaearctic species are documented in North America: L. villosulum (Kirby) and L. buccale (Pérez). The male of L. subobscurum (Cockerell) is described for the first time. Lasioglossum vanduzeei (Sandhouse & Cockerell) is resurrected from synonymy with L. arizonense. Lasioglossum aspilurum (Cockerell) is considered a senior subjective synonym of Halictus humboldtensis Michener. Six western Nearctic species in the L. nitidiusculum species-group are included in two species complexes: L. ruficorne and L. diatretum species complexes, which likely include unverified synonymies.University of Manitoba Graduate Enhancement of Tri-agency StipendsMay 202
Exploring the experiences of physiotherapists who engaged as knowledge users in integrated knowledge translation research partnerships related to balance measurement practices in Canadian hospitals: a qualitative descriptive study
No full textBackground: Integrated knowledge translation (IKT) is an approach to doing health research that engages academic researchers and knowledge users (KU) as equal partners. IKT intends to increase the chances that resulting research evidence will be useful to those engaged, striving toward improved health system functioning and public health outcomes. With this study, I set out to learn what physiotherapists (PTs) had to say about their experience engaging as KUs in an IKT research partnership related to balance measurement practices in Canadian hospitals.
Methods: I used basic qualitative descriptive research methodology, in vivo coding, and conventional content analysis to answer the research questions. Five PTs (n=5) who had engaged as KUs on three balance measurement studies in two provinces were purposefully selected. All five (n=5) participated in online semi-structured interviews. PTs were asked to describe their IKT engagement experience, identify environmental factors that affected their engagement, and discuss how their engagement influenced the research process and evidence use. PTs also characterized themselves using an independently completed pre-interview questionnaire.
Results: Participants described their experiences as positive, meaningful, and associated with benefits such as more clinical treatment options, greater sense of personal pride and professional recognition among PTs, increased research capacity for host organizations, and specific contributions to a body of knowledge. PTs said factors conducive to IKT engagement were supportive organizational culture, as well as devoted time, money, material resources, and human resources. PTs described their contributions to research as brokering trusting relationships; providing an insider point-of-view, project management, and resource coordination; and contributing to increased organizational capacity for research. Participants described how evidence-use was impacted by PT career-stage, individual risk perception, usefulness to the profession, organizational culture, treatment environment (especially since COVID-19 introduced pressures to deliver health care online), and third-party endorsement for change.
Conclusions: KU engagement in IKT health research partnerships provides researchers with increased clinical access, an insider point-of-view, and stronger research evidence. KU engagement increases the accessibility of resulting research evidence, but sustaining desired outcomes is another issue. The KU engagement experience is greatly affected by organizational culture. KU engagement concepts in IKT research partnerships must include feasibility and resource planning, as well as strategies for organizational change and risk management. PTs described external factors such as professional endorsement as being stronger influences on evidence use outcomes than research engagement. The IKT approach may be strengthened if issues related to change, risk, and resources are addressed early and often throughout the partnership.Several people and agencies helped to fund this work, especially during the COVID-19 pandemic, which extended the duration and associated costs of this study. Thank you to the University of Manitoba for awarding me the following: FKRM Graduate Assistance Scholarship; COVID-19 Bursary; FKRM Research Expense Fund; and the FGS Research Completion Scholarship. Thank you to the Integrated Knowledge Translation Research Network (IKTRN) for providing me with additional funding through the IKTRN Trainee Fund, which helped me to present this work, and the IKTRN Trainee Open Access Fund, which will help me to publish this work. Finally, I would also like to thank Dr. Sibley for sharing your own research budget with me and providing additional learning opportunities along the way. These generous acts meant I could take important moments to enjoy the process.May 202
Screening for harmful substance use in emergency departments: a systematic review
No full textBackground
Substance use-related emergency department (ED) visits have increased substantially in North America. Screening for substance use in EDs is recommended; best approaches are unclear. This systematic review synthesizes evidence on diagnostic accuracy of ED screening tools to detect harmful substance use.
Methods
We included derivation or validation studies, with or without comparator, that included adult (≥ 18 years) ED patients and evaluated screening tools to identify general or specific substance use disorders or harmful use. Our search strategy combined concepts Emergency Department AND Screening AND Substance Use. Trained reviewers assessed title/abstracts and full-text articles for inclusion, extracted data, and assessed risk of bias (QUADAS-2) independently and in duplicate. Reviewers resolved disagreements by discussion. Primary investigators adjudicated if necessary. Heterogeneity precluded meta-analysis. We descriptively summarized results.
Results
Our search strategy yielded 2696 studies; we included 33. Twenty-one (64%) evaluated a North American population. Fourteen (42%) applied screening among general ED patients. Screening tools were administered by research staff (n = 21), self-administered by patients (n = 10), or non-research healthcare providers (n = 1). Most studies evaluated alcohol use screens (n = 26), most commonly the Alcohol Use Disorders Identification Test (AUDIT; n = 14), Cut down/Annoyed/Guilty/Eye-opener (CAGE; n = 13), and Rapid Alcohol Problems Screen (RAPS/RAPS4/RAPS4-QF; n = 12). Four studies assessing six tools and screening thresholds for alcohol abuse/dependence in North American patients (AUDIT ≥ 8; CAGE ≥ 2; Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV-2] ≥ 1; RAPS ≥ 1; National Institute on Alcohol Abuse and Alcoholism [NIAAA]; Tolerance/Worry/Eye-opener/Amnesia/K-Cut down [TWEAK] ≥ 3) reported both sensitivities and specificities ≥ 83%. Two studies evaluating a single alcohol screening question (SASQ) (When was the last time you had more than X drinks in 1 day?, X = 4 for women; X = 5 for men) reported sensitivities 82–85% and specificities 70–77%. Five evaluated screening tools for general substance abuse/dependence (Relax/Alone/Friends/Family/Trouble [RAFFT] ≥ 3, Drug Abuse Screening Test [DAST] ≥ 4, single drug screening question, Alcohol, Smoking and Substance Involvement Screening Test [ASSIST] ≥ 42/18), reporting sensitivities 64%-90% and specificities 61%-100%. Studies’ risk of bias were mostly high or uncertain.
Conclusions
Six screening tools demonstrated both sensitivities and specificities ≥ 83% for detecting alcohol abuse/dependence in EDs. Tools with the highest sensitivities (AUDIT ≥ 8; RAPS ≥ 1) and that prioritize simplicity and efficiency (SASQ) should be prioritized
Policy Brief
No full textLocal politicians play a key role in determining policies and allocating resources that could help improve transportation equity. While transportation equity has been examined at some length at an academic level, there has been little direct research about how local politicians understand it. The goal of this brief is to help planners and advocates work effectively with politicians when trying to advance transportation equity. It draws on recent research that surveyed and interviewed local politicians in Canada about their values, experiences, and perspectives on transportation equity. This brief addresses these key questions:
(1) How do elected officials get their information about transportation issues?
(2) What do they think of when talking about transportation equity?
(3) What are their values and priorities
Exploring physiotherapists’ experiences and perceptions about the factors influencing the delivery of care via videoconferencing. A qualitative description design.
No full textIntroduction: The delivery of care via videoconferencing (VC) allows physiotherapists (PTs) to connect with patients at a distance. VC requires an entirely hands-off approach, which does not align with physiotherapy’s ‘hands-on’ identity. A hands-off approach requires a change in practice and a change in clinician behaviour. Previous studies have utilised behaviour change theory to explore PTs’ delivery of care via VC, but there is no account of the unique Manitoban contextual or jurisdictional factors.
Purpose: The purpose of this study was to explore PTs’ experiences and perceptions about the factors influencing the delivery of care via VC to the Manitoban population.
Method: A qualitative description design allowed for an exploration of the lived experiences of Manitoban PTs delivering care via VC. Purposive and snowball sampling resulted in a diverse sample of 20 participants. Semi-structured virtual interviews were conducted between June and August, 2023. Directed content analysis (DCA) was used to analyse the interview data, using the COM-B (Capability, Opportunity, Motivation, and Behaviour) change model.
Results: The majority of factors influencing PTs’ delivery of care via VC were categorised in the opportunity components of COM-B and included the internet and technology; patient conditions; and patient expectations. Many PTs gained VC experience during COVID-19, which facilitated clinicians’ psychological capability. Participants described a need for ‘adaptive expertise’. PTs’ motivation to deliver care via VC was limited, predominantly due to the elimination of hands-on care. Conversely, the lack of physical contact was described as a facilitator for PTs who experienced their own physical disabilities or ill health, which limited or prohibited the delivery of care in person.
Conclusion: A multitude of factors impeded PTs’ ability to deliver equitable care via VC. Although the knowledge-to-practice gap has narrowed, it has not closed. A lack of motivation remains a barrier for PTs delivering care via VC. Participants envisioned a hybrid future: a combination of care of delivered via VC and in-person. The barriers and facilitators identified in this study have created a valuable foundation from which to develop targeted solutions to enable PTs to deliver care via VC.October 202