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High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or "smart" malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.
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Antineoplásicos , Neoplasias , Humanos , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Oncologia , Terapia CombinadaRESUMO
The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.
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Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Recidiva Local de Neoplasia , Microambiente Tumoral , Humanos , Glioblastoma/patologia , Glioblastoma/terapia , Recidiva Local de Neoplasia/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , AnimaisRESUMO
Infantile haemangioma (IH), the most common vascular tumour of infancy, is comprised of diverse cell types including endothelial cells, pericytes, fibroblasts and immune cells. IH is characterized by rapid proliferation followed by slow involution over 1 - 10 years. Most lesions regress spontaneously, but up to 10% can be disfiguring with complications that require further medical treatment. Recent research has revealed the biological characteristics of IH, highlighting the involvement of angiogenesis and vasculogenesis during tumour formation. Gene expression profiling has provided vital insights into these underlying biological processes, with some of the key IH-related pathways identified, including VEGF, RAAS, HIF-1α, Notch, PDGF, PI3K/Akt/mTOR, JAK/STAT, FGF, PPARγ, IGF. Further evidence suggests extracellular matrix factors and hormone receptors regulate IH progression. In this review, we explore the molecular mechanisms involved in the proliferating, plateau and involuting phases of IH. This involves identifying differentially expressed genes, targeted proteins, and key signalling pathways. This knowledge will increase the broader understanding of vascular development, tissue remodelling and angiogenesis.
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NEW FINDINGS: What is the topic of this review? Thermal extremes disproportionately affect populations with cardiovascular conditions. Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a non-modifiable risk factor for cardiovascular disease. The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes. What advances does it highlight? Cardiovascular stress tests performed in preterm-born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood. This dysfunction has many similarities with populations known to be at risk in thermal extremes. ABSTRACT: Preterm-born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro- and micro-physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later-life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes.
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Doenças Cardiovasculares , Nascimento Prematuro , Criança , Feminino , Adolescente , Recém-Nascido , Humanos , Lactente , Populações Vulneráveis , Idade Gestacional , Fatores de RiscoRESUMO
Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Stress tests are frequently employed to expose early signs of cardiovascular dysfunction or disease and can be employed, for example, in the context of preterm birth. We aimed to establish a safe and effective thermal stress test to examine cardiovascular function. Guinea pigs were anaesthetized using a 0.8% isoflurane, 70% N2O mix. ECG, non-invasive blood pressure, laser Doppler flowmetry, respiratory rate, and an array of skin and rectal thermistors were applied. A physiologically relevant heating and a cooling thermal stress test was developed. Upper and lower thermal limits for core body temperature were set at 41.5 OC and 34 OC, for the safe recovery of animals. This protocol therefore presents a viable thermal stress test for use in guinea pig models of health and disease that facilitates exploration of whole-system cardiovascular function.
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Sistema Cardiovascular , Nascimento Prematuro , Recém-Nascido , Humanos , Feminino , Cobaias , Animais , Teste de Esforço , Pele/irrigação sanguínea , Temperatura BaixaRESUMO
Development from early conceptus to a complex, multi-cellular organism is a highly ordered process that is dependent on an adequate supply of nutrients. During this process, the pattern of organ growth is robust, driven by a genetic blueprint and matched to anticipated body mass with high precision and with built-in physiological reserve capacity. This apparent canalisation of the developmental process is particularly sensitive to variation in environmental stimuli, such as inappropriate drug or hormone exposure, or pattern of nutrient delivery. Significant variation in any of these factors can profoundly affect fetal and neonatal growth patterns, with later detriment for physiological function and/or reserve capacity of the resultant adult, with potential health impact. This paradigm shift in science has become known as the Developmental Origins of Health and Disease (DOHaD). Over the last 30 years, many animal and clinical studies have vastly expanded our fundamental knowledge of developmental biology, particularly in the context of later effects on health. In this horizons article, we discuss DOHaD through the lens of nutritional quality (e.g. micronutrient, amino acid, NSP intake). The concept of 'Quality' was considered undefinable by Robert Persig in his book, 'Zen and the Art of Motorcycle Maintenance'. Here, development and the art of nutritional maintenance will define quality in terms of the pattern of nutrient intake, the quality of development and how each interact to influence later health outcomes.
