The Anti-Breast Cancer Stem Cell Potency of Copper(I)-Non-Steroidal Anti-Inflammatory Drug Complexes.

Cancer stem cells (CSCs) are thought to be partly responsible for metastasis and cancer relapse. Currently, there are no effective therapeutic options that can remove CSCs at clinically safe doses. Here, we report the synthesis, characterisation, and anti-breast CSC properties of a series of copper(I) complexes, comprising of non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine ligands (1-3). The copper(I) complexes are able to reduce the viability of breast CSCs grown in two- and three-dimensional cultures at micromolar concentrations. The potency of the copper(I) complexes towards breast CSCs was similar to salinomycin (an established anti-breast CSC agent) and cisplatin (a clinically used metallopharmaceutical). Cell-based studies showed that the copper(I) complexes are readily, and similarly, internalised by breast CSCs. The copper(I) complexes significantly increase the intracellular reactive oxygen species (ROS) levels in breast CSCs, and their ROS generation profile with respect to time is dependent on the NSAID component present. The generation of intracellular ROS by the copper(I) complexes could be part of the underlying mechanism by which they evoke breast CSC death. As far as we are aware, this is the first study to explore the anti-breast CSC properties of copper(I) complexes.

The anti-breast cancer stem cell properties of gold(i)-non-steroidal anti-inflammatory drug complexes.

The anti-breast cancer stem cell (CSC) properties of a series of gold(i) complexes comprising various non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine 1-8 are reported. The most effective gold(i)-NSAID complex 1, containing indomethacin, exhibits greater potency for breast CSCs than bulk breast cancer cells (up to 80-fold). Furthermore, 1 reduces mammosphere viability to a better extent than a panel of clinically used breast cancer drugs and salinomycin, an established anti-breast CSC agent. Mechanistic studies suggest 1-induced breast CSC death results from breast CSC entry, cytoplasm localisation, an increase in intracellular reactive oxygen species levels, cyclooxygenase-2 downregulation and inhibition, and apoptosis. Remarkably, 1 also significantly inhibits tumour growth in a murine metastatic triple-negative breast cancer model. To the best of our knowledge, 1 is the first gold complex of any geometry or oxidation state to demonstrate anti-breast CSC properties.

Putting nutrition education on the table: development of a curriculum to meet future doctors' needs.

COVID-19 has further exacerbated trends of widening health inequalities in the UK. Shockingly, the number of years of life lived in general good health differs by over 18 years between the most and least deprived areas of England. Poor diets and obesity are established major risk factors for chronic cardiometabolic diseases and cancer, as well as severe COVID-19. For doctors to provide the best care to their patients, there is an urgent need to improve nutrition education in undergraduate medical school training.With this imperative, the Association for Nutrition established an Interprofessional Working Group on Medical Education (AfN IPG) to develop a new, modern undergraduate nutrition curriculum for medical doctors. The AfN IPG brought together expertise from nutrition, dietetic and medical professionals, representing the National Health Service (NHS), royal colleges, medical schools and universities, government public health departments, learned societies, medical students, and nutrition educators. The curriculum was developed with the key objective of being implementable through integration with the current undergraduate training of medical doctors.Through an iterative and transparent consultative process, thirteen key nutritional competencies, to be achieved through mastery of eleven graduation fundamentals, were established. The curriculum to facilitate the achievement of these key competencies is divided into eight topic areas, each underpinned by a learning objective statement and teaching points detailing the knowledge and skills development required. The teaching points can be achieved through clinical teaching and a combination of facilitated learning activities and practical skill acquisition. Therefore, the nutrition curriculum enables mastery of these nutritional competencies in a way that will complement and strengthen medical students' achievement of the General Medical Council (GMC) Outcome for Graduates.As nutrition is an integrative science, the AfN IPG recommends that the curriculum is incorporated into initial undergraduate medical studies before specialist training. This will enable our future doctors to recognise how nutrition is related to multiple aspects of their training, from physiological systems to patient-centred care, and acquire a broad, inclusive understanding of health and disease. In addition, it will facilitate medical schools to embed nutrition learning opportunities within the core medical training, without the need to add in a large number of new components to an already crowded programme or with additional burden for teaching staff.The undergraduate nutrition curriculum for medical doctors is designed to support medical schools to create future doctors who will understand and recognise the role of nutrition in health. Moreover, it will equip frontline staff to feel empowered to raise nutrition-related issues with their patients as a fundamental part of enhanced care and to appropriately refer on for nutrition support with a registered associate nutritionist/registered nutritionist (ANutr/RNutr) or registered dietitian (RD) where this is likely to be beneficial.

