Publications by authors named "Stephen Brown"

725 Publications

Resolution of post-traumatic chronic testicular pain in a pediatric patient after microsurgical denervation of the spermatic cord: a case report.

Can J Anaesth 2021 Jul 21. Epub 2021 Jul 21.

Department of Anesthesia and Pain Medicine, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.

Purpose: Chronic scrotal content pain, chronic orchialgia, or testicular pain can present after trauma, vasectomy, and hernia repair, among other triggers. Microsurgical denervation of the spermatic cord is an option for definitive pain control. While this practice is established in adult urology, access to diagnostic intervention and definitive denervation surgery is limited in the pediatric population.

Clinical Features: We report a case of definitive resolution of testicular pain with microsurgical denervation of the spermatic cord in a pediatric patient with post-traumatic chronic orchialgia that significantly reduced his daily activities and worsened his anxiety prior to this treatment. The patient underwent attempts at conservative medication-based management, followed by diagnostic spermatic cord nerve block before definitive denervation surgery.

Conclusions: The incidence of chronic pain in pediatrics is substantial and is estimated to be around 20%. Orchialgia remains difficult and problematic to treat. Mental health diagnoses such as anxiety and depression are also significantly associated with chronic pain. Following consideration and implementation of steps for all these concerns, a diagnostic block and microsurgical denervation led to successful resolution of chronic testicular pain in a pediatric patient.
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http://dx.doi.org/10.1007/s12630-021-02072-5DOI Listing
July 2021

The Effect of Posterior Lumbar Spinal Surgery on Biomechanical Properties of Rat Paraspinal Muscles 13 Weeks Post-Surgery.

Spine (Phila Pa 1976) 2021 Mar 22. Epub 2021 Mar 22.

aDepartment of Orthopaedics, The University of British Columbia, Vancouver Canada bInternational Collaboration on Repair Discoveries (ICORD), The University of British Columbia cDepartment of Orthopaedic Surgery, Jikei University School of Medicine,Tokyo, Japan dDepartment of Mechanical Engineering, The University of British Columbia eSchool of Biomedical Engineering, The University of British Columbia fDepartment of Medical Genetics, The University of British Columbia gDepartment of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada.

Study Design: Pre-clinical study in rodents.

Objective: To investigate changes in biomechanical properties of paraspinal muscles following a posterior spinal surgery in an animal model SUMMARY OF BACKGROUND DATA.: Posterior spine surgery damages paraspinal musculature per histological and imaging studies. The biomechanical effects of these changes are unknown.

Methods: 12 Sprague-Dawley rats were divided equally into sham and surgical injury (SI) groups. For sham, the skin and lumbodorsal fascia were incised at midline. For SI, the paraspinal muscles were detached from the vertebrae, per normal procedure. Thirteen weeks post-surgery, multifidus and longissimus biopsies at L1, L3 and L5 levels were harvested on the right. From each biopsy, 3 fibers and 3-6 bundles of fibers (∼10-20 fibers ensheathed in their extracellular matrix) were tested mechanically to measure their passive elastic modulus. The collagen content and fatty infiltration of each biopsy were also examined histologically by immunofluorescence staining. Nonparametric statistical methods were used with a 1.25% level of significance.

Results: 220 fibers and 279 bundles of fibers were tested. The elastic moduli of the multifidus and longissimus fibers and longissimus fiber bundles were not significantly different between the SI and sham groups. However, the elastic modulus of multifidus fiber bundles was significantly greater in the SI group compared to sham (SI median 82 kPa, range 23-284; sham median 38 kPa, range 23-50, p = 0.0004). The elastic modulus of multifidus fiber bundles in the SI group was not statistically different between spinal levels (p = 0.023). For histology, only collagen I deposition in multifidus was significantly greater in the SI group (median 20.8% vs. 5.8% for sham, p < 0.0001).

Conclusions: The surgical injury increased the passive stiffness of the multifidus fiber bundles. Increased collagen content in the extracellular matrix is the likely reason and these changes may be important in the post-operative compensation of the spine.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000004036DOI Listing
March 2021

Developmental exposure to a POPs mixture or PFOS increased body weight and reduced swimming ability but had no effect on reproduction or behavior in zebrafish adults.

Aquat Toxicol 2021 Jun 4;237:105882. Epub 2021 Jun 4.

Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O Box 369 Sentrum, 0102 Oslo, Norway. Electronic address:

Complex mixtures of persistent organic pollutants (POPs) are regularly detected in the environment and animal tissues. Often these chemicals are associated with latent effects following early-life exposures, following the developmental origin of health and disease paradigm. We investigated the long-term effects of a human relevant mixture of 29 POPs on adult zebrafish following a developmental exposure, in addition to a single PFOS exposure for comparison, as it was the compound with the highest concentration within the mixture. Zebrafish embryos were exposed from 6 to 96 h post fertilization to x10 and x70 the level of POP mixture or PFOS (0.55 and 3.83 μM) found in human blood before being transferred to clean water. We measured growth, swimming performance, and reproductive output at different life stages. In addition, we assessed anxiety behavior of the adults and their offspring, as well as performing a transcriptomic analysis on the adult zebrafish brain, as the POP mixture and PFOS concentrations used are known to affect larval behavior. Exposure to POP mixture and PFOS reduced swimming performance and increased length and weight, compared to controls. No effect of developmental exposure was observed on reproductive output or anxiety behavior. Additionally, RNA-seq did not reveal pathways related to anxiety although pathways related to synapse biology were affected at the x10 PFOS level. Furthermore, pathway analysis of the brain transcriptome of adults exposed as larvae to the low concentration of PFOS revealed enrichment in pathways such as calcium, MAPK, and GABA signaling, all of which are important for learning and memory. Based on our results we can conclude that some effects on the endpoints measured were apparent, but if these effects lead to adversities at population levels remains elusive.
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http://dx.doi.org/10.1016/j.aquatox.2021.105882DOI Listing
June 2021

Investigating how combined multifidus injury and facet joint compression influence changes in surrounding muscles and facet degeneration in the rat.

Eur Spine J 2021 May 29. Epub 2021 May 29.

Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Road East, Guelph, ON, N1G 2W1, Canada.

Purpose: To examine whether unilateral multifidus damage could promote degeneration at the L5-6 facet joint (FJ) and compensatory changes in lumbo-pelvic muscles in rats.

Methods: 12 facet clamp, 12 facet sham and 7 control rats were studied. Facet clamp and sham animals had the left L5-6 FJ exposed, and the clamp group had a mild compressive clamp applied using hemostatic forceps to model post-traumatic arthritis. Both groups then had the left multifidus detached from the L1-L6 spinous processes. Animals were euthanized 28 days post-surgery. Muscle mass and fascicle length were evaluated bilaterally for the paraspinal muscles, gluteal muscles and biceps femoris. Intra-muscular collagen of the paraspinal muscles was measured histologically. FJ transverse plane angles were measured from micro-computed tomography scans. L5-6 FJ degeneration was evaluated through the 24-point OARSI scale.

Results: Differences, compared to control, were observed in the detached multifidus from both facet clamp and sham groups; namely decreased mass and fascicle length and increased collagen content. However, no between group differences were found for any other muscle. Further, mild FJ degeneration was more prevalent in the groups that had experienced multifidus injury but was not exacerbated by the mild compressive clamping of the FJ.

Conclusion: Unilateral multifidus injury with or without FJ compressive clamping does not have a clear impact on the characteristics of surrounding spinal musculature within 28 days post-surgery in rats. Mild FJ degeneration was present in some animals from all three groups, and the impact of multifidus injury on this degeneration is inconclusive.
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http://dx.doi.org/10.1007/s00586-021-06877-2DOI Listing
May 2021

Evaluation of Vitamin B12 Monitoring in Patients on Concomitant Metformin and Proton Pump Inhibitors.

Innov Pharm 2020 28;11(4). Epub 2020 Oct 28.

Samford University McWhorter School of Pharmacy.

Background: Type 2 diabetes mellitus and gastroesophageal reflux disease are highly prevalent in the United States. First-line therapies for these disease states include metformin and proton pump inhibitors, respectively. Both of these medications have been associated with a decreased absorption of vitamin B12.

Objective: The objective of this study was to assess the prevalence of B12 monitoring and supplementation in patients receiving concomitant metformin and PPI therapy.

Methods: A retrospective data analysis was performed at a single federally qualified health center. Patients receiving concomitant metformin and PPI therapy (specifically omeprazole and pantoprazole) over the past year were included. Data collected included demographics, dosing, therapy duration, and vitamin B12 level. Data were analyzed using descriptive statistics.

Results: A total of 104 patients met the inclusion criteria for this study. Metformin 1000 mg immediate release tablets was the most common dose and formulation prescribed. Omeprazole and pantoprazole were the most commonly prescribed PPIs. The most frequent duration of therapy was 1 to 4 years. Fourteen patients had a documented B12 level and no patients were categorized as deficient. Seven patients were prescribed a B12 supplement during the study period.

Conclusion: In this single center, retrospective chart review of patients receiving concomitant metformin and PPI therapy, the average duration of therapy for both agents was 1-4 years. Only 13.5% of patients had a documented B12 level. Of those patients, none were categorized as deficient. Though routine monitoring of B12 levels may be important for patients on long-term therapy with both agents or who present with symptoms of B12 deficiency, this study does not support routine monitoring of B12 levels for patients with duration of therapy of 4 years or less.
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http://dx.doi.org/10.24926/iip.v11i4.3355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127105PMC
October 2020

Using Engineering With Nature® (EWN®) principles to manage erosion of watersheds damaged by large-scale wildfires.

Integr Environ Assess Manag 2021 May 17. Epub 2021 May 17.

US Army Corps of Engineers-Albuquerque District, Albuquerque, New Mexico, USA.

The US Army Corps of Engineers (USACE) manages hundreds of reservoirs and thousands of miles of navigation channels that provide invaluable flood control, commercial transport of materials, water supply, recreation, and stream flow regulation. This capability is being threatened by the continued occurrence of large-scale wildfires across the western United States. The wildfires damage watersheds in part by denuding landscapes, reducing infiltration rates, and increasing runoff rates, thereby dramatically increasing the potential for the erosion of denuded slopes, destabilizing stream channels, increasing the infilling potential of reservoirs and, hence, reducing their capacity. The increased erosion rates highlight the need to develop innovative solutions to reduce erosion of watersheds laid bare after wildfires engulf the area. The Santa Clara Pueblo in northern New Mexico extends from the top of the eastern Jemez Mountains to the floodplains of the Rio Grande River. The Pueblo designed and constructed thousands of structures built from natural materials, consistent with Engineering With Nature (EWN) principles for erosion control incorporating low-cost and readily available materials such as logs, mulch, vegetation, and local rock to stabilize highly erodible parts of the watershed. The watersheds where these natural structures were constructed were monitored after construction to assess their effectiveness, guiding a series of recommendations for broader implementation. As part of a continued emphasis on updating USACE engineering guidance, research, and development, funding has been focused on developing sustainable and resilient project designs using natural materials like those implemented by the Santa Clara Pueblo. This paper focuses on the innovative EWN-based watershed stabilization practices that were implemented in the upper section of this wildfire affected canyon and tributary streams. Recommendations for future implementation based on lessons learned from this project are also provided. Integr Environ Assess Manag 2021;00:1-9. Published 2021. This article is a US Government work and is in the public domain in the USA.
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http://dx.doi.org/10.1002/ieam.4453DOI Listing
May 2021

Ethical challenges in child abuse: what is the harm of a misdiagnosis?

Authors:
Stephen D Brown

Pediatr Radiol 2021 May 17;51(6):1070-1075. Epub 2021 May 17.

Department of Radiology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA, 02115, USA.

In this article the author examines ethical tensions inherent to balancing harms of false-negative and false-positive child abuse diagnoses, and he describes how such tensions manifest in courtroom proceedings. Child abuse physicians, including pediatric radiologists, shoulder heavy responsibilities weighing the potential consequences of not diagnosing child abuse when it could have been diagnosed (false negatives) against the consequences of making the diagnosis when it has not occurred (false positives). These physicians, who practice under ethical obligations to serve children's best interests and protect them from harm, make daily practice decisions knowing that, on balance, abuse is substantially more underdiagnosed than over diagnosed. Legal justice advocates, however, emphasize that clinical decision-making around abuse is not disassociated from endemic injustices that unduly incriminate individuals from socioeconomically underprivileged populations. Some defense advocates charge that child abuse physicians are insufficiently sensitive to harms of erroneous diagnoses, and they have characterized these clinicians as frankly biased. To support their claims in court, defense advocates have enlisted likeminded physician witnesses whose credentials as experts flout professional standards and who provide consistently flawed testimony based upon deficiently peer-reviewed literature. This article concludes that, to help mitigate these unhealthy circumstances, child abuse physicians might build trust with criminal defense advocates by instituting measures to alleviate perceptions of biases and by more explicitly acknowledging the potential harms of erroneous diagnoses. Professional societies representing these physicians, such as the Society for Pediatric Radiology, could take concurrent measures to help better prepare their constituent clinicians for expert testimony and make them more available to testify.
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http://dx.doi.org/10.1007/s00247-020-04845-4DOI Listing
May 2021

Rapid mobilization of a virtual pediatric chronic pain clinic in Canada during the COVID-19 pandemic.

Can J Pain 2020 Aug 5;4(1):162-167. Epub 2020 Aug 5.

Department of Anesthesia and Pain Medicine, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

Background: Studies have been conducted describing the potential for using virtual care software during disasters and public health emergencies. However, limited data exist on ways in which the Canadian health care system utilizes virtual care during disasters or public health emergencies.

Aims: Due to the need for social distancing and reduction of nonessential ambulatory services during the COVID-19 pandemic, the SickKids Chronic Pain Clinic sought to transition care delivery from in person to virtual. The virtual clinic aimed to reduce risks associated with physical contact and environmental exposure without reducing access to care itself.

Methods: Harnessing of various digital tools including Ontario Telemedicine Network Guestlink, Zoom, and Microsoft Teams. The Chronic Pain Clinic Team worked together to communicate with patients and families, schedule virtual visits, establish remote access to clinical data collection tools, digitize the after-visit summary, and add resources on pain self-management to the clinic's website.

Results: The Chronic Pain Clinic successfully transitioned all clinic appointments (multidisciplinary and individual; 77 appointments) over a 2-week period to virtual care. Virtual clinics did not surpass the usual time taken pre-COVID-19, suggesting that the clinic workflow was readily adaptable to virtual care.

Conclusions: Access to quality virtual care is essential to prevent chronic pain from taking a toll on the lives of patients and families. Rapid establishment of a virtual clinic without gaps in service delivery to patients is possible given institutional support and a team culture centered around collaboration and flexibility.
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http://dx.doi.org/10.1080/24740527.2020.1771688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951167PMC
August 2020

Estimation and assessment of sagittal spinal curvature and thoracic muscle morphometry in different postures.

Proc Inst Mech Eng H 2021 Aug 12;235(8):883-896. Epub 2021 May 12.

ICORD, University of British Columbia, Vancouver, BC, Canada.

Spine models are typically developed from supine clinical imaging data, and hence clearly do not fully reflect postures that replicate subjects' clinical symptoms. Our objectives were to develop a method to: (i) estimate the subject-specific sagittal curvature of the whole spine in different postures from limited imaging data, (ii) obtain muscle lines-of-action in different postures and analyze the effect of posture on muscle fascicle length, and (iii) correct for cosine between the magnetic resonance imaging (MRI) scan plane and dominant fiber line-of-action for muscle parameters (cross-sectional area (CSA) and position). The thoracic spines of six healthy volunteers were scanned in four postures (supine, standing, flexion, and sitting) in an upright MRI. Geometry of the sagittal spine was approximated with a circular spline. A pipeline was developed to estimate spine geometry in different postures and was validated. The lines-of-action for two muscles, erector spinae (ES) and transversospinalis (TS) were obtained for every posture and hence muscle fascicle lengths were computed. A correction factor based on published literature was then computed and applied to the muscle parameters. The maximum registration error between the estimated spine geometry and MRI data was small (average RMSE∼1.2%). The muscle fascicle length increased (up to 20%) in flexion when compared to erect postures. The correction factor reduced muscle parameters (∼5% for ES and ∼25% for TS) when compared to raw MRI data. The proposed pipeline is a preliminary step in subject-specific modeling. Direction cosines of muscles could be used while improving the inputs of spine models.
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http://dx.doi.org/10.1177/09544119211014668DOI Listing
August 2021

Environmental adaptation of E. coli within private groundwater sources in southeastern Ontario: Implications for groundwater quality monitoring and human health.

Environ Pollut 2021 Apr 28;285:117263. Epub 2021 Apr 28.

School of Environmental Studies, Queen's University, Kingston, Ontario, Canada; Public Health Ontario, Kingston, Ontario, Canada.

Groundwater quality monitoring typically employs testing for the presence of E. coli as a fecal indicator of recent ingress of human or animal fecal material. The efficacy of fecal indicator organisms is based on the primary criteria that the organism does not reproduce in the aquatic environment. However, recent studies have reported that E. coli may proliferate (i.e., has adapted to) in the external environment, including soil and surface water. To date, the presence of environmentally-adapted E. coli in groundwater has not been examined. The current study employed Clermont phylotyping and the presence of six accessory genes to identify the likely presence of adapted E. coli in private groundwater sources. E. coli isolates (n = 325) from 76 contaminated private water wells located in a southeastern Ontario watershed were compared with geographically analogous human and animal fecal E. coli isolates (n = 234). Cryptic clades III-V, a well-described environmentally-adapted Escherichia population, were identified in three separate groundwater wells, one of which exclusively comprised this adapted population. Dimensionality reduction (via Principal Component Analysis) was used to develop an "E. coli adaptation model", comprising three distinct components (groundwater, animal feces, human feces) and suggests adaptation occurs frequently in the groundwater environment. Model findings indicate that 23/76 (30.3%) wells had an entirely adapted community. Accordingly, the use of E. coli as a FIO returned a false positive result in these instances, while an additional 23/76 (30.3%) wells exhibited some evidence of adaptation (i.e., not all isolates were adapted) representing an over-estimate of the magnitude (concentration) of contamination. Study findings highlight the need to further characterize environmentally-adapted E. coli in the groundwater environment and the potential implications with respect to water quality policy, legislation and determinants of human health risk both regionally and internationally.
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http://dx.doi.org/10.1016/j.envpol.2021.117263DOI Listing
April 2021

Guidelines for expert testimony in pediatric radiology.

Pediatr Radiol 2021 Jun 27;51(7):1275-1280. Epub 2021 Apr 27.

Department of Radiology, Columbia University, New York, NY, USA.

Pediatric radiologists have the professional and ethical duty to assist, inform and educate the legal system in regard to matters involving medical imaging in children. These guidelines, drafted by the Society for Pediatric Radiology Ethics Committee and approved by the Society for Pediatric Radiology Board of Directors, provide recommendations for expert legal testimony in pediatric radiology and codify minimal ethical norms for the pediatric radiology expert witness in legal proceedings.
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http://dx.doi.org/10.1007/s00247-021-05046-3DOI Listing
June 2021

The impact of COVID-19 on development assistance.

Authors:
Stephen Brown

Int J 2021 Mar 19;76(1):42-54. Epub 2021 Jan 19.

School of Political Studies, University of Ottawa, Ottawa, Canada.

This article analyzes the impact of the COVID-19 pandemic on foreign aid. Using examples from Canadian foreign aid, it argues that, despite the terrible toll it is exacting, the crisis has accelerated some significant positive pre-existing trends, both by destabilizing the perception of aid as flowing essentially from the Global North to Global South and by reinforcing awareness of the importance of joint efforts for global public goods and humanitarian assistance, as well as debt relief. However, it has also reinforced potentially harmful self-interested justifications for aid, which could align assistance more with donors' priorities than the needs of the poor. An important trend reversal is the renewed emphasis on well-being. Two other crucial trends remain unclear-the COVID-19 pandemic's impact on multilateral approaches and on aid flows. How donors respond to the COVID-19 pandemic and its aftermath over the next few years will depend on their political will, and will profoundly shape the future of development co-operation.
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http://dx.doi.org/10.1177/0020702020986888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041439PMC
March 2021

Sensory Function and Psychological Factors in Children With Complex Regional Pain Syndrome Type 1.

J Child Neurol 2021 Apr 21:8830738211007685. Epub 2021 Apr 21.

Applied Psychology, Western University, London, Ontario, Canada.

Objective: To assess thermal-sensory thresholds and psychosocial factors in children with Complex Regional Pain Syndrome Type 1 (CRPS-I) compared to healthy children.

Methods: We conducted quantitative sensory testing on 34 children with CRPS-I and 56 pain-free children. Warm, cool, heat, and cold stimuli were applied to the forearm. Children with CRPS-I had the protocol administered to the pain site and the contralateral-pain site. Participants completed the self-report Behavior Assessment System for Children.

Results: Longer pain durations (>5.1 months) were associated with decreased sensitivity to cold pain on the pain site ( = .04). Higher pain-intensity ratings were associated with elevated anxiety scores ( = .03). Anxiety and social stress were associated with warmth sensitivity (both < .05) on the contralateral-pain site.

Conclusions: Pain duration is an important factor in assessing pediatric CRPS-I. Hyposensitivity in the affected limb may emerge due to degeneration of nociceptive nerves. Anxiety may contribute to thermal-sensory perception in childhood CRPS-I.
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http://dx.doi.org/10.1177/08830738211007685DOI Listing
April 2021

Is accurate routine cancer prognostication psychologically harmful? 5-year outcomes of life expectancy prognostication in uveal melanoma survivors.

J Cancer Surviv 2021 Apr 19. Epub 2021 Apr 19.

Department of Primary Care and Mental Health, University of Liverpool, Liverpool, L69 3GB, UK.

Purpose: Prognostication in cancer is growing in importance as increasingly accurate tools are developed. Prognostic accuracy intensifies ethical concerns that a poor prognosis could be psychologically harmful to survivors. Uveal melanoma (UM) prognostication allows survivors to be reliably told that life expectancy is either normal (good prognosis) or severely curtailed because of metastatic disease (poor prognosis). Treatment cannot change life expectancy. To identify whether prognosis is associated with psychological harm, we compared harm in UM survivors with good and poor prognoses and those who declined testing and compared these outcomes to general population norms.

Methods: Non-randomized 5-year study of a consecutive series of 708 UM survivors (51.6% male, mean age 69.03, SD=12.12) with observations at 6, 12, 24, 36, 48 and 60 months. We operationalized psychological harm as anxiety and depression symptoms, worry about cancer recurrence (WREC) and poor quality of life (QoL).

Results: Compared to other groups, survivors with poor prognoses showed initially elevated anxiety and depression and consistently elevated worry about local or distant recurrence over 5 years. Good prognoses were not associated with outcomes. Generally, no prognostic groups reported anxiety, depression and WREC or QoL scores that exceeded general population norms.

