A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy

SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m−2 was established as MTD. Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal. Patients had tumours 3 cm in diameter and 4 cm deep. Measurements were performed using 1H/19F surface coils and localised 19F MRS acquisition. SR4554 was administered at 1400 mg m−2, with subsequent increase to 2600 mg m−2 using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. 19Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)*100. A total of 26 patients enrolled at: 1400 (n=16), 1800 (n=1), 2200 (n=1) and 2600 mg m−2 (n=8). SR4554 was well tolerated and toxicities were all grade 1; mean plasma elimination half-life was 3.7±0.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised 19F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6-43.7) compared with 4.1 (range 0.6-7.3) for plasma samples taken at the same times (P=0.001) suggesting 19F retention in tumour and, therefore, the presence of hypoxia. We have demonstrated the feasibility of using 19F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of 19F retention in tumour, supporting further development of this technique for detection of tumour hypoxia

H-WORK project: Multilevel interventions to promote mental health in SMEs and public workplaces

The paper describes the study design, research questions and methods of a large, international intervention project aimed at improving employee mental health and well-being in SMEs and public organisations. The study is innovative in multiple ways. First, it goes beyond the current debate on whether individual- or organisational-level interventions are most effective in improving employee health and well-being and tests the cumulative effects of multilevel interventions, that is, interventions addressing individual, group, leader and organisational levels. Second, it tailors its interventions to address the aftermaths of the Covid-19 pandemic and develop suitable multilevel interventions for dealing with new ways of working. Third, it uses realist evaluation to explore and identify the working ingredients of and the conditions required for each level of intervention, and their outcomes. Finally, an economic evaluation will assess both the cost-effectiveness analysis and the affordability of the interventions from the employer perspective. The study integrates the training transfer and the organisational process evaluation literature to develop toolkits helping end-users to promote mental health and well-being in the workplace

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth.

The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2–2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids

Author correction to: Structure and distribution of an unrecognized interstitium in human tissues

© 2018 The Author(s). The Supplementary Figure file that accompanies this Article contains an error in Supplementary Figure S1, where the Small Intestine CD34 panel was duplicated from the Gallbladder CD34 panel. The correct Figure S1 appears below as Figure 1. (Figure Presented)

COMBINING ABILITY AND GENETIC ANALYSIS OF FRUIT AND LEAF YIELD IN GBOMA EGGPLANT

Gboma eggplant ( Solanum macrocapon L.) of the family Solanaceae is an important fruit and leafy indigenous vegetable in Africa. Despite the numerous nutritional, medicinal and economic benefits derived from the crop, little is known about the genetic parameters governing the inheritance and combining ability of the yield components. Thus, a study was conducted to investigate genetic information on the relevant yield components of the crop. Results showed significant mean squares for General Combining Ability, Specific Combining Ability effects for number of leaves per plant, fruit width and plant height, indicating the combining effect of additive, non-additive and maternal effects for expression for those traits. Conversely, significant (P< 0.05) SCA effects for number of branches per plant, leaf length, leaf width and fresh leaf weight indicated the preponderance of non-additive gene effect. GCA/SCA ratios for the various traits indicated that the relative contribution of additive to non-additive effects varied widely from trait to trait. Significant reciprocal effects for most of the traits were an indication that cytoplasmic or maternal gene effects played a major role in modifying the inheritance of the yield parameters, and that the choice of the maternal parent is relevant in breeding for these traits. Estimated GCA effect among the parents revealed that CAGRIC 03 has a breeding value for number of branches, plant height, fruit length, leaf length and fresh leaf weight, which makes it a valuable material for development of improved varieties. CAGRIC 01 was the promising combiner to increase fruit weight and number of leaves per plant. Hybrid P1xP2 was the best specific combiner to increase fruit width, leaf width and fruit width. High heritability estimates for most of the traits indicate that genetic variation was higher than the environmental variation in the study.Aubergine gboma ( Solanum macrocapon L.) de la famille des solanac\ue9esest un fruit important et l\ue9gumes indig\ue8nes feuillues en Afrique. Malgr\ue9 de nombreux avantages nutritionnels, m\ue9dicinaux et \ue9conomiques d\ue9coulant de la culture, peu est connu sur les param\ue8tres g\ue9n\ue9tiques r\ue9gissant l\u2019h\ue9ritage et la capacit\ue9 de combinaison des composants de rendement. Ainsi, une \ue9tude \ue9tait initi\ue9e pour g\ue9n\ue9rer del\u2019information g\ue9n\ue9tique sur d\u2019importants composants de rendementde la culture. Les r\ue9sultats ont montr\ue9 des carr\ue9s moyens significatifs pour \ue0 l\u2019aptitude generale de combinaison, les effets de la capacit\ue9 sp\ue9cifique de combinaison pour le nombre de feuilles par plante, la largeur des fruits et la hauteur de plant, ce qui t\ue9moign edes effets additifs et non additif et maternels combin\ue9s pour l\u2019expression de ces traits. Inversement, les effets significatifs (P <0,05) de CCSsur le nombre de branches par plant, la longueuret la largeur des feuilles ainsi que le poids de feuilles fra\ueeches indiquent la pr\ue9pond\ue9rance de l\u2019effet du g\ue8ne non-additif. Les rapports GCA/SCA pour les diff\ue9rents traits indiquent que la contribution relative de l\u2019additif aux effets non additifs variait largement d\u2019un trait \ue0 l\u2019autre. Des effets r\ue9ciproques significatifs pour la plupart des traits indiqueque les effets g\ue9n\ue9tiques cytoplasmique sou maternels ont jou\ue9 un r\uf4le majeur dans la modification de l\u2019h\ue9ritage des param\ue8tres de rendement et que le choix du parent maternel est pertinent dans l\u2019am\ue9lioration de ces traits. L\u2019effetestim\ue9 deGCA chez les parents a r\ue9v\ue9l\ue9 que CAGRIC 03 est d\u2019 une valeur ameliorative pour le nombre de branches, la hauteur de la plante, la longueur des fruits, la longueur des feuilles et le poids des feuilles fra\ueeches, ce qui en fait un mat\ue9riel pr\ue9cieux pour le d\ue9veloppement de vari\ue9t\ue9s am\ue9lior\ue9es. CAGRIC 01 \ue9tait le combinateur prometteur pour augmenter le poids de fruits et le nombre de feuilles par plant. L\u2019hybride P1xP2 \ue9tait le meilleur combineur sp\ue9cifique pour augmenter la largeur du fruit, la largeur des feuilles et la largeur du fruit. Des valeurs \ue9lev\ue9es d\u2019h\ue9ritabilit\ue9 pour la plupart des traits indiquent que la variation g\ue9n\ue9tique \ue9tait plus \ue9lev\ue9e que la variation environnementale dans l\u2019\ue9tude

Adapting clonally propagated crops to climatic changes: a global approach for taro (Colocasia esculenta (L.) Schott)

Clonally propagated crop species are less adaptable to environmental changes than those propagating sexually. DNA studies have shown that in all countries where taro (Colocasia esculenta (L.) Schott) has been introduced clonally its genetic base is narrow. As genetic variation is the most important source of adaptive potential, it appears interesting to attempt to increase genetic and phenotypic diversity to strengthen smallholders’ capacity to adapt to climatic changes. A global experiment, involving 14 countries from America, Africa, Asia and the Pacific was conducted to test this approach. Every country received a set of 50 indexed genotypes in vitro assembling significant genetic diversity. After onstation agronomic evaluation trials, the best genotypes were distributed to farmers for participatory on-farm evaluation. Results indicated that hybrids tolerant to taro leaf blight (TLB, Phytophthora colocasiae Raciborski), developed by Hawaii, Papua New Guinea and Samoa breeding programmes outperformed local cultivars in most locations. However, several elite cultivars from SE Asia, also tolerant to TLB, outperformed improved hybrids in four countries and in one country none of the introductions performed better than the local cultivars. Introduced genotypes were successfully crossed (controlled crossing) with local cultivars and new hybrids were produced. For the first time in the history of Aroids research, seeds were exchanged internationally injecting tremendous allelic diversity in different countries. If climatic changes are going to cause the problems envisaged, then breeding crops with wide genetic diversity appears to be an appropriate approach to overcome the disasters that will otherwise ensue.This research was financially supported by the Europe-Aid project ‘‘Adapting clonally propagated crops to climatic and commercial changes’’ (Grant No. DCI-FOOD/ 2010/230-267 SPC). Thanks are due to the 14 different countries technicians working on research stations and to farmers and their families for their enthusiastic contributioninfo:eu-repo/semantics/publishedVersio

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

In vitro selectivity, in vivo biodistribution and tumour uptake of annexin V radiolabelled with a positron emitting radioisotope

The availability of a noninvasive method to detect and quantify apoptosis in tumours will enable tumour response to several cancer therapies to be assessed. We have synthesised two radiotracers, annexin V and the N-succinimidyl-3-iodobenzoic acid (SIB) derivative of annexin V, labelled with radio-iodine (124I and 125I) and provided proof of the concept by assessing specific binding and biodistribution of these probes to apoptotic cells and tumours. We have also assessed the tumour uptake of [124I]annexin V in a mouse model of apoptosis. RIF-1 cells induced to undergo apoptosis in vitro showed a drug concentration-dependent increased binding of [125I]annexin V and [125I]SIB–annexin V. In the same model system, there was an increase in terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL)-positive cells and a decrease in clonogenic survival. Radiotracer binding was completely inhibited by preincubation with unlabelled annexin V. In RIF-1 tumour-bearing mice, rapid distribution of [125I]SIB–annexin V-derived radioactivity to kidneys was observed and the radiotracer accumulated in urine. The binding of [125I]SIB–annexin V to RIF-1 tumours increased by 2.3-fold at 48 h after a single intraperitoneal injection of 5-fluorouracil (165 mg kg−1 body weight), compared to a 4.4-fold increase in TUNEL-positive cells measured by immunostaining. Positron emission tomography images with both radiotracers demonstrated intense localisation in the kidneys and bladder. Unlike [124I]SIB–annexin V, [124I]annexin V also showed localisation in the thyroid region presumably due to deiodination of the radiolabel. [124I]SIB–annexin V is an attractive candidate for in vivo imaging of apoptosis by PET

Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin

There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone→Raf1→Mitogenic Extracellular Kinase→Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-14C)choline and (methyl-14C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-14C)choline uptake, (methyl-14C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-11C)choline may be a useful pharmacodynamic marker for the non-invasive evaluation of geldanamycin analogues