A bioinspired redox-modulating copper(II)-macrocyclic complex bearing non-steroidal anti-inflammatory drugs with anti-cancer stem cell activity.

Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from in vitro studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex 1 comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of 1 is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that 1 kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that 1 is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that 1 evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)-NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates.

Putting nutrition education on the table: development of a curriculum to meet future doctors' needs.

COVID-19 has further exacerbated trends of widening health inequalities in the UK. Shockingly, the number of years of life lived in general good health differs by over 18 years between the most and least deprived areas of England. Poor diets and obesity are established major risk factors for chronic cardiometabolic diseases and cancer, as well as severe COVID-19. For doctors to provide the best care to their patients, there is an urgent need to improve nutrition education in undergraduate medical school training. With this imperative, the Association for Nutrition established the Inter-Professional Working Group on Medical Education (AfN IPG) to develop a new, modern undergraduate nutrition curriculum for medical doctors. The AfN IPG brought together expertise from nutrition, dietetic and medical professionals, representing the National Health Service, royal colleges, medical schools and universities, government public health departments, learned societies, medical students and nutrition educators. The curriculum was developed with the key objective of being implementable through integration with the current undergraduate training of medical doctors. Through an iterative and transparent consultative process, 13 key nutritional competencies, to be achieved through mastery of 11 graduation fundamentals, were established. The curriculum to facilitate the achievement of these key competencies is divided into eight topic areas, each underpinned by a learning objective statement and teaching points detailing the knowledge and skills development required. The teaching points can be achieved through clinical teaching and a combination of facilitated learning activities and practical skills acquisition. Therefore, the nutrition curriculum enables mastery of these nutritional competencies in a way that will complement and strengthen medical students' achievement of the General Medical Council Outcomes for Graduates. As nutrition is an integrative science, the AfN IPG recommends the curriculum is incorporated into initial undergraduate medical studies before specialist training. This will enable our future doctors to recognise how nutrition is related to multiple aspects of their training, from physiological systems to patient-centred care, and acquire a broad, inclusive understanding of health and disease. In addition, it will facilitate medical schools to embed nutrition learning opportunities within the core medical training, without the need to add in a large number of new components to an already crowded programme or with additional burden to teaching staff. The undergraduate nutrition curriculum for medical doctors is designed to support medical schools to create future doctors who will understand and recognise the role of nutrition in health. Moreover, it will equip front-line staff to feel empowered to raise nutrition-related issues with their patients as a fundamental part of enhanced care and to appropriately refer on for nutrition support with a registered nutritionist (RNutr)/registered associate nutritionist (ANutr) or a registered dietitian (RD) where this is likely to be beneficial.

Paediatric eye injuries during a COVID-19 pandemic lockdown.

CLINICAL RELEVANCE: Eye injuries, both accidental and non-accidental, are a significant cause of long-term visual impairment in children. An understanding of when and how such injuries occur is key to development of adequate prevention strategies. BACKGROUND: To evaluate accidental and non-accidental eye injuries in children presenting to the major tertiary emergency department and outpatient ophthalmology clinic in Western Australia during the nationwide COVID-19 lockdown and to determine whether the frequency or nature of these injuries differed from pre-pandemic presentations. METHODS: Retrospective review of the medical records of paediatric patients presenting to the emergency department and specialist ophthalmology clinic with an ocular injury and those presenting to the hospital Child Protection Unit with physical injuries during March-August 2020 and the same period in 2019. RESULTS: There was no significant difference in the total number of accidental eye injury presentations during the lockdown period despite a significant decrease in emergency department attendance overall. Closed-globe injuries were the most common accidental eye injury presentation during lockdown (70/110, 64%), followed by adnexal injuries (39/110, 35%) and open-globe injuries (1/110, 1%). In contrast, referrals to the hospital Child Protection Unit for suspicious injuries declined during lockdown.Although eye injury presentations have changed in other parts of the world since the start of the pandemic, during COVID-19 lockdown in Western Australia, accidental paediatric ocular and adnexal trauma sustained at home continues to be a significant cause for hospital attendance. Public education regarding in-home eye injury prevention must be ongoing.

