Fetus morphology changes by second-trimester ultrasound in pregnant women drinking alcohol.

Fetal alcohol spectrum disorders (FASDs) are a group of negative conditions occurring in children exposed to alcohol during gestation. The early discovery of FASD is crucial for mother and infant follow-ups. In this study, we investigated in pregnant women the association between urine ethylglucuronide (EtG-a biomarker of alcohol drinking) and indicators of the physical characteristics of FASD by prenatal ultrasound in the second trimester of gestation. We also correlated these data with the AUDIT-C, T-ACE/TACER-3, TWEAK, and food habit diary, screening questionnaires used to disclose alcohol drinking during pregnancy. Forty-four pregnant women were randomly enrolled and examined for ultrasound investigation during the second trimester of gestation. Urine samples were provided by pregnant women immediately after the routine interviews. EtG determinations were performed with a cutoff established at 100 ng/mL, a value indicating occasional alcohol drinking. Fifteen of the enrolled pregnant women overcame the EtG cutoff (34.09%). Analysis of variance (ANOVA) revealed that the fetuses of the positive EtG pregnant women had significantly longer interorbital distance and also significantly increased frontothalamic distance (P's < 0.02). Quite interestingly, no direct correlation was found between EtG data and both food diary and AUDIT-C. However, a significant correlation was observed between urinary EtG and T-ACE (r = 0.375; P = 0.012) and between urinary EtG and TWEAK (r = 0.512; P < 0.001) and a concordance with all questionnaire for EtG values higher than 500 ng/mL. This study provides clinical evidence that the diagnosis of maternal alcohol consumption during pregnancy by urine EtG may disclose FASD-related damage in the fetus.

VEGF inhibition alters neurotrophin signalling pathways and induces caspase-3 activation and autophagy in rabbit retina.

This study sought to evaluate the prospective role exerted by vascular endothelial growth factor (VEGF) in the modulation of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) signalling pathways in the rabbit retina. To reach this aim, the anti-VEGF agents aflibercept and ranibizumab were used as a pharmacological approach to evaluate the putative consequences elicited by VEGF inhibition on neurotrophin signalling. VEGF inhibition determined a marked imbalance in proneurotrophin expression, a significant reduction in TrkA and TrkB phosphorylation states and a decrease in the pan-neurotrophin receptor p75. Importantly, VEGF blockade also caused a strong increase in cleaved caspase-3, beclin-1 and lipidated LC3. The effects were more pronounced in the aflibercept group when compared with ranibizumab-treated rabbits, particularly 1 week after injection. This study demonstrates that VEGF exerts pivotal physiological roles in regulating NGF and BDNF pathways in the retina, as its inhibition by anti-VEGF agents deeply impacts neurotrophin homeostasis. These events are accompanied by a sustained induction of apoptotic and autophagic markers, suggesting that anti-VEGF-dependent impairments in neurotrophin signalling could be responsible for the activation of retinal cell death pathways.

How alcohol drinking affects our genes: an epigenetic point of view.

This work highlights recent studies in epigenetic mechanisms that play a role in alcoholism, which is a complex multifactorial disorder. There is a large body of evidence showing that alcohol can modify gene expression through epigenetic processes, namely DNA methylation and nucleosomal remodeling via histone modifications. In that regard, chronic exposure to ethanol modifies DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol-mediated chromatin remodeling in the brain promotes the transition from use to abuse and addiction. Unravelling the multiplex pattern of molecular modifications induced by ethanol could support the development of new therapies for alcoholism and drug addiction targeting epigenetic processes.

In vivo antivascular endothelial growth factor treatment induces corneal endothelium apoptosis in rabbits through changes in p75NTR-proNGF pathway.

Intravitreal injection (IVT) of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of retinal vascular diseases. Recently, the injection of anti-VEGF agents in the ocular anterior chamber has been proposed for the treatment of neovascular glaucoma and potential side effects on the corneal structures have been investigated with contrasting results. Increasing evidence has demonstrated that VEGF inhibition is associated with cellular apoptotic changes and that this effect may be mediated by alterations in nerve growth factor (NGF) pathway. In this study, we demonstrated that anterior chamber injection (IC), but not IVT injection of two different anti-VEGF agents, aflibercept and ranibizumab, affects rabbit corneal endothelium in terms of survival and apoptosis and is associated with changes in endothelial expression of NGF precursor (proNGF) and p75 neurotrophin receptor (p75NTR) receptor. We observed an increase in corneal endothelial cell incorporation of trypan blue and expression of cleaved-caspase 3 (c-Casp3), p75NTR, and RhoA after IC injection of both anti-VEGF drugs when compared with the vehicle. Our results showed that apoptosis induction by aflibercept was more pronounced when compared with that of ranibizumab. Aflibercept also mediated a significant increase in endothelial expression of proNGF when compared with the vehicle. In line with these data, IC administration of both anti-VEGF agents induced the activation of apoptotic signals in endothelial cells, including an increase in c-Casp3, decrease in Bad Ser 112 phosphorylation, and unbalance of AKT phosphorylation. These results demonstrated that administration of anti-VEGF in the anterior chamber of rabbit affects endothelial cell survival by inducing apoptosis through alteration of NGF pathway.

Virtual Morris task responses in individuals in an abstinence phase from alcohol.

