A single centre service evaluation of patients’ experiences participating in Radiotherapy Clinical Trials during and post COVID-19 in Northern Ireland, UK

Introduction: Radiotherapy (RT) clinical trials allow patients to access cutting-edge innovative cancer treatments. Clinical Research Therapy Radiographers (CRRs) play an important role in the management and care of RT trial patients. The COVID-19 pandemic caused major disruption to RT trial delivery. Measures to mitigate COVID-19 risk continue to have an effect on patient contact and communication within cancer centres in the United Kingdom (UK). This study aimed to explore patient perspectives regarding their recent RT trial experience in Northern Ireland (NI), UK.Methods: A single centre service evaluation was conducted in NI. Patients who were recruited into a RT clinical trial from January 2020 to January 2023 were invited to participate. Surveys were posted to 50 participants in April 2023. Quantitative and qualitative data was captured and analysed using descriptive statistics and Braun and Clarke’s six-step thematic analysis framework respectively. Ethical approval was obtained through Ulster University and the NHS Trust.Results: Forty-three of the 50 invited participants responded (86%). Forty-two respondents (79%) had a prostate cancer diagnosis. Forty-one (98%) participants indicated that CRRs were always approachable, polite and courteous and would recommend taking part in a RT trial to friends and family. Identified areas for improvement included aspects regarding consent and participant decision-making. Conclusion: This study suggests that despite the implemented measures to suspend research and mitigate COVID-19 risk, patients remained highly satisfied with the quality of care that they received through their participation in RT trials. Implications for practice: The results of this service evaluation will facilitate maintenance and improvement of patient focused delivery of cancer trials within the host centre. This study builds on evidence highlighting the importance of the CRR role and role development for radiographers. <br/

Distress Tolerance Trajectories Following Substance Use Treatment

OBJECTIVE: Distress tolerance (DT), the ability to withstand aversive internal states, represents an important risk factor for substance use relapse and a potential treatment target. Neurobiological research in substance using populations suggests that continued substance use could erode DT, whereas abstinence could bolster it. The current study characterized trajectories of behavioral and self-reported indices of DT and examined the prospective effect of substance use on DT trajectories among those seeking treatment for substance use. METHOD: Individuals (N = 263, Mage = 42.68, SD = 11.8, 70.7% male, 94.7% African American) in residential substance use treatment completed subjective (Distress Tolerance Scale) and behavioral (Mirror Tracing Persistence Task-computerized version) DT measures, as well as report of daily substance use (timeline follow-back) over 5 assessment time-points from pretreatment to 12 months posttreatment. Latent curve modeling estimated DT trajectories and their associations with substance use behavior, including abstinence duration (days until first use) and substance use frequency (percentage of substance use days between assessments). RESULTS: Self-reported and behavioral DT indicators both exhibited positive, nonlinear change over time (standardized slope parameter estimates: Distress Tolerance Scale β = 0.61, p &lt; .01; Mirror Tracing Persistence Task β = 0.34, p &lt; .01). Abstinence duration was associated with greater improvement in behavioral (β = .20, p = .03) DT specifically. Frequency of use was statistically significantly associated with attenuated behavioral DT at 6-month (β = -.12, p = .03) and 12-month follow-ups (β = -.08, p = .045). CONCLUSIONS: DT appears to improve appreciably posttreatment, and return to substance use may shape the degree of this improvement. Collectively, these findings support the conceptualization of DT as a malleable treatment target and emphasize the benefit of abstinence on improvement in DT

Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue

E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments

Morphological convergence in "river dolphin" skulls

Convergent evolution can provide insights into the predictability of, and constraints on, the evolution of biodiversity. One striking example of convergence is seen in the ‘river dolphins’. The four dolphin genera that make up the ‘river dolphins’ (Inia geoffrensis, Pontoporia blainvillei, Platanista gangetica and Lipotes vexillifer) do not represent a single monophyletic group, despite being very similar in morphology. This has led many to using the ‘river dolphins’ as an example of convergent evolution. We investigate whether the skulls of the four ‘river dolphin’ genera are convergent when compared to other toothed dolphin taxa in addition to identifying convergent cranial and mandibular features. We use geometric morphometrics to uncover shape variation in the skulls of the ‘river dolphins’ and then apply a number of phylogenetic techniques to test for convergence. We find significant convergence in the skull morphology of the ‘river dolphins’. The four genera seem to have evolved similar skull shapes, leading to a convergent morphotype characterised by elongation of skull features. The cause of this morphological convergence remains unclear. However, the features we uncover as convergent, in particular elongation of the rostrum, support hypotheses of shared feeding mode or diet and thus provide the foundation for future work into convergence within the Odontoceti.Open access. Distributed under Creative Commons CC-BY 4.

Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: a randomised controlled trial

Purpose Dietary polyphenols have been demonstrated to favourably modify a number of cardiovascular risk markers such as blood pressure (BP), endothelial function and plasma lipids. We conducted a randomised, double-blind, controlled, crossover trial to investigate the effects of a phenolic-rich olive leaf extract (OLE) on BP and a number of associated vascular and metabolic measures. Methods A total of 60 pre-hypertensive [systolic blood pressure (SBP): 121–140 mmHg; diastolic blood pressure (DBP): 81–90 mmHg] males [mean age 45 (±SD 12.7 years, BMI 26.7 (±3.21) kg/m2] consumed either OLE (136 mg oleuropein; 6 mg hydroxytyrosol) or a polyphenol-free control daily for 6 weeks before switching to the alternate arm after a 4-week washout. Results Daytime [−3.95 (±SD 11.48) mmHg, p = 0.027] and 24-h SBP [−3.33 (±SD 10.81) mmHg, p = 0.045] and daytime and 24-h DBP [−3.00 (±SD 8.54) mmHg, p = 0.025; −2.42 (±SD 7.61) mmHg, p = 0.039] were all significantly lower following OLE intake, relative to the control. Reductions in plasma total cholesterol [−0.32 (±SD 0.70) mmol/L, p = 0.002], LDL cholesterol [−0.19 (±SD 0.56) mmol/L, p = 0.017] and triglycerides [−0.18 (±SD 0.48), p = 0.008] were also induced by OLE compared to control, whilst a reduction in interleukin-8 [−0.63 (±SD 1.13) pg/ml; p = 0.026] was also detected. Other markers of inflammation, vascular function and glucose metabolism were not affected. Conclusion Our data support previous research, suggesting that OLE intake engenders hypotensive and lipid-lowering effects in vivo

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 x 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 x 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 x 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers

Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in diverse tissues, including in individual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications