Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer.

Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 Ki = 0.09 ± 0.02 nM; cellular Mps1 EC50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors.

[18F]Florbetapir positron emission tomography: identification of muscle amyloid in inclusion body myositis and differentiation from polymyositis.

OBJECTIVES: With the tools available currently, confirming the diagnosis of inclusion body myositis (IBM) can be difficult. Many patients are initially misdiagnosed with polymyositis (PM). In this observational study at a UK adult neuromuscular centre, we investigated whether amyloid positron emission tomography could differentiate between IBM and PM. METHODS: Ten patients with IBM and six with PM underwent clinical review, [18F]florbetapir positron emission tomography and MRI of skeletal musculature. Differences in [18F]florbetapir standardised uptake value ratios in skeletal muscle regions of interest were evaluated. Relationships between [18F]florbetapir standardised uptake value ratios and measures of disease severity (clinical and by MRI of skeletal muscle) were assessed. RESULTS: [18F]florbetapir standardised uptake value ratios were significantly higher in those with IBM compared with PM for all assessed regions (total-[18F]florbetapir standardised uptake value ratio 1.45 (1.28 to 2.05) vs 1.01 (0.80 to 1.22), p=0.005). For total-[18F]florbetapir standardised uptake value ratios≥1.28, sensitivity and specificity for IBM was 80% and 100%, respectively. CONCLUSIONS: [18F]florbetapir amyloid positron emission tomography differentiates IBM from PM. Successful development could facilitate accurate diagnosis, inclusion in clinical trials and help avoid unnecessary exposure to potentially harmful treatments.

Measurement of synovial tissue volume in knee osteoarthritis using a semiautomated MRI-based quantitative approach.

PURPOSE: Synovitis is common in knee osteoarthritis and is associated with both knee pain and progression of disease. Semiautomated methods have been developed for quantitative assessment of structure in knee osteoarthritis. Our aims were to apply a novel semiautomated assessment method using 3D active appearance modeling for the quantification of synovial tissue volume (STV) and to compare its performance with conventional manual segmentation. METHODS: Thirty-two sagittal T1 -weighted fat-suppressed contrast-enhanced MRIs were assessed for STV by a single observer using 1) manual segmentation and 2) a semiautomated approach. We compared the STV analysis using the semiautomated and manual segmentation methods, including the time taken to complete the assessments. We also examined the reliability of STV assessment using the semiautomated method in a subset of 12 patients who had participated in a clinical trial of vitamin D therapy in knee osteoarthritis. RESULTS: There was no significant difference in STV using the semiautomated quantitative method compared to manual segmentation, mean difference = 207.2 mm3 (95% confidence interval -895.2 to 1309.7). The semiautomated method was significantly quicker than manual segmentation (18 vs. 71 min). For the semiautomated method, intraobserver agreement was excellent (intraclass correlation coefficient (3,1) = 0.99) and interobserver agreement was very good (intraclass correlation coefficient (3,1) = 0.83). CONCLUSION: We describe the application of a semiautomated method that is accurate, reliable, and quicker than manual segmentation for assessment of STV. The method may help increase efficiency of image assessment in large imaging studies and may also assist investigation of treatment efficacy in knee osteoarthritis.

Recommendations for acquisition and interpretation of MRI of the spine and sacroiliac joints in the diagnosis of axial spondyloarthritis in the UK.

OBJECTIVES: To develop evidence-based recommendations on the use of MRI in the diagnosis of axial SpA (axSpA). METHODS: A working group comprising nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA was established, with support from the British Society of Spondyloarthritis (BRITSpA). Two meetings were held. In the first meeting, research questions were formulated. In the second meeting, the results of a systematic literature review designed to inform the recommendations were reviewed. An anonymized Delphi process was used to formulate the final set of recommendations. For each recommendation, the level of evidence and strength of recommendation was determined. The level of agreement was assessed using a 0-10 numerical rating scale. RESULTS: Two overarching principles were formulated, as follows: The diagnosis of axSpA is based on clinical, laboratory and imaging features (overarching principle 1), and patients with axSpA can have isolated inflammation of either the sacroiliac joints or the spine (overarching principle 2). Seven recommendations addressing the use of MRI in the assessment of patients with suspected axSpA were formulated, covering topics including recommended sequences, anatomical coverage, acquisition parameters and interpretation of active and structural MRI lesions. The level of agreement for each recommendation was very high (range 8.8-9.8). CONCLUSION: A joint rheumatology and radiology consensus on the acquisition and interpretation of MRI in axSpA diagnosis was achieved, and a research agenda formulated. This consensus should help standardize practice around MRI and ensure a more informed, consistent approach to the diagnosis of axSpA.

