Toxicity Death Research Articles

Population-based Drug Toxicity Death Rate in Newfoundland and Labrador With a Highlight on Opioid-related Deaths: A Retrospective Cohort Study

ABSTRACT Objective: The opioid crisis has been an ongoing, complex public health issue in Canada since 2016 and has become a catalyst for substance use disorder. Prescription opioid use has increased steadily for the past 3 decades, and opioid and other drug use continues to contribute to morbidity and mortality in Canada. This study has 3 objectives: to analyze toxicology findings in drug-related deaths, specifically focusing on fatal opioid-related toxicities and detailing patient demographics within the sample in NL annually from 2016 to 2022. Methods: Drug toxicity represents the consumption of toxic levels of substances including, but not limited to, illicit and pharmaceutical opioids, illicit and pharmaceutical stimulants, illicit and pharmaceutical benzodiazepines, alcohol, antidepressants, and other prescription medications. Results: The total number of suicide deaths caused by total drug toxicity ranged from a frequency of 9 in 2016 to 15 in 2022. The number of undetermined deaths from total drug toxicity ranged from a frequency of 2 in 2021 to 7 in 2019. The manner of death for all opioid-related toxicity deaths in this study is considered accident (not intentional) or other (meaning suicides and undetermined deaths). Accidental death was the most prevalent manner of death for opioid-related toxicity deaths occurring in NL between 2016 and 2022, comprising 72% (n=13) of total opioid-related deaths in 2016, 70% (n=23) in 2017, 83% (n=10) in 2018, 72% (n=13) in 2019, 75% (n=18) in 2020, 88% (n=23) in 2021, and 77% (n=23) in 2022. Conclusions: Subsequent research using more granular data is needed in this area to identify other risk factors contributing to drug-related harms and toxicity deaths in NL. Objectif: La crise des opioïdes est un problème de santé publique complexe et permanent au Canada depuis 2016 et est devenue un catalyseur des troubles liés à l’utilisation de substances. La consommation d’opioïdes sur ordonnance a augmenté régulièrement au cours des trois dernières décennies et la consommation d’opioïdes et d’autres drogues contribuent à la morbidité et à la mortalité au Canada. Méthodes: Cette étude a examiné le nombre total de décès dus à la toxicité des drogues, en mettant l’accent sur les décès dus à la toxicité des drogues liées aux opioïdes aux TNL chaque année entre 2016 et 2022. La toxicité des drogues représente la consommation de substances à des niveaux toxiques incluant, mais sans s’y limiter, les opioïdes illicites et pharmaceutiques, les stimulants illicites et pharmaceutiques, les benzodiazépines illicites et pharmaceutiques, l’alcool, les antidépresseurs et d’autres médicaments sur ordonnance. Résultats: Le nombre total de décès par suicide causés par la toxicité totale des drogues a varié d’un taux annuel de 9 en 2016 à 15 en 2022. Le nombre de décès indéterminés dus à une toxicité totale des drogues est passé d’un taux annuel de 2 en 2021 à 7 en 2019. Le mode de décès pour tous les décès liés à la toxicité des opioïdes dans cette étude est considéré comme accidentel (non intentionnel) ou autre (c’est-à-dire les suicides et les décès indéterminés). La mort accidentelle était le mode de décès le plus fréquent pour les décès par toxicité liés aux opioïdes survenus aux TNL entre 2016 et 2022, comprenant 72% (n=13) du total des décès liés aux opioïdes en 2016, 70% (n=23) en 2017, 83% (n=10) en 2018, 72% (n=13) en 2019, 75% (n=18) en 2020, 88% (n=23) en 2021, et 77% (n=23) en 2022. Conclusion: Des recherches ultérieures utilisant des données plus granulaires sont nécessaires dans ce domaine pour identifier d’autres facteurs de risque contribuant aux méfaits liés aux drogues et aux décès dus à la toxicité aux TNL.

Ignored inequities: Critical analysis of the pre-launch development of British Columbia's “Stop Overdose” campaign

BackgroundSubstance use stigma has been positioned as a major driver of drug toxicity mortality. In response, governmental and public health organizations across Canada have invested significant resources into mass media campaigns that target stigma. Many of these campaigns feature images or stories about people who use drugs (PWUD). Although stigma and drug toxicity death disproportionately impact racially and economically marginalized PWUD, these campaigns often over-represent White, middle-class individuals. This effectively ignores intersecting roles of racism and classism in the experience of stigma and drug toxicity mortality. MethodsTo investigate how this pattern of representation might occur, we examined the development process of the British Columbia (BC) Government's “Stop Overdose” anti-stigma campaign launched in 2018. We aimed to identify strategic goals, decisions, and underlying ideas that could help explain the campaign's eventual focus on White, middle-class PWUD. Through a Freedom of Information request we obtained 320 pages of documents from the BC Government outlining the real-time development, testing, and evaluation of the first wave of the campaign. We analyzed these documents using reflexive thematic analysis. ResultsWe identified that campaign developers had a marked focus on challenging stereotypes about PWUD and humanizing PWUD, while ensuring the campaign was relevant to BC residents. To achieve these goals, campaign developers ultimately avoided images of what they deemed the inaccurately “stereotypical” marginalized drug user. Instead, they featured PWUD in more privileged social positions. By attaching labels like “co-worker” to this imagery, developers felt mainstream BC residents could relate to and have more empathy for these PWUD compared to marginalized PWUD. ConclusionsIn effect, these strategies perpetuated the exclusion and dehumanization of marginalized PWUD facing disproportionate harms of the drug toxicity crisis. Since anti-stigma campaigns remain a common intervention, we highlight a need for strategic approaches informed by more critical perspectives on substance use stigma.

A comparison of the characteristics of accidental substance-related acute toxicity deaths in Canada across life stages, 2016-2017.

The acute toxicity (sometimes called "overdose" or "poisoning") crisis has affected Canadians across all stages of life, including youth, adults and older adults. Our biological risks and exposures to substances change as we age. Based on a national chart review study of coroner and medical examiner data on acute toxicity deaths in 2016 and 2017, this analysis compares the burden of deaths and circumstances of death, locations of acute toxicity event and death, health history and substances contributing to death of people, by sex and life stage.

Chronic pain and accidental acute toxicity deaths in Canada, 2016-2017.

Multiple Canadian jurisdictions have reported a pattern of chronic pain among people who died from substance-related acute toxicity. This study examined the prevalence and characteristics of those with chronic pain using data from a national study of people who died of accidental acute toxicity. A cross-sectional analysis of accidental substance-related acute toxicity deaths that occurred in Canada between 1 January 2016 and 31 December 2017 was conducted. The prevalence of pain and pain-related conditions were summarized as counts and percentages of the overall sample. Subgroups of people with and without a documented history of chronic pain were compared across sociodemographic characteristics, health history, contextual factors and substances involved. From the overall sample (n = 7902), 1056 (13%) people had a history of chronic pain while 6366 (81%) had no documented history. Those with chronic pain tended to be older (40 years and older), unemployed, retired and/or receiving disability supports around the time of death. History of mental health conditions, trauma and surgery or injury was significantly more prevalent among people with chronic pain. Of the substances that most frequently contributed to death, opioids typically prescribed for pain (hydromorphone and oxycodone) were detected in toxicology more often among those with chronic pain than those without. Findings underscore the cross-cutting role of multiple comorbidities and unmanaged pain, which could compound the risk of acute toxicity death. Continued prioritization of harm reduction and regular patient engagement to assess ongoing needs are among the various opportunities for intervention.

The silibinin-loaded Zein-β cyclodextrin nano-carriers (SZBC-NCs) as a novel selective cancer cell drug delivery system in HT-29 cell line

Entrapping phytochemical bioactive compounds into nano-structured biocompatible polymers has been successfully utilized for improving cancer treatment efficiency. Silibinin is a potent compound that shows promising anticancer properties. In the present study, the Zein-β-cyclodextrin complex was used to encapsulate silibinin and evaluate the induced cell death type and cytotoxic impacts on human cancer cells. The silibinin-loaded Zein-β cyclodextrin nano-carriers (SZBC-NCs) were synthesized utilizing a gradual ultrasound-mediated homogenization technique and characterized by Zeta potential, DLS, FESEM, and FTIR analysis. The SZBC-NCs’ antioxidant activity was studied by conducting ABTS and DPPH radical scavenging assays. Finally, the SZBC-NCs selective toxicity and cellular death induction mechanism were studied on the HT-29 and AGS cancer cells by measuring the cell survival and apoptotic gene (Caspase 3, 9), respectively, which were verified by conducting the DAPI staining analysis. The negatively charged (− 27.47 mV) nanoparticles (286.55 nm) showed significant ABTS and DPPH radical scavenging activity. Moreover, the remarkable decrease in the IC50 concentrations of the SZBC-NCs among the HT-29 and AGS cancer cell lines exhibited their selective cytotoxic potential. Also, the overexpressed apoptotic (Caspases 3 and 9) and down-regulated necrotic (NFKB) gene expressions following the SZBC-NCs treatment doses indicated the apoptotic activity of SZBC-NCs, which were verified by the increased apoptotic morphology of the DAPI-stained HT-29 cancer cells. The antioxidant and colon cancer cell-related apoptotic activity of the SZBC-NCs make it an appropriate anti-colon cancer nano delivery system. Therefore, they can potentially be used as a safe efficient colon cancer treatment strategy. However, further in vivo experiments including animal cancer models have to be studied.

Nesfatin-1 ameliorates pathological abnormalities in Drosophila hTau model of Alzheimer's disease

In human Alzheimer's disease (AD), the aggregation of tau protein is considered a significant hallmark, along with amyloid-beta. The formation of neurofibrillary tangles due to aberrant phosphorylation of tau disrupts microtubule stability, leading to neuronal toxicity, dysfunction, and subsequent cell death. Nesfatin-1 is a neuropeptide primarily known for regulating appetite and energy homeostasis. However, the function of Nesfatin-1 in a neuroprotective role has not been investigated. In this study, we aimed to elucidate the effect of Nesfatin-1 on tau pathology using the Drosophila model system. Our findings demonstrate that Nesfatin-1 effectively mitigates the pathological phenotypes observed in Drosophila human Tau overexpression models. Nesfatin-1 overexpression rescued the neurodegenerative phenotypes in the adult fly's eye and bristle. Additionally, Nesfatin-1 improved locomotive behavior, neuromuscular junction formation, and lifespan in the hTau AD model. Moreover, Nesfatin-1 controls tauopathy by reducing the protein level of hTau. Overall, this research highlights the potential therapeutic applications of Nesfatin-1 in ameliorating the pathological features associated with Alzheimer's disease.

Safety and efficacy of B7-H3 targeting CAR-T cell therapy for patients with recurrent GBM.

2062 Background: Glioblastoma Multiforme (GBM) is one of the most deadly cancers, and nearly all patients experience recurrence upon the current standard of care for newly diagnosed GBM. The recurrent GBM (rGBM) exhibits a median survival of less than 8 months with limited therapeutic options. We have previously cloned the B7-H3 gene, characterized its function, demonstrated altered B7-H3 expression in human solid tumors, and identified B7-H3 as a promising therapeutic target. We present herein the preliminary findings of an investigator-initiated trial (NCT05241392), where patients with rGBM were treated with autologous chimeric antigen receptor-T (CAR-T) cells targeting B7-H3 (TX103). Methods: This is an open, single-arm, "3+3" dose-escalation and multiple-dose study. The primary objective was to evaluate the safety and the maximal-tolerated dose. Secondary objectives included survival outcomes, tumor responses, immunological responses, and pharmacokinetic parameters. Patients aged 18 to 75 were enrolled with confirmed recurrence by image scan and B7-H3 expression >= 30% by immunohistochemistry analysis. TX103 was administered intracavity and/or intraventricularly to patients via an Ommaya reservoir. TX103 was given biweekly to patients each cycle at dose levels 1, 2, and 3 (20, 60, 150 million cells, respectively), with four cycles as one course. Results: Between March 2022 and January 2024, 13 patients received at least one intracranial infusion of TX103, with 3, 4, and 6 patients in dose levels 1, 2, and 3, respectively. The median number of infusion cycles was 4 (Min, Max 1,9). All patients were included in the safety analysis, revealing no dose-limiting toxicity or CAR-T treatment-related death. All patients experienced at least one adverse event (AE), and the treatment-related AEs (TRAEs) included cytokine release syndrome, increased intracranial pressure (ICP), headache, epilepsy, decreased level of consciousness, vomiting, and pyrexia. Most TRAEs were grade 1-2, while three grade-3 TRAEs were observed: one case of increased ICP in dose level 2, one case of epilepsy, and another case of decreased level of consciousness in dose level 3. As of January 2024, six patients from dose levels 1 and 2 were eligible for a 12-month survival assessment; the 12-month overall survival (OS) rate was 83.3% (95% CI: 58.3%~100%), and the median OS was 20.3 mo (95% CI: 20.3~not reach). Two of the three patients from dose level 2 achieved partial and complete responses, respectively. Following CAR-T administration, significant increases in cytokines, including IL-6 and IFN-γ, and elevated copy numbers of the CAR gene were observed in the cerebrospinal fluid, while only minimal elevations were noted in the peripheral blood. Conclusions: In this trial, treating rGBM with TX103 is deemed safe and tolerated. These interim results support further study using TX103 to enhance the survival outcomes in patients with rGBM.

Abstract LB272: Sequential inhibition of PARP and BET as a rational therapeutic strategy for glioblastoma multiforme

Abstract Glioblastoma multiforme (GBM), characterized as one of the most aggressive brain cancers, presents significant treatment challenges due to its rapid growth, heterogeneity, and robust defensive mechanisms. Despite advancements in neuro-oncology, GBM's prognosis remains grim, with the median survival of approximately 15 months, underscoring the urgent need for innovative therapeutic strategies. Facing these challenges, PARP inhibitors (PARPi) hold substantial promise in treating GBM, evidenced by over 20 ongoing clinical trials. However, their application has been limited by side effects such as nausea, fatigue, and particularly anemia, as well as a narrow therapeutic spectrum focusing mainly on patients with homologous recombination deficiency (HRDness). Through unbiased transcriptomic and proteomic sequencing, and employing Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA), and Transcriptome-Proteome Correlation Analysis, we discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, extending beyond the previously known impact of BET inhibition on homologous recombination repair. In vitro experiments using GBM cell lines and patient-derived primary GBM cells demonstrated that concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, we observed that DNA damage persists after the discontinuation of PARPi monotherapy. Leveraging these residual effects of PARPi, subsequent BETi administration elevated replication stress levels, leading to the inactivation of GBM cell cycle checkpoints, with efficacy comparable to concurrent treatment. The treatment-induced prolonged stalling of replication forks resulted in their collapse and the formation of double-ended double-strand breaks (DSBs). In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, while protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. In vivo orthotopic transplantation tumor experiments in zebrafish and nude mice demonstrated consistent effects, indicating that sequential administration of PARPi followed by BETi maintained anti-tumor efficacy, similar to concurrent treatment, while reducing toxicity, as evident by the reduced impact on hemoglobin levels. Our findings provide a broader and deeper understanding of the synergistic interaction between BETi and PARPi than previously recognized. This study offers compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy. Citation Format: Xin Peng, Xin Huang, Shaolu Zhang, Naixin Zhang, Shengfan Huang, Yingying Wang, Zhenxing Zhong, Shan Zhu, Haiwang Gao, Zixiang Yu, Xiaotong Yan, Zhennan Tao, Yuxiang Dai, Zhe Zhang, Xi Chen, Feng Wang, Francois X. Claret, Ning Ji, Yuxu Zhong, Dexin Kong. Sequential inhibition of PARP and BET as a rational therapeutic strategy for glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB272.