Conclusions: Using a large sample, we found that harm accruing from a poor prognosis was statistically significant over 5 years, but did not exceed general non-cancer population norms.

Implications For Cancer Survivors: Survivors desire prognostic information. At a population level, we do not believe that our findings show sufficiently strong links between prognostication outcome and psychological harm to deny patients the option of knowing their prognosis. Nonetheless, it is important that patients are informed of potential adverse psychological consequences of a poor prognosis.
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http://dx.doi.org/10.1007/s11764-021-01036-4DOI Listing
April 2021

Rate of force development is Ca-dependent and influenced by Ca-sensitivity in human single muscle fibres from older adults.

Exp Gerontol 2021 07 14;150:111348. Epub 2021 Apr 14.

Department of Human Health and Nutritional Sciences, College of Biological Sciences, University of Guelph, Guelph, Ontario, Canada. Electronic address:

Natural adult aging is associated with declines in skeletal muscle performance, including impaired Ca sensitivity and a slowing of rapid force production (rate of force redevelopment; k). The purpose of this study was to investigate the relationship between impaired Ca sensitivity and k of single muscle fibres from young and older adults. Participants included 8 young (22-35 yrs) and 8 older (60-81 yrs) males who were living independently. A percutaneous muscle biopsy of the vastus lateralis of each participant was performed. Single muscle fibre mechanical tests included maximal Ca-activated force (P), force-pCa curves, and k. We showed a decrease in pCa in old type II fibres compared to young, indicating impaired Ca sensitivity in older adults. The k behaved in a Ca-dependent manner such that with increasing [Ca], k increases, to a plateau. Interestingly, k was not different between young and old muscle fibres. Furthermore, we found strong associations between pCa and k in both old type I and type II fibres, such that those fibres with lower Ca sensitivity had a slowed k. This Ca association, combined with impaired Ca handling in older adults suggests a potential Ca-dependent mechanism affecting the transition from weakly- to strongly-bound cross-bridge states, leading to a decline in skeletal muscle performance. Future research is needed to explore the role alterations to Ca sensitivity/handling could be playing in age-related whole muscle performance declines.
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http://dx.doi.org/10.1016/j.exger.2021.111348DOI Listing
July 2021

Is there a role for pregabalin as premedication in pediatric anesthesia?

J Anesth 2021 Apr 9. Epub 2021 Apr 9.

Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Ave, #2211, Toronto, ON, M5G 1X8, Canada.

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http://dx.doi.org/10.1007/s00540-021-02929-5DOI Listing
April 2021

Exploration of E. coli contamination drivers in private drinking water wells: An application of machine learning to a large, multivariable, geo-spatio-temporal dataset.

Water Res 2021 Jun 27;197:117089. Epub 2021 Mar 27.

Department of Civil Engineering, McMaster University, 1280 Main St. W, Hamilton, Ontario, L8S 4L8, Canada; Department of Geography and Planning and Global Institute for Water Security, University of Saskatchewan, 117 Science Place, Saskatoon, Saskatchewan, S7N 5C8, Canada.

Groundwater resources are under increasing threats from contamination and overuse, posing direct threats to human and environmental health. The purpose of this study is to better understand drivers of, and relationships between, well and aquifer characteristics, sampling frequencies, and microbiological contamination indicators (specifically E. coli) as a precursor for improving knowledge and tools to assess aquifer vulnerability and well contamination within Ontario, Canada. A dataset with 795, 023 microbiological testing observations over an eight-year period (2010 to 2017) from 253,136 unique wells across Ontario was employed. Variables in this dataset include date and location of test, test results (E. coli concentration), well characteristics (well depth, location), and hydrogeological characteristics (bottom of well stratigraphy, specific capacity). Association rule analysis, univariate and bivariate analyses, regression analyses, and variable discretization techniques were utilized to identify relationships between E. coli concentration and the other variables in the dataset. These relationships can be used to identify drivers of contamination, their relative importance, and therefore potential public health risks associated with the use of private wells in Ontario. Key findings are that: i) bedrock wells completed in sedimentary or igneous rock are more susceptible to contamination events; ii) while shallow wells pose a greater risk to consumers, deep wells are also subject to contamination events and pose a potentially unanticipated risk to health of well users; and, iii) well testing practices are influenced by results of previous tests. Further, while there is a general correlation between months with the greatest testing frequencies and concentrations of E. coli occurring in samples, an offset in this timing is observed in recent years. Testing remains highest in July while peaks in adverse results occur up to three months later. The realization of these trends prompts a need to further explore the bases for such occurrences.
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http://dx.doi.org/10.1016/j.watres.2021.117089DOI Listing
June 2021

Imaging acute effects of bevacizumab on tumor vascular kinetics in a preclinical orthotopic model of U251 glioma.

NMR Biomed 2021 Jul 4;34(7):e4516. Epub 2021 Apr 4.

Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.

The effect of a human vascular endothelial growth factor antibody on the vasculature of human tumor grown in rat brain was studied. Using dynamic contrast-enhanced magnetic resonance imaging, the effects of intravenous bevacizumab (Avastin; 10 mg/kg) were examined before and at postadministration times of 1, 2, 4, 8, 12 and 24 h (N = 26; 4-5 per time point) in a rat model of orthotopic, U251 glioblastoma (GBM). The commonly estimated vascular parameters for an MR contrast agent were: (i) plasma distribution volume (v ), (ii) forward volumetric transfer constant (K ) and (iii) reverse transfer constant (k ). In addition, extracellular distribution volume (V ) was estimated in the tumor (V ), tumor edge (V ) and the mostly normal tumor periphery (V ), along with tumor blood flow (TBF), peri-tumoral hydraulic conductivity (K) and interstitial flow (Flux) and tumor interstitial fluid pressure (TIFP). Studied as % changes from baseline, the 2-h post-treatment time point began showing significant decreases in v , V V and V , as well as K, with these changes persisting at 4 and 8 h in v , K, V and (t-tests; p < 0.05-0.01). Decreases in K were observed at the 2- and 4-h time points (p < 0.05), while interstitial volume fraction (v ; = K /k ) showed a significant decrease only at the 2-h time point (p < 0.05). Sustained decreases in Flux were observed from 2 to 24 h (p < 0.01) while TBF and TIFP showed delayed responses, increases in the former at 12 and 24 h and a decrease in the latter only at 12 h. These imaging biomarkers of tumor vascular kinetics describe the short-term temporal changes in physical spaces and fluid flows in a model of GBM after Avastin administration.
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http://dx.doi.org/10.1002/nbm.4516DOI Listing
July 2021

Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy.

J Natl Cancer Inst 2021 Apr 1. Epub 2021 Apr 1.

Departments of Neurosurgery and Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
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http://dx.doi.org/10.1093/jnci/djab064DOI Listing
April 2021

The effect of vertebral level on biomechanical properties of the lumbar paraspinal muscles in a rat model.

J Mech Behav Biomed Mater 2021 06 15;118:104446. Epub 2021 Mar 15.

Department of Mechanical Engineering, University of British Columbia, Vancouver, Canada; ICORD, University of British Columbia, Vancouver, Canada; Department of Orthopaedics, University of British Columbia, Vancouver, Canada. Electronic address:

Introduction: Passive mechanical properties of the paraspinal muscles are important to the biomechanical functioning of the spine. In most computational models, the same biomechanical properties are assumed for each paraspinal muscle group, while cross-sectional area or fatty infiltration in these muscles have been reported to differ between the vertebral levels. Two important properties for musculoskeletal modeling are the slack sarcomere length and the tangent modulus. This study aimed to investigate the effect of vertebral level on these biomechanical properties of paraspinal muscles in a rat model.

Methods: The left paraspinal muscles of 13 Sprague-Dawley rats were exposed under anesthesia. Six muscle biopsies were collected from each rat: three from multifidus (one per each of the L1, L3, and L5 levels) and similarly three from longissimus. Each biopsy was cut into two halves. From one half, two to three single muscle fibers and two to six muscle fiber bundles (14 ± 7 fibers surrounded in their connective tissue) were extracted and mechanically tested in a passive state. From the resulting stress-strain data, tangent modulus was calculated as the slope of the tangent at 30% strain and slack sarcomere length (beyond which passive force starts to develop) was recorded. The other half of each biopsy, which represented the muscle at the fascicle level, was snap frozen, sectioned, stained for Collagen I and its area fraction was measured. To evaluate the effect of spinal level on these biomechanical properties of multifidus and longissimus, one-way repeated measures ANOVA (p < 0.05) was performed for tangent modulus and slack sarcomere length, while for collagen I content linear mixed-models analysis was adopted.

Results: In total, 192 fibers and 262 fiber bundles were mechanically tested. For both muscle groups, no significant difference in tangent modulus of the single fibers was detected between the three spinal levels (p = 0.9 for multifidus and p = 0.08 for longissimus). Similarly, the tangent modulus values for the fiber bundles were not significantly different between the three spinal levels (p = 0.13 for multifidus and p = 0.49 for longissimus). In both muscle groups, the slack sarcomere lengths were not different among the spinal levels except for multifidus fibers (p = 0.02). Collagen I area fraction in muscle fascicles averaged 6.8% for multifidus and 5.3% for longissimus and was not different between the spinal levels.

Discussion: The results of this study highlighted that the tangent modulus, slack sarcomere length, and collagen I content of the lumbar paraspinal muscles are independent of spinal level. This finding provides the basis for the assumption of similar mechanical properties along a paraspinal muscle group.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104446DOI Listing
June 2021

Preliminary investigation of spinal level and postural effects on thoracic muscle morphology with upright open MRI.

JOR Spine 2021 Mar 8;4(1):e1139. Epub 2021 Feb 8.

ICORD University of British Columbia Vancouver Canada.

Objective: Spinal-muscle morphological differences between weight-bearing and supine postures have potential diagnostic, prognostic, and therapeutic applications. While the focus to date has been on cervical and lumbar regions, recent findings have associated spinal deformity with smaller paraspinal musculature in the thoracic region. We aim to quantitatively investigate the morphology of trapezius (TZ), erector spinae (ES) and transversospinalis (TS) muscles in upright postures with open upright MRI and also determine the effect of level and posture on the morphological measures.

Methods: Six healthy volunteers (age 26 ± 6 years) were imaged (0.5 T MROpen, Paramed, Genoa, Italy) in four postures (supine, standing, standing with 30° flexion, and sitting). Two regions of the thorax, middle (T4-T5), and lower (T8-T9), were scanned separately for each posture. 2D muscle parameters such as cross-sectional area (CSA) and position (radius and angle) with respect to the vertebral body centroid were measured for the three muscles. Effect of spinal level and posture on muscle parameters was examined using 2-way repeated measures ANOVA separately for T4-T5 and T8-T9 regions.

Results: The TZ CSA was smaller (40%, = .0027) at T9 than at T8. The ES CSA was larger at T5 than at T4 (12%, = .0048) and at T9 than at T8 (10%, = .0018). TS CSA showed opposite trends at the two spinal regions with it being smaller (16%, = .0047) at T5 than at T4 and larger (11%, = .0009) at T9 than at T8. At T4-T5, the TZ CSA increased (up to 23%), and the ES and TS CSA decreased (up to 10%) in upright postures compared to supine.