Effect of Vitamin D supplementation on synovial tissue volume and subchondral bone marrow lesion volume in symptomatic knee osteoarthritis.

BACKGROUND: Data from a recent clinical trial of vitamin D therapy in knee OA suggests that, compared to placebo, vitamin D therapy may be associated with a reduction in effusion-synovitis. Our aim was, using contrast-enhanced (CE) magnetic resonance imaging (MRI), to examine the effect of vitamin D therapy on synovial tissue volume (STV) and also subchondral bone marrow lesion (BML) volume in men and women with symptomatic knee OA. METHODS: Data was acquired from participants who took part in a randomised placebo-controlled trial (UK VIDEO) investigating the effect of vitamin D therapy (800 IU cholecalciferol daily) on radiographic joint space narrowing. A subsample had serial CE MRI scans acquired during the trial. Subjects with serial images were assessed (N = 50) for STV and subchondral BML volume. The difference in the mean change from baseline in these structural outcomes between intervention and placebo groups was assessed using random-effects modelling. RESULTS: The mean age of the 50 subjects (24 active group, 26 placebo group) who contributed data to the analysis was 63.3 years (SD 6.5) and 74% were female. There was no significant difference at 2 years follow-up between the vitamin D and placebo groups in the mean change from baseline for STV (93.9 mm3, 95% CI -1605.0 to 1792.7) and subchondral BML volume (- 313.5 mm3, 95% CI -4244.7 to 3617.7). CONCLUSIONS: Vitamin D supplementation does not appear to have an effect on synovitis or BML volume in patients with symptomatic knee OA. TRIAL REGISTRATION: VIDEO was registered with EudraCT: ref. 2004-000169-37. The protocol for the trial can be accessed at https://www.ctu.mrc.ac.uk/studies/all-studies/v/video/.

An assessment of 18 F-FDG PET/CT for thoracic screening and risk stratification of pulmonary nodules in multiple endocrine neoplasia type 1.

CONTEXT: Bronchopulmonary neuroendocrine tumours (bpNETs) and thymic carcinoid (ThC) are features of multiple endocrine neoplasia type 1 (MEN 1), and surveillance guidelines recommend periodic thoracic imaging. The optimal thoracic imaging modality and screening frequency remain uncertain as does the prognosis of small lung nodules when identified. OBJECTIVES: To evaluate fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) for identification and prognostic assessment of thoracic lesions in MEN 1. DESIGN: Retrospective observational study. SETTING AND PARTICIPANTS: Fifty consecutive MEN 1 patients undergoing screening with 18 F-FDG PET/CT at a tertiary referral hospital between July 2011 and December 2016. INTERVENTIONS: 18 F-FDG PET/CT. OUTCOME MEASURES: Pulmonary and thymic lesion prevalence, size, functional characteristics and behaviour. RESULTS: Thirteen patients (26.0%) exhibited pulmonary nodules with multiple nodules identified in nine (18.0%). An asymptomatic 31 mm FDG-avid ThC was identified in one patient (2%). Of the 13 patients with pulmonary nodules, four (8.0%) exhibited 13 FDG-avid nodules (mean size 10.1 ± 9.1 mm), and nine (18.0%) demonstrated 26 FDG nonavid nodules (mean size 6.9 ± 5.8 mm). All FDG-avid lesions increased in size vs 11 (42.3%) FDG nonavid lesions (P = .0004). For FDG-avid and nonavid nodules, the median doubling time was 24.2 months (IQR 11.4-40.7) and 48.6 months (IQR 37.0-72.2), respectively. Nodule resection was undertaken in two patients, typical bronchial carcinoid diagnosed in one (FDG nonavid) and metastatic renal cell carcinoma in the second (FDG avid). CONCLUSION: Thoracic imaging with 18 F-FDG PET/CT effectively identifies pulmonary nodules and ThC. FDG-avid pulmonary lesions are significantly more likely to progress than nonavid lesions.

Developing a toolkit for the assessment and monitoring of musculoskeletal ageing.

