The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes ...G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphorylation is a well-described consequence of TMZ treatment, we find that TMZ also robustly induces CDK1 expression. Analysis of this pathway demonstrates that CDK1 is regulated by NF-κB via a putative κB-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor κB protein, BCL-3. Treatment with TMZ induced binding of NF-κB to the κB-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the κB-site and underlined the requirement of p50 and BCL-3 for activation. Targeted knockdown of CDK1 or chemical inhibition with the selective CDK1 inhibitor, RO-3306, potentiated the cytotoxic effect of TMZ. These results identify CDK1 as an NF-κB target gene regulated by p50 and BCL-3 and suggest that targeting CDK1 may be a strategy to improve the efficacy of TMZ against GBM.
Nuclear factor-κB (NF-κB) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-κB response as a prerequisite to ...identifying novel factors that affect sensitivity to DNA damaging chemotherapy.
Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with κB DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-κB activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-β. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis.
These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.
Despite higher rates of seizure freedom, a large proportion of patients with medically refractory seizures who could benefit from epilepsy surgery do not receive surgical treatment. This literature ...review describes the association of race and insurance status with epilepsy surgery access and outcomes.
Searches in Scopus and PubMed databases related to disparities in epilepsy surgery were conducted. The inclusion criteria consisted of data that could be used to compare epilepsy surgery patient access and outcomes by insurance or race in the United States. Two independent reviewers determined article eligibility.
Of the 289 studies reviewed, 26 were included. Most of the studies were retrospective cohort studies (23 of 26) and national admissions database studies (13 of 26). Of the 17 studies that evaluated epilepsy surgery patient demographics, 11 showed that Black patients were less likely to receive surgery than were White patients or had an increased time to surgery from seizure onset. Nine studies showed that patients with private insurance were more likely to undergo epilepsy surgery and have shorter time to surgery compared with patients with public insurance. No significant association was found between the seizure recurrence rate after surgery with insurance or race.
Black patients and patients with public insurance are receiving epilepsy surgery at lower rates after a prolonged waiting period compared with other patients with medically refractory epilepsy. These results are consistent across the current reported literature. Future efforts should focus on additional characterization and potential causes of these disparities to develop successful interventions.
Virtual care has become an increasingly useful tool for the virtual delivery of care across the globe. With the unexpected emergence of COVID-19 and ongoing public health restrictions, it has become ...evident that the delivery of high-quality telemedicine is critical to ensuring the health and wellbeing of Indigenous peoples, especially those living in rural and remote communities.
We conducted a rapid evidence review from August to December 2021 to understand how high quality Indigenous primary healthcare is defined in virtual modalities. After completing data extraction and quality appraisal, a total of 20 articles were selected for inclusion. The following question was used to guide the rapid review: How is high quality Indigenous primary healthcare defined in virtual modalities?
We discuss key limitations to the delivery of virtual care, including the increasing cost of technology, lack of accessibility, challenges with digital literacy, and language barriers. This review further yielded four main themes that highlight Indigenous virtual primary healthcare quality: (1) limitations and barriers of virtual primary healthcare, (2) Indigenous-centred virtual primary healthcare, (3) virtual Indigenous relationality, (4) collaborative approaches to ensuring holistic virtual care.
For virtual care to be Indigenous-centred, Indigenous leadership and users need to be partners in the development, implementation and evaluation of the intervention, service or program. In terms of virtual models of care, time must be allocated to educate Indigenous partners on digital literacy, virtual care infrastructure, benefits and limitations. Relationality and culture must be prioritized as well as digital health equity.
These findings highlight important considerations for strengthening virtual primary healthcare approaches to meet the needs of Indigenous peoples worldwide.
Abstract
p50, the mature product of
NFKB1
, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT ...domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.
Patient-physician communication is key to better clinical outcomes and patient well-being. Communication between trauma patients and their physicians remains relatively unexplored. We aimed to ...identify and characterize the range of strengths and challenges in patient-physician communication in the setting of trauma care.
A qualitative, grounded theory approach was used to explore communication strengths and challenges for patients and residents. Patients previously admitted to the trauma service for violent injuries were recruited and interviewed in-person during their trauma clinic appointments. Surgical residents were recruited via email and interviewed virtually via Zoom. Anonymous, semistructured interviews were conducted until thematic saturation was reached.
Twenty-nine interviews with patients and 14 interviews with residents were conducted. Patients reported feeling ignored and misunderstood and having inadequate communication with physicians. Residents cited lack of time, patients' lack of health literacy, differences in background, and emotional responses to trauma as barriers to effective communication with patients. Patients and residents reported an understanding of each other's stressors, similar emotional experiences regarding traumatic stress, and a desire to communicate with each other in greater depth both inside and outside of the hospital.
Trauma patients and residents can feel disconnected due to the lack of time for thorough communication and differences in background; however, they understand each other's stressors and share similar emotional responses regarding trauma and a desire for increased communication, connection, and solidarity. Leveraging these shared values to guide interventions, such as a resident curriculum, may help bridge disconnects and improve their communication.
Therapeutic/Care Management; Level IV.
BackgroundPerspectives from Indigenous peoples and their primary care providers about the quality and impacts of virtual primary care for Indigenous patients are currently limited. This study engaged ...Indigenous patients and their primary care providers, resulting in four domains being established for an Indigenous patient experience tool for use in virtual primary care. In this paper, we explore the development and finalisation of the Access, Relationships, Quality and Safety (ARQS) tool.MethodsWe re-engaged five Indigenous patient participants who had been involved in the semistructured interviews that established the ARQS tool domains. Through cognitive interviews, we tested the tool statements, leading to modifications. To finalise the tool statements, an Indigenous advisory group was consulted.ResultsThe ARQS tool statements were revised and finalised with twelve statements that reflect the experiences and perspectives of Indigenous patients.DiscussionThe ARQS tool statements assess the four domains that reflect high-quality virtual care for Indigenous patients. By centring Indigenous peoples and their lived experience with primary care at every stage in the tool’s development, it captures Indigenous-centred understandings of high-quality virtual primary care and has validity for use in virtual primary care settings.ConclusionThe ARQS tool offers a promising way for Indigenous patients to provide feedback and for clinics to measure the quality and safety of virtual primary care practice on the provider and/or clinic level. This is important, as such feedback may help to promote improvements in virtual primary care delivery for Indigenous patients and more widely, may help advance Indigenous health equity.
BackgroundAmong Indigenous peoples in Canada, access to high-quality healthcare remains an important determinant of health. The shift to virtual and remote-based approaches, expedited during the ...COVID-19 pandemic, influenced the ways in which individuals accessed care and the quality of care received. This study sought to determine which elements are required for effective and sustainable virtual care approaches for delivery of primary care to Indigenous patients and develop quality indicators grounded in Indigenous community and experience. We share a conceptual framework to understand how Indigenous patients access and define high-quality virtual care, grounded in Indigenous patient experiences and worldviews.MethodsUsing principles of patient-oriented research, we grounded this work in social justice and participatory action research. We sought to gain an in-depth understanding of the Indigenous experiences of virtual care and specifically of primary care. This was developed through semistructured interviews with Indigenous patients and Indigenous virtual primary care providers.ResultsThirteen participants were interviewed between 5 August 2021 and 25 October 2021. Using Framework Analysis, we constructed four domains including access, relationships, quality and safety as being primary facets of defining high-quality Indigenous virtual primary care.DiscussionThe results presented here indicate that the shift to virtual care, largely seen in response to the COVID-19 pandemic, does not compromise quality of care, nor does it lead to negative patient experiences. Optimal care is possible in virtual settings for some care needs and types of appointments and has the potential to decrease barriers to access and improve patient experiences of safety and quality while facilitating patient/provider relationships.ConclusionIn summary, high-quality Indigenous virtual care benefits from attention to patients’ experiences of access, relationships, safety and quality with their service providers and healthcare teams.
Nuclear factor-?B (NF-?B) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-?B response as a prerequisite to ...identifying novel factors that affect sensitivity to DNA damaging chemotherapy. Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with ?B DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-?B activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-beta. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis. These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.
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