Feasibility of Data-Driven, Model-Free Quantitative MRI Protocol Design: Application to Brain and Prostate Diffusion-Relaxation Imaging

Brain; Protocol design; Quantitative MRI (qMRI)Cerebro; Diseño de protocolo; Resonancia magnética cuantitativa (qMRI)Cervell; Disseny del protocol; Ressonància magnètica quantitativa (qMRI)Purpose: We investigate the feasibility of data-driven, model-free quantitative MRI (qMRI) protocol design on in vivo brain and prostate diffusion-relaxation imaging (DRI). Methods: We select subsets of measurements within lengthy pilot scans, without identifying tissue parameters for which to optimise for. We use the “select and retrieve via direct upsampling” (SARDU-Net) algorithm, made of a selector, identifying measurement subsets, and a predictor, estimating fully-sampled signals from the subsets. We implement both using artificial neural networks, which are trained jointly end-to-end. We deploy the algorithm on brain (32 diffusion-/T1-weightings) and prostate (16 diffusion-/T2-weightings) DRI scans acquired on three healthy volunteers on two separate 3T Philips systems each. We used SARDU-Net to identify sub-protocols of fixed size, assessing reproducibility and testing sub-protocols for their potential to inform multi-contrast analyses via the T1-weighted spherical mean diffusion tensor (T1-SMDT, brain) and hybrid multi-dimensional MRI (HM-MRI, prostate) models, for which sub-protocol selection was not optimised explicitly. Results: In both brain and prostate, SARDU-Net identifies sub-protocols that maximise information content in a reproducible manner across training instantiations using a small number of pilot scans. The sub-protocols support T1-SMDT and HM-MRI multi-contrast modelling for which they were not optimised explicitly, providing signal quality-of-fit in the top 5% against extensive sub-protocol comparisons. Conclusions: Identifying economical but informative qMRI protocols from subsets of rich pilot scans is feasible and potentially useful in acquisition-time-sensitive applications in which there is not a qMRI model of choice. SARDU-Net is demonstrated to be a robust algorithm for data-driven, model-free protocol design.This project was funded by the Engineering and Physical Sciences Research Council (EPSRC EP/R006032/1, M020533/1, G007748, I027084, N018702). This project has received funding under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 634541 and 666992, and from: Rosetrees Trust (United Kingdom, funding FG); Prostate Cancer United Kingdom Targeted Call 2014 (Translational Research St.2, project reference PG14-018-TR2); Cancer Research United Kingdom grant ref. A21099; Spinal Research (United Kingdom), Wings for Life (Austria), Craig H. Neilsen Foundation (United States) for jointly funding the INSPIRED study; Wings for Life (#169111); United Kingdom Multiple Sclerosis Society (grants 892/08 and 77/2017); the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centres and UCLH NIHR Biomedical Research Centre; Champalimaud Centre for the Unknown, Lisbon (Portugal); European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 101003390. FG is currently supported by the investigator-initiated PREdICT study at the Vall d’Hebron Institute of Oncology (Barcelona), funded by AstraZeneca and CRIS Cancer Foundation

Polaronic Correlations in Magnetic Behavior of Oxygen Deficient V2O5

The undoped V2O5 sample is synthesized by thermal decomposition resulting in oxygen deficient polycrystalline nature. It has a crystallite size of about 80 nm and a chemical stoichiometry of V2O4.65 with a significant V4+ states in addition to V5+ as seen from X-ray diffraction and X-ray photoelectron spectroscopy respectively. The optical studies reveal a bandgap of 2.2 eV and a significant emission due to defects (1.8 eV) as well as Moss-Burstein effect(3.1 eV) which arises due to gap states and split in conduction band respectively. The temperature dependant electrical conductivity and thermopower measurements clearly demonstrate a polaronic conduction mechanism of small polaron hopping with hopping energy of 0.112 eV. The V2O5 sample is found to show a strong field as well as temperature dependent magnetic behaviour when measured using sensitive SQUID magnetometer. It shows a positive magnetic susceptibility at all temperatures (5-300 K) at low field (0.1 T). The observed behavior is found to be a mix of ferromagnetism (FM) and antiferromagnetism (AFM, {\theta}=-2.1 K in CW fit). On the other hand, for high field (1 T), it showed FM only at low temperatures and abruptly becomes diamagnetic at 31.2 K. This varied magnetic behavior has been attributed to small polaron hopping which arises because of oxygen vacancy defects compensated by charge defects of V4+ and transition from bound to free polarons seen from transport. This is further revealed as strong hybridization of V bonded to oxygen vacancy VO and neighboring V5+ ions, resulting in net magnetic moment per vacancy (3.959 {\mu}_B) as predicted from first principle calculations. The insignificantly low energy difference between FM and AFM interactions observed from calculations and their critical dependence on oxygen vacancy concentrations justify the varied magnetic behaviour of V2O5 reported in the literatur