The complexities and heterogeneity of the ageing process have slowed the development of consensus on appropriate biomarkers of healthy ageing. The Medical Research Council-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between researchers and clinicians at the Universities of Liverpool, Sheffield and Newcastle. One of CIMA's objectives is to 'Identify and share optimal techniques and approaches to monitor age-related changes in all musculoskeletal tissues, and to provide an integrated assessment of musculoskeletal function'-in other words to develop a toolkit for assessing musculoskeletal ageing. This toolkit is envisaged as an instrument that can be used to characterise and quantify musculoskeletal function during 'normal' ageing, lend itself to use in large-scale, internationally important cohorts, and provide a set of biomarker outcome measures for epidemiological and intervention studies designed to enhance healthy musculoskeletal ageing. Such potential biomarkers include: biochemical measurements in biofluids or tissue samples, in vivo measurements of body composition, imaging of structural and physical properties, and functional tests. This review assesses candidate biomarkers of musculoskeletal ageing under these four headings, details their biological bases, strengths and limitations, and makes practical recommendations for their use. In addition, we identify gaps in the evidence base and priorities for further research on biomarkers of musculoskeletal ageing.

Plantar plate pathology is associated with erosive disease in the painful forefoot of patients with rheumatoid arthritis.

BACKGROUND: Disease-related foot pathology is recognised to have a significant impact on mobility and functional capacity in the majority of patients with rheumatoid arthritis (RA). The forefoot is widely affected and the metatarsophalangeal (MTP) joints are the most common site of symptoms. The plantar plates are the fibrocartilaginous distal attachments of the plantar fascia inserting into the five proximal phalanges. Together with the transverse metatarsal ligament they prevent splaying of the forefoot and subluxation of the MTP joints. Damage to the plantar plates is a plausible mechanism therefore, through which the forefoot presentation, commonly described as 'walking on pebbles', may develop in patients with RA. The aims of this study were to investigate the relationship between plantar plate pathology and clinical, biomechanical and plain radiography findings in the painful forefoot of patients with RA. Secondly, to compare plantar plate pathology at the symptomatic lesser (2nd-5th) MTP joints in patients with RA, with a group of healthy age and gender matched control subjects without foot pain. METHODS: In 41 patients with RA and ten control subjects the forefoot was imaged using 3T MRI. Intermediate weighted fat-suppressed sagittal and short axis sequences were acquired through the lesser MTP joints. Images were read prospectively by two radiologists and consensus reached. Plantar plate pathology in patients with RA was compared with control subjects. Multivariable multilevel modelling was used to assess the association between plantar plate pathology and the clinical, biomechanical and plain radiography findings. RESULTS: There were significant differences between control subjects and patients with RA in the presence of plantar plate pathology at the lesser MTP joints. No substantive or statistically significant associations were found between plantar plate pathology and clinical and biomechanical findings. The presence of plantar plate pathology was independently associated with an increase in the odds of erosion (OR = 52.50 [8.38-326.97], p < 0.001). CONCLUSION: The distribution of plantar plate pathology at the lesser MTP joints in healthy control subjects differs to that seen in patients with RA who have the consequence of inflammatory disease in the forefoot. Longitudinal follow-up is required to determine the mechanism and presentation of plantar plate pathology in the painful forefoot of patients with RA.

With a biomechanical treatment in knee osteoarthritis, less knee pain did not correlate with synovitis reduction.

BACKGROUND: Braces are used to treat pain in patellofemoral joint osteoarthritis (PFJOA). In a trial, we previously reported pain improvement after 6-weeks brace use. The pain reduction did not correlate with changes in Magnetic Resonance Imaging (MRI) assessed Bone Marrow Lesion volume or static synovial volume. Studies show that changes in the synovium on dynamic contrast enhanced (DCE) MRI are more closely associated with symptom change than static synovial volume changes. We hypothesised change in synovitis assessed using dynamic imaging could explain the reduction in pain. METHOD: One hundred twenty-six men and women aged 40-70 years with painful radiographically confirmed PFJOA were randomised to either brace wearing or no brace for 6-weeks. Pain assessment and DCE-MRI were performed at baseline and 6 weeks. DCE data was analysed using Tofts's equation. Pain measures included a VAS of pain on nominated aggravating activity (VASNA), and the KOOS pain subscale. Paired t-tests were used to determine within person change in outcome measures and Spearman's correlation coefficients were used to determine the correlation between change in pain and change in the DCE parameters. RESULTS: Mean age of subjects was 55.5 years (SD = 7.5) and 57% were female. There was clear pain improvement in the brace users compared to controls (VASNA - 16.87 mm, p = <0.001). There was no significant change to the dynamic synovitis parameters among brace users nor was pain change correlated with change in dynamic synovitis parameters. CONCLUSION: The reduction in knee pain following brace wearing in patients with PFJOA is not explained by changes in synovitis. TRIAL REGISTRATION: Trial registration number UK. ISRCTN50380458 /Registered 21.5.2010.

BMI independently relates to glycaemia in patients with severe enduring mental illness (SMI).

BACKGROUND: People with severe mental illness (SMI) have higher rates of diabetes than the general population. AIMS: To assess the type-2 diabetes screening rates in primary care and the relation between body mass index (BMI) and dysglycaemia for patients on the SMI register in the Cheshire region of the United Kingdom. METHODS: The setting was 24 general practices in Central and Eastern Cheshire, United Kingdom. Subjects were identified through a semianonymized search of GP registers. RESULTS: About 451 of the 787 SMI patients were screened for dysglycaemia and dyslipidaemia. Fasting glucose was in the impaired fasting glycaemia range (6.1-6.9 mmol/l) in 6.5%, and indicative of type-2 diabetes (≥7.0 mmol/l) in 17.3%. There was a positive univariate relation between BMI and fasting glucose (normalized ß = 0.26, p < 0.001). In multivariate models, adjusting for age, gender, smoking and blood pressure, each unit increase in BMI [OR = 1.07 (1.01, 1.13); p = 0.031] and triglycerides [OR = 1.28 (1.06, 1.55); p = 0.009] were independently associated with an increased risk of having type-2 diabetes. CONCLUSION: Increasing BMI relates to dysglycaemia in patients with severe enduring mental illness (SMI). All patients with SMI whether or not receiving neuroleptic treatment should undergo routine monitoring of weight and metabolic parameters.

Synovial tissue volume: a treatment target in knee osteoarthritis (OA).

BACKGROUND: Synovitis occurring frequently in osteoarthritis (OA) may be a targeted outcome. There are no data examining whether synovitis changes following intra-articular intervention. METHODS: Persons aged 40 years and older with painful knee OA participated in an open label trial of intra-articular steroid therapy. At all time points they completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. They had a contrast-enhanced (CE) MRI immediately prior to an intra-articular steroid injection with a repeat scan within 20 days. Response status was assessed using the Osteoarthritis Research Society International (OARSI) response criteria. OARSI responders were followed until their pain relapsed either within 20% of baseline or 6 months, shortly after which a third MRI was performed. Synovial tissue volume (STV) was measured on postcontrast knee images. We looked at changes in the STV and in pain, and their association. RESULTS: 120 subjects with preinjection and postinjection CE MRI were followed. Their mean age was 62.3 years (SD=10.3) and 62 (52%) were women. The median time between injection and follow-up scan was 8 days (IQR 7-14 days). 85/120 (71%) were OARSI responders. Pain decreased (mean change in KOOS=+23.9; 95% CI 20.1 to 27.8, p<0.001) following steroid injection, as did mean STV (mean change=-1071 mm(3); 95% CI -1839 mm(3) to -303 mm(3), p=0.01). Of the 80 who returned for a third MRI, pain relapsed in 57, and in the 48 of those with MRI data, STV increased between follow-up and final visit (+1220 mm(3); 95% CI 25 mm(3) to 2414 mm(3), p=0.05). 23 were persistent responders at 6 months and, in these, STV did not increase (mean change=-202 mm(3); 95% CI -2008 mm(3) to 1604 mm(3), p=0.83). Controlling for variation over time, there was a significant association between synovitis volume and KOOS pain (b coefficient-change in KOOS pain score per 1000 mm(3) change in STV=-1.13; 95% CI -1.87 to -0.39, p=0.003), although STV accounted for only a small proportion of the variance in change in pain. CONCLUSIONS: Synovial tissue volume in knee OA shrinks following steroid therapy, and rebounds in those whose pain relapses. It can be considered a treatment target in symptomatic knee OA. TRIAL REGISTRATION NUMBER: ISRCTN07329370.

Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK.

TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%).

Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.

A prospective, single-centre, randomised study evaluating the clinical, imaging and immunological depth of remission achieved by very early versus delayed Etanercept in patients with Rheumatoid Arthritis (VEDERA).

