Publications by authors named "J L Brown"

17,543 Publications

PI3K inhibitors are finally coming of age.

Nat Rev Drug Discov 2021 Jun 14. Epub 2021 Jun 14.

Department of Pathology, University of Cambridge, Cambridge, UK.

Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
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http://dx.doi.org/10.1038/s41573-021-00209-1DOI Listing
June 2021

Embedding supervised exercise training for men on androgen deprivation therapy into standard prostate cancer care: a feasibility and acceptability study (the STAMINA trial).

Sci Rep 2021 Jun 14;11(1):12470. Epub 2021 Jun 14.

Allied Health Professionals, Radiotherapy and Oncology, Sheffield Hallam University, Sheffield, UK.

Lifestyle interventions involving exercise training offset the adverse effects of androgen deprivation therapy in men with prostate cancer. Yet provision of integrated exercise pathways in cancer care is sparse. This study assessed the feasibility and acceptability of an embedded supervised exercise training intervention into standard prostate cancer care in a single-arm, multicentre prospective cohort study. Feasibility included recruitment, retention, adherence, fidelity and safety. Acceptability of behaviourally informed healthcare and exercise professional training was assessed qualitatively. Despite the imposition of lockdown for the COVID-19 pandemic, referral rates into and adherence to, the intervention was high. Of the 45 men eligible for participation, 79% (n = 36) received the intervention and 47% (n = 21) completed the intervention before a government mandated national lockdown was enforced in the United Kingdom. Patients completed a mean of 27 min of aerobic exercise per session (SD = 3.48), at 77% heart rate maximum (92% of target dose), and 3 sets of 10 reps of 3 resistance exercises twice weekly for 12 weeks, without serious adverse event. The intervention was delivered by 26 healthcare professionals and 16 exercise trainers with moderate to high fidelity, and the intervention was deemed highly acceptable to patients. The impact of societal changes due to the pandemic on the delivery of this face-to-face intervention remain uncertain but positive impacts of embedding exercise provision into prostate cancer care warrant long-term investigation.
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http://dx.doi.org/10.1038/s41598-021-91876-yDOI Listing
June 2021

A hypothesis test of feasibility for external pilot trials assessing recruitment, follow-up, and adherence rates.

Stat Med 2021 Jun 14. Epub 2021 Jun 14.

Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

The power of a large clinical trial can be adversely affected by low recruitment, follow-up, and adherence rates. External pilot trials estimate these rates and use them, via prespecified decision rules, to determine if the definitive trial is feasible and should go ahead. There is little methodological research underpinning how these decision rules, or the sample size of the pilot, should be chosen. In this article we propose a hypothesis test of the feasibility of a definitive trial, to be applied to the external pilot data and used to make progression decisions. We quantify feasibility by the power of the planned trial, as a function of recruitment, follow-up, and adherence rates. We use this measure to define hypotheses to test in the pilot, propose a test statistic, and show how the error rates of this test can be calculated for the common scenario of a two-arm parallel group definitive trial with a single normally distributed primary endpoint. We use our method to redesign TIGA-CUB, an external pilot trial comparing a psychotherapy with treatment as usual for children with conduct disorders. We then extend our formulation to include using the pilot data to estimate the standard deviation of the primary endpoint and incorporate this into the progression decision.
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http://dx.doi.org/10.1002/sim.9091DOI Listing
June 2021

Epigenetic clock and methylation studies in elephants.

Aging Cell 2021 Jun 12:e13414. Epub 2021 Jun 12.

Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA.

Age-associated DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age ("epigenetic clocks") in humans, mice, dogs, and other species. Here we present epigenetic clocks for African and Asian elephants. These clocks were developed using novel DNA methylation profiles of 140 elephant blood samples of known age, at loci that are highly conserved between mammalian species, using a custom Infinium array (HorvathMammalMethylChip40). We present epigenetic clocks for Asian elephants (Elephas maximus), African elephants (Loxodonta africana), and both elephant species combined. Two additional human-elephant clocks were constructed by combining human and elephant samples. Epigenome-wide association studies identified elephant age-related CpGs and their proximal genes. The products of these genes play important roles in cellular differentiation, organismal development, metabolism, and circadian rhythms. Intracellular events observed to change with age included the methylation of bivalent chromatin domains, and targets of polycomb repressive complexes. These readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.
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http://dx.doi.org/10.1111/acel.13414DOI Listing
June 2021

Agreement Between Clinical Examination and Magnetic Resonance Imaging in Acute Knee Trauma With Hemarthrosis.

Clin J Sport Med 2021 Jun 9. Epub 2021 Jun 9.

Department of Orthopaedics, NU-Hospital Group, Uddevalla/Trollhättan, Sweden; Department of Clinical Sciences Lund, Orthopaedics, Lund University, Lund, Sweden; and Department of Orthopaedics, Helsingborg Hospital, Helsingborg, Sweden.

Objective: Hemarthrosis after knee trauma often indicates serious joint injury. Few studies have evaluated agreement between clinical examination and findings from magnetic resonance imaging (MRI). We aimed to describe the agreement between acute clinical examination and subacute MRI findings after acute knee trauma with hemarthrosis and the importance of the subspecialty of the examiner.

Design: Longitudinal cohort study. Agreement with MRI findings was evaluated by logistic regression.

Setting: Helsingborg hospital.

Patients: Thousand one hundred forty-five consecutive patients with hemarthrosis after knee trauma.

Interventions: Clinical examination and MRI.

Main Outcome Measures: agreement between clinical examination and findings from MRI. We considered the radiologist's report as the gold standard.

Results: Median time (25th, 75th percentile) from injury to clinical examination was 2 (1, 7) days, and from injury to imaging was 8 (5, 15) days. The overall sensitivity and specificity of clinical examination versus MRI for major ligament injury or lateral patella dislocation (LPD) were 70% [95% confidence interval 67-73) and 66% (61-72), respectively. Orthopedic subspecialist knee had the highest agreement with anterior cruciate ligament rupture (adjusted odds ratios were 1.7 (95% confidence interval 1.2-2.3), 1.9 (1.2-3.0) and 5.9 (3.7-9.5) for orthopedic trainees, orthopedic subspecialists other, and orthopedic subspecialist knee, respectively]. For other ligament injuries and LPD, we did not find statistically significant differences.

Conclusions: Clinical diagnosis after acute knee injury is relatively unreliable versus MRI findings even when performed by orthopedic specialists. However, the agreement is improved when the examination is performed by an orthopedic knee subspecialist.
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http://dx.doi.org/10.1097/JSM.0000000000000950DOI Listing
June 2021