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  • 1
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    Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 2574-2574
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 2574-2574
    Abstract: 2574 Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.2574
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 2
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    To which world regions does the valence–dominance model of social perception apply?
    Springer Science and Business Media LLC ; 2021
    In:  Nature Human Behaviour Vol. 5, No. 1 ( 2021-01-04), p. 159-169
    Details
    In: Nature Human Behaviour, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2021-01-04), p. 159-169
    Type of Medium: Online Resource
    ISSN: 2397-3374
    URL: Article
    DOI: 10.1038/s41562-020-01007-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2885046-4
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  • 3
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    Urine leaks in renal transplant patients
    Elsevier BV ; 1999
    In:  Clinical Imaging Vol. 23, No. 1 ( 1999-01), p. 35-39
    Details
    In: Clinical Imaging, Elsevier BV, Vol. 23, No. 1 ( 1999-01), p. 35-39
    Type of Medium: Online Resource
    ISSN: 0899-7071
    URL: Article
    DOI: 10.1016/S0899-7071(98)00037-0
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1999
    detail.hit.zdb_id: 2004578-5
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  • 4
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    Wastewater surveillance for rapid identification of infectious diseases in prisons
    Elsevier BV ; 2022
    In:  The Lancet Microbe Vol. 3, No. 8 ( 2022-08), p. e556-e557
    Details
    In: The Lancet Microbe, Elsevier BV, Vol. 3, No. 8 ( 2022-08), p. e556-e557
    Type of Medium: Online Resource
    ISSN: 2666-5247
    URL: Article
    DOI: 10.1016/S2666-5247(22)00154-9
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 3028547-1
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  • 5
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    Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐Binding Agent, in Subjects With Advanced Solid Tumors
    Wiley ; 2021
    In:  Clinical Pharmacology in Drug Development Vol. 10, No. 8 ( 2021-08), p. 940-949
    Details
    In: Clinical Pharmacology in Drug Development, Wiley, Vol. 10, No. 8 ( 2021-08), p. 940-949
    Abstract: PTC596 is a novel, orally bioavailable, small‐molecule tubulin‐binding agent that reduces B‐cell–specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open‐label, multiple‐ascending‐dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration–time curve increased proportionally with body weight–adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels 〉 2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half‐life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half‐life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596‐related treatment‐emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose‐limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.
    Type of Medium: Online Resource
    ISSN: 2160-763X , 2160-7648
    URL: Issue
    URL: Article
    DOI: 10.1002/cpdd.v10.8
    DOI: 10.1002/cpdd.904
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2649010-9
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  • 6
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    The impact of COVID-19 vaccination in prisons in England and Wales: a metapopulation model
    Springer Science and Business Media LLC ; 2022
    In:  BMC Public Health Vol. 22, No. 1 ( 2022-12)
    Details
    In: BMC Public Health, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2022-12)
    Abstract: High incidence of cases and deaths due to coronavirus disease 2019 (COVID-19) have been reported in prisons worldwide. This study aimed to evaluate the impact of different COVID-19 vaccination strategies in epidemiologically semi-enclosed settings such as prisons, where staff interact regularly with those incarcerated and the wider community. Methods We used a metapopulation transmission-dynamic model of a local prison in England and Wales. Two-dose vaccination strategies included no vaccination, vaccination of all individuals who are incarcerated and/or staff, and an age-based approach. Outcomes were quantified in terms of COVID-19-related symptomatic cases, losses in quality-adjusted life-years (QALYs), and deaths. Results Compared to no vaccination, vaccinating all people living and working in prison reduced cases, QALY loss and deaths over a one-year period by 41%, 32% and 36% respectively. However, if vaccine introduction was delayed until the start of an outbreak, the impact was negligible. Vaccinating individuals who are incarcerated and staff over 50 years old averted one death for every 104 vaccination courses administered. All-staff-only strategies reduced cases by up to 5%. Increasing coverage from 30 to 90% among those who are incarcerated reduced cases by around 30 percentage points. Conclusions The impact of vaccination in prison settings was highly dependent on early and rapid vaccine delivery. If administered to both those living and working in prison prior to an outbreak occurring, vaccines could substantially reduce COVID-19-related morbidity and mortality in prison settings.
    Type of Medium: Online Resource
    ISSN: 1471-2458
    URL: Article
    DOI: 10.1186/s12889-022-13219-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041338-5
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  • 7
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    Structural violence: Prison health is public health, and it needs fixing
    Sociological Review Foundation ; 2022
    In:  The Sociological Review Magazine
    Details
    In: The Sociological Review Magazine, Sociological Review Foundation
    Type of Medium: Online Resource
    ISSN: 2754-1371
    URL: Journal
    URL: Article
    DOI: 10.51428/tsr
    DOI: 10.51428/tsr.rebf9627
    Language: Unknown
    Publisher: Sociological Review Foundation
    Publication Date: 2022
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  • 8
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    Determining the Prevalence and Incidence of SARS-CoV-2 Infection in Prisons in England: Protocol for a Repeated Panel Survey and Enhanced Outbreak Study
    JMIR Publications Inc. ; 2022
    In:  JMIR Research Protocols Vol. 11, No. 1 ( 2022-1-12), p. e30749-
    Details
    In: JMIR Research Protocols, JMIR Publications Inc., Vol. 11, No. 1 ( 2022-1-12), p. e30749-
    Abstract: There are over 80,000 people imprisoned in England and Wales in 117 prisons. The management of the COVID-19 pandemic presents particular challenges in this setting where confined, crowded, and poorly ventilated conditions facilitate the rapid spread of infectious diseases. Objective The COVID-19 in Prison Study aims to examine the epidemiology of SARS-CoV-2 in prisons in England in order to inform public health policy and practice during the pandemic and recovery. The primary objective is to estimate the proportion of positive tests of SARS-CoV-2 infection among residents and staff within selected prisons. The secondary objectives include estimating the incidence rate of SARS-CoV-2 infection and examining how the proportion of positive tests and the incidence rate vary among individual, institutional, and system level factors. Methods Phase 1 comprises a repeated panel survey of prison residents and staff in a representative sample of 28 prisons across England. All residents and staff in the study prisons are eligible for inclusion. Participants will be tested for SARS-CoV-2 using a nasopharyngeal swab twice (6 weeks apart). Staff will also be tested for antibodies to SARS-CoV-2. Phase 2 focuses on SARS-CoV-2 infection in prisons with recognized COVID-19 outbreaks. Any prison in England will be eligible to participate if an outbreak is declared. In 3 outbreak prisons, all participating staff and residents will be tested for SARS-CoV-2 antigens at the following 3 timepoints: as soon as possible after the outbreak is declared (day 0), 7 days later (day 7), and at day 28. They will be swabbed twice (a nasal swab for lateral flow device testing and a nasopharyngeal swab for polymerase chain reaction testing). Testing will be done by external contractors. Data will also be collected on individual, prison level, and community factors. Data will be stored and handled at the University of Southampton and Public Health England. Summary statistics will summarize the prison and participant characteristics. For the primary objective, simple proportions of individuals testing positive for SARS-CoV-2 and incidence rates will be calculated. Linear regression will examine the individual, institutional, system, and community factors associated with SARS-CoV-2 infection within prisons. Results The UK Government’s Department for Health and Social Care funds the study. Data collection started on July 20, 2020, and will end on May 31, 2021. As of May 2021, we had enrolled 4192 staff members and 6496 imprisoned people in the study. Data analysis has started, and we expect to publish the initial findings in summer/autumn 2021. The main ethical consideration is the inclusion of prisoners, who are vulnerable participants. Conclusions This study will provide unique data to inform the public health management of SARS-CoV-2 in prisons. Its findings will be of relevance to health policy makers and practitioners working in prisons. International Registered Report Identifier (IRRID) DERR1-10.2196/30749
    Type of Medium: Online Resource
    ISSN: 1929-0748
    URL: Article
    DOI: 10.2196/30749
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2022
    detail.hit.zdb_id: 2719222-2
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  • 9
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    Factors influencing terrestriality in primates of the Americas and Madagascar
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 42 ( 2022-10-18)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 42 ( 2022-10-18)
    Abstract: Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2121105119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
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    Insights gained from early modelling of COVID-19 to inform the management of outbreaks in UK prisons
    Emerald ; 2021
    In:  International Journal of Prisoner Health Vol. 17, No. 3 ( 2021-10-18), p. 380-397
    Details
    In: International Journal of Prisoner Health, Emerald, Vol. 17, No. 3 ( 2021-10-18), p. 380-397
    Abstract: In this work, the authors present some of the key results found during early efforts to model the COVID-19 outbreak inside a UK prison. In particular, this study describes outputs from an idealised disease model that simulates the dynamics of a COVID-19 outbreak in a prison setting when varying levels of social interventions are in place, and a Monte Carlo-based model that assesses the reduction in risk of case importation, resulting from a process that requires incoming prisoners to undergo a period of self-isolation prior to admission into the general prison population. Design/methodology/approach Prisons, typically containing large populations confined in a small space with high degrees of mixing, have long been known to be especially susceptible to disease outbreaks. In an attempt to meet rising pressures from the emerging COVID-19 situation in early 2020, modellers for Public Health England’s Joint Modelling Cell were asked to produce some rapid response work that sought to inform the approaches that Her Majesty’s Prison and Probation Service (HMPPS) might take to reduce the risk of case importation and sustained transmission in prison environments. Findings Key results show that deploying social interventions has the potential to considerably reduce the total number of infections, while such actions could also reduce the probability that an initial infection will propagate into a prison-wide outbreak. For example, modelling showed that a 50% reduction in the risk of transmission (compared to an unmitigated outbreak) could deliver a 98% decrease in total number of cases, while this reduction could also result in 86.8% of outbreaks subsiding before more than five persons have become infected. Furthermore, this study also found that requiring new arrivals to self-isolate for 10 and 14 days prior to admission could detect up to 98% and 99% of incoming infections, respectively. Research limitations/implications In this paper we have presented models which allow for the studying of COVID-19 in a prison scenario, while also allowing for the assessment of proposed social interventions. By publishing these works, the authors hope these methods might aid in the management of prisoners across additional scenarios and even during subsequent disease outbreaks. Such methods as described may also be readily applied use in other closed community settings. Originality/value These works went towards informing HMPPS on the impacts that the described strategies might have during COVID-19 outbreaks inside UK prisons. The works described herein are readily amendable to the study of a range of addition outbreak scenarios. There is also room for these methods to be further developed and built upon which the timeliness of the original project did not permit.
    Type of Medium: Online Resource
    ISSN: 1744-9200 , 1744-9200
    URL: Article
    DOI: 10.1108/IJPH-09-2020-0075
    Language: English
    Publisher: Emerald
    Publication Date: 2021
    detail.hit.zdb_id: 2220160-9
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