Association of Inflammatory and Oxidative Stress Markers with Metabolic Syndrome in Asian Indians in India

Metabolic syndrome (MetS) is a primary risk factor for cardiovascular disease and is associated with a proinflammatory state. Here, we assessed the contribution of inflammatory and oxidative stress markers towards prediction of MetS. A total of 2316 individuals were recruited in Phase I of the Indian Atherosclerosis Research Study (IARS). Modified ATPIII guidelines were used for classification of subjects with MetS. Among the inflammatory and oxidative stress markers studied, levels of hsCRP (P < .0001), Neopterin (P = .036), and oxLDL (P < .0001) were significantly higher among subjects with MetS. Among the markers we tested, oxLDL stood out as a robust predictor of MetS in the IARS population (OR 4.956 95% CI 2.504–9.810; P < .0001) followed by hsCRP (OR 1.324 95% CI 1.070–1.638; P = .010). In conclusion, oxLDL is a candidate predictor for MetS in the Asian Indian population

Usefulness of C-Reactive Protein as a Marker for Prediction of Future Coronary Events in the Asian Indian Population: Indian Atherosclerosis Research Study

Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 (r = .373; P = <.0001), sPLA2 (r = .544; P = <.0001) as also with fibrinogen (r = .579; P = <.0001). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP (>3.58 mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population

Antithrombotic therapy and survival in patients with malignant disease

A broad range of studies suggest a two-way relationship between cancer and venous thromboembolism (VTE). Patients with cancer have consistently been shown to be at elevated risk for VTE; this risk is partly driven by an intrinsic hypercoagulable state elicited by the tumour itself. Conversely, thromboembolic events in patients without obvious risk factors are often the first clinical manifestation of an undiagnosed malignancy. The relationship between VTE and cancer is further supported by a number of trials and meta-analyses which, when taken together, strongly suggest that antithrombotic therapy can extend survival in patients with cancer by a mechanism that extends beyond its effect in preventing VTE. Moreover, accumulating evidence from in vitro and in vivo studies has shown that tumour growth, invasion, and metastasis are governed, in part, by elements of the coagulation system. On 22 May 2009, a group of health-care providers based in the United Kingdom met in London, England, to examine recent advances in cancer-associated thrombosis and its implications for UK clinical practice. As part of the discussion, attendees evaluated evidence for and against an effect of antithrombotic therapy on survival in cancer. This paper includes a summary of the data presented at the meeting and explores potential mechanisms by which antithrombotic agents might exert antitumour effects. The summary is followed by a consensus statement developed by the group

Prevalence and component analysis of metabolic syndrome: An Indian atherosclerosis research study perspective

Asian Indians have a high predisposition to metabolic syndrome (MS) and coronary artery disease (CAD). The present study aimed to estimate MS prevalence in 531 Asian Indian families comprising of 2318 individuals. Anthropometrics and lipid profile were assessed. MS prevalence was estimated using standard Adult Treatment Panel III (ATP-III) and World Health Organisation (WHO) criteria and modified definitions which included lowered cut-offs for waist circumference (WC) (≥90 cm for men and ≥80 cm for women], body mass index (BMI) (≥23 kg/m2) and impaired fasting glucose (IFG) levels. ATP-III criteria identified a significantly higher proportion of people with MS (N = 933; 40.3%) compared with WHO (N = 708; 30.6%; p < 0.0001) while modified ATP-III showed maximum gain in percent prevalence among the revised criteria (17.3%; p = 0.0056). The IDF criteria identified similar proportion of subjects with MS (N = 809; 34.9%) as the revised WHO criteria (N = 792; 34.2%). The number of MS subjects was highest in the 50–59 years age group. MS was diagnosed a decade earlier in unaffected subjects compared with those with CAD/diabetes using the modified MS criteria. WC correlated significantly with BMI and waist–hip ratio (WHR) (p = 0.000). Among MS components, high density lipoprotein cholesterol and BMI contributed significantly in males (71.4% and 85.9%) and females (86.8% and 88.8%), respectively. The higher percentage contribution of WC among males and WHR among females indicates the influence of gynecoid/android pelvis on WHR measures. In conclusion, the revision of definition criteria for MS with lowered cut-offs for WC and BMI is critical for the accurate assessment of MS among Asian Indians

Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history.</p> <p>Methods & results</p> <p>Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h²48% – 70%; <it>P </it>< 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi-point analysis (LOD score 7.42, <it>P </it>< 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (<it>P </it>< 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (<it>P </it>< 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (<it>P </it>< 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis.</p> <p>Conclusion</p> <p>The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians.</p

Synthesis and cytotoxicity of a biotinylated CC-1065 analogue

BACKGROUND: The use of pretargeting technology for cancer imaging and treatment has made significant progress in the last few years. This approach takes advantage of the fact that biotin binds strongly to proteins avidin and streptavidin. Thus, a non-toxic tumor cell specific antibody is conjugated with avidin/streptavidin, and is administered to patients. After the antibody binds to tumor cells (usually 24–48 h); a clearing agent is given to remove the residual circulating antibodies in blood. Lastly, a toxic biotin-radioisotope conjugate is administered. Due to the small size of the biotin-radioisotope molecule and tight binding between biotin and avidin/streptavidin, the biotin-radioisotope rapidly binds to tumor cells with high specificity. CC-1065 (1) is one of a few classes of extremely potent antitumor agents, and a biotinalyted CBI-bearing CC-1065 analogue is a promising candidate to be used in the pretargeting technology to treat cancer. RESULTS: A biotinalyted CBI-bearing CC-1065 analogue, 6, was synthesized. The IC(50) of 6 was 0.7 nM against U937 cells. Compound 6 caused apototsis of U937 cells. CONCLUSIONS: For the first time, a biotinalyted CBI-bearing CC-1065 analogue, 6, was synthesized. The biotinylated 6 can serve as a model compound to explore the usefulness of non-radioactive small molecule anticancer drugs in the pretargeting strategy for cancer imaging and therapy

FRAGMATIC: A randomised phase III clinical trial investigating the effect of fragmin® added to standard therapy in patients with lung cancer

Background Venous thromboembolism (VTE) occurs when blood clots in the leg, pelvic or other deep vein (deep vein thrombosis) with or without transport of the thrombus into the pulmonary arterial circulation (pulmonary embolus). VTE is common in patients with cancer and is increased by surgery, chemotherapy, radiotherapy and disease progression. Low molecular weight heparin (LMWH) is routinely used to treat VTE and some evidence suggests that LMWH may also have an anticancer effect, by reduction in the incidence of metastases. The FRAGMATIC trial will assess the effect of adding dalteparin (FRAGMIN), a type of LMWH, to standard treatment for patients with lung cancer. Methods/Design The study design is a randomised multicentre phase III trial comparing standard treatment and standard treatment plus daily LMWH for 24 weeks in patients with lung cancer. Patients eligible for this study must have histopathological or cytological diagnosis of primary bronchial carcinoma (small cell or non-small cell) within 6 weeks of randomisation, be 18 or older, and must be willing and able to self-administer 5000 IU dalteparin by daily subcutaneous injection or have it administered to themselves or by a carer for 24 weeks. A total of 2200 patients will be recruited from all over the UK over a 3 year period and followed up for a minimum of 1 year after randomisation. Patients will be randomised to one of the two treatment groups in a 1:1 ratio, standard treatment or standard treatment plus dalteparin. The primary outcome measure of the trial is overall survival. The secondary outcome measures include venous thrombotic event (VTE) free survival, serious adverse events (SAEs), metastasis-free survival, toxicity, quality of life (QoL), levels of breathlessness, anxiety and depression, cost effectiveness and cost utility. Trial registration Current Controlled Trials ISRCTN8081276