Estimates of genetic parameters of distal limb fracture and superficial digital flexor tendon injury in UK Thoroughbred racehorses

A retrospective cohort study of distal limb fracture and superficial digital flexor tendon (SDFT) injury in Thoroughbred racehorses was conducted using health records generated by the British Horseracing Authority (BHA) between 2000 and 2010. After excluding records of horses that had both flat and jump racing starts, repeated records were reduced to a single binary record per horse (<i>n</i> = 66,507, 2982 sires), and the heritability of each condition was estimated using residual maximum likelihood (REML) with animal logistic regression models. Similarly, the heritability of each condition was estimated for the flat racing and jump racing populations separately. Bivariate mixed models were used to generate estimates of genetic correlations between SDFT injury and distal limb fracture. The heritability of distal limb fracture ranged from 0.21 to 0.37. The heritability of SDFT injury ranged from 0.31 to 0.34. SDFT injury and distal limb fracture were positively genetically correlated. These findings suggest that reductions in the risk of the conditions studied could be attempted using targeted breeding strategies

Estimates of genetic parameters of distal limb fracture and superficial digital flexor tendon injury in UK Thoroughbred racehorses

A B S T R A C T A retrospective cohort study of distal limb fracture and superficial digital flexor tendon (SDFT) injury in Thoroughbred racehorses was conducted using health records generated by the British Horseracing Authority (BHA) between 2000 and 2010. After excluding records of horses that had both flat and jump racing starts, repeated records were reduced to a single binary record per horse (n = 66,507, 2982 sires), and the heritability of each condition was estimated using residual maximum likelihood (REML) with animal logistic regression models. Similarly, the heritability of each condition was estimated for the flat racing and jump racing populations separately. Bivariate mixed models were used to generate estimates of genetic correlations between SDFT injury and distal limb fracture. The heritability of distal limb fracture ranged from 0.21 to 0.37. The heritability of SDFT injury ranged from 0.31 to 0.34. SDFT injury and distal limb fracture were positively genetically correlated. These findings suggest that reductions in the risk of the conditions studied could be attempted using targeted breeding strategies

Measuring the impact and costs of a universal group based parenting programme : protocol and implementation of a trial

Background Sub-optimal parenting is a common risk factor for a wide range of negative health, social and educational outcomes. Most parenting programmes have been developed in the USA in the context of delinquency prevention for targeted or indicated groups and the main theoretical underpinning for these programmes is behaviour management. The Family Links Nurturing Programme (FLNP) focuses on family relationships as well as behaviour management and is offered on a universal basis. As a result it may be better placed to improve health and educational outcomes. Developed in the UK voluntary sector, FLNP is popular with practitioners, has impressed policy makers throughout the UK, has been found to be effective in before/after and qualitative studies, but lacks a randomised controlled trial (RCT) evidence base. Methods/Design A multi-centre, investigator blind, randomised controlled trial of the FLNP with a target sample of 288 south Wales families who have a child aged 2-4 yrs living in or near to Flying Start/Sure Start areas. Changes in parenting, parent child relations and parent and child wellbeing are assessed with validated measures immediately and at 6 months post intervention. Economic components include cost consequences and cost utility analyses based on parental ranking of states of quality of life. Attendance and completion rates and fidelity to the FLNP course delivery are assessed. A nested qualitative study will assess reasons for participation and non-participation and the perceived value of the programme to families. By the end of May 2010, 287 families have been recruited into the trial across four areas of south Wales. Recruitment has not met the planned timescales with barriers including professional anxiety about families entering the control arm of the trial, family concern about video and audio recording, programme facilitator concern about the recording of FLNP sessions for fidelity purposes and delays due to the new UK research governance procedures. Discussion Whilst there are strong theoretical arguments to support universal provision of parenting programmes, few universal programmes have been subjected to randomised controlled trials. In this paper we describe a RCT protocol with quantitative and qualitative outcome measures and an economic evaluation designed to provide clear evidence with regard to effectiveness and costs. We describe challenges implementing the protocol and how we are addressing these

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

Funder: NIHR Cambridge Biomedical Research CentreFunder: Addenbrooke’s Charitable TrustFunder: National Institute for Health Research (NIHR)Funder: Mark Foundation For Cancer ResearchFunder: Cambridge Commonwealth, European and International TrustFunder: Cancer Research UKFunder: Cambridge Clinical Trials UnitFunder: Cancer Research UK Cambridge CentreFunder: Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and ManchesterFunder: Cambridge Experimental Cancer Medicine CentrePURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). CONCLUSIONS: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. TRIAL REGISTRATION: EudraCtNo: 2005-004502-82

The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy.

BACKGROUND: The gut microbiome is implicated as a marker of response to  immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types. METHODS: Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome. DISCUSSION: There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes. TRIAL REGISTRATION: NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021)

Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth

Tumors are comprised of cancer cells and a network of non-cancerous stromal cells. Cancer-associated fibroblasts (CAFs) are well known to support tumorigenesis and are emerging as immune modulators. While many leukocyte populations are well studied in cancer, neutrophils have received less attention. Neutrophils can release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NETs) in a process termed NETosis. Here, we show that CAFs induce formation of NETs both within the tumor microenvironment and at systemic levels in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on PAD4 and CD11b. Remarkably, CAF-derived Amyloid β was identified as the key factor driving t-NETosis, a protein with significance in both neurodegenerative and inflammatory disorders. Therapeutic inhibition of NETs in established tumors prevented growth, skewing neutrophils to a pro-inflammatory phenotype. Reciprocally, t-NETs enhanced CAF activation phenotypes. Mirroring murine observations, NETs were detected juxtaposed to CAFs in human melanoma and pancreatic adenocarcinoma, and elevated expression of amyloid and β-Secretase correlated with poor prognosis. In summary, we report the existence of cross-talk between CAFs and neutrophils within the tumour microenvironment whereby CAF-induced t-NETosis supports cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target. Significance This study defines the existence of a pro-tumor immunomodulatory function of the stroma showing the induction of Neutrophil Extracellular Traps through CAF-derived Amyloid β. We term this novel process “Tumor-induced NETosis” (t-NETosis) and propose that therapeutic inhibition of this mechanism, which we observe in human melanoma and pancreatic cancer, has the potential to improve patient outcome

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib

A Randomized Ph2 Study of MEDI0680 in Combination With Durvalumab vs. Nivolumab Monotherapy in Patients With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

BACKGROUND: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase 2 study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy naïve patients with advanced clear cell renal cell carcinoma who received at least one prior line of anti-angiogenic therapy. METHODS: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all IV Q2W. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden (TMB), and tumor-infiltrated immune cell profiles. RESULTS: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% (7/42; 95% CI, 7.0-31.4) with combination treatment and 23.8% (5/21; 95% CI, 8.2- 47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Due to AEs, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. CONCLUSIONS: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy