Although almost 90% of the world population of children and adolescents live in low-and middle-income countries, few trials of psychosocial interventions to prevent child mental health problems have been conducted in these countries. 1 Early-onset conduct problems are the most common mental health concern in childhood, affecting 5-8% of the population at the severity level for an ICD-10 diagnosis. 2 Long-term outcomes are very poor, with three-to sixfold increases in the prevalence of adult criminal violence, drug misuse, school failure, teenage pregnancy and unemployment. 3 Although proven preventative interventions exist, they reach few children, even in high-income countries. This problem is amplified in low-and middle-income countries where child mental health services are extremely limited. 4,5 Schools offer a logical setting for interventions for children, and school-based violence prevention programmes in high-income countries have shown significant reductions to children's aggressive and disruptive behaviour and increases in child competencies. Universal interventions promote the mental health of all children, avoid stigmatisation and generally attract community support. 6 However, there is limited information on the effectiveness of these programmes in low-and middle-income countries where schools often have few resources and poor conditions. In Jamaica, violence among youth and adults is particularly prevalent. 7 However, there are good opportunities for early intervention as 98% of 3-to 6-year-old children attend pre-schools so there is potential for almost universal coverage. In pilot studies we implemented the Incredible Years Teacher Training programme and showed large benefits to teachers' practices and to class-wide measures of child behaviour, 8 and also demonstrated that the intervention was acceptable, feasible and relevant. 9 The aim of this study was to evaluate on a larger scale the effect of the intervention on the behaviour of high-risk children at home and at school. Method Study design and participants A cluster randomised trial was conducted in the school year in 24 community pre-schools in inner-city areas of Kingston, Jamaica. Over 75% of preschool children in Jamaica attend community pre-schools, which are provided through community organisations with government oversight. Parents pay a small fee and also provide school materials such as books and pencils. Most teachers are paraprofessionals and the schools generally have poor physical conditions, including overcrowding and few teaching and learning materials. We used 'pre-school' as the unit of randomisation to prevent contamination among teachers. Inclusion criteria for pre-schools were: three to four classes of children, at least 20 children per class, situated in a specified geographical area and all teachers consented to the trial. In total, 50 pre-schools were approached and 24 meeting the inclusion criteria were recruited (Fig. 1). Children at high risk for subsequent externalising problems were selected for evaluation. 2 An interviewer-administered screening questionnaire was conducted with each teacher. Teachers rated each child on ten items from the ICD-10 Diagnostic Criteria for Research 10 for conduct disorder (loses temper, back chats, disobedient/breaks rules, annoys others, blames others, easily annoyed, often angry, spiteful to others, fights or bullies and destroys property), using a four-point scale. The three children from each class with the highest scores were enrolled. Background There is an urgent need for effective, affordable interventions to prevent child mental health problems in low-and middle-income countries.

Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective. To solve this problem, herein, we report that perfluorocarbon nanoparticles (PNPs) can be used to create a long-lasting, penetrable and hypoxic tumour microenvironment for ensuring both the delivery and activation of subsequently administered HBAs. In addition to the increased permeability and enhanced hypoxia caused by the PNPs, the PNPs can be retained to further achieve the long-term inhibition of intratumoural O2 reperfusion while enhancing HBA accumulation for over 24 h. Therefore, perfluorocarbon materials may have great potential for reigniting clinical research on hypoxia-based drugs.

Aging is a physiological process in which multifactorial processes determine a progressive decline. Several alterations contribute to the aging process, including telomere shortening, oxidative stress, deregulated autophagy and epigenetic modifications. In some cases, these alterations are so linked with the aging process that it is possible predict the age of a person on the basis of the modification of one specific pathway, as proposed by Horwath and his aging clock based on DNA methylation. Because the energy metabolism changes are involved in the aging process, in this work, we propose a new aging clock based on the modifications of glucose catabolism. The biochemical analyses were performed on mononuclear cells isolated from peripheral blood, obtained from a healthy population with an age between 5 and 106 years. In particular, we have evaluated the oxidative phosphorylation function and efficiency, the ATP/AMP ratio, the lactate dehydrogenase activity and the malondialdehyde content. Further, based on these biochemical markers, we developed a machine learning-based mathematical model able to predict the age of an individual with a mean absolute error of approximately 9.7 years. This mathematical model represents a new non-invasive tool to evaluate and define the age of individuals and could be used to evaluate the effects of drugs or other treatments on the early aging or the rejuvenation.

Cytoglobin is important in the progression of oral squamous cell carcinoma but the molecular and cellular basis remain to be elucidated. In the current study, we develop a new cell model to study the function of cytoglobin in oral squamous carcinoma and response to cisplatin. Transcriptomic profiling showed cytoglobin mediated changes in expression of genes related to stress response, redox metabolism, mitochondrial function, cell adhesion, and fatty acid metabolism. Cellular and biochemical studies show that cytoglobin expression results in changes to phenotype associated with cancer progression including: increased cellular proliferation, motility and cell cycle progression. Cytoglobin also protects cells from cisplatin-induced apoptosis and oxidative stress with levels of the antioxidant glutathione increased and total and mitochondrial reactive oxygen species levels reduced. The mechanism of cisplatin resistance involved inhibition of caspase 9 activation and cytoglobin protected mitochondria from oxidative stress-induced fission. To understand the mechanism behind these phenotypic changes we employed lipidomic analysis and demonstrate that levels of the redox sensitive and apoptosis regulating cardiolipin are significantly up-regulated in cells expressing cytoglobin. In conclusion, our data shows that cytoglobin expression results in important phenotypic changes that could be exploited by cancer cells in vivo to facilitate disease progression.

Drug therapy unavoidably brings toxic side effects and drug content-limited therapeutic efficacy although many nanocarriers have been developed to improve them to a certain extent. In this work, a concept of drug-free therapeutics is proposed and defined as a therapeutic methodology without the use of traditional toxic drugs, without the consumption of therapeutic agents during treatment but with the inexhaustible therapeutic capability to maximize the benefit of treatment, and a Z-scheme SnS1.68-WO2.41 nanocatalyst is developed to achieve near infrared (NIR)-photocatalytic generation of oxidative holes and hydrogen molecules for realizing combined hole/hydrogen therapy by the drug-free therapeutic strategy. Without the need of any drug and other therapeutic agent assistance, the nanocatalyst oxidizes/consumes intratumoral over-expressed glutathione (GSH) by holes and simultaneously generates hydrogen molecules in a lasting and controllable way under NIR irradiation. Mechanistically, generated hydrogen molecules and GSH consumption inhibit cancer cell energy and destroy intratumoral redox balance, respectively, to synergistically damage DNA and induce tumor cell apoptosis. High efficacy and biosafety of combined hole/hydrogen therapy of tumors are achieved by the nanocatalyst. The proposed catalysis-based drug-free therapeutic strategy breaks a pathway to realize high efficacy and low toxicity of cancer treatment.

The acidic tumor microenvironment modifies malignant cell behavior. Here, we study consequences of the microenvironment in breast carcinomas. Beginning at carcinogen-based breast cancer induction, we supply either regular or NaHCO3-containing drinking water to female C57BL/6j mice. We evaluate urine and blood acid-base status, tumor metabolism (microdialysis sampling), and tumor pH (pH-sensitive microelectrodes) in vivo. Based on freshly isolated epithelial organoids from breast carcinomas and normal breast tissue, we assess protein expression (immunoblotting, mass spectrometry), intracellular pH (fluorescence microscopy), and cell proliferation (bromodeoxyuridine incorporation). Oral NaHCO3 therapy increases breast tumor pH in vivo from 6.68 ± 0.04 to 7.04 ± 0.09 and intracellular pH in breast epithelial organoids by ~0.15. Breast tumors develop with median latency of 85.5 ± 8.2 days in NaHCO3-treated mice vs. 82 ± 7.5 days in control mice. Oral NaHCO3 therapy does not affect tumor growth, histopathology or glycolytic metabolism. The capacity for cellular net acid extrusion is increased in NaHCO3-treated mice and correlates negatively with breast tumor latency. Oral NaHCO3 therapy elevates proliferative activity in organoids from breast carcinomas. Changes in protein expression patterns—observed by high-throughput proteomics analyses—between cancer and normal breast tissue and in response to oral NaHCO3 therapy reveal complex influences on metabolism, cytoskeleton, cell-cell and cell-matrix interaction, and cell signaling pathways. We conclude that oral NaHCO3 therapy neutralizes the microenvironment of breast carcinomas, elevates the cellular net acid extrusion capacity, and accelerates proliferation without net effect on breast cancer development or tumor growth. We demonstrate unexpected pro-neoplastic consequences of oral NaHCO3 therapy that in breast tissue cancel out previously reported anti-neoplastic effects.