bluuebunny/crossref_metadata_2025 huggingface dataset:
INTERCEPTING BRAIN METASTASES THROUGH METABOLIC VULNERABILITIES
Authors: Kieliszek A M , Mobilio D , Bassey-Archibong B I , Johnson J W , Piotrowski M L , Aghaei N , Gwynne W D , Escudero L , Chafe S , Zhang K Zhai1 C , Quaile A , McKenna D , Subapanditha M , de Araujo E D , Sedighi A , Gunning P T , Tokar T , Venugopal C , Montenegro-Burke J R , Magolan J , Singh S K
Published: July 2023

BTFC travel award recipient

Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis because the current standard of care is mainly palliative. Our patient-derived xenograft models have successfully recapitulated all the stages of the metastatic cascade and captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. We applied RNA sequencing of premetastatic BM cells to reveal a unique deregulated transcriptomic profile that is specific to premetastatic cells despite the tumor of origin. Subsequent Connectivity Map analysis led us to identify a tool compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Follow up preclinical studies showed that treatment with this tool compound reduces the tumor burden of mice compared to placebo, while providing a significant survival advantage. Mass spectrometry-based metabolomics and CRISPR knock-out studies directly validated our tool compound’s target as a targetable therapeutic vulnerability in BM, where pharmacological and genetic perturbation of the target attenuates BM cell proliferation both in vitro and in vivo. We have now begun a large-scale medicinal chemistry campaign to develop novel, brain penetrant inhibitors of this target with drug-like pre-clinical profiles validated by our in vivo experimental models for later stage preclinical development and subsequent clinical development. This potential first-in-class anti-metastatic therapy may provide an alternative treatment strategy for at-risk patients that are otherwise limited to palliation and could open the gate to future development of other anti-metastatic therapies.
EXPRESSION OF ANDROGEN RECEPTOR IN BREAST CANCER BRAIN METASTASES
Authors: Fan Kevin Yijun , Chehade Rania , Qazi Maleeha A , Moravan Veronika , Nofech-Moses Sharon , Jerzak Katarzyna J
Published: July 2023

Given availability of central nervous system (CNS)-penetrant systemic therapies that target the androgen receptor (AR), we evaluated the expression of the AR “target” in breast cancer brain metastases (BrM).

METHODS: An established, retrospective cohort of 57 patients with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre (SOCC) between 1999 and 2013 was studied. AR expression in BrM samples was assessed in triplicate using immunohistochemistry (IHC). AR positive status was defined as nuclear AR expression ≥10% in tumor-infiltrating cells as a percentage of tumor area using the SP107 antibody. RESULTS: The median age of patients was 52 years (range 32-85 years). 17 (30%) patients had hormone receptor positive (HR+) /HER2-negative, 28 (49%) had HER2+, and 12 (21%) had triple negative breast cancer (TNBC) BrM. The median expression of AR was 20% (CI 1.6-38.3%) and 32 of 57 (56%) BrM were AR positive based on a cut-point of ≥10%. A significantly smaller proportion of patients with TNBC had AR+ BrM (n=2/12, 17%), compared to patients with HR+/HER2-ve (n= 9/17, 53%) or HER2+ (n=21/28, 75%) disease (p=0.04). Patients with AR positive versus AR negative BrM had similar overall survival (12.5 vs. 7.9 months, p= 0.6), brain-specific progression-free survival (8.0 vs. 5.1 months, p= 0.95), and time from breast cancer diagnosis to BrM diagnosis (51 vs. 29 months, p=0.16). CONCLUSION: AR is expressed in the majority of breast cancer BrM and represents a promising therapeutic target.
TREATMENT, HEALTHCARE UTILIZATION AND OUTCOMES IN PATIENTS WITH GLIOBLASTOMA IN ONTARIO: A 10-YEAR COHORT STUDY
Authors: Rzadki Kathryn , Baqri Wafa , Habbous Steven , Das Sunit
Published: July 2023

Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Receipt of adjuvant therapies has been shown to exert a significant positive effect on patient survival. Little is known however about how changes in standards of care and healthcare system factors, such as access, affect real-world outcomes. In this study, we provide an overview of GBM in Ontario and examine elements of care, including treatment patterns and healthcare utilization, from 2010-2019. Using linked health- administrative databases from Ontario, Canada, we conducted a population-based cohort study to examine the clinical and biological characteristics, treatment, and healthcare utilization patterns of adult GBM patients diagnosed between 2010-2019. The primary outcomes were enrollment in adjuvant chemoradiation treatment and 1-, 2-, and 5-year survival. All analyses were performed using the Statistical Analysis Software (SAS). 5392 patients were diagnosed with GBM in Ontario from 2010-2019 (58% male, 42% female). The median age at diagnosis was 64. Receipt of adjuvant chemoradiation within one year of diagnosis increased from 51% in 2010 to 63% in 2019. 1-year, 2-year, and 5-year overall survival plateaued, ranging between 40-43%, 15-19%, and 5-7%, respectively. For patients above the age of 65, however, 1-year survival increased from 19% in 2010 to 26% in 2019. This Ontario- based study provides insight into the effect of practice evolution and healthcare utilization on the real-world overall survival of patients with GBM. Overall survival for most patients with glioblastoma has remained stagnant over the past decade. Changes intreatment standards and expansion of access to treating centres have been associated with prolonged survival in elderly glioblastoma patients.
CHOREOGRAPHED EXPANSION OF SERVICES RESULTS IN DECREASED PATIENT BURDEN WITHOUT COMPROMISE OF OUTCOMES: AN ASSESSMENT OF THE ONTARIO EXPERIENCE
Authors: Rzadki Kathryn , Baqri Wafa , Yermahanova Olga , Habbous Steven , Das Sunit
Published: July 2023

