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Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44 Hi CD24 Hi chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer. Adaptive resistance is an emerging cause of chemotherapy failure in cancer. Here the authors show that adaptive resistance to taxanes is mediated by the upregulation of SFK/Hck survival signalling, and that sequential administration of taxanes and SFK/Hck inhibition restores tumor cell chemosensitivity.

Fetal Alcohol Spectrum Disorder (FASD) encompasses the deleterious consequences of Prenatal Alcohol Exposure (PAE), including developmental delay, microcephaly, dysmorphologies, and cognitive and behavioral issues. The dose and timing of alcohol exposure, maternal and environmental factors, and genetics all impact FASD outcomes, but differential susceptibility and resiliency to PAE remains poorly understood. In this study, we examined the differential effects of PAE during early mouse development on brain growth and gene expression. Brains were weighed and collected either 24 hours or five days after treatment. We then performed transcriptomics to determine whether offspring differentially affected by PAE, by brain weight, also differ in gene expression, despite having the same genetic background, alcohol exposure, and maternal factors. We found within litter variation in brain weights after PAE, and classified offspring as having normal, middle, and low-weight brains relative to saline-treated controls. The normal-weight brains showed no significant differences in gene expression, suggesting these offspring were both phenotypically and transcriptionally unaffected by PAE. While both middle- and low-weight brains showed changes in gene expression, the middle-weight brains showed the most robust transcriptome differences. Twenty-four hours after PAE, we saw an upregulation of cell cycle and apoptosis in affected offspring, whereas at roughly a week later, we saw a downregulation of metabolic processes. Overall, these findings highlight variability in response to PAE and demonstrate the molecular processes involved in offspring phenotypically affected by alcohol.

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)–infected individuals, (2) organ transplant recipients, and (3) non–HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

Following St. Isidore of Seville's mission to the Visigoths and St. Gregory of Tours's mission to the Merovingians in the sixth century, the Catholic Church upheld the Davidic Kingdom as the model for Western polity after the collapse of Roman Empire. Derby Day, Henley Regatta, Cowes, the 12th of August, a cup final, the dog races, the pin table, the dart board, Wensleydale cheese, boiled cabbage cut into sections, beetroot in vinegar, 19th century Gothic churches, and the music of Elgar. Huck's successors are the cowboy who rids the town of evildoers and then rides off into the sunset, the gunslinger with a heart of gold, the private detective who avenges wrongdoing and then fades into the urban nightscape, the loner with authority problems: By contrast, we have adoptedasour national story the history of Israel, in the same way that evangelical Christians identify the souls journey to salvation with the journey of the Children of Israel to the Promised Land.

Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S -adenylsmethionine 1 , 2 . Folate deficiency is associated with a number of developmental, immune and neurological disorders 3 – 5 . Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body 3 , 6 . The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus 4 , 7 , and is an important route for the delivery of antifolate drugs in cancer chemotherapy 8 – 10 . How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT. Cryo-electron microscopy structures of PCFT in a substrate-free state and bound to the antifolate drug pemetrexed provide insights into how this protein recognizes folates and mediates their transport into cells.

Studies suggest that endurance athletes are at higher-than-average risk for atherosclerosis and myocardial damage. The ability of plant-based regimens to reduce risk and affect performance was reviewed. The effect of plant-based diets on cardiovascular risk factors, particularly plasma lipid concentrations, body weight, and blood pressure, and, as part of a healthful lifestyle, reversing existing atherosclerotic lesions, may provide a substantial measure of cardiovascular protection. In addition, plant-based diets may offer performance advantages. They have consistently been shown to reduce body fat, leading to a leaner body composition. Because plants are typically high in carbohydrate, they foster effective glycogen storage. By reducing blood viscosity and improving arterial flexibility and endothelial function, they may be expected to improve vascular flow and tissue oxygenation. Because many vegetables, fruits, and other plant-based foods are rich in antioxidants, they help reduce oxidative stress. Diets emphasizing plant foods have also been shown to reduce indicators of inflammation. These features of plant-based diets may present safety and performance advantages for endurance athletes. The purpose of this review was to explore the role of nutrition in providing cardioprotection, with a focus on plant-based diets previously shown to provide cardiac benefits.

Key Points Addictions are common chronic psychiatric diseases that are characterized by persistent, compulsive and uncontrolled use. Addictions are a worldwide public-health issue, causing 12.4% of deaths. Addictions are among the most heritable psychiatric diseases; heritabilities range from 0.39 (hallucinogens) to 0.72 (cocaine). Monozygotic:dizygotic twin concordance ratios for addictions are approximately 2:1, indicating that interactions among multiple genes (polygenicity) might not be required for vulnerability. Animal studies model addiction-relevant behaviours and have led to an understanding of addiction neurobiology and the identification of several genes that mediate variation in drug preference and response. The neurobiological pathways that modulate reward, stress resiliency and behaviour inhibition are among those that also underlie general addiction liability. Across the addictions, the correlation of addiction liability with heritability indicates that variation in the core neurobiology of addiction is genetically influenced. Cross-inheritance studies in twins indicate that both substance-specific and substance-nonspecific genetic factors are important in addictions, and that there is cross-inheritance between addictions and other psychiatric disorders. Linkage studies have identified genes that are of both these general types. Treatment and prevention of addictions are partially successful because medical management targets the acute phase of illness and is not individualized. The individualization of treatment and prevention is likely to be advanced by the discovery of genetic predictors of the neurobiological pathways that underlie addiction. The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods. The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioural control and the anxiety or stress response. Our future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors and a role in shared vulnerabilities such as variation in reward or stress resiliency.

Plant-based diets are associated with numerous health benefits, including reduced risks of chronic diseases. However, questions persist regarding the implications of lower dietary intakes of certain non-essential nutrients, such as retinol, vitamin K2, carnitine, and creatine, which are primarily found in animal-derived foods. This narrative review evaluates the roles of these nutrients in human physiology and examines whether their absence in plant-based diets is likely to impact health outcomes. Retinol requirements can be met through the consumption of provitamin A carotenoids in plant foods, even in individuals with reduced conversion efficiency. Endogenous synthesis adequately supports physiological needs for vitamin K2, and currently available evidence does not consistently demonstrate that dietary vitamin K2 provides additional benefits for bone or cardiovascular health. Carnitine and creatine levels may differ between individuals following omnivorous and plant-based diets, but these differences do not result in compromised muscle function, cognitive health, or metabolic outcomes. Current evidence does not indicate that the absence of these non-essential nutrients in plant-based diets adversely affects health or confers disadvantages compared to omnivorous diets.

Key Points Addictive disorders are common, account for a tremendous disease burden and are in need of improved medical treatments. Alcohol use accounts for more disease burden than any other addictive drug with the exception of nicotine. The discovery of naltrexone as a medication for alcoholism was conceptually groundbreaking, because it demonstrated the feasibility of pharmacotherapy for an addictive disorder using a mechanism other than replacement therapy. Overall, however, the effect size of naltrexone turned out to be small, and despite its evidence base, this medication has not gained widespread clinical use. Clinical experience and meta-analyses have long indicated that clinical response to naltrexone is remarkably variable. Over a decade ago, functional genetic variation was discovered at the locus encoding the target for naltrexone, the mu-opioid receptor (MOR), and this was shortly followed by the suggestion that efficacy of naltrexone may be restricted to carriers of the minor allele at this locus. Recently, a series of translational studies in humans, non-human primates and humanized mice has provided consistent support for the notion that alcohol reward is in part mediated by an alcohol–endogenous opioid–dopamine cascade, that this cascade is more vigorously activated by alcohol in carriers of the minor allele at the OPRM1 gene locus that encodes the MOR, and that these subjects are thereby rendered particularly or maybe selectively sensitive to naltrexone. Alcohol reinforcement is mediated by multiple systems, among which opioids and dopamine are but two, and are mostly involved in pleasurable, positively reinforcing alcohol effects experienced mostly in earlier stages of the addictive process. As patients continue heavy alcohol use, a pathological activation of brain stress systems occurs, and sets the scene for negatively reinforced alcohol use — that is, alcohol use aimed at eliminating anxiety and dysphoria that emerges during abstinence. Corticotropin-releasing factor (CRF), the hypothalamic release factor for pituitary adrenocorticotropic hormone (ACTH), is also widely expressed in extrahypothalamic networks that mediate behavioural and emotional stress responses. Recent work has shown that the CRF system becomes activated following a prolonged history of brain alcohol exposure, and its activity is key to negatively reinforced alcohol seeking and use. Genetic variation that influences the functional activity of the CRF system has been found in rats, non-human primates and humans, and has been shown to be associated with various alcohol use phenotypes in all three species. This suggests that pharmacogenetic effects may need to be considered when CRF receptor 1 (CRF 1 ) antagonists are developed for the treatment of alcoholism. GABAergic and serotonergic transmission are also involved in the pathophysiology of alcoholism, and pharmacogenetic effects of variants within both these systems have also been suggested. A potential implication of these findings is that pharmacogenetic effects may turn out to be the rule rather than the exception, and that much more attention will have to be paid to personalizing pharmacotherapy of addictive disorders. Current addiction pharmacotherapies have limited success. Focusing on alcohol addiction, Heilig and colleagues review the evidence that genetic heterogeneity in the opioid, corticotropin-releasing factor, GABA and serotonin systems may underlie differential treatment responses, and that personalized therapies tailored to patient genotype may lead to more successful treatment for alcohol addiction. Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.