Acute toxicity test of tablets containing α-mangosteen, piperine, curcumin, methyl cinnamate and vitamin C in female wistar rats

Acute toxicity test of tablets containing α-mangosteen, piperine, curcumin, methyl cinnamate and vitamin C in female wistar rats

Copper and Copper Complexes in Tumor Therapy.

Copper (Cu), a crucial trace element in physiological processes, has garnered significant interest for its involvement in cancer progression and potential therapeutic applications. The regulation of cellular copper levels is essential for maintaining copper homeostasis, as imbalances can lead to toxicity and cell death. The development of drugs that target copper homeostasis has emerged as a promising strategy for anticancer treatment, with a particular focus on copper chelators, copper ionophores, and novel copper complexes. Recent research has also investigated the potential of copper complexes in cancer therapy.

Efficacy of MUC1-targeted CAR-NK cells against human tongue squamous cell carcinoma.

The clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. We assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSC-derived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively. MUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CAR-NK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. The MUC1-targeted CAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials.

Cuproptosis: Unraveling the Mechanisms of Copper-Induced Cell Death and Its Implication in Cancer Therapy

Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.

Enfortumab vedotin treatment regimens and efficacy in urothelial carcinoma: The Mayo Clinic experience.

627 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate recently approved to treat locally advanced or metastatic bladder cancer (la/mUC). Initial trials have shown promising response to EV in advanced urothelial cancers (UC), where prognosis is currently poor. Here, we report real-world experience using EV at a tertiary center. Methods: This study reports treatment details and outcomes in 92 patients (pts) that received at least one complete cycle of EV monotherapy in treatment of la/mUC. Treatment details include intent of cycle duration, 21 days (treatment on days 1 and 8) or 28 days (treatment on days 1, 8 and 15), dose reductions, and median number of cycles completed. Interruptions in treatment are reported as intentional (i.e. holding EV after achieving positive response) or unintentional (i.e. secondary to drug toxicity or other delay). Image-based best clinical response consists of progressive disease (PD), stable (SD), partial (PR), complete response (CR), and not evaluable (NE). Clinical benefit rate (CBR) is defined as either SD, PR, and CR outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Results: Patients mean age was 71.1 years (IQR: 66.8 - 78), 72 (79.2%) are male and 20 (20.8%) female, 89 (96.7%) pts received EV in the setting of metastatic UC, 3 (3.3%) in locally advanced UC. 13 (13.5%) pts were previously chemotherapy exposed, 9 (9.8%) were immunotherapy exposed, 60 (65.2%) were both chemo and immunotherapy exposed, and 11 (12.0%) received EV first line. 46 (50%) pts underwent 21-day treatment cycles, and 46 underwent 28-day treatment cycles. The median number of EV cycles was 3 (range 1-16) in the overall cohort, 3 in the 21-day cycle group, and 4 in the 28-day cycle group. 50 (54.3%) pts required dose reductions secondary to toxicity. 11 (12.0%) pts had planned interruptions, and 33 (35.9%) had unplanned interruptions. Best clinical response consisted of 24 (26.0%) pts with PD, 12 (13.0%) with SD, 25 (27.2%) with PR, 17 (18.5%) with CR, and 14 (15.2%) NE. CBR was 54 (58.7%) in the overall sample. CBR in the 21-day and 28-day cycle groups was identical at 27 (29.3%). EV therapy was discontinued most for cancer progression (34, 37.0%), therapy toxicity (18, 19.6%), and pt death (12, 13.0%). In 13 (14.1%) pts therapy is still ongoing. 73 (76.0%) pts had mild to moderate toxicities, and 19 (19.7%) reported severe toxicities that required hospitalization. Median OS in the total cohort was 11.01 months (95% CI: 8.51-14.6). Median PFS is 5.49 months (95% CI: 4.60-8.19). Conclusions: Real-world utilization of EV showed significant heterogeneity in administration patterns (21 days vs 28 days) and across a range of settings (first line, chemo exposed, IO exposed, chemo and IO exposed). Although EV has high response rates, more than 3/4th of patients suffered mild to moderate toxicities and 1/5th required hospitalization.

Factors associated with obtaining prescribed safer supply among people accessing harm reduction services: findings from a cross-sectional survey

BackgroundWith growing rates of unregulated drug toxicity death and concerns regarding COVID-19 transmission among people who use drugs, in March 2020, prescribed safer supply guidance was released in British Columbia. This study describes demographic and substance use characteristics associated with obtaining prescribed safer supply and examines the association between last 6-month harm reduction service access and obtaining prescribed safer supply.MethodsData come from the 2021 Harm Reduction Client Survey administered at 17 harm reduction sites across British Columbia. The sample included all who self-reported use of opioids, stimulants, or benzodiazepines in the prior 3 days (N = 491), given active use of these drugs was a requirement for eligibility for prescribed safer supply. The dependent variable was obtaining a prescribed safer supply prescription (Yes vs. No). The primary independent variables were access to drug checking services and access to overdose prevention services in the last 6 months (Yes vs. No). Descriptive statistics (Chi-square tests) were used to compare the characteristics of people who did and did not obtain a prescribed safer supply prescription. Multivariable logistic regression models were run to examine the association of drug checking services and overdose prevention services access with obtaining prescribed safer supply.ResultsA small proportion (n = 81(16.5%)) of the sample obtained prescribed safer supply. After adjusting for gender, age, and urbanicity, people who reported drug checking services access in the last 6 months had 1.67 (95% CI 1.00–2.79) times the odds of obtaining prescribed safer supply compared to people who had not contacted these services, and people who reported last 6 months of overdose prevention services access had more than twice the odds (OR 2.08 (95% CI 1.20–3.60)) of prescribed safer supply access, compared to people who did not access these services.ConclusionsOverall, the proportion of respondents who received prescribed safer supply was low, suggesting that this intervention is not reaching all those in need. Harm reduction services may serve as a point of contact for referral to prescribed safer supply. Additional outreach strategies and service models are needed to improve the accessibility of harm reduction services and of prescribed safer supply in British Columbia.

Biomarkers of chemotherapy-induced cardiotoxicity: toward precision prevention using extracellular vesicles.

Detrimental side effects of drugs like doxorubicin, which can cause cardiotoxicity, pose barriers for preventing cancer progression, or treating cancer early through molecular interception. Extracellular vesicles (EVs) are valued for their potential as biomarkers of human health, chemical and molecular carcinogenesis, and therapeutics to treat disease at the cellular level. EVs are released both during normal growth and in response to toxicity and cellular death, playing key roles in cellular communication. Consequently, EVs may hold promise as precision biomarkers and therapeutics to prevent or offset damaging off-target effects of chemotherapeutics. EVs have promise as biomarkers of impending cardiotoxicity induced by chemotherapies and as cardioprotective therapeutic agents. However, EVs can also mediate cardiotoxic cues, depending on the identity and past events of their parent cells. Understanding how EVs mediate signaling is critical toward implementing EVs as therapeutic agents to mitigate cardiotoxic effects of chemotherapies. For example, it remains unclear how mixtures of EV populations from cells exposed to toxins or undergoing different stages of cell death contribute to signaling across cardiac tissues. Here, we present our perspective on the outlook of EVs as future clinical tools to mitigate chemotherapy-induced cardiotoxicity, both as biomarkers of impending cardiotoxicity and as cardioprotective agents. Also, we discuss how heterogeneous mixtures of EVs and transient exposures to toxicants may add complexity to predicting outcomes of exogenously applied EVs. Elucidating how EV cargo and signaling properties change during dynamic cellular events may aid precision prevention of cardiotoxicity in anticancer treatments and development of safer chemotherapeutics.

ANTIOXIDANTS ENHANCE CHROMIUM (VI) MEDIATED TOXICITY IN NEUROSPORA CRASSA

Chromium can be found in the environment in two main valence states: hexavalent Cr (VI) and trivalent Cr (III). Reduction activation of carcinogenic Cr (VI) is required for the induction of DNA damage and mutations. There is a controversy over antioxidants’ role in Cr (VI) toxicity and cell death in mammalian systems. In the present study we compared the effect of antioxidants and insulin on Cr (VI) induced genotoxicity in wall-less mutant of Neurospora crassa (slime), which contains insulin receptor on its cell surface as a model system. Analysis by comet assay indicated Potassium dichromate (K2 Cr2 O7 ) induced DNA damage in slime cells, as increase in comet tail moment and the effect was dose dependent. Simultaneous addition of N-acetyl cysteine (NAC) & Sodium ascorbate (ASC) increased the extent of DNA damage whereas insulin decreased the extent of DNA damage induced by Cr (VI). The simultaneous exposure of antioxidants and insulin in presence of Cr (VI) showed enhanced cytotoxicity as observed by MTT assay. The results obtained suggest that N-acetyl cysteine and Sodium ascorbate reduce Cr (VI) to Cr (III) enhancing the levels of reactive oxygen species. Absence of protective role of insulin in presence of antioxidants indicate that a differential route may be adopted by the cells in response to metallic stress.

Neuroprotective action of honey bee venom (melittin) against hypoxiainduced oxidative toxicity and cell death via inhibition of the TRPM2 channel

One bioactive element of honeybee venom is melittin (MEL). MEL induced oxidant and apoptotic activities through the increase of mitochondrial Zn2+ and Ca2+ in tumor cells, but it also induced neuroprotective activity by inhibiting the cell death, intracellular reactive oxygen species (iROS), and mitochondrial ROS (mROS) productions in neurons. By stimulating the TRPM2 channel, hypoxia (HPO) enhances the effects of oxidative stress and neuronal death; however, its inhibition prevents the alterations. I studied the neuroprotective effect of MEL on HPO-mediated oxidative neurotoxicity and cell death in SH-SY5Y neuronal cells by altering the TRPM2 signaling pathways. In the SH-SY5Y cells, five groups were induced as control, MEL (1 ug/ml for 24 hrs), HPO (CoCl2 and 200 M for 24 hrs), HPO + MEL, and HPO + TRPM2 antagonist (2-aminoethoxydiphenyl borate, 2APB) (100 M for 2 hrs). The amounts of cytosolic free Ca2+ were increased in the HPO group by the stimulation of hydrogen peroxide, although they were decreased in the cells by the treatment of 2APB and MEL. The amount of cytosolic free Ca2+ was higher in the HPO group than in the control group. The amounts of cell death (propidium iodide positive cell number), oxidants (mROS and iROS), mitochondrial membrane depolarization, and cytosolic free Zn2+ were higher in the HPO group than in the control and MEL groups, although their amounts were lower in the HPO + MEL and HPO + 2APB groups than in the HPO group only. In conclusion, MEL therapy reduced the amount of HPO-induced oxidative stress and neuronal deaths in SH-SY5Y cells by inhibiting TRPM2. The MEL could be considered as a potential protective component against oxidative neuronal damage caused by HPO.

Opioid toxicity deaths in Black persons who experienced provincial incarceration in Ontario, Canada 2015–2020: A population-based study

ObjectiveIn the context of mass incarceration and the opioid toxicity crisis in North America, there is a lack of data on the burden of opioid toxicity deaths in Black persons who experience incarceration. We aimed to describe absolute and relative opioid toxicity mortality for Black persons who experienced incarceration in Ontario, Canada between 2015 and 2020. MethodsWe linked data for all persons incarcerated in provincial correctional facilities and all persons who died from opioid toxicity in Ontario between 2015 and 2020, and accessed public data on population sizes. We described the characteristics of Black persons who were incarcerated and died from opioid toxicity, and calculated absolute mortality rates, as well as age-standardized mortality rates compared with all persons in Ontario not incarcerated during this period. ResultsBetween 2015 and 2020, 0.9% (n = 137) of 16,177 Black persons who experienced incarceration died from opioid toxicity in custody or post-release, for an opioid toxicity death rate of 0.207 per 100 person years. In the two weeks post-release, the opioid toxicity death rate was 1.34 per 100 person years. Standardized for age and compared with persons not incarcerated, the mortality ratio (SMR) was 17.8 (95%CI 16.4–23.1) for Black persons who experienced incarceration. ConclusionsWe identified a large, inequitable burden of opioid toxicity death for Black persons who experience incarceration in Ontario, Canada. Work is needed to support access to culturally appropriate prevention and treatment in custody and post-release for persons who are Black, and to prevent incarceration and improve determinants of health.

The impact of COVID-19 on opioid toxicity deaths for people who experience incarceration compared to the general population in Ontario: A whole population data linkage study.

To inform preparedness and population health action, we need to understand the effects of COVID-19 on health inequities. In this study, we assess the impact of COVID-19 on opioid toxicity deaths among people who experience incarceration compared to others in the general population in Ontario, Canada. We conducted a retrospective cohort study for the period of January 1, 2015 to December 31, 2020. We accessed and linked coronial data on all opioid toxicity deaths in Ontario with correctional data for people aged 18 years and older who were incarcerated in a provincial correctional facility. We used data from the Statistics Canada Census to calculate whole population rates. We used an interrupted time series design and segmented regression to assess for change in the level or rate of increase in deaths due to opioid toxicity coinciding with the COVID-19 pandemic. We compared the impact of COVID-19 on the opioid toxicity death rates for people exposed and not exposed to incarceration. Rates of opioid toxicity death increased with a linear positive slope in both persons exposed to incarceration and those not exposed over the study period. The start of COVID-19 measures coincided with a marked upward shift in the trend lines with modification of the effect of COVID-19 by both sex and exposure to incarceration. For persons exposed to incarceration, the risk ratio (RR) was 1.50 (95%CI 1.35-1.69) for males and 1.21 (95%CI 1.06-1.42) for females, and for persons not exposed to incarceration, the RR was 1.25 (95%CI 1.13-1.38) for males and not significant for females. COVID-19 substantially exacerbated the risk of opioid toxicity death, impacting males and females who experienced incarceration more than those who had not, with an immediate stepwise increase in risk but no change in the rate of increase of risk over time. Public health work, including pandemic preparedness, should consider the specific needs and circumstances of people who experience incarceration.

Revealing the DNA Binding Modes of CsoR by EPR Spectroscopy.

In pathogens, a unique class of metalloregulator proteins, called gene regulatory proteins, sense specific metal ions that initiate gene transcription of proteins that export metal ions from the cell, thereby preventing toxicity and cell death. CsoR is a metalloregulator protein found in various bacterial systems that "sense" Cu(I) ions with high affinity. Upon copper binding, CsoR dissociates from the DNA promoter region, resulting in initiation of gene transcription. Crystal structures of CsoR in the presence and absence of Cu(I) from various bacterial systems have been reported, suggesting either a dimeric or tetrameric structure of these helical proteins. However, structural information about the CsoR-DNA complex is missing. Here, we applied electron paramagnetic resonance (EPR) spectroscopy to follow the conformational and dynamical changes that Mycobacterium tuberculosis CsoR undergoes upon DNA binding in solution. We showed that the quaternary structure is predominantly dimeric in solution, and only minor conformational and dynamical changes occur in the DNA bound state. Also, labeling of the unresolved C- terminus revealed no significant change in dynamics upon DNA binding. These observations are unique, since for other bacterial copper metalloregulators, such as the MerR and CopY families, major conformational changes were observed upon DNA binding, indicating a different mode of action for this protein family.