Neuro-oncology care in Ontario has been historically centralized, at times requiring significant travel on the part of patients. Toward observing the goal of patient-centred care and reducing patient burden, two additional regional cancer centres (RCC) capable of neuro-oncology care delivery were introduced in 2016. This study evaluates the impact of increased regionalization of neuro-oncology services on healthcare utilization and travel burden for glioblastoma (GBM) patients in Ontario. We present a cohort of GBM patients diagnosed between 2010-2019. Incidence of GBM and treatment modalities were identified using provincial health administrative databases. A geographic information system and spatial analysis were used to estimate travel time from patient residences to neuro-oncology RCCs. Among the 5242 GBM patients, 79% received radiation as part of treatment. Median travel time to the closest RCC was higher for patients who did not receive radiation as part of treatment than for patients who did (p=0.03). After 2016, the volume of patients receiving radiation at their local RCC increased from 62% to 69% and median travel time to treatment RCCs decreased (p=0.0072). The two new RCCs treated 35% and 41% of patients within their respective catchment areas. Receipt of standard of care, surgery, and CRT, increased by 11%. Regionalization resulted in changes in the health care utilization patterns in Ontario consistent with decreased patient travel burden for patients with GBM. Focused regionalization did not come at the cost of decreased quality of care, as determined by delivery of a standard of care.
BIOMARKER STATUS PREDICTS FOR LOCAL CONTROL (LC) FOLLOWING SPINE STEREOTACTIC BODY RADIOTHERAPY (SBRT) IN NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS WITH SPINAL METASTASES
Authors: Shor Dana , Zeng Kang Liang , Chen Hanbo , Menjak Ines , Atenafu Eshetu , Tseng Chia-Lin , Detsky Jay , Larouche Jeremie , Zhang Beibei , Soliman Hany , Maralani Pejman , Myrehaug Sten , Louie Alexander V , Sahgal Arjun
Published: July 2023

Report of spine SBRT outcomes in NSCLC patients and impact of death-ligand 1 (PD-L1) status and epidermal growth factor (EGFR) mutation on LC.

METHODS: 165 patients and 389 spinal segments were retrospectively reviewed. Primary endpoint was LF and secondary outcomes included overall survival (OS) and vertebral compression fracture (VCF) rates. RESULTS: Median follow-up, OS and age was 13 months (range, 0.5-95 months), 18.4 months (95% CI 11.4-24.6), and 67 years (range, 28.2-89.9) respectively. 52% were female and 76% had adenocarcinoma. 29% had an EGFR mutation, 16% were PD-L1 ≥ 50%, 20% PD-L1 1-49% and 35% PD-L1 <1%. Of 389 segments, 79% were denovo. At baseline, 35% had VCF, 27% epidural disease and 27% paraspinal extension. 61% were treated with 24 or 28 Gy in 2 SBRT fractions. LF cumulative incidence (CI) at 2-years was 25.4% (95% CI 20.9%-30%). EGFR positivity (p<0.0001), PD-L1≥50% (p=0.013) and treatment with IO within 1 month of SBRT (p=0.004) predicted for LC on multivariable analysis (MVA). The 2-year LF rate in EGFR-positive vs. negative patients were 17.7% vs. 28.8%, and in those PD-L1 ≥50% vs PD-L1<50% were 7.8% vs. 38.1%. CI of VCF at 2-years were 8.8% (95% CI 6.1-12.0%). Prior SBRT to the same segment (P<0.0001) and baseline VCF (p<0.0001) were predictors on MVA. CONCLUSION: We identify predictability of EGFR mutation, PD-L1 ≥50% and peri-SBRT IO on LC following spine SBRT in NSCLC.
PERCEPTION AND KNOWLEDGE OF BRAIN TUMOR BANKING AMONG CANADIAN NEUROSURGEONS
Authors: Ranger Adrianna , Megyesi Joseph , Zhang Qi
Published: July 2023

Brain tumor banking provides an important resource for understanding the underlying pathophysiology of brain tumors. It requires a multidisciplinary team, including neurosurgeons who must recognize the importance of these banks and actively contribute. The perceptions and involvement of neurosurgeons regarding Canadian brain tumor banking remains to be studied.

OBJECTIVE: This study aims to 1) assess current Canadian tumor tissue banking practices 2) determine the perception of neurosurgeons towards brain tumor tissue banks, and 3) uncover obstacles to tissue sample access. METHODS: A 26 question survey was conducted using Qualtrics and distributed to 178 Canadian neurosurgeons. Questions pertained to respondent demographics, tissue samples being banked, funding, and collaboration. RESULTS: 35 neurosurgeons completed the survey (19.66%). The majority of respondents treated adult populations (65.71%) and practiced in Ontario (57.14%). Most centers banked a variety of primary and metastatic brain tumors. 25.00% of respondents stated that their center collaborates with others. Personal communication was the most frequently stated method (58.33%) used to raise awareness of tumor banks. Funding was the most commonly mentioned obstacle to successful banking (70.37%). Banks are funded through research grants (30.76%), departmental support (30.76%), government funding (11.54%) and donations (26.92%). CONCLUSIONS: This study investigated neurosurgeons’ perceptions of brain tumor banking and the state of Canadian tumor banking. Despite numerous centers banking a variety of brain tumors, collaboration between institutes was limited. The greatest perceived obstacle is funding. Canadian brain banking may benefit from improved communication, collaboration, and funding.
CLINICAL APPLICATION OF SATURATION TRANSFER MRI FOR DIFFERENTIATING TUMOUR PROGRESSION FROM RADIATION NECROSIS IN BRAIN METASTASES
Authors: Chan Rachel W , Lam Wilfred W , Murray Leedan , Chen Hanbo , Zhang Beibei , Theriault Aimee , Endre Ruby , Moon Sangkyu , Liebig Patrick , Djayakarsana Daniel , Mehrabian Hatef , Myrehaug Sten , Tseng Chia-Lin , Detsky Jay , Maralani Pejman J , Sahgal Arjun , Soliman Hany , Stanisz Greg J
Published: July 2023

Stereotactic radiosurgery for the treatment of brain metastases delivers a high dose of radiation with excellent local control, but increases the likelihood of radiation necrosis. As shown in our previous work, saturation transfer MRI, consisting of quantitative magnetization transfer (qMT) and chemical exchange saturation transfer (CEST), is a promising technique for distinguishing radiation necrosis (RN) from tumour progression (TP) in brain metastases. A 3D qMT/CEST acquisition was recently implemented and over 100 patients have been scanned to date. The purpose of this work is to assess the ability of advanced MRI parameters, including qMT and CEST metrics, which are sensitive to macromolecules and metabolism. The specific metrics that were explored included the amide and NOE contributions of the magnetization transfer ratio (MTR), the MTR asymmetry, the apparent exchange-dependent relaxation (AREX), the qMT semi-solid pool fraction and the T1 and T2 relaxation times. For a subset of the patients, dynamic susceptibility contrast (DSC) perfusion images were acquired. Examples of confirmed tumour progression and radiation necrosis cases will be presented, comparing the structural images (pre- and post-contrast T1-weighted and FLAIR images) with parameter maps from qMT and CEST and also the relative cerebral blood flow (rCBF) from DSC perfusion imaging. Interim cohort results will be presented. Approaches for standardizing the parameters across multiple MRI vendors are also explored.
EXPLORING THE ROLE OF GAT1 AND GABA IN TEMOZOLOMIDE TREATED GLIOMA
Authors: Poole Alisha , Lun Xueqing , Dufour Antoine , Senger Donna , Robbins Stephen
Published: July 2023

Approximately 3000 Canadians a year are diagnosed with the most aggressive and fatal form of brain cancer called glioma. Even with surgical resection, chemotherapy, and radiotherapy these patients have an average survival of less than 20 months. Research in the past has primarily focused on identifying and targeting specific genetic mutations in the tumor. However, it is apparent that the environment surrounding the tumor can influence tumor growth, tumor spread into the brain, and drug resistance. The brain presents many challenges to glioma treatment, one of which is the unique environment in which gliomas grow, which contributes to poor patient outcomes. The interaction between tumor cells, surrounding normal brain tissue, and immune cells supports the aggressiveness of glioma. Using a model of chemosensitive and chemoresistant tumors, we have identified an increase in the GABA transporter GAT1 in the chemosensitive tumor treated with the standard chemotherapy temozolomide. GAT1 is primarily expressed on neurons, but has also been shown to be expressed on astrocytes and immune cells such as macrophages. Our lab has identified that macrophages tend to concentrate in the same region as GAT1 expressing cells within the tumor environment. In addition, multiple papers have shown that an increase in GABA promotes a glioma-promoting immune microenvironment. Thus, we believe that treatment with temozolomide causes an increase in environmental GAT1 expression, resulting in a reuptake of GABA, and promoting a glioma-inhibitory macrophage phenotype. We believe that understanding how the glioma-inhibitory macrophage phenotype occurs will help improve patient outcomes.
HER2-LOW BREAST CANCER BRAIN METASTASES: INCIDENCE AND TREATMENT IMPLICATIONS
Authors: Chehade Rania , Nofech-Mozes Sharon , Plotkin Anna , Moravan Veronika , Jerzak Katarzyna J
Published: July 2023

Brain metastases (BrM) are a major cause of morbidity and mortality among women with breast cancer (BC). Central nervous system (CNS)-penetrating systemic therapies for patients with HER2-negative BrM are lacking; given CNS activity of trastuzumab deruxtecan, efficacy for patients with HER2-low BrM is of interest.

METHODS: A retrospective study of two cohorts of consecutive patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre were identified. BrM subtype was assessed based on 2018 ASCO/CAP guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or 2+ and fluorescence in situ hybridization (FISH) negative status. HER2-positive was defined as IHC 3+ or IHC 2+ with positive FISH. We also assessed the prognostic association between extent of HER2 expression and i) brain-specific progression free survival (bsPFS), as well as ii) overall survival (OS). RESULTS: Out of 137 patients with resected BrM, tissue for HER2 assessment was available in 74.5% (n=102) of cases. In this cohort, the median age at BrM diagnosis was 53.5 (range, 32- 85). 68.6% (n=70) had extracranial disease. 53% (n=54) of the BrM were HER2-positive; 29.4% (n=30) were HER2-low and 17.6% (n=18) had HER2-zero status. Among BrM that were triple negative based on ASCO/CAP guidelines, 14 out of 22 cases (63.6%) were re-classified as being HER2-low. 15/25 (60%) BrM that were hormone receptor positive/HER2 negative (HR+/HER2-) based on ASCO/CAP guidelines were re-classified as being HER2-low. There was no significant association between the extent of HER2 expression (HER2-zero, HER2-low versus HER2-positive status) in BrM and either bsPFS or OS. CONCLUSION: Among patients with surgically resected BrM, a high proportion of those with metastatic TNBC and HR+/HER2-negative disease have “HER2-low” BrM with potential to benefit from HER2-targeted therapy.
JAK/STAT PATHWAY COOPERATES WITH CIC FUSIONS TO DRIVE CIC-REARRANGED SARCOMAS
Authors: Kaloti R K , Bunda S B , Zadeh G Z
Published: July 2023

CIC-rearranged sarcoma is a rare disease driven by a specific fusion protein involving the CIC gene. Native CIC protein is a transcriptional repressor of the (RTK)/Ras/ERK signaling pathway, which is one of the most tumorigenic pathways in cancer. The most common rearrangement is with the double homeobox 4 (DUX4) transcription factor (CIC-DUX4), and others, such as CIC-NUTM1 fusions, have been identified in a subset of pediatric primitive neuroectodermal tumors. However, the molecular mechanisms by which CIC fusions induce tumorigenesis remains unknown. Hypothesis: Our preliminary data shows that CIC- DUX4/NUTM1 fusions activate JAK (cytokine receptors) and its downstream effector STAT1/3(transcription factors). We hypothesize that the JAK/STAT1/3 signal transduction pathway cooperates with CIC-fusions to induce the expression of oncogenic transcription factors ETV1/4/5 and drive these sarcomas.

METHODS AND RESULTS: JAK1 is a potential target for CIC-fusions- We show high levels of JAK1/STAT1/3 activation in CIC-fusion patient-derived sarcoma cell lines (NCC-SCC-89/C) as compared to other sarcoma cell lines without the fusion. JAK1 inhibition using Solicitinub and Ruxolitinib reduced phosphorylation of STAT1/3 as well as protein and mRNA expression of transcriptional oncogenic factors ETV1/4/5 and cell proliferation. JAK1/STAT1/3 inhibition in patient-derived CIC-DUX4 xenograft models- To evaluate the pre-clinical effect of targeting the JAK1/STAT1/3 pathway, the CIC-DUX4 cell line was grafted into NSG mice. Ruxolitinib treatment significantly reduced tumor volume, STAT1 activation, and oncogenic transcriptional factors ETV1/4/5. CONCLUSION: We show that the JAK1/STAT1/3 pathway plays a critical role in cooperating with CIC-fusions to drive CIC-rearranged sarcomas providing insight into potential therapeutic avenues for these aggressive tumors.
MOLECULAR PROFILING TO UNDERSTAND TREATMENT RESISTANCE AND RESPONSE IN GLIOBLASTOMA
Authors: Nikolopoulos Marina , Wu Megan , Bahcheli Alexander , Kellett Sorcha , Erickson Anders , Myrehaug Sten , Sahgal Arjun , Spears Melanie , Bayani Jane , Das Sunit
Published: July 2023

Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 7% surviving more than 5 years. CEST-MRI is sensitive to treatment-induced changes in tumour metabolism and can be used to evaluate treatment response, allowing for the differentiation between early and late progressors before treatment initiation.

OBJECTIVE: The purpose of this study is to establish genomic and transcriptomic profiles of early and late progressors in patients with glioblastoma who have undergone CEST-MRI. METHODS: Patients (n=25) were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from 25 fresh-frozen matched normal and tumour pairs and processed for whole genome sequencing and gene expression analysis using Nanostring. RESULTS: Early progressors (n = 12) and late progressors (n =13) had significant differences in OS and PFS (log rank <0.0001) as well as in gene expression and pathway deregulation. Genes significantly expressed in early progressors compared to late progressors include CCNA1 (p =0.000557), IGFBP3 (p = 0.000602), ASS1 (p = 0.000698), and ID1 (p= 0.000993), which were also prognostic of PFS and OS in a Cox regression model. CONCLUSION: Upon validation in a larger cohort, this data may serve as a radiogenomic biomarker to assess treatment response within early phases of treatment and adapt the treatment plan to individual biology.
EVALUATING HUMAN MICROBIOME SIGNATURES ASSOCIATED WITH DEVELOPMENT, OUTCOME, AND TREATMENT RESPONSE IN GLIOMA AND BRAIN METASTASIS: A SCOPING REVIEW
Authors: Leigh J , Hutton B , Maleki Vareki S , Ng T L
Published: July 2023

The human microbiome is made up of over 500 species of bacteria in the body. Microbiome dysbiosis has been implicated in cancer development and treatment response, including in both primary brain tumors and brain metastases, by acting through the gut-brain axis. We conducted a scoping review of the current evidence surrounding the human microbiome and brain tumors.

METHODS: A systematic search of relevant studies and abstracts from 5 electronic databases from 1946-2023 was conducted based on a search strategy developed by an information specialist. Eligible studies included human, in vivo, or in vitro studies that focused on the relationship between microbiome and glioma and brain metastasis development, response to therapies, and outcomes. RESULTS: Of 383 citations, 31 studies met inclusion criteria, including 15 articles and 16 conference abstracts. There were 19 human studies and 18 mouse studies, of which 24 studies focused on glioma and 7 studies focused on brain metastases. They either characterized the microbiome in patients with brain tumors (n=19) or its correlation to systemic therapies for glioma (n=12). Changes in the Firmicutes/Bacteroidetes ratio, which is a marker of dysbiosis in patients with brain tumors was observed in 7 studies; however, the direction of change varied. Microbiome dysbiosis seemed to occur in response to both immunotherapy (5 studies) and temozolomide (3 studies), with variable impacts on treatment response. CONCLUSION: Evidence surrounding the impact of the gut-brain axis on brain tumors remains in its infancy with a large amount of heterogeneity.
EXPLORING THE EFFECT OF A VISUAL TELEREHABILITATION PROGRAM ON VISUAL PERCEPTION IN CHILDREN AND ADOLESCENTS WITH HEMIANOPIA CONSECUTIVE TO A BRAIN TUMOUR, PRELIMINARY RESULTS OF A PILOT STUDY
Authors: Bajin Inci Yaman , Bartels Ute , Reginald Arun , Daibert-Nido Monica , Markowitz Samuel , Bouffet Eric , Reber Michael
Published: July 2023

Brain tumours (BT) in children often lead to visual impairment, which represents a significant morbidity for long-term survivors. A recent Children Cancer Survivor Study showed that 22.5% of patients with astroglial tumours had visual impairment 5 years after the diagnosis. In the pediatric population with hemianopia, there are no standardized protocols for managing vision loss. In this pilot study, a 6-week home-based visual telerehabilitation program (VTP) evaluated visual changes in 10 children with hemianopia consecutive to a BT.

METHOD: The study included 10 patients aged 8-18 years old with hemianopia consecutive to a pediatric BT. Five patients had a chiasmatic tumour (CT), other 5 had a tumour located outside of the chiasm (OCT). Patients followed a 6-week VTP on a virtual reality device at home with remote control of the device from the UHN laboratory. Visual assessments performed at baseline, 2, 4, 6 weeks with follow-ups at 1 and 6 months to check the visual field, contrast sensitivity and reading speed. A quality-of-life (QoL) questionnaire was also filled by patients and parents at every visit. RESULTS: The preliminary results of 8 patients have been analyzed. Four patients (3 CT, 1 OCT) showed visual field improvement with increased luminance perception in the monocular Humphrey test. Four patients (2 CT, 2 OCT) showed visual field improvement in the binocular Esterman field analysis. Reading speed improved in 6 patients (3CT, 3OCT). All patients had significant improvement in contrast sensitivity and QoL. CONCLUSION: Preliminary results of this study showed that this VTP was feasible in children. The program was effective, especially for patients with CT in improving visual field with an impact on contrast sensitivity, reading speed and QoL. Further studies are in development to confirm these results and identify the most appropriate schedules to optimize visual outcomes.

POSTER CATEGORIES:

BS = BASIC SCIENCE

CS = CLINICAL SCIENCE

RO = RADIATION ONCOLOGY

MO = MEDICAL ONCOLOGY

M = MISCELLANEOUS

POSTER/TRAVEL AWARDS provided by:

BTFC = Brain Tumour Foundation of Canada

OHRI = Ottawa Hospital Research Institute
The Paradox Test in Climate Litigation
Authors: Parr Adam
Published: July 2023

The common law and natural law traditions have both sought authority in ‘reason’ and the ‘laws of nature’. Pollock applied this logic in explaining judicial development of negligence: the application of reason to emerging science and technology. The equivalent today is a growing body of scientific evidence that humans are destroying their own habitat through climate change, biodiversity destruction and pollution. Humanity depends on its habitat for survival and therefore each step in this direction increases the risk of its extinction. The courts are already being asked to declare as unlawful governmental decisions that breach human rights and statutory or constitutional protection of the environment. This perspective article proposes that when presented with scientific evidence of habitat destruction in judicial review cases, the courts could examine whether a decision is unlawful and/or irrational. This ‘Paradox Test’ would ask: (1) will the decision contribute to the destruction of the human habitat and (2) if so, is it justified on the ground of necessity? It is proposed that a decision that failed such a test would be unlawful and irrational as contrary to what is arguably the most fundamental law of nature: species survival. The essay defines the Paradox Test, sets it in an historical context and positions it as implicitly inside the boundaries of current English doctrine of judicial review, where it would need to be judicially recognized. Consequently, practitioners are invited to apply the test in court and to share their experience.
Host adaptation and specialization in Tetranychidae mites
Authors: Bruinsma Kristie , Rioja Cristina , Zhurov Vladimir , Santamaria Maria Estrella , Arbona Vicent , Navarro Marie , Cazaux Marc , Auger Philippe , Migeon Alain , Wybouw Nicky , Van Leeuwen Thomas , Diaz Isabel , Gómez-Cadenas Aurelio , Grbic Miodrag , Navajas Maria , Grbic Vojislava
Published: July 2023

