Scalable Synthesis of an Acid Stable Analogue of Hippuristanol.

Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. We addressed this limitation by replacing one of the oxygen atoms of the spiroketal moiety with a carbon atom.

Protein engineering enables a soakable crystal form of human CDK7 primed for high-throughput crystallography and structure-based drug design.

Cyclin dependent kinase 7 (CDK7) is an important therapeutic kinase best known for its dual role in cell cycle regulation and gene transcription. Here, we describe the application of protein engineering to generate constructs leading to high resolution crystal structures of human CDK7 in both active and inactive conformations. The active state of the kinase was crystallized by incorporation of an additional surface residue mutation (W132R) onto the double phosphomimetic mutant background (S164D and T170E) that yielded the inactive kinase structure.

Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ.

The impact of non-medical cannabis legalization and other exposures on retention in longitudinal cannabis research: a survival analysis of a prospective study of Canadian medical cannabis patients.

Background: Despite repeated calls by medical associations to gather evidence on the harms and benefits of cannabis, there are ongoing methodological challenges to conducting observational and clinical studies on cannabis, including a high rate of patients that are lost to follow-up (LTFU). This study explores factors potentially associated with retention in a large prospective study of Canadian medical cannabis patients, with the goal of reducing the probability that patients will be lost to follow-up in future cannabis research.

Methods: The Tilray Observational Patient Study (TOPS) was a multi-site, prospective study assessing the impact of medical cannabis over 6 months in a broad population of authorized Canadian cannabis patients.

Self-reported reductions in tobacco and nicotine use following medical cannabis initiation: Results from a cross-sectional survey of authorized medical cannabis patients in Canada.

Background: Despite decades of campaigns aimed at reducing tobacco/nicotine (T/N) use and the development of many different T/N reduction and cessation strategies, the impacts on international public health remain significant. Some studies have found an association between medical and non-medical cannabis use and T/N use, although the evidence on whether cannabis/cannabinoids increase or decrease the odds of reducing or ceasing T/N use remain contradictory. This paper explores the self-reported use of cannabis and associated changes in T/N use among a Canadian medical cannabis patient population.

Cannabis Significantly Reduces the Use of Prescription Opioids and Improves Quality of Life in Authorized Patients: Results of a Large Prospective Study.

Objectives: This article presents findings from a large prospective examination of Canadian medical cannabis patients, with a focus on the impacts of cannabis on prescription opioid use and quality of life over a 6-month period.

Methods: The Tilray Observational Patient Study took place at 21 medical clinics throughout Canada. This analysis includes 1,145 patients who had at least one postbaseline visit, with follow-up at 1, 3, and 6 months.

Heroin and the illegal drug overdose death epidemic: A history of missed opportunities and resistance.

Background: Due to prohibitionist policies and practices, a poisoned illegal drug supply, and inadequate access to flexible substitution programs, Canada is currently experiencing the worst illegal drug overdose death epidemic in its history. In examining past policies, practices, and discourse that support heroin regulation and drug prohibition, the drivers of the current illegal drug overdose death epidemic in Canada are brought more clearly into focus.

Methods: This article provides a critical socio-historical analysis of heroin (opioid) regulation with a focus on Canadian federal and provincial policies in the province of B.

Reductions in alcohol use following medical cannabis initiation: results from a large cross-sectional survey of medical cannabis patients in Canada.

Background: Evidence details how cannabis can influence the use of other psychoactive substances, including prescription medications, alcohol, tobacco and illicit drugs, but very little research has examined the factors associated with these changes in substance use patterns. This paper explores the self-reported use of cannabis as a substitute for alcohol among a Canadian medical cannabis patient population.

Methods: Data was derived from a survey of 2102 people enrolled in the Canadian medical cannabis program.

A highly charged field: Mapping energies, currents and desires for reform in Canadian expert responses to drug law.

While many experts consider major changes to legal approaches to drug use necessary, achieving such change has proven to be difficult. The political process is often seen as integral to bringing about change, largely due to orthodox understandings of the 'nature' of law, in which law is made by parliaments and capable of revision in only limited instances. In recent years, theorists such as Bruno Latour (2009, 2013), Andreas Philippopoulos-Mihalopoulos (2015) and Serge Gutwirth (2015) have taken a more expansive view of the nature of law and its effects.

Sustainably reducing device utilization and device-related infections with DeCATHlons, device alternatives, and decision support.

Engagement of frontline staff, along with senior leadership, in competition-style healthcare-associated infection reduction efforts, combined with electronic clinical decision support tools, appeared to reduce antibiotic regimen initiations for urinary tract infections (P = .01). Mean monthly standardized infection and device utilization ratios also decreased (P < .

Problematizing the DSM-5 criteria for opioid use disorder: A qualitative analysis.

Background: This paper includes the voices of people who are members of a peer-led drug user group (SNAP) in Canada who are receiving heroin-assisted treatment (HAT) outside of a clinical trial. Drawing from critical drug studies, we problematize the criteria for severe opioid use disorder (OUD) from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, by exploring SNAP members' experiences in relation to heroin-assisted treatment, and examining how SNAP participants' narratives challenge conventional notions of what constitutes severe opioid use disorder.

Method: Drawing on critical analysis and research guidelines developed by drug user unions and organizations, and critical methodological frameworks on ethical community-based-and-responsive research for social justice, in this paper we focus on semi-structured interviews conducted with 36 SNAP members at the Vancouver Area Network of Drug Users site in the Downtown Eastside of Vancouver, Canada.

A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.

Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1.

From risky places to safe spaces: Re-assembling spaces and places in Vancouver's Downtown Eastside.

Vancouver's Downtown Eastside (DTES) neighbourhood is commonly associated with stigmatized and criminalized activities and attendant risks and harms. Many spaces/places in this urban neighbourhood are customarily portrayed and experienced as risky and harmful, and are implicated in experiences of structural (and physical) violence and marginalization. Drawing on 50 qualitative interviews, this paper explores how spaces/places frequently used by structurally vulnerable people who use drugs (PWUD) in the DTES that are commonly associated with risk and harm (e.

Gendered drug policy: Motherisk and the regulation of mothering in Canada.

Background: Due to misinformation and enduring discourses about pregnant women and mothers suspected of using drugs, these women continue to experience systemic discrimination. In 2014, this fact was once again made public in Canada when the Ontario government established an independent review of hair testing practices conducted by Motherisk Drug Testing Laboratory (MDTL) at Toronto's Hospital for Sick Kids. Between 2005 and 2015, MDTL tested the hair of more than 16,000 individuals for drug consumption.

BioTIME: A database of biodiversity time series for the Anthropocene.

Motivation: The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series.

Persistent reticulocytosis in a case of poodle macrocytosis.

A healthy 14-year-old, male neutered, Miniature Poodle was found to have a persistent erythrocyte macrocytosis and reticulocytosis with a normal and stable HCT. The hematologic features of macrocytosis, increased Howell-Jolly bodies, and metarubricytosis, in the absence of anemia or other cytopenias, combined with the cytologic evidence of bone marrow erythroid dysplasia, including megaloblastosis, binuclearity, increased mitotic activity, and nuclear fragmentation, are consistent with previous reports of congenital dyserythropoiesis termed poodle macrocytosis. We speculate that the additional presence of persistent reticulocytosis in the absence of an identifiable stimulus for accelerated erythropoiesis may represent a phenotypic variation of this inherited condition, and the morphologic abnormalities of the dyserythropoiesis are described.

Telling our stories: heroin-assisted treatment and SNAP activism in the Downtown Eastside of Vancouver.

Background: This article highlights the experiences of a peer-run group, SALOME/NAOMI Association of Patients (SNAP), that meets weekly in the Downtown Eastside of Vancouver, British Columbia, Canada. SNAP is a unique independent peer- run drug user group that formed in 2011 following Canada's first heroin-assisted treatment trial (HAT), North America Opiate Medication Initiative (NAOMI). SNAP's members are now made up of former research participants who participated in two heroin-assisted trials in Vancouver.

Discovery of potent inhibitors of the lysophospholipase autotaxin.

The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties.

Evaluation of an integrated group cognitive-behavioral treatment for comorbid mood, anxiety, and substance use disorders: A pilot study.

This paper presents the development and preliminary evaluation of an integrated group cognitive-behavioral treatment (CBT) for comorbid mood, anxiety, and substance use disorders. The 12-session, manualized treatment was developed collaboratively by a mental health program in a teaching hospital and a community-based addictions service and administered in both settings. Results from an uncontrolled effectiveness trial of 29 treatment completers suggest that integrated group CBT may reduce stress and alcohol use symptoms and improve substance refusal self-efficacy.

Hematology of dugongs (Dugong dugon) in southern Queensland.

Background: Little is known of the hematology of the dugong (Dugong dugon), a secretive and endangered coastal marine mammal.

Objectives: This paper reports hematologic reference intervals (RI) for dugongs and characterizes morphologic, cytochemical, and ultrastructural features of dugong leukocytes.

Methods: Blood was collected from live, apparently healthy dugongs and analyzed using Cell-Dyn 3700 or Sysmex XT-2000iV hematology analyzers.

Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties.

As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.