Conclusion: Geometrical parameters that describe muscle morphology in the thorax change with level and posture. The increase in TZ CSA in upright postures could result from greater activation while upright. The decrease in ES CSA in flexed positions likely represents passive stretching compared to neutral posture.
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http://dx.doi.org/10.1002/jsp2.1139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984016PMC
March 2021

Stiffness-tuneable nanocarriers for controlled delivery of ASC-J9 into colorectal cancer cells.

J Colloid Interface Sci 2021 Jul 18;594:513-521. Epub 2021 Mar 18.

Department of Chemical and Biological Engineering, University of Sheffield, Sheffield S1 3JD, UK; School of Pharmacy, Changzhou University, Changzhou 213164, China. Electronic address:

Hypothesis: One of the main challenges in cancer therapy is the poor water solubility of many anticancer drugs which results in low bioavailability at the tumour sites and reduced efficacy. The currently available polymer-based anticancer drug delivery systems often suffer from low encapsulation efficiency, uncontrolled release, and lack of long-term stability. Herein, we report the development of novel stiffness-tuneable core-shell nanocarriers composed of naturally derived polymers silk fibroin (SF) and sodium alginate (SA) inside a liposomal shell for enhanced cellular uptake and controlled release of hydrophobic anticancer agent ASC-J9 (Dimethylcurcumin). It is anticipated that the stiffness of the nanocarriers has a significant effect on their cellular uptake and anticancer efficacy.

Experiments: The nanocarriers were prepared by thin film hydration method followed by extrusion and cross-linking of SA to obtain a uniform size and shape, avoiding harsh processing conditions. The structural transformation of SF in the nanocarriers induced by SA crosslinking was determined using Fourier transform infrared (FTIR) spectroscopy. The size, zeta potential, morphology and stiffness of the nanocarriers were measured using dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). Drug loading and release were measured using UV-Vis spectrophotometry. The cellular uptake and anticancer efficacy of the nanocarriers were studied in HCT 116 human colorectal adenocarcinoma cells and 3D tumour spheroids using high content microscopy.

Findings: The synthesized nanocarriers had high encapsulation efficiency (62-78%) and were physically stable for up to 5 months at 4 ˚C. The release profile of the drug from the nanocarriers was directed by their stiffness and was easily tuneable by changing the ratio of SF to SA in the core. Furthermore, the designed nanocarriers improved the cellular uptake and anticancer activity of ASC-J9, and enhanced its tumour penetration in HCT 116 3D colorectal cancer spheroids. These findings suggest that the designed core-shell nanocarriers can be used as a highly efficient drug delivery system for cancer therapy.
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http://dx.doi.org/10.1016/j.jcis.2021.03.086DOI Listing
July 2021

Experimentally induced spine osteoarthritis in rats leads to neurogenic inflammation within neurosegmentally linked myotomes.

Exp Gerontol 2021 07 17;149:111311. Epub 2021 Mar 17.

Human Health and Nutritional Science, University of Guelph, Guelph, Ontario N1G2W1, Canada. Electronic address:

Naturally occurring spine osteoarthritis is clinically associated with the manifestation of chronic inflammatory muscle (myofascial) disease. The purpose of this study was to investigate the causal association between experimentally induced spine osteoarthritis and neurogenic inflammatory responses within neurosegmentally linked myotomes. Wistar Kyoto rats were randomly assigned to spine facet compression surgery (L4-L6) or sham surgery. Animals exposed to facet compression surgery demonstrated radiographic signs of facet-osteoarthritis (L4-L6 spinal levels) and sensory changes (allodynia, thermal hyperalgesia) at 7, 14 and 21 days post-intervention, consistent with the induction of central sensitization; no radiologic or sensory changes were observed after sham surgery. Increased levels of proinflammatory biomarkers including substance P (SP), calcitonin gene related peptide (CGRP), protease-activated receptor-2 (PAR2) and calcium/calmodulin dependent protein kinase II (CaMKII) were observed post-surgery within neurosegmentally-linked rectus femoris (L2-L5) muscle when compared to the non-segmentally linked biceps brachii (C4-C7) muscle; no differences were observed between muscles in the sham surgery group. These findings offer novel insight into the potential role of spine osteoarthritis and neurogenic inflammatory mechanisms in the pathophysiology of chronic inflammatory muscle (myofascial) disease.
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http://dx.doi.org/10.1016/j.exger.2021.111311DOI Listing
July 2021

Predictors of real-world utilisation of docetaxel combined with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer.

Intern Med J 2021 Mar 12. Epub 2021 Mar 12.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Background: Docetaxel has emerged as a standard-of-care for metastatic hormone-sensitive prostate cancer (mHSPC). Uptake of docetaxel for mHSPC in Australia has not previously been reported.

Aims: i) To investigate the real-world uptake of docetaxel in mHSPC; and ii) To identify predictors of utilisation of Docetaxel in mHSPC.

Methods: Men diagnosed from June 2014 to December 2018 and enrolled in the Prostate Cancer Outcomes Registry-Victoria (PCOR-Vic) were included. Data collected includes demographics, diagnosis method and institution, staging investigations, and treatments within 12 months of diagnosis. Wilcoxon rank-sum, chi-square and trend tests were used to identify predictors of docetaxel utilisation. All predictors were entered as covariates simultaneously into a multivariable logistic regression model. Statistical significance was set at 0.05 (two-sided).

Results: 1014 men with mHSPC were analysed, 25% of whom received docetaxel with androgen deprivation therapy (ADT). Uptake of docetaxel increased from 20% in 2014 to 33% in 2018. Predictors of higher usage of docetaxel were younger age and treatment in a private hospital, with both remaining significant on multivariable analysis. Notably, the proportion of men under 70 receiving docetaxel increased from 54% in 2014-15 to 64% in 2016-18, while in men aged 70 and over the comparative figures were 15% and 22% respectively.

Conclusions: Although docetaxel was not used in a majority of cases, there was a clear increase in docetaxel uptake especially in younger men following publication of the CHAARTED and STAMPEDE trials. Identifying barriers to real-world implementation of pivotal clinical trial data is critical to improving outcomes in mHSPC. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15288DOI Listing
March 2021

Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma.

