Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Background: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Results: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Conclusion: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer

A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.

Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3

Derivation of the Statistical Distribution of the Mass Peak Centroids of Mass Spectrometers Employing Analog-to-Digital Converters and Electron Multipliers

The statistical distribution of mass peak centroids recorded on mass spectrometers employing analog-to-digital converters (ADCs) and electron multipliers is derived from the first principles of the data generation process. The resulting Gaussian model is discussed and is validated with experimental data and with Monte Carlo simulations

Psychological factors not strength deficits are associated with severity of gluteal tendinopathy: a cross-sectional study

Gluteal tendinopathy is the most common lower limb tendinopathy presenting to general practice. It has a high prevalence amongst middle-aged women and impacts on daily activities, work participation and quality of life. The aim was to compare physical and psychological characteristics between subgroups of severity of pain and disability.A multicentre cross-sectional cohort of 204 participants (mean age 55\ua0years, 82% female) who had a clinical diagnosis of gluteal tendinopathy with magnetic resonance imaging confirmation were assessed. A range of physical and psychosocial characteristics were recorded. Pain and disability were measured with the VISA-G questionnaire. A cluster analysis was used to identify mild, moderate and severe subgroups based on total VISA-G scores. Between-group differences were then evaluated with a MANCOVA, including sex and study site as covariates, followed by a Bonferroni post hoc test. Significance was set at 0.05.There were significantly higher pain catastrophizing and depression scores in the more severe subgroups. Lower pain self-efficacy scores were found in the severe group compared to the moderate and mild groups. Greater waist girth and body mass index (BMI), lower activity levels and poorer quality of life were reported in the severe group compared to the mild group. Hip abductor muscle strength and hip circumference did not differ between subgroups of severity.Individuals with severe gluteal tendinopathy present with psychological distress, poorer quality of life, greater BMI and waist girth. Given these features, the consideration of psychological factors in more severe patients may be important to optimize patient outcomes and reduce healthcare utilization.Patients with severe gluteal tendinopathy exhibit greater psychological distress, poorer quality of life and greater waist girth and BMI when compared to less severe cases. This implies that clinicians ought to consider psychological factors in the management of more severe gluteal tendinopathy

An engaged approach to exploring issues around poverty and mental health: A reflective evaluation of the research process from researchers and community partners involved in the DeStress study

Background Involving patients, service users, carers and members of the public in research has been part of health policy and practice in the UK for the last 15 years. However, low‐income communities tend to remain marginalized from the co‐design and delivery of mental health research, perpetuating the potential for health inequalities. Greater understanding is therefore needed on how to meaningfully engage low‐income communities in mental health research. Objectives To explore and articulate whether and how an engaged research approach facilitated knowledge coproduction relating to poverty and mental distress. Setting A reflective evaluation of community and researcher engagement in the DeStress study that took place in two low‐income areas of South‐west England. Design Reflective evaluation by the authors through on‐going feedback, a focus group and first‐person writing and discussion on experiences of working with the DeStress project, and how knowledge coproduction was influenced by an engaged research approach. Results An engaged research approach influenced the process and delivery of the DeStress project, creating a space where community partners felt empowered to coproduce knowledge relating to poverty‐related mental distress, treatment and the training of health professionals that would otherwise have been missed. We examine motivations for involvement, factors sustaining engagement, how coproduction influenced research analysis, findings and dissemination of outputs, and what involvement meant for different stakeholders. Conclusion Engaged research supported the coproduction of knowledge in mental health research with low‐income communities which led to multiple impacts

SUMOylation inhibits FOXM1 activity and delays mitotic transition

The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia.

The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage

Kernel reconstruction for delayed neural field equations

Understanding the neural field activity for realistic living systems is a challenging task in contemporary neuroscience. Neural fields have been studied and developed theoretically and numerically with considerable success over the past four decades. However, to make effective use of such models, we need to identify their constituents in practical systems. This includes the determination of model parameters and in particular the reconstruction of the underlying effective connectivity in biological tissues. In this work, we provide an integral equation approach to the reconstruction of the neural connectivity in the case where the neural activity is governed by a delay neural field equation. As preparation, we study the solution of the direct problem based on the Banach fixed point theorem. Then we reformulate the inverse problem into a family of integral equations of the first kind. This equation will be vector valued when several neural activity trajectories are taken as input for the inverse problem. We employ spectral regularization techniques for its stable solution. A sensitivity analysis of the regularized kernel reconstruction with respect to the input signal u is carried out, investigating the Frechet differentiability of the kernel with respect to the signal. Finally, we use numerical examples to show the feasibility of the approach for kernel reconstruction, including numerical sensitivity tests, which show that the integral equation approach is a very stable and promising approach for practical computational neuroscience