A dithiacyclam-coordinated silver(i) polymer with anti-cancer stem cell activity.

A cancer stem cell (CSC) active, solution stable, silver(i) polymeric complex bearing a dithiacyclam ligand is reported. The complex displays similar potency towards CSCs to salinomycin in monolayer and three-dimensional cultures. Mechanistic studies suggest CSC death results from cytosol entry, an increase in intracellular reactive oxygen species, and caspase-dependent apoptosis.

The Discrete Breast Cancer Stem Cell Mammosphere Activity of Group 10-Bis(azadiphosphine) Metal Complexes.

We report the anti-breast cancer stem cell (CSC) properties of a series of Group 10-bis(azadiphosphine) complexes 1-3 under exclusively three-dimensional cell culture conditions. The breast CSC mammosphere potency of 1-3 is dependent on the Group 10 metal present, increasing in the following order: 1 (nickel complex) <2 (palladium complex) <3 (platinum complex). Notably, 3 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-active compound, or any reported anti-CSC metal complex tested under similar conditions. Mechanistic studies suggest that the most effective complexes 2 and 3 readily penetrate CSC mammospheres, enter CSC nuclei, induce genomic DNA damage, and trigger caspase-dependent apoptosis. To the best of our knowledge, this is the first study to systematically probe the anti-CSC activity of a series of structurally related Group 10 complexes and to be conducted entirely using three-dimensional CSC culture conditions.

Heterobimetallic propargyl gold complexes with π-bound copper or silver with enhanced anticancer activity.

Several propargyl functionalised substrates with different heteroatoms (N, O or S) have been used for the preparation of propargyl gold(i) phosphine complexes. The complexes were prepared in high yields either by reaction of the substrate with [Au(acac)PPh3] or by reaction of [AuCl(PPh3)] with potassium hydroxide and the substrate in methanol. Several of the complexes have been characterised by X-ray diffraction showing the presence of secondary bonds such as π-stacking and aurophilic interactions. The reaction of the propargyl gold(i) phosphine complexes with [Cu(NO3)(PPh3)2] or [Ag(OTf)(PPh3)2] afforded heterobimetallic complexes with π-coordination of {Cu(PPh3)2} or {Ag(PPh3)2} to the alkyne bond. When the substituent of the propargyl unit contained more strongly coordinating pyridine moieties, [(PyCH2)2NCH2C[triple bond, length as m-dash]CAuPPh3], coordination of the heterometal to the pyridine units occurred, displacing the phosphine groups and giving rise to a dimeric structure. The antiproliferative activity of the complexes against cisplatin resistant lung cancer cell line A549 was determined by MTT assay. The mononuclear gold complexes showed excellent activities with IC50 values < 14 µM. Coordination of copper of silver to the alkynyl fragment resulted in a significant increase in activity suggesting a synergistic effect between the two metal centres.

Immunogenic Cell Death of Breast Cancer Stem Cells Induced by an Endoplasmic Reticulum-Targeting Copper(II) Complex.

Immunogenic cell death (ICD) offers a method of stimulating the immune system to attack and remove cancer cells. We report a copper(II) complex containing a Schiff base ligand and a polypyridyl ligand, 4, capable of inducing ICD in breast cancer stem cells (CSCs). Complex 4 kills both bulk breast cancer cells and breast CSCs at sub-micromolar concentrations. Notably, 4 exhibits greater potency (one order of magnitude) towards breast CSCs than salinomycin (an established breast CSC-potent agent) and cisplatin (a clinically approved anticancer drug). Epithelial spheroid studies show that 4 is able to selectively inhibit breast CSC-enriched HMLER-shEcad spheroid formation and viability over non-tumorigenic breast MCF10 A spheroids. Mechanistic studies show that 4 operates as a Type II ICD inducer. Specifically, 4 readily enters the endoplasmic reticulum (ER) of breast CSCs, elevates intracellular reactive oxygen species (ROS) levels, induces ER stress, evokes damage-associated molecular patterns (DAMPs), and promotes breast CSC phagocytosis by macrophages. As far as we are aware, 4 is the first metal complex to induce ICD in breast CSCs and promote their engulfment by immune cells.

Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs.

We report the breast cancer stem cell (CSC) potency of two nickel(II)-3,4,7,8-tetramethyl-1,10-phenanthroline complexes, 1 and 3, containing the non-steroidal anti-inflammatory drugs (NSAIDs), naproxen and indomethacin, respectively. The nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin, an established CSC-active agent. The complexes, 1 and 3 also display significantly lower toxicity towards non-cancerous epithelial breast cells than breast CSCs or bulk breast cancer cells (up to 4.6-fold). Mechanistic studies suggest that 1 and 3 downregulate cyclooxygenase-2 (COX-2) in breast CSCs and kill breast CSCs in a COX-2 dependent manner. Furthermore, the potency of 1 and 3 towards breast CSCs decreased upon co-treatment with necroptosis inhibitors (necrostatin-1 and dabrafenib), implying that 1 and 3 induce necroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is a hallmark of CSCs, compounds like 1 and 3, which potentially provide access to alternative (non-apoptotic) cell death pathways could hold the key to overcoming hard-to-kill CSCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX-2 inhibition and necroptosis induction in CSCs.

A tri-metallic palladium complex with breast cancer stem cell potency.

A multi-nuclear, triangular-shaped palladium(ii) complex is shown to equipotently kill bulk cancer cells and cancer stem cells (CSCs) in the micromolar range. The palladium(ii) complex evokes CSC apoptosis by entering CSC nuclei and damaging genomic DNA.

Ylide Ligands as Building Blocks for Bioactive Group†11 Metal Complexes.

The reactivity of the phosphonium salt (cyanomethyl)triphenylphosphonium chloride and the ylide (triphenylphosphonio)cyanomethanide towards Group 11 metal complexes is described. Mononuclear neutral gold(I) and gold(III) complexes of the type [AuX{CH(CN)PPh3 }] or [AuX3 {CH(CN)PPh3 }] and cationic derivatives such as [AuL{CH(CN)PPh3 }]X have been prepared. Surprisingly, the cationic gold species could only be prepared with ligands with a large steric hindrance, such as bulky NHCs or the JohnPhos phosphine, in contrast to silver and copper derivatives, which have dimeric structures through the coordination of the metal to the cyano group of the ylide of a second complex. Bis(ylide) metal complexes have also been synthesised in which a different structure is observed for the gold complexes compared with the copper and silver complexes. Although gold forms mononuclear species, the silver complex presents a two-dimensional polymeric structure as a result of further coordination of the silver centre to the nitrogen atoms of cyano groups of further silver complexes. These complexes possess two chiral centres; the gold compound was obtained as a mixture of diastereoisomers, whereas the copper and silver derivatives afford only one diastereoisomer. These compounds were screened for their in vitro cytotoxic activity against the human lung carcinoma cell line (A549). The IC50 values reveal an excellent cytotoxic activity for these metal complexes compared with cisplatin.

Opportunistic adolescent health assessment in the child protection unit.

AIM: Adolescent health assessments are recommended to identify health-risk behaviours. Adolescents who experience maltreatment are more likely to engage in such behaviours. This study (i) describes the frequency of health-risk behaviours amongst adolescents attending a hospital-based child protection unit (CPU) and (ii) determines whether use of a health assessment questionnaire increases the identification of these behaviours. METHODS: A retrospective audit was performed of case notes of adolescents (aged ≥ 12 years) presenting to the CPU over 5 years (2007-2011). Data regarding health-risk behaviours were extracted. In 2012, following the introduction of a standardised HEADSS-based four-page questionnaire, health-risk data were collected prospectively over 18 months. The proportion of subjects reporting health-risk behaviours, before and after questionnaire introduction, was analysed. RESULTS: Two hundred fifty-eight subjects, median age 13 (range 12-18) years, 78% female, were included in the pre-questionnaire period; and 85 subjects, median age 14 (range 12-17) years, 86% female, were included following introduction of the questionnaire. Questionnaire use was associated with an increase in the frequency of health-risk behaviours identified in the following domains: Education (odds ratio 4.48 [confidence interval 2.56-7.96] P < 0.001), Activities (16.18 [6.70-42.74] P < 0.001), Drugs/alcohol (4.00 [2.23-7.16] P < 0.001) and Suicidality (8.27 [4.59-14.92] P < 0.001). Participants reported higher rates of health-risk behaviours than the national population. CONCLUSION: Adolescents attending a hospital-based CPU report high rates of health-risk behaviours. A standardised questionnaire results in increased identification of such behaviours.

Prediction of outcome from the chest radiograph appearance on day 7 of very prematurely born infants.

UNLABELLED: Our aim was to determine whether the chest radiograph appearance at 7 days predicted chronic lung disease development (oxygen dependency at 36 weeks post-menstrual age) or death before discharge and if it was a better predictor than readily available clinical data. Two consecutive studies were performed. In both, chest radiographs taken at 7 days for clinical purposes were assessed using a scoring system for the presence of fibrosis/interstitial shadows, cystic elements and hyperinflation and data were collected regarding gestational age, birth weight, use of antenatal steroids and post-natal surfactant and requirement for ventilation at 7 days. Oxygenation indices were calculated in the first study (study A) at 120 h and in the second (study B) at 168 h. In study A, there were 59 infants with a median gestational age of 26 weeks (range 24 to 28 weeks) and in study B, 40 infants with a median gestational age of 27 weeks (range 25-31 weeks). In both studies, infants who developed chronic lung disease had a significantly higher total chest radiograph score, with a higher score for fibrosis/interstitial shadowing than the rest of the cohort. Infants who died before discharge differed significantly from the rest with regard to significantly higher scores for cysts. In both studies, the areas under the receiver operator characteristic curves with regard to prediction of chronic lung disease were higher for the total chest radiograph score compared to those for readily available clinical data. CONCLUSION: In infants who require a chest radiograph for clinical purposes at 7 days, the chest radiograph appearance can facilitate prediction of outcome of infants born very prematurely.

High-frequency oscillatory ventilation for the prevention of chronic lung disease of prematurity.

BACKGROUND: There remains uncertainty concerning the safety and efficacy of high-frequency oscillatory ventilation as compared with those of conventional ventilation for the respiratory support of very preterm infants. We conducted a multicenter trial to determine whether early intervention with high-frequency oscillatory ventilation reduced mortality and the incidence of chronic lung disease among newborns with a gestational age of 28 weeks or less. METHODS: We randomly assigned preterm infants with a gestational age of 23 to 28 weeks to either conventional ventilation or high-frequency oscillatory ventilation within one hour after birth. Randomization was stratified according to center and gestational age (23 to 25 weeks or 26 to 28 weeks). RESULTS: A total of 400 infants were assigned to high-frequency oscillatory ventilation, and 397 were assigned to conventional ventilation. The composite primary outcome (death or chronic lung disease, diagnosed at 36 weeks of postmenstrual age) occurred in 66 percent of the infants assigned to receive high-frequency oscillatory ventilation and 68 percent of those in the conventional-ventilation group (relative risk in the group assigned to high-frequency oscillatory ventilation, 0.98; 95 percent confidence interval, 0.89 to 1.08). Similar proportions of infants died or had chronic lung disease in each gestational-age group. In both treatment groups treatment failure occurred in 10 percent of infants (relative risk in the group assigned to high-frequency oscillatory ventilation, 0.99; 95 percent confidence interval, 0.66 to 1.50). There were no significant differences between the groups in a range of other secondary outcome measures, including serious brain injury and air leak. CONCLUSIONS: The results obtained with high-frequency oscillatory ventilation and conventional ventilation do not differ significantly in the early treatment of respiratory disease in very preterm infants. Assessment of long-term effects will require additional follow-up.