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Ingestão de Energia , Nutrientes , Animais , Valor NutritivoRESUMO
Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring.
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Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Fenômenos Fisiológicos da Nutrição Materna , Frutose/efeitos adversos , Desenvolvimento Fetal , Doenças Metabólicas/complicações , Mitocôndrias , Efeitos Tardios da Exposição Pré-Natal/etiologiaRESUMO
Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of ß-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.
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Frutose/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteômica/métodos , Animais , Cromatografia Líquida , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Ácidos Graxos Monoinsaturados/sangue , Feminino , Cobaias , Humanos , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas em Tandem , Triglicerídeos/metabolismo , DesmameRESUMO
BACKGROUND AND AIMS: Insulin-like growth factor (IGF)-1 deficiency is associated with a range of metabolic disorders. Cyclic glycine-proline (cGP) is a natural nutrient and regulates the amount of active IGF-1 in plasma. Plasma cGP decreases in hypertensive women whereas increases in obese women, suggesting its involvement in cardio-metabolic function. We therefore examined the effects of cGP on metabolic profiles and blood pressure in high-fat diet (HFD)-induced obese male rats. METHODS: Male rats were fed either a HFD or a standard chow diet (STD) ad-libitum from 3 to 15 weeks of age. Rats were administered either saline or cGP from 11 to 15 weeks of age. At 14 weeks of age, systolic-blood pressure (SBP) was measured by tail-cuff plethysmography and body composition quantified by DEXA. Blood and retroperitoneal fat tissues were collected. Plasma concentrations of insulin, IGF-1, IGF binding protein (IGFBP)-3 and cGP were evaluated using ELISA and HPLC-MS respectively. RESULTS: Compared to STD, HFD feeding increased SBP, total fat mass and fat/lean ratio, retroperitoneal fat weight, fasting plasma insulin and cGP concentrations whereas decreased plasma IGF-1 and IGFBP-3 concentrations. Administration of cGP reduced SBP and retroperitoneal fat weight, but had no effect on body composition and plasma insulin concentrations. CONCLUSION: HFD-associated decreases in IGFBP-3 and increases in cGP represent an autocrine response to normalize IGF-1 function through improving the amount of bioavailable IGF-1 in the circulation of obese male rats. The beneficial effects of cGP on SBP and retroperitoneal fat mass may suggest a therapeutic potential for cGP in HFD-associated cardio-metabolic complications.
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Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Dieta Hiperlipídica , Hipertensão/prevenção & controle , Obesidade/tratamento farmacológico , Peptídeos Cíclicos/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/etiologia , Hipertensão/fisiopatologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/etiologia , Obesidade/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Children born preterm, especially boys, are at increased risk of developing attention deficit hyperactivity disorder (ADHD) and learning difficulties. We propose that neurosteroid-replacement therapy with ganaxolone (GNX) following preterm birth may mitigate preterm-associated neurodevelopmental impairment. METHODS: Time-mated sows were delivered preterm (d62) or at term (d69). Male preterm pups were randomized to ganaxolone (Prem-GNX; 2.5 mg/kg subcutaneously twice daily until term equivalence), or preterm control (Prem-CON). Surviving male juvenile pups underwent behavioural testing at d25-corrected postnatal age (CPNA). Brain tissue was collected at CPNA28 and mature myelinating oligodendrocytes of the hippocampus and subcortical white matter were quantified by immunostaining of myelin basic protein (MBP). RESULTS: Ganaxolone treatment returned the hyperactive behavioural phenotype of preterm-born juvenile males to a term-born phenotype. Deficits in MBP immunostaining of the preterm hippocampus and subcortical white matter were also ameliorated in animals receiving ganaxolone. However, during the treatment period weight gain was poor, and pups were sedated, ultimately increasing the neonatal mortality rate. CONCLUSION: Ganaxolone improved neurobehavioural outcomes in males suggesting that neonatal treatment may be an option for reducing preterm-associated neurodevelopmental impairment. However, dosing studies are required to reduce the burden of unwanted side effects.
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Transtorno do Deficit de Atenção com Hiperatividade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Locomoção/efeitos dos fármacos , Neuroesteroides/farmacologia , Pregnanolona/análogos & derivados , Nascimento Prematuro , Animais , Animais Recém-Nascidos , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Modelos Animais de Doenças , Moduladores GABAérgicos/toxicidade , Cobaias , Masculino , Proteína Básica da Mielina/metabolismo , Neuroesteroides/toxicidade , Pregnanolona/farmacologia , Pregnanolona/toxicidade , Estudo de Prova de Conceito , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Comportamento SocialRESUMO
Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.
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Desenvolvimento Fetal , Modelos Animais , Pesquisa Translacional Biomédica , Animais , Feminino , Cobaias , GravidezRESUMO
Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.
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Feto/metabolismo , Placenta/metabolismo , Resultado da Gravidez , Ovinos/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Gravidez , PrenhezRESUMO
Fish oil is commonly taken by pregnant women, and supplements sold at retail are often oxidized. Using a rat model, we aimed to assess the effects of supplementation with oxidized fish oil during pregnancy in mothers and offspring, focusing on newborn viability and maternal insulin sensitivity. Female rats were allocated to a control or high-fat diet and then mated. These rats were subsequently randomized to receive a daily gavage treatment of 1 ml of unoxidized fish oil, a highly oxidized fish oil, or control (water) throughout pregnancy. At birth, the gavage treatment was stopped, but the same maternal diets were fed ad libitum throughout lactation. Supplementation with oxidized fish oil during pregnancy had a marked adverse effect on newborn survival at day 2, leading to much greater odds of mortality than in the control (odds ratio 8.26) and unoxidized fish oil (odds ratio 13.70) groups. In addition, maternal intake of oxidized fish oil during pregnancy led to increased insulin resistance at the time of weaning (3 wks after exposure) compared with control dams (HOMA-IR 2.64 vs. 1.42; P = 0.044). These data show that the consumption of oxidized fish oil is harmful in rat pregnancy, with deleterious effects in both mothers and offspring.
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Óleos de Peixe/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/fisiopatologia , Mortalidade Infantil , Resistência à Insulina , Complicações na Gravidez/fisiopatologia , Animais , Animais Recém-Nascidos , Suplementos Nutricionais/efeitos adversos , Feminino , Humanos , Lactente , Oxirredução , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
The Western diet is typically high in salt and fructose, which have pressor activity. Maternal diet can affect offspring blood pressure, but the extent to which maternal intake of excess salt and fructose may influence cardiovascular function of the offspring is unknown. We sought to determine the effect of moderate maternal dietary intake of salt and/or fructose on resting and stimulated cardiovascular function of the adult male and female offspring. Pregnant rats were fed purified diets (± 4% salt) and water (± 10% fructose) before and during gestation and through lactation. Male and female offspring were weaned onto standard laboratory chow. From 9 to 14 weeks of age, cardiovascular parameters (basal, circadian and stimulated) were assessed continuously by radiotelemetry. Maternal salt intake rendered opposite-sex siblings with a 25-mmHg difference in blood pressure as adults; male offspring were hypertensive (15 mmHg mean arterial pressure (MAP)) and female offspring were hypotensive (10 mmHg MAP) above and below controls, respectively. Sex differences were unrelated to endothelial nitric oxide activity in vivo, but isolation-induced anxiety revealed a significantly steeper coupling between blood pressure and heart rate in salt-exposed male offspring but not in female offspring. MAP of all offspring was refractory to salt loading but sensitive to subsequent dietary fructose, an effect exacerbated in female offspring from fructose-fed dams. Circadian analyses of pressure in all offspring revealed higher mean set-point for heart rate and relative non-dipping of nocturnal pressure. In conclusion, increased salt and fructose in the maternal diet has lasting effects on offspring cardiovascular function that is sex-dependent and related to the offspring's stress-response axis.
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Dieta Ocidental/efeitos adversos , Desenvolvimento Fetal , Frutose/efeitos adversos , Hipertensão/etiologia , Hipotensão/etiologia , Fenômenos Fisiológicos da Nutrição Materna , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Sistema Cardiovascular/fisiopatologia , Feminino , Hipertensão/fisiopatologia , Hipertensão/psicologia , Hipotensão/fisiopatologia , Hipotensão/psicologia , Lactação , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Distribuição Aleatória , Ratos Sprague-Dawley , Caracteres Sexuais , Isolamento Social/psicologia , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologiaRESUMO
A maternal high-fat (HF) diet during pregnancy and lactation can result in adverse metabolic and reproductive outcomes in female offspring independent of postnatal diet. Interventions during critical windows of developmental plasticity may prevent developmental programming in offspring. The effects of maternal supplementation with the anti-inflammatory lipid conjugated linoleic acid (CLA) on early-onset puberty, metabolic dysfunction, and estrous cycle dysfunction was assessed. Sprague-Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA). Diets were fed ad libitum for 10 days prior to time mating and throughout gestation and lactation. Offspring plasma/tissues were taken at Day 24 (prepubertal) or Day 150 (adult). Puberty was assessed from Day 26 and estrous cycle from Day 128. Female offspring from HF mothers had lower birth weights but by Postnatal Day 24 had exhibited catch-up growth concomitant with increased fat mass, hyperleptinemia, and dyslipidemia. Maternal CLA supplementation reversed these effects. Early-onset puberty was only observed in HF offspring; this was reversed in HFCLA offspring. In adulthood, despite no evidence of glucose intolerance or altered insulin sensitivity, HF offspring displayed increased fat mass, dyslipidemia, disrupted estrous cyclicity. and hyperleptinemia; this was reversed by maternal CLA supplementation. Data presented in this study demonstrate the importance of diet in women of reproductive age and during pregnancy on reproductive and metabolic parameters in their offspring and that supplementation with CLA during critical windows of development may represent a therapeutic strategy in the prevention of early-life programming of metabolic and reproductive dysfunction.
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Hiperlipidemias/prevenção & controle , Lactação/fisiologia , Ácidos Linoleicos Conjugados/administração & dosagem , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Maturidade Sexual/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Suplementos Nutricionais , Feminino , Hiperlipidemias/metabolismo , Leptina/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Maternal diet can significantly skew the secondary sex ratio away from the expected value of 0.5 (proportion males), but the details of how diet may do this are unclear. Here, we altered dietary levels of salt (4% salt in the feed) and/or fructose (10% in the drinking water) of pregnant rats to model potential effects that consumption of a "Western diet" might have on maternofetal growth, development, and sex ratio. We demonstrate that excess fructose consumption before and during pregnancy lead to a marked skew in the secondary sex ratio (proportion of males, 0.60; P < 0.006). The effect was not mediated by selective developmental arrest of female embryos or influenced by fetal position in the uterine horn or sex-specific effects on sperm motility, suggesting a direct effect of glycolyzable monosaccharide on the maternal ovary and/or ovulated oocyte. Furthermore, combined excess maternal consumption of salt and fructose-sweetened beverage significantly reduced fertility, reflected as a 50% reduction in preimplantation and term litter size. In addition, we also noted birth order effects in the rat, with sequential implantation sites tending to be occupied by the same sex.
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Ordem de Nascimento , Fertilidade/efeitos dos fármacos , Frutose/administração & dosagem , Crescimento e Desenvolvimento/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Pré-Natal , Reprodução/efeitos dos fármacos , Razão de Masculinidade , Cloreto de Sódio na Dieta/administração & dosagem , Animais , Ingestão de Alimentos/fisiologia , Feminino , Masculino , Gravidez , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)-a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/ß-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a 'silver-bullet' single-target approach.
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Glioblastoma, a grade IV astrocytoma, is regarded as the most aggressive primary brain tumour with an overall median survival of 16.0 months following the standard treatment regimen of surgical resection, followed by radiotherapy and chemotherapy with temozolomide. Despite such intensive treatment, the tumour almost invariably recurs. This poor prognosis has most commonly been attributed to the initiation, propagation, and differentiation of cancer stem cells. Despite the unprecedented advances in biomedical research over the last decade, the current in vitro models are limited at preserving the inter- and intra-tumoural heterogeneity of primary tumours. The ability to understand and manipulate complex cancers such as glioblastoma requires disease models to be clinically and translationally relevant and encompass the cellular heterogeneity of such cancers. Therefore, brain cancer research models need to aim to recapitulate glioblastoma stem cell function, whilst remaining amenable for analysis. Fortunately, the recent development of 3D cultures has overcome some of these challenges, and cerebral organoids are emerging as cutting-edge tools in glioblastoma research. The opportunity to generate cerebral organoids via induced pluripotent stem cells, and to perform co-cultures with patient-derived cancer stem cells (GLICO model), has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. In this article, we review the recent literature on the use of patient-derived glioblastoma organoid models and their applicability for drug screening, as well as provide a potential workflow for screening using the GLICO model. The proposed workflow is practical for use in most laboratories with accessible materials and equipment, a good first pass, and no animal work required. This workflow is also amenable for analysis, with separate measures of invasion, growth, and viability.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Recidiva Local de Neoplasia/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Neoplasias Encefálicas/patologia , OrganoidesRESUMO
Importance: Gamma irradiation of leukoreduced red blood cells (RBCs) prevents transfusion-associated graft-vs-host disease but also exacerbates storage lesion formation in RBCs. It is unknown whether freshly irradiated RBCs are more efficacious than irradiated and stored RBCs in preterm infants with high transfusion requirements. Objective: To examine whether transfusion of freshly irradiated vs irradiated and stored RBC components improves cerebral oxygen delivery in preterm infants with anemia. Design, Setting, and Participants: This single-center, double-blinded, proof-of-concept randomized clinical trial was conducted at the neonatal intensive care unit of Wellington Regional Hospital in Wellington, New Zealand, between December 1, 2017, and November 30, 2018. Participants were preterm infants (<34 weeks' gestation at birth) who were at least 14 days of age and had anemia. Participants underwent nonurgent transfusions, and these episodes were randomized to the intervention group (in which the infants received a transfusion of RBCs that were freshly irradiated on the day of transfusion) or control group (in which the infants received a transfusion of RBCs that were irradiated and stored for up to 14 days). Data were analyzed using the evaluable population approach. Intervention: Transfusion of freshly irradiated RBCs. Main Outcomes and Measures: The prespecified primary outcome was the change in cerebral regional oxygen saturation (crSO2) from baseline (immediately before) to immediately after the transfusion. The prespecified secondary outcomes were the change in cerebral fractional tissue oxygen extraction (cFTOE) at different time points (immediately after, 24 hours after, and 120 hours or 5 days after transfusion). Outcomes were measured by blinded clinicians using near-infrared spectroscopy. A covariate-adjusted linear mixed model was used to quantify mean treatment effects and account for multiple transfusions in some infants. Results: A total of 42 infants (mean [SD] gestational age, 26 [10] weeks and 3 days; 29 [69%] boys) were enrolled in the trial and underwent 64 transfusion episodes, which were randomized to the intervention (n = 31) or control (n = 33) group. Compared with infants in the control group, those in the intervention group showed a covariate-adjusted mean increase in crSO2 (2.0 percentage points; 95% CI, 1.2-2.8 percentage points) and a mean decrease in cFTOE (0.02; 95% CI, 0.01-0.04) immediately after transfusion. These differences were sustained up to 120 hours or 5 days after transfusion. There were negligible mean changes in crSO2 or cFTOE in infants in the control group at any of the follow-up time points. Conclusions and Relevance: Results of this trial showed that transfusion of freshly irradiated RBCs conferred a small advantage in cerebral oxygenation for at least 5 days after transfusion compared with transfusion of irradiated and stored RBC components. On-demand irradiation of RBC components may be considered to optimize oxygen delivery in the recipient, but this physiological finding requires further research. Trial Registration: ANZCTR Identifier: ACTRN12617001581358.