Targeting DNA topoisomerase IIα ( TOP2A ) in the hypoxic tumour microenvironment using unidirectional hypoxia‐activated prodrugs ( uHAPs )

The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy. The hTME impairs the delivery of a range of anti-cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia-Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme-DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by co-addressing the therapeutic challenge presented by the hTME

The unidirectional hypoxia-activated prodrug OCT1002 inhibits growth and vascular development in castrate-resistant prostate tumors

Background OCT1002 is a unidirectional hypoxia-activated prodrug (uHAP) OCT1002 that can target hypoxic tumor cells. Hypoxia is a common feature in prostate tumors and is known to drive disease progression and metastasis. It is, therefore, a rational therapeutic strategy to directly target hypoxic tumor cells in an attempt to improve treatment for this disease. Here we tested OCT1002 alone and in combination with standard-of-care agents in hypoxic models of castrate-resistant prostate cancer (CRPC). Methods The effect of OCT1002 on tumor growth and vasculature was measured using murine PC3 xenograft and dorsal skin fold (DSF) window chamber models. The effects of abiraterone, docetaxel, and cabazitaxel, both singly and in combination with OCT1002, were also compared. Results The hypoxia-targeting ability of OCT1002 effectively controls PC3 tumor growth. The effect was evident for at least 42 days after exposure to a single dose (30 mg/kg) and was comparable to, or better than, drugs currently used in the clinic. In DSF experiments OCT1002 caused vascular collapse in the PC3 tumors and inhibited the revascularization seen in controls. In this model OCT1002 also enhanced the anti-tumor effects of abiraterone, cabazitaxel, and docetaxel; an effect which was accompanied by a more prolonged reduction in tumor vasculature density. Conclusions These studies provide the first evidence that OCT1002 can be an effective agent in treating hypoxic, castrate-resistant prostate tumors, either singly or in combination with established chemotherapeutics for prostate cancer

A reference library for Canadian invertebrates with 1.5 million barcodes, voucher specimens, and DNA samples

The synthesis of this dataset was enabled by funding from the Canada Foundation for Innovation, from Genome Canada through Ontario Genomics, from NSERC, and from the Ontario Ministry of Research, Innovation and Science in support of the International Barcode of Life project. It was also enabled by philanthropic support from the Gordon and Betty Moore Foundation and from Ann McCain Evans and Chris Evans. The release of the data on GGBN was supported by a GGBN – Global Genome Initiative Award and we thank G. Droege, L. Loo, K. Barker, and J. Coddington for their support. Our work depended heavily on the analytical capabilities of the Barcode of Life Data Systems (BOLD, www.boldsystems.org). We also thank colleagues at the CBG for their support, including S. Adamowicz, S. Bateson, E. Berzitis, V. Breton, V. Campbell, A. Castillo, C. Christopoulos, J. Cossey, C. Gallant, J. Gleason, R. Gwiazdowski, M. Hajibabaei, R. Hanner, K. Hough, P. Janetta, A. Pawlowski, S. Pedersen, J. Robertson, D. Roes, K. Seidle, M. A. Smith, B. St. Jacques, A. Stoneham, J. Stahlhut, R. Tabone, J.Topan, S. Walker, and C. Wei. For bioblitz-related assistance, we are grateful to D. Ireland, D. Metsger, A. Guidotti, J. Quinn and other members of Bioblitz Canada and Ontario Bioblitz. For our work in Canada’s national parks, we thank S. Woodley and J. Waithaka for their lead role in organizing permits and for the many Parks Canada staff who facilitated specimen collections, including M. Allen, D. Amirault-Langlais, J. Bastick, C. Belanger, C. Bergman, J.-F. Bisaillon, S. Boyle, J. Bridgland, S. Butland, L. Cabrera, R. Chapman, J. Chisholm, B. Chruszcz, D. Crossland, H. Dempsey, N. Denommee, T. Dobbie, C. Drake, J. Feltham, A. Forshner, K. Forster, S. Frey, L. Gardiner, P. Giroux, T. Golumbia, D. Guedo, N. Guujaaw, S. Hairsine, E. Hansen, C. Harpur, S. Hayes, J. Hofman, S. Irwin, B. Johnston, V. Kafa, N. Kang, P. Langan, P. Lawn, M. Mahy, D. Masse, D. Mazerolle, C. McCarthy, I. McDonald, J. McIntosh, C. McKillop, V. Minelga, C. Ouimet, S. Parker, N. Perry, J. Piccin, A. Promaine, P. Roy, M. Savoie, D. Sigouin, P. Sinkins, R. Sissons, C. Smith, R. Smith, H. Stewart, G. Sundbo, D. Tate, R. Tompson, E. Tremblay, Y. Troutet, K. Tulk, J. Van Wieren, C. Vance, G. Walker, D. Whitaker, C. White, R. Wissink, C. Wong, and Y. Zharikov. For our work near Canada’s ports in Vancouver, Toronto, Montreal, and Halifax, we thank R. Worcester, A. Chreston, M. Larrivee, and T. Zemlak, respectively. Many other organizations improved coverage in the reference library by providing access to specimens – they included the Canadian National Collection of Insects, Arachnids and Nematodes, Smithsonian Institution’s National Museum of Natural History, the Canadian Museum of Nature, the University of Guelph Insect Collection, the Royal British Columbia Museum, the Royal Ontario Museum, the Pacifc Forestry Centre, the Northern Forestry Centre, the Lyman Entomological Museum, the Churchill Northern Studies Centre, and rare Charitable Research Reserve. We also thank the many taxonomic specialists who identifed specimens, including A. Borkent, B. Brown, M. Buck, C. Carr, T. Ekrem, J. Fernandez Triana, C. Guppy, K. Heller, J. Huber, L. Jacobus, J. Kjaerandsen, J. Klimaszewski, D. Lafontaine, J-F. Landry, G. Martin, A. Nicolai, D. Porco, H. Proctor, D. Quicke, J. Savage, B. C. Schmidt, M. Sharkey, A. Smith, E. Stur, A. Tomas, J. Webb, N. Woodley, and X. Zhou. We also thank K. Kerr and T. Mason for facilitating collections at Toronto Zoo and D. Iles for servicing the trap at Wapusk National Park. This paper contributes to the University of Guelph’s Food from Thought research program supported by the Canada First Research Excellence Fund. The Barcode of Life Data System (BOLD; www.boldsystems.org)8 was used as the primary workbench for creating, storing, analyzing, and validating the specimen and sequence records and the associated data resources48. The BOLD platform has a private, password-protected workbench for the steps from specimen data entry to data validation (see details in Data Records), and a public data portal for the release of data in various formats. The latter is accessible through an API (http://www.boldsystems.org/index.php/resources/api?type=webservices) that can also be controlled through R75 with the package ‘bold’76.Peer reviewedPublisher PD

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes