Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment

The evidence base for emergency use authorizations for COVID-19 treatments : A rapid review

Background and Aims During the COVID-19 pandemic, US Food and Drug Administration (FDA) permitted emergency use authorizations (EUAs) for vaccines/treatments with promising data. Eight treatments were issued EUAs by May 31, 2021; one of these was approved (Remdesivir for certain populations) and two were revoked (chloroquine phosphate/hydroxychloroquine and bamlanivimab) by September 30, 2021. The aim of this study is to find out what evidence the EUAs were based on and how many studies were published while they remained active (up to September 30, 2021). Methods A review of published clinical studies for the 6 months before each EUA was issued, and the time after (until September 30, 2021, or until revoked). PubMed and the identified systematic reviews were the sources for identifying published literature. Results The number of clinical studies published pre-EUA varied from a single case study (for chloroquine phosphate/hydroxychloroquine) to numerous studies of multiple types (for convalescent plasma). Four treatments had a single randomized controlled trial (RCT) as evidence (bamlanivimab monotherapy, REGN-COV, bamlanivimab + etesevimab,sotrovimab) and two also had other study types (remdesivir and baricitinib). The number of clinical studies published post-EUA (for those active on September 30, 2021) was widely varied. Eighteen RCTs were published for Convalescent plasma, while Remdesivir had eight. Baricitinib, REGN-COV, and bamlanivimab + etesevimab all had one, but none were published for sotrovimab. Conclusion The number of trials for treatments with EUAs was limited in all cases before the EUA was issued, and in most cases for those with EUAs ongoing at the end of September 2021. The presence of EUAs may discourage participation in relevant clinical trials, which delays the widespread implementation of evidenced-based therapies. Large, robust RCTs should be completed, such as the RECOVERY trial in the United Kingdom, to quickly find the answers desperately required during a pandemic

Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms-uncoupling from upstream signals and splice isoform ratios-drive the activity of LYN in aggressive breast cancers

Dupuytren’s Interventions Surgery versus Collagenase (DISC) Trial : Study Protocol for a pragmatic, two arm parallel group, non-inferiority randomised controlled trial

Background: Dupuytren’s contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment, however recent studies have indicated that an alternative to surgery - Collagenase Clostridium Histolyticum (Collagenase) - is better than placebo in the treatment of Dupuytren’s contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of Collagenase compared with limited fasciectomy surgery. The Dupuytren’s Interventions Surgery vs Collagenase Trial (DISC) Trial was therefore designed to fill this evidence gap. Methods/Design: The DISC Trial is a multi-centre pragmatic two arm parallel group, randomised controlled trial. Participants will be assigned 1:1 to receive either Collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren’s contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported Patient Evaluation Measure assessed at 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following Collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost effectiveness of treatments and a qualitative sub-study will assess participants experiences and preferences of the treatments. Discussion: The DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost effectiveness of Collagenase compared to limited fasciectomy surgery for patients with Dupuytren’s contracture. ISRCTN registry identifier: ISRCTN18254597. Prospectively registered on 11th April 2017. https://doi.org/10.1186/ISRCTN18254597 Keywords: Dupuytren’s contracture, Collagenase clostridium histolyticum, limited fasciectomy, surgery, correction, randomised controlled tria

Effects of rapid recruitment and dissemination on Covid-19 mortality: the RECOVERY trial

Abstract The RECOVERY trial is a large multi-armed, adaptive randomised controlled trial of treatments for Covid-19. It has rapidly recruited and demonstrated that hydroxychloroquine is ineffective in reducing mortality for hospitalised patients, whilst dexamethasone significantly reduces mortality among those patients using supplemental oxygen or on a ventilator. We estimate that the speed of recruitment and dissemination has probably decreased mortality in the UK by at least 200 hospitalised patients in the first month since the British Prime Minister announced the results. Despite its impressive speed, the trial only recruited about 15% of eligible patients, with recruitment rates ranging between 3% to 80% at participating hospitals. Had the trial recruited 50% of the eligible patients then our analysis suggests that more than 2,000 additional lives could have been saved. In a pandemic, rapid recruitment with high centre recruitment is absolutely essential to reduce deaths. Methods of improving site specific recruitment rates need investigating urgently. Key Words: Covid-19; RECOVERY trial; recruitment

The evidence base for emergency use authorizations for COVID‐19 treatments: A rapid review

Abstract Background and Aims During the COVID‐19 pandemic, US Food and Drug Administration (FDA) permitted emergency use authorizations (EUAs) for vaccines/treatments with promising data. Eight treatments were issued EUAs by May 31, 2021; one of these was approved (Remdesivir for certain populations) and two were revoked (chloroquine phosphate/hydroxychloroquine and bamlanivimab) by September 30, 2021. The aim of this study is to find out what evidence the EUAs were based on and how many studies were published while they remained active (up to September 30, 2021). Methods A review of published clinical studies for the 6 months before each EUA was issued, and the time after (until September 30, 2021, or until revoked). PubMed and the identified systematic reviews were the sources for identifying published literature. Results The number of clinical studies published pre‐EUA varied from a single case study (for chloroquine phosphate/hydroxychloroquine) to numerous studies of multiple types (for convalescent plasma). Four treatments had a single randomized controlled trial (RCT) as evidence (bamlanivimab monotherapy, REGN‐COV, bamlanivimab + etesevimab, sotrovimab) and two also had other study types (remdesivir and baricitinib). The number of clinical studies published post‐EUA (for those active on September 30, 2021) was widely varied. Eighteen RCTs were published for Convalescent plasma, while Remdesivir had eight. Baricitinib, REGN‐COV, and bamlanivimab + etesevimab all had one, but none were published for sotrovimab. Conclusion The number of trials for treatments with EUAs was limited in all cases before the EUA was issued, and in most cases for those with EUAs ongoing at the end of September 2021. The presence of EUAs may discourage participation in relevant clinical trials, which delays the widespread implementation of evidenced‐based therapies. Large, robust RCTs should be completed, such as the RECOVERY trial in the United Kingdom, to quickly find the answers desperately required during a pandemic

Examination of early treatment effects and related biases during the conduct of two UK-wide pragmatic orthopaedic surgical trials: ProFHER and UK FROST

Aims: Early large treatment effects can arise in small studies, which lessen as more data accumulate. This study aimed to retrospectively examine whether early treatment effects occurred for two multicentre orthopaedic randomized controlled trials (RCTs) and explore biases related to this. Methods: Included RCTs were ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation), a two-arm study of surgery versus non-surgical treatment for proximal humerus fractures, and UK FROST (United Kingdom Frozen Shoulder Trial), a three-arm study of two surgical and one non-surgical treatment for frozen shoulder. To determine whether early treatment effects were present, the primary outcome of Oxford Shoulder Score (OSS) was compared on forest plots for: the chief investigator’s (CI) site to the remaining sites, the first five sites opened to the other sites, and patients grouped in quintiles by randomization date. Potential for bias was assessed by comparing mean age and proportion of patients with indicators of poor outcome between included and excluded/non-consenting participants. Results: No bias in treatment effect was observed overall for the CI site, or the first five sites, compared with the remaining sites in either trial. An early treatment effect on the OSS was observed for the first quintile of participants recruited to ProFHER only (clinically relevant difference of seven points). Selection bias for age was observed in the ProFHER trial only, with slightly younger patients being recruited into the study. Both trials showed some selection bias for markers of poor prognosis, although these did not appear to change over time. Conclusion: No bias in treatment effects overall were found at the CI or early sites set-up. An early treatment effect was found in one of the two trials, which was likely a chance effect as this did not continue during the study. Selection bias was observed in both RCTs, however this was minimal and did not impact on outcome. Cite this article: Bone Jt Open 2023;4(2):96–103