Cancers (Basel) 2021 Feb 24;13(5). Epub 2021 Feb 24.

Weston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UK.

Brain tumours kill more children and adults under 40 than any other cancer, with approximately half of primary brain tumours being diagnosed as high-grade malignancies known as glioblastomas. Despite de-bulking surgery combined with chemo-/radiotherapy regimens, the mean survival for these patients is only around 15 months, with less than 10% surviving over 5 years. This dismal prognosis highlights the urgent need to develop novel agents to improve the treatment of these tumours. To address this need, we carried out a human kinome siRNA screen to identify potential drug targets that augment the effectiveness of temozolomide (TMZ)-the standard-of-care chemotherapeutic agent used to treat glioblastoma. From this we identified ERK5/MAPK7, which we subsequently validated using a range of siRNA and small molecule inhibitors within a panel of glioma cells. Mechanistically, we find that ERK5 promotes efficient repair of TMZ-induced DNA lesions to confer cell survival and clonogenic capacity. Finally, using several glioblastoma patient cohorts we provide target validation data for ERK5 as a novel drug target, revealing that heightened ERK5 expression at both the mRNA and protein level is associated with increased tumour grade and poorer patient survival. Collectively, these findings provide a foundation to develop clinically effective ERK5 targeting strategies in glioblastomas and establish much-needed enhancement of the therapeutic repertoire used to treat this currently incurable disease.
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http://dx.doi.org/10.3390/cancers13050944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956595PMC
February 2021

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study.

Int J Cardiol 2021 06 16;333:119-126. Epub 2021 Feb 16.

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, USA.

Background: Heart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans.

Method: The African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study.

Conclusion: The IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.026DOI Listing
June 2021

Oral Immunotherapy with Human Secretory IgA Improves Survival in the Hamster Model of Clostridioides difficile Infection.

J Infect Dis 2021 Feb 15. Epub 2021 Feb 15.

tcgBIOMICS GmbH, Bingen, Germany.

Co-administration of human secretory IgA (sIgA) together with subtherapeutic vancomycin significantly enhanced survival in the Clostridioides difficile infection (CDI) hamster model . Vancomycin (5 or 10 mg/kgx5 days) + healthy donor plasma sIgA/monomeric IgA (TIDx21 days) or hyperimmune sIgA/monomeric IgA (BIDx13 days) enhanced survival of CDI hamsters. Survival curves were significantly improved compared to vancomycin alone (p=0.018 and 0.039 by log-rank (Mantel-Cox) for healthy, and hyperimmune, sIgA, respectively. Passive immunization with sIgA made with recombinant human secretory component and IgA dimer/polymer from pooled human plasma can be administered orally, and prevents lethal infection in a partially treated CDI hamster model.
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http://dx.doi.org/10.1093/infdis/jiab087DOI Listing
February 2021

MicroRNA-155 Controls NKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways.

Front Cell Dev Biol 2020 12;8:619220. Epub 2021 Jan 12.

Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health System, Detroit, MI, United States.

The development of invariant natural killer T (NKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early NKT cells upon thymic selection, and then its expression is gradually downregulated during NKT cell development. However, the mice with miR-155 germline deletion had normal NKT cell development. To address if downregulated miR-155 is required for NKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of NKT cell development, diminished NKT17 and NKT1 cells, augmented NKT2 cells, and these defects were cell intrinsic. Furthermore, defective NKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune NKT cell development. MiR-155 modulated , a critical component of a histone modification complex, and , the upstream activation kinase complex component of NF-κB, which function additively in NKT development and in promoting balanced NKT1/NKT2 differentiation. In addition, miR-155 also targeted , a signature component of mTORC2 that controls NKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate NKT cell development and functional lineage, as well as secondary innate CD8 T cell development.
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http://dx.doi.org/10.3389/fcell.2020.619220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874147PMC
January 2021

The impact of initial tumor microenvironment on imaging phenotype.

Cancer Treat Res Commun 2021 19;27:100315. Epub 2021 Jan 19.

Department of Neurosurgery, Henry Ford Hospital, Detroit, MI; Department of Neurology, Henry Ford Hospital, Detroit, MI, United States; Department of Physics, Oakland University, Rochester, MI, United States; Department of Neurology, Wayne State University, Detroit, MI, United States.

Models of human cancer, to be useful, must replicate human disease with high fidelity. Our focus in this study is rat xenograft brain tumors as a model of human embedded cerebral tumors. A distinguishing signature of such tumors in humans, that of contrast-enhancement on imaging, is often not present when the human cells grow in rodents, despite the xenografts having nearly identical DNA signatures to the original tumor specimen. Although contrast enhancement was uniformly evident in all the human tumors from which the xenografts' cells were derived, we show that long-term contrast enhancement in the model tumors may be determined conditionally by the tumor microenvironment at the time of cell implantation. We demonstrate this phenomenon in one of two patient-derived orthotopic xenograft (PDOX) models using cancer stem-like cell (CSC)-enriched neurospheres from human tumor resection specimens, transplanted to groups of immune-compromised rats in the presence or absence of a collagen/fibrin scaffolding matrix, Matrigel. The rats were imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and their brains were examined by histopathology. Targeted proteomics of the PDOX tumor specimens grown from CSC implanted with and without Matrigel showed that while the levels of the majority of proteins and post-translational modifications were comparable between contrast-enhancing and non-enhancing tumors, phosphorylation of Fox038 showed a differential expression. The results suggest key proteins determine contrast enhancement and suggest a path toward the development of better animal models of human glioma. Future work is needed to elucidate fully the molecular determinants of contrast-enhancement.
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http://dx.doi.org/10.1016/j.ctarc.2021.100315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127413PMC
January 2021
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