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis, with significant impact on quality of life and functional status. Whilst biologic disease modifying anti-rheumatic drugs (bDMARD) such as tumour necrosis factor-inhibitor (TNFi) agents have revolutionised outcomes in RA, early diagnosis with immediate conventional therapy, titrated in a treat to target approach is also associated with high remission rates. The main aim of the VEDERA study (Very Early versus Delayed Etanercept in Rheumatoid Arthritis) is to assess the depth of remission, sustainability of remission and immunological normalisation induced by very early TNFi with etanercept (ETN) or standard of care +/- delayed ETN. METHODS/DESIGN: VEDERA is a pragmatic, phase IV single-centre open-label randomised superiority trial of 120 patients with early, treatment-naive RA. Patients will be randomised 1:1 to first-line ETN and methotrexate (MTX) or MTX with additional synthetic disease modifying anti-rheumatic drugs (sDMARDs) according to a treat to target (TT) protocol with further step up to ETN and MTX after 24 weeks if remission is not achieved. Participants will have regular disease activity assessments and imaging evaluation including musculoskeletal ultrasound and MRI. The main objective of this study is to assess the proportion of patients with early RA that achieve clinical remission at 48 weeks, following either treatment strategy. In addition, the participants are invited to take part in a cardio-vascular sub-study (Coronary Artery Disease in RA, CADERA), which aims to identify the incidence of cardiovascular abnormalities in early RA. DISCUSSION: The hypothesis underlining this study is that very early treatment with first-line ETN increases the proportion of patients with rheumatoid arthritis achieving clinical remission, in comparison to conventional therapy. TRIAL REGISTRATION: NCT02433184 , 23/04/2015.

Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids.

OBJECTIVES: To determine whether whole-body MRI defines clinically relevant subgroups within polymyalgia rheumatica (PMR) including glucocorticoid responsiveness. METHODS: 22 patients with PMR and 16 with rheumatoid arthritis (RA), untreated and diagnosed by consultant rheumatologists, underwent whole-body, multiple-joint MRI, scored by two experts. Patients with PMR reported whether they felt 'back to normal' on glucocorticoid therapy and were followed for a median of 2 years. RESULTS: All patients with PMR were deemed to respond to glucocorticoids clinically. A characteristic pattern of symmetrical, extracapsular inflammation, adjacent to greater trochanter, acetabulum, ischial tuberosity and/or symphysis pubis, was observed in 14/22 of the PMR cases. In PMR, this pattern was associated with complete glucocorticoid response (p=0.01), higher pretreatment C-reactive protein (CRP) and serum interleukin-6 (IL-6), and better post-treatment fatigue and function. Only 1/14 in the extracapsular group could stop glucocorticoids within 1 year, compared with 4/7 of the others. A score derived from the five sites discriminating best between PMR and RA correlated with IL-6 (p<0.002). IL-6 levels ≥16.8 pg/mL had 86% sensitivity and 86% specificity for the extracapsular MRI pattern. CONCLUSIONS: A subset of patients with rheumatologist-diagnosed PMR had a characteristic, extracapsular pattern of MRI inflammation, associated with elevated IL-6/CRP and with complete patient-reported glucocorticoid responsiveness.

Anatomical location of erosions at the metatarsophalangeal joints in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this study was to identify the anatomical location of erosions at the MTP joints in patients with RA using high-resolution 3T MRI. METHODS: In 24 patients with RA, the more symptomatic forefoot was imaged using 3T MRI. T1-weighted, intermediate-weighted and T2-weighted fat-suppressed sequences were acquired through the MTP joints, together with three-dimensional volumetric interpolated breath-hold examination (3D VIBE) and T1-weighted fat-suppressed post-gadolinium contrast sequences. Images were scored for bone erosion in the distal and proximal part of the MTP joints using the RA MRI scoring (RAMRIS) system. The base of the proximal phalanx and the head of the metatarsal were divided into quadrants to determine the location of erosions (octants) in the dorsal-medial, dorsal-lateral, plantar-medial and plantar-lateral regions. RESULTS: Seventeen females and seven males with a mean age of 55.5 years and disease duration of 10.6 years (range 0.6-36) were included. Eighteen patients were RF positive, the mean 44-joint DAS for CRP and ESR (DAS44CRP and DAS44ESR) were 2.5 (s.d. 0.8) and 2.6 (s.d. 0.9), respectively. In this cohort of patients with RA, irrespective of MTP joint location, octants located in the proximal part (metatarsal) of the joint and the plantar aspect of the joint were more eroded. CONCLUSION: This is the first study to report the anatomical location of erosions at the MTP joints in patients with RA. We noted that erosions were more commonly seen on the plantar aspect of the metatarsal head in RA, supporting the hypothesis of a relationship between biomechanical demands and bone changes in the forefoot.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

Modeling DCE-MRI at low temporal resolution: a case study on rheumatoid arthritis.

PURPOSE: To identify the optimal tracer-kinetic modeling strategy for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data acquired at low temporal resolution. MATERIALS AND METHODS: DCE-MRI was performed on 13 patients with rheumatoid arthritis of the hand before and after anti-tumor necrosis factor alpha (TNFα) therapy, using a 3D sequence with a temporal resolution of 13 seconds, imaging for 4 minutes postcontrast injection. Concentration-time curves were extracted from regions of interest (ROIs) in enhancing synovium and fitted to the 3-parameter modified Tofts model (MT) and the 4-parameter two-compartment exchange model (2CXM). To assist the interpretation of the data, the same analysis was applied to simulated data with similar characteristics. RESULTS: Both models fitted the data closely, and showed similar therapy effects. The MT plasma volume was significantly lower than with 2CXM, but the differences in permeability and interstitial volume were not significant. 2CXM was less precise than MT, with larger standard deviations relative to the mean in most parameters. The additional perfusion parameter determined with 2CXM did not provide a statistically significant trend due to low precision. CONCLUSION: The standard MT model is the optimal modeling strategy at low temporal resolution. Advanced models improve the accuracy and generate an additional parameter, but these benefits are offset by low precision.

Magnetic resonance transverse relaxation time T2 of knee cartilage in osteoarthritis at 3-T: a cross-sectional multicentre, multivendor reproducibility study.

OBJECTIVE: The transverse relaxation time (T2) in MR imaging has been identified as a potential biomarker of hyaline cartilage pathology. This study investigates whether MR assessments of T2 are comparable between 3-T scanners from three different vendors. DESIGN: Twelve subjects with symptoms of knee osteoarthritis and one or more risk factors had their knee scanned on each of the three vendors' scanners located in three sites in the U.K. MR data acquisition was based on the United States National Institutes of Health Osteoarthritis Initiative protocol. Measures of cartilage T2 and R2 (inverse of T2) were computed for precision error assessment. Intrascanner reproducibility was also assessed with a phantom (all three scanners) and a cohort of 5 subjects (one scanner only). RESULTS: Whole-organ magnetic resonance (WORM) semiquantitative cartilage scores ranged from minimal to advanced degradation. Intrascanner R2 root-mean-square coefficients of variation (RMSCOV) were low, within the range 2.6 to 6.3% for femoral and tibial regions. For one scanner pair, mean T2 differences ranged from -1.2 to 2.8 ms, with no significant difference observed for the medial tibia and patella regions (p < 0.05). T2 values from the third scanner were systematically lower, producing interscanner mean T2 differences within the range 5.4 to 10.0 ms. CONCLUSION: Significant interscanner cartilage T2 differences were found and should be accounted for before data from scanners of different vendors are compared.

Comparison of two ultrashort echo time sequences for the quantification of T1 within phantom and human Achilles tendon at 3 T.

Ultrashort echo time (UTE) techniques enable direct imaging of musculoskeletal tissues with short T2 allowing measurement of T1 relaxation times. This article presents comparison of optimized 3D variable flip angle UTE (VFA-UTE) and 2D saturation recovery UTE (SR-UTE) sequences to quantify T1 in agar phantoms and human Achilles tendon. Achilles tendon T1 values for asymptomatic volunteers were compared to Achilles tendon T1 values calculated from patients with clinical diagnoses of spondyloarthritis (SpA) and Achilles tendinopathy using an optimized VFA-UTE sequence. T1 values from phantom data for VFA- and SR-UTE compare well against calculated T1 values from an assumed gold standard inversion recovery spin echo sequence. Mean T1 values in asymptomatic Achilles tendon were found to be 725±42 ms and 698±54 ms for SR- and VFA-UTE, respectively. The patient group mean T1 value for Achilles tendon was found to be 957±173 ms (P<0.05) using an optimized VFA-UTE sequence with pulse repetition time of 6 ms and flip angles 4, 19, and 24°, taking a total 9 min acquisition time. The VFA-UTE technique appears clinically feasible for quantifying T1 in Achilles tendon. T1 measurements offer potential for detecting changes in Achilles tendon due to SpA without need for intravenous contrast agents.