There is considerable evidence pointing to genetic risk in the development of EDs, with the highest heritability conferred for AN [33, 34]. Females are also at greater genetic risk for disordered eating in comparison to males [39]. When considering the specific genetic variations thought to contribute to increased ED risk, genetic associations have been found between EDs and other psychiatric comorbidities, however the type of comorbidity differs according to the ED diagnosis. For binge-type EDs (BN and BED) strongest genetic correlations are observed with ADHD [42, 43] whilst AN has strong correlations with OCD, MDD, suicidality, schizophrenia, neuroticism, autism, and neurodevelopmental delay [44,44,45,46,48]. In a similar manner, genetic correlations with metabolic traits appear to differ between ED diagnoses, such that BN and BED have been found to share genomic variants with overweight and obesity [49] whereas potential AN genes uphold a bi-directional relationship with low BMI [38]. Genes associated with other metabolic functions, including appetite and weight control endocrines (leptin, melanocortin, neurotrophin) have also been implicated in ED development and severity, however fewer differences between ED diagnoses are apparent. Polymorphisms in the genetic loci responsible for neurotransmitters associated with reward processing and appetite regulation hormones, including dopamine, serotonin, and cannabinoid have been identified as a risk factor across several ED diagnoses including AN, BN, and EDNOS [45, 50,50,51,52,53,54,55,56,57,58,59,60,62]. Additionally, genetic polymorphisms in the glucocorticoid receptor pathway responsible for the stress response have been linked to individuals who have experienced trauma and are associated with increased risk for BN [51, 65, 66].
Several studies have observed high levels of impulsivity in individuals with BN, with these individuals commonly displaying negative urgency, lack of planning and sensation seeking. Farstadt et al. (2016) in their meta-analysis also argue a role for compulsiveness (i.e., the tendency towards overcontrolled behaviour), suggesting that the interaction of personality traits such as impulsiveness and compulsiveness can have implications for ED symptomology and disorder severity [161, 180, 183, 184]. In this manner, impulsivity was found to have a significant impact on the types of ED symptomatology displayed by the individual and clinical presentation [178, 195]. In contrast, Waxman [195] found no significant differences in impulsivity between ED diagnoses. Waxman [195] suggested that while there is a lack of evidence from longitudinal studies to determine conclusively that impulsivity is a risk factor in the development of ED, evidence from studies using proxy measures such as delinquency found these behaviours preceded BN onset. One further study has reported an association between NES and impulse control disorder [202]. It has also been suggested that impulsivity and addiction-like mechanisms may explain the association between ED psychopathology and both high-risk sexual behaviours and substance misuse [203, 204].
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The findings of the current review can be used to determine which risk factors are differentially appropriate targets for prevention, early intervention, and/or treatment efforts [322]. For example, modifiable risk factors such as negative parental comments towards weight and eating behaviours may be best approached using targeted prevention parenting programs to assist with modelling of healthy eating patterns and family dialogue. There is evidence to suggest targeted prevention programs addressing early signs of disordered eating in adolescents (e.g., the Body Project, StudentBodies2-BED) are effective in significantly reducing future onset of EDs [323, 324]. They represent a targeted, efficient way of addressing modifiable risk factors rather than approaching the population as a whole in a largely non-specific manner.
Given the attempt to summarise peer-reviewed ED literature in a broad-reaching and prompt manner, there are some limitations of the review. First broad search terms, required to fulfil the purpose of the large series of rapid reviews, of which this paper forms part, were used to collate evidence, which may have compromised the specificity of the included studies for individual ED diagnoses and/or phenotypes and individual risk factors. Additionally, research studies were excluded if they reported on unpublished data, implementation research, or if they were observational studies; and included studies were mostly limited to those conducted in Western cultures with high-resource health systems. Finally, having a specified time period for the review meant that seminal studies conducted prior to the start date were not included.
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Four main mechanisms of acquired resistance to AMCDs have been described so far (Horwitz et al. 1993, Wani & Horwitz 2014, Barbuti & Chen 2015). We will highlight particular mechanisms of resistance to AMCDs in prostate cancer; however, some of these are common to the many cancer histotypes that acquire resistance to the drugs. First, AMCD-resistant tumors can upregulate the expression of the ABC transmembrane efflux transporters (Childs et al. 1998, Ambudkar et al. 1999). The enhanced efflux leads to a reduced intracellular concentration of the drug, below the level necessary to obtain an effect. To overcome ABC transporter-mediated resistance, various approaches have been exploited, including the development of drugs that specifically inhibit ABC family members. However, up to now, most of the phase III clinical trials with such inhibitors have failed (Robert & Jarry 2003, Shukla et al. 2011, Bugde et al. 2017). Interestingly, it has been recently reported that the antiandrogens bicalutamide and enzalutamide inhibit ABCB1 efflux activity. These data suggest that combinational therapies with bicalutamide/enzalutamide and docetaxel might be effective in CRPC, independent of AR status. Indeed, preclinical studies have demonstrated that bicalutamide reverses docetaxel resistance in xenograft mice (Zhu et al. 2015). Another approach actively pursued to overcome ABC-induced resistance is the identification of chemically modified AMCDs with lower affinity for the efflux transporter. In 2010, FDA approved cabazitaxel, a second-generation taxane, for CRPC patients with disease progression on or after therapy with docetaxel-based chemotherapy (de Bono et al. 2010). Cabazitaxel differs from docetaxel in the side chain, in which methoxy groups replace hydroxyl groups, lowering affinity for the ABC transmembrane efflux transporters (Nightingale & Ryu 2012).
Of note, AMCD clinical benefits are curtailed not only by resistance but also by dose-limiting collateral damage. The most relevant AMCD side effects are neutropenia, a consequence of toxicity on hematopoietic precursor cells, and peripheral neuropathy, due to the critical role of microtubules in neuronal axoplasmic transport (Zhou & Giannakakou 2005). In addition, AMCDs are highly insoluble and the vehicles used for their administration are quite often responsible for the worsening of the side effects. For example, peripheral neurotoxicity can be greatly exacerbated by Cremophor EL (CrEL), a polyethoxylated castor oil used as vehicle for the intravenous administration of the highly hydrophobic paclitaxel (ten Tije et al. 2003, Barbuti & Chen 2015). Despite premedication with corticosteroids and histamine antagonists, AMCDs cause acute hypersensitivity reactions in about 40% of the patients characterized by respiratory distress, hypotension, angioedema, generalized urticaria and rash (Kadoyama et al. 2011). In addition, the cumulative toxicities of dexamethasone used as a premedication may contribute to treatment-related morbidity. In CRPC, docetaxel is often given in combination with prednisone; however, the use of prednisone in CRPC is highly controversial. On the one hand, prednisone, besides its common anti-inflammatory and anti-emetics effects, can be particularly beneficial to CRPC patients. Prednisone is directly cytotoxic to prostate cells and also decreases the release of the protumorigenic adrenal androgens by inhibiting the secretion of pituitary adrenocorticotropic hormone (Ndibe et al. 2015). On the other hand, it has been shown that glucocorticoid receptor is overexpressed in docetaxel-resistant prostate cells, and this upregulation is functionally relevant as resistance is reverted by receptor antagonisms (Kroon et al. 2016). Thus, it can be beneficial to find a way other than premedication with corticosteroids to limit side effects in AMCD-treated patients. To avoid AMCD-induced reactions and also to optimize delivery and distribution, many new AMCD formulations have been developed and tested; for example, albumin nanoparticles, liposomes and microspheres are currently being tested as AMCD vehicles (Hennenfent & Govindan 2006, Yassine et al. 2016). Docetaxel-carboxymethylcellulose nanoparticles displayed enhanced antitumor activity in murine models of CRPCs (Hoang et al. 2014). This formulation is more tolerable, allowing administration of greater doses that could result in enhanced antitumor activity. Moreover, carboxymethylcellulose provides enhanced docetaxel solubilization. Intensive research has also been focused on using nanoparticle drug delivery systems to improve specific delivery of AMCDs to tumor cells. For example, micelles conjugated with the prostate-specific membrane antigen (PSMA) ligand and loaded with docetaxel are specifically targeted to prostate cancer cells that overexpress PSMA. The PSMA formulation has shown enhanced antitumor activity in preclinical studies in prostate xenograft nude mice when compared to free docetaxel. However, the data relative to the utilization of improved AMCD formulations in humans are still limited (Ganju et al. 2014), with the remarkable exception of the albumin-bound paclitaxel approved by the FDA for the treatment of breast cancers after a very successful phase III clinical trial (Gradishar et al. 2005). In addition, new drugs targeting microtubules have been identified, like epothilones and halicondrins, that may have fewer side effects compared to the classical AMCDs (Zhou & Giannakakou 2005). Epothilones are microtubule-stabilizing agents with a mechanism of action similar to that of taxanes; halicondrins suppress the growth of microtubules, inhibiting polymerization. Both ixabepilone, a semi-synthetic epothilone derivative, and eribulin mesylate, an analogue of halichondrin B, have been FDA approved for patients with metastatic breast cancer whose disease has progressed despite prior anthracycline and taxane therapy (Dybdal-Hargreaves et al. 2015, Li et al. 2017). Many other epothilone and halichondrin derivatives have shown promising antitumoral activity in preclincal studies; some of them are in clinical trials for the treatment of tumors of different histotypes and the results are eagerly awaited (Perez 2009, Cortes & Vidal 2012, Forli 2014). 2ff7e9595c
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