The present study was aimed at examining spatial learning and memory, in 33 men and 12 women with alcohol use disorder (AUD) undergoing ethanol detoxification, by using a virtual Morris task. As controls, we recruited 29 men and 10 women among episodic drinkers without a history of alcohol addiction or alcohol-related diseases. Elevated latency to the first movement in all trials was observed only in AUD persons; furthermore, control women had longer latencies compared with control men. Increased time spent to reach the hidden platform in the learning phase was found for women of both groups compared with men, in particular during trial 3. As predicted, AUD persons (more evident in men) spent less time in the target quadrant during the probe trial; however, AUD women had longer latencies to reach the platform in the visible condition during trials 6 and 7 that resulted in a greater distance moved. As for the probe trial, men of both groups showed increased virtual locomotion compared with the women of both groups. The present investigation confirms and extends previous studies showing (i) different gender responses in spatial learning tasks, (ii) some alterations due to alcohol addiction in virtual spatial learning, and (iii) differences between AUD men and AUD women in spatial-behaviour-related paradigms.

Ocular nerve growth factor administration (oNGF) affects disease severity and inflammatory response in the brain of rats with experimental allergic encephalitis (EAE).

The rat acute experimental autoimmune encephalomyelitis (EAE) model was used to investigate the effects of ocularly administered nerve growth factor (oNGF) on disease development and brain inflammation. It was found that oNGF affects clinical scores. However, EAE rats receiving oNGF treatment showed reduced expression of pro-inflammatory cytokines and chemokines in the cerebellum and the hippocampus, but not in the frontal cortex. These data confirm the ability of oNGF to counteract the effects of EAE in the brain and suggest a role for oNGF in the regulation of local inflammatory responses observed in the acute phase of EAE.

Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring.

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75(NTR) , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75(NTR) in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.

Human kidney podocyte cell population as a novel biological target of nerve growth factor.

Human podocytes are highly specialized cells with a key role in kidney physiology. Alteration of their structure as a consequence of injury or developmental failure leads to severe renal diseases. Although several studies have tried to elucidate the molecular framework of this cellular system, the functional bases for the maintenance of podocytes in their specialized state to sustain kidney barrier filtration are not completely understood. In this study, the capability of podocytes to produce and secrete the nerve growth factor (NGF) has been demonstrated via a validated in vitro model. During the process of cell differentiation, NGF and its receptors are modulated in human podocytes just as NGF-responsive neurons. Blockade of NGF biological activity results in severe changes of cell morphology. Collectively, our results outline a novel function of the neurotrophin and add a new cellular target in the complex biological framework of NGF.

Ocular nerve growth factor administration counteracts the impairment of neural precursor cell viability and differentiation in the brain subventricular area of rats with streptozotocin-induced diabetes.

The ocular administration of nerve growth factor (NGF) as eye drops (oNGF) has been shown to exert protective effects in forebrain-injured animal models, including adult diabetes induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). This type 1 diabetes model was used in this study to investigate whether oNGF might extend its actions on neuronal precursors localised in the subventricular zone (SVZ). NGF or saline was administrated as eye drops twice daily for 2 weeks in rats with STZ-induced diabetes and healthy control rats. The expression of mature and precursor NGF and the NGF receptors, tropomyosin-related kinase A and neurotrophin receptor p75, and the levels of DNA fragmentation were analysed by ELISA and western blotting. Incorporation of bromodeoxyuridine was used to trace newly formed cells. Nestin, polysialylated neuronal cell adhesion molecule (PSA-NCAM), doublecortin (DCX) and glial fibrillary acidic protein antibodies were used to identify the SVZ cells by confocal microscopy. It was found that oNGF counteracts the STZ-induced cell death and the alteration of mature/pro-NGF expression in the SVZ. It also affects the survival and differentiation of SVZ progenitors. In particular, oNGF counteracts the reduction in the number of cells expressing PSA-NCAM/DCX (neuroblast type A cells) and the related reductions in the number and distribution of nestin/DCX-positive cells (C-type cells), or glia-committed cells (type B cells), observed in the SVZ of diabetic rats. These findings show that oNGF treatment counteracts the effect of type 1 diabetes on neuronal precursors in the SVZ, and further support the neuroprotective and reparative role of oNGF in the brain.

Localization of nerve growth factor (NGF) receptors in the mitochondrial compartment: characterization and putative role.

BACKGROUND: The neurotrophin NGF receptors trkA and p75NTR are expressed in the central and peripheral nervous system as well as in non-neuronal tissues; originally described to localize to the plasma membrane, recent studies have suggested other intracellular localizations for both NGF receptors. SCOPE OF REVIEW: In order to determine whether NGF receptors localize to the mitochondrial compartment mitochondria isolated from human kidney, rat tissues and a human podocyte as cell line before and after differentiation were used. MAJOR CONCLUSIONS: Our results demonstrate that NGF receptors are localized in the mitochondrial compartment of undifferentiated human podocytes and in all tissues analyzed including rat central nervous system. In mitochondria p75NTR, but not trkA, co-immunoprecipitates with the adenine nucleotide translocator (ANT) and the phosphodiesterase 4 isoform A5 (PDE4A5). Moreover, NGF, via trkA, protects isolated mitochondria of rat brain cortex from mitochondrial permeability transition induced by Ca(2+). GENERAL SIGNIFICANCE: Although NGF receptors have been described as mainly citoplasmatic so far, we proved evidence of their expression at the mitochondrial level and their interaction with specific proteins. Our results demonstrating the expression of NGF receptors in the mitochondria provide new insights into the role of NGF at subcellular level, in different areas of the organism, including CNS.

Neuroimmune Dysregulation in Prepubertal and Adolescent Individuals Affected by Klinefelter Syndrome.

BACKGROUND: The syndrome Klinefelter syndrome (KS) is a genetic disorder due to an extra X chromosome in males. Many cases remain undiagnosed until the onset of major manifestations, which include hypergonadotropic hypogonadism and infertility. This condition is associated with many comorbidities that involve the cardiovascular, endocrine, and immune systems. Last but not the least, individuals with KS show a high risk