Composite generalist herbivores are comprised of host-adapted populations that retain the ability to shift hosts. The degree and overlap of mechanisms used by host-adapted generalist and specialist herbivores to overcome the same host plant defenses are largely unknown. Tetranychidae mites are exceptionally suited to address the relationship between host adaptation and specialization in herbivores as this group harbors closely related species with remarkably different host ranges—an extreme generalist the two-spotted spider mite (Tetranychus urticae Koch [Tu]) and the Solanaceous specialist Tetranychus evansi (Te). Here, we used tomato-adapted two-spotted spider mite (Tu-A) and Te populations to compare mechanisms underlying their host adaptation and specialization. We show that both mites attenuate induced tomato defenses, including protease inhibitors (PIs) that target mite cathepsin L digestive proteases. While Te solely relies on transcriptional attenuation of PI induction, Tu and Tu-A have elevated constitutive activity of cathepsin L proteases, making them less susceptible to plant anti-digestive proteins. Tu-A and Te also rely on detoxification of tomato constitutive defenses. Te uses esterase and P450 activities, while Tu-A depends on the activity of all major detoxification enzymatic classes to disarm tomato defensive compounds to a lesser extent. Thus, even though both Tu-A and Te use similar mechanisms to counteract tomato defenses, Te can better cope with them. This finding is congruent with the ecological and evolutionary times required to establish mite adaptation and specialization states, respectively.
Ethnic inequities in the patterns of personalized care adjustments for ‘informed dissent’ and ‘patient unsuitable’: a retrospective study using Clinical Practice Research Datalink
Authors: Hayanga Brenda , Stafford Mai , Ashworth Mark , Hughes Jay , Bécares Laia
Published: July 2023

Background

In England, general practitioners voluntarily take part in the Quality and Outcomes Framework, which is a program that seeks to improve care by rewarding good practice. They can make personalized care adjustments (PCAs), e.g. if patients choose not to have the treatment/intervention offered (‘informed dissent’) or because they are considered to be clinically ‘unsuitable’.

Methods

Using data from the Clinical Practice Research Datalink (Aurum), this study examined patterns of PCA reporting for ‘informed dissent’ and ‘patient unsuitable’, how they vary across ethnic groups and whether ethnic inequities were explained by sociodemographic factors or co-morbidities.

Results

The odds of having a PCA record for ‘informed dissent’ were lower for 7 of the 10 minoritized ethnic groups studied. Indian patients were less likely than white patients to have a PCA record for ‘patient unsuitable’. The higher likelihood of reporting for ‘patient unsuitable’ among people from Black Caribbean, Black Other, Pakistani and other ethnic groups was explained by co-morbidities and/or area-level deprivation.

Conclusions

The findings counter narratives that suggest that people from minoritized ethnic groups often refuse medical intervention/treatment. The findings also illustrate ethnic inequities in PCA reporting for ‘patient unsuitable’, which are linked to clinical and social complexity and should be tackled to improve health outcomes for all.
Presence of periodontal disease and the incidence of inflammatory arthritides in the general population: data from the UK Biobank
Authors: Yun Hae-Ryong , Koh Hee Byung , Park Jung Tak , Han Seung Hyeok , Kang Shin-Wook , Yoo Tae-Hyun , Ahn Sung Soo
Published: July 2023

Objectives

To investigate the association between periodontal disease and the development of inflammatory arthritides in the general population.

Methods

In total, 489 125 participants from the UK Biobank without a previous history of RA, AS and PsA were enrolled. The primary outcome was the incidence of inflammatory arthritides, which was a composite of RA, AS and PsA according to the presence of periodontal disease based on self-reported oral health indicators. Multivariate Cox proportional hazard regression analyses using four different models were performed to assess the association between periodontal disease and inflammatory arthritides development.

Results

In all, 86 905 and 402 220 individuals were categorized as with and without periodontal disease, respectively. Cox hazard analysis indicated that the presence of periodontal disease was an independent predictor of the occurrence of composite outcomes of inflammatory arthritides, which was also consistent for RA and AS. Significant associations were found to be consistent in the four Cox models and were replicated even when different criteria were used to define periodontal disease. Subgroup analyses indicated that periodontal disease was associated with an increased RA risk in those aged <60 years, and this risk was persistent for both male and female patients and for patients with seropositive/seronegative RA.

Conclusion

Self-reported periodontal disease is associated with inflammatory arthritides incidence in participants included in the UK Biobank, particularly for RA and AS. Higher clinical attention and optimal dental care in patients with signs of periodontal disease may be recommended for early disease detection and for reducing this risk.
Lead exposure suppresses the Wnt3a/β-catenin signaling to increase the quiescence of hematopoietic stem cells via reducing the expression of CD70 on bone marrow-resident macrophages
Authors: Zhao Yifan , Wu Jiaojiao , Xu Hua , Li Qian , Zhang Yufan , Zhai Yue , Tang Mengke , Liu Yalin , Liu Ting , Ye Yao , He Miao , He Rui , Xu Yanyi , Zhou Zhou , Kan Haidong , Zhang Yubin
Published: July 2023

Lead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/β-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/β-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/β-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/β-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/β-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans.
1Affect Theory
Authors: Jones Rhys Steven
Published: July 2023

This chapter reviews a range of scholarship working at the intersection of theories of digitality, affect, and labour published in 2022 under the following headings: 1. Introduction; 2. Work (Daniel Nehring and Kristina Brunila, Affective Capitalism in Academia: Revealing Public Secrets; Anna Deumert, ‘Wash Your Hands! Domestic Labor and the Affective Economy of Racial Capitalism’; Carlo Perrotta, Neil Selwyn, and Carrie Ewin, ‘Artificial Intelligence and the Affective Labour of Understanding: The Intimate Moderation of a Language Model’); 3. Play (Aleena Chia, ‘The Artist and the Automaton in Digital Game Production’; Stephanie Jennings, ‘Only You Can Save the World (of Videogames): Authoritarian Agencies in the Heroism of Videogame Design, Play, and Culture’; Paolo Ruffino, ‘There Is No Cure: Paratexts as Remediations of Agency in Red Dead Redemption 2’); 4. Queer Affects (Jacob Gaboury, ‘Queer Affects at the Origins of Computation’; Bo Ruberg, ‘After Agency: The Queer Posthumanism of Video Games That Cannot Be Played’; Charnell Peters, ‘Asexuality, Affect Aliens, and Digital Affect Cultures: Relationality with the Happy Objects of Sexual and Romantic Relationships’); 5. Conclusion.
Phylogenetic position, validity and diversity of the genus Milnesioides (Eutardigrada: Apochela)
Authors: Morek Witold , Wałach Karol , Lamond Emerson , Michalczyk Łukasz
Published: July 2023

The order Apochela, the only exclusively carnivorous tardigrade lineage, comprises four genera, of which Milnesium contains multiple species and is common and cosmopolitan, whereas the remaining genera (Bergtrollus, Limmenius and Milnesioides) are monotypic, rare and have restricted geographical distributions. More importantly, although there are ample genetic data for numerous Milnesium species, no other apochelan genus has been sequenced so far, which limits our understanding of milnesiid evolution. In this contribution, we analysed two populations of Milnesioides from the south coast of Western Australia. The obtained molecular phylogenetic tree clearly indicated Milnesioides as a sister lineage to all remaining Milnesium species, supporting the validity of the genus. Moreover, the sister relationship of Milnesioides and Milnesium lends support to the Gondwanan origin of the order Apochela. Phenotypic differences between the type population of Milnesioides exsertum from New South Wales and the populations from Western Australia analysed in this study suggest that the latter represent a new species. The new data and morphological differences between populations reported in the original description of Milnesioides strongly suggest that the genus is not monotypic.
Clearance of Persistent Methicillin-Susceptible Staphylococcus lugdunensis Bacteremia Using Nafcillin Plus Ertapenem Combination Therapy
Authors: Sharma Ishrya , Hodges Jacqueline , Moonah Shannon , Shirley Debbie-Ann
Published: July 2023

Staphylococcus lugdunensis is a coagulase-negative staphylococcus that can cause serious infection similar to Staphylococcus aureus. Limited therapeutic options are available for patients with staphylococcal bacteremia who fail to respond to standard monotherapy, particularly when source control of infection is not feasible, driving the need for improved synergistic antibiotic combinations to enhance medical management. We present the case of a 58-year-old patient with persistent S. lugdunensis bacteremia for over 1 week despite appropriate therapy with nafcillin. Blood cultures were successfully sterilized following the addition of ertapenem salvage therapy, with rapid blood culture clearance within 2 days of initiation. To our knowledge, this is the first report of using ertapenem in combination with an antistaphylococcal penicillin to specifically clear persistent S. lugdunensis bacteremia. Similar success has been reported using this combination to treat methicillin-susceptible S. aureus infections; hence, our report provides further support for the benefit of this combination for staphylococcal infections.
The Real Relevance of Nonacid Reflux in Pediatric Patients
Authors: Hirsch Suzanna , Rosen Rachel
Published: July 2023

Gastroesophageal reflux (GER) is one of the most common presenting complaints to pediatric gastroenterologists, and a wide variety of symptoms in children are potentially attributable to typical or atypical GER. While reflux diagnosis and treatment paradigms classically have focused on targeting acid, there is a growing recognition of the prevalence and significance of nonacid GER in both children and adults. This review explores the role of nonacid reflux in pediatric patients, including definitions, associations with symptoms, pathophysiologic mechanisms, and treatment implications.
Approach to the hospitalized patient with pulmonary arterial hypertension
Authors: Deshwal Himanshu , Sulica Roxana
Published: July 2023

Purpose of review

Hospitalization in pulmonary arterial hypertension (PAH) patients is an important clinical worsening event significantly associated with subsequent mortality. Furthermore, irrespective of the cause of hospitalization, the overall outcome is closely related to the severity of the right ventricular (RV) dysfunction. Therefore, understanding the pathophysiology of pulmonary hypertension and RV failure is paramount in successfully managing PAH patients requiring hospitalization. This review highlights diagnostic and therapeutic approaches in various clinical scenarios that might be encountered during hospitalization of the World Health Organization group I PAH patient.

Recent findings

This article covers recent literature describing risk factors, predictors of outcome and state-of the art management approach to a hospitalized PAH patients with a special focus on management of RV failure and common complications in PAH requiring hospitalization.

The review highlights the importance of multidisciplinary approach to a hospitalized PAH patient and highlight important implications in clinical practice and knowledge gaps for potential future research.
Delayed vs. Early Laparoscopic Appendectomy (DELAY) for Adult Patients with Acute Appendicitis
Authors: Patel Sunil V. , Zhang Lisa , Mir Zuhaib M. , Lemke Madeline , Leeper William R. , Allen Laura J. , Walser Eric , Vogt Kelly
Published: July 2023

Objective:

To assess whether delaying appendectomy until the following morning is non-inferior to immediate surgery in those with acute appendicitis presenting at night.

Background:

Despite a lack of supporting evidence, those with acute appendicitis who present at night frequently have surgery delayed until the following morning.

Methods:

The delay trial is a non-inferiority randomized controlled trial conducted between 2018 – 22 at two tertiary care hospital in Canada. Adults with imaging confirmed acute appendicitis who presented at night (2000 – 0400). Delaying surgery until after 0600 was compared with immediate surgery. The primary outcome was 30 day post operative complications. An a prior non-inferiority margin of 15% was deemed clinically relevant.

Results:

127 of a planned 140 patients were enrolled in the DELAY trial (59 in the delayed group, 68 in the immediate group). The two groups were similar at baseline. The mean time between decision to operate and surgery was longer in the delayed group (11.0 hours vs. 4.4 hours, P<0.0001). The primary outcome occurred in 6/59 (10.2%) of those in the delayed group versus 15/67 (22.4%) of those in the immediate group (P=0.07). The difference between groups met the a priori non-inferiority criteria of +15% (risk difference -12.2%, 95%CI -24.4% to +0.4%, test of non-inferiority P<0.0001).

Conclusions and Relevance:

The DELAY study is the first trial to assess delaying appendectomy in those with acute appendicitis. We demonstrate non-inferiority of delaying surgery until the following morning.

Trail Registration:

This trial was registered with ClinicalTrials.gov (NCT03524573).
A continuum description of the buckling of a line of spheres in a transverse harmonic confining potential
Authors: Hutzler S. , Ryan-Purcell J. , Mughal A. , Weaire D.
Published: July 2023

A line of contacting hard spheres, placed in a transverse confining potential, buckles under compression or when tilted away from the horizontal, once a critical tilt angle is exceeded. This interesting nonlinear problem is enriched by the combined application of both compression and tilt. In a continuous formulation, the profile of transverse sphere displacement is well described by numerical solutions of a second-order differential equation (provided that buckling is not of large amplitude). Here we provide a detailed discussion of these solutions, which are approximated by analytic expressions in terms of Jacobi, Whittaker and Airy functions. The analysis in terms of Whittaker functions yields an exact result for the critical tilt for buckling without compression.
Determining large-strain metal plasticity parameters using
in situ
measurements of plastic flow past a wedge
Authors: Chawla Harshit , Yadav Shwetabh , Aprahamian Hrayer , Sagapuram Dinakar
Published: July 2023

We present a novel approach to determine the constitutive properties of metals under large plastic strains and strain rates that otherwise are difficult to access using conventional materials testing methods. The approach exploits large-strain plastic flow past a sharp wedge, coupled with high-speed photography and image velocimetry to capture the underlying plastic flow dynamics. The inverse problem of estimating material parameters from the flow field is solved using an iterative optimization procedure that minimizes the gap between internal and external plastic work. A major advantage of the method is that it neither makes any assumptions about the flow nor requires computational simulations. To counter the problem of non-unique parameter estimates, we propose a parameterization scheme that takes advantage of the functional form of the constitutive model and reformulates the problem into a more tractable form to identify plasticity parameters uniquely. We present studies to illustrate the principle of the method with two materials with widely different plastic flow characteristics: copper (strain hardening) and a lead-free solder alloy (rate sensitive and deformation history dependent). The results demonstrate the efficacy of the method in reliably determining the material parameters under high strain/strain rate conditions of relevance to a range of practical engineering problems.
New actuation modes of composite dielectric elastomers
Authors: Liguori Pietro , Gei Massimiliano
Published: July 2023

The typical actuation mode of a dielectric elastomer membrane subjected to an electric field across its thickness is in-plane expansion. We show that, by selecting properly the contrast between phases (i.e. shear moduli and permittivity ratios), a hierarchical laminate may display longitudinal contraction when actuated in the same way. In particular, simple and second rank laminates are investigated. The latter performs in general better; however, we provide a guideline on how to optimize the microstructure to limit the values of the contrast parameters at which the new ‘non-conventional’ mode becomes available. As the requirements in terms of permittivity ratio of the two phases are somewhat extreme, we review the availability of materials that have been processed so far to assess the viability of such composite devices.
Knowing the fishery to know the bycatch: bias-corrected estimates of harbour porpoise bycatch in gillnet fisheries
Authors: Kindt-Larsen Lotte , Glemarec Gildas , Berg Casper W. , Königson Sara , Kroner Anne-Mette , Søgaard Mathias , Lusseau David
Published: July 2023

Incidental captures (bycatch) remain a key global conservation threat for cetaceans. Bycatch of harbour porpoise
Phocoena phocoena
in set gillnets is routinely monitored in European Union fisheries, but generally relies on data collected at low spatio-temporal resolution or over short periods. In Denmark, a long-term monitoring programme started in 2010 using electronic monitoring to collect data on porpoise bycatch and gillnet fishing effort at a fine spatial and temporal scale, including time and position of each fishing operation, together with every associated bycatch event. We used these observations to model bycatch rates, given the operational and ecological characteristics of each haul observed in Danish waters. Data on fishing effort from the Danish and Swedish gillnet fleets were collected to predict fleet-wide porpoise bycatch in gillnets at regional level. Between 2010 and 2020, yearly total bycatch averaged 2088 animals (95% Cl: 667–6798). For the Western Baltic assessment unit, bycatch levels were above sustainability thresholds. These results demonstrate that fishing characteristics are key determinants of porpoise bycatch and that classical approaches ignoring these features would produce biased estimates. It emphasizes the need for efficient and informative monitoring methods to understand possible conservation impacts of marine mammal bycatch and to implement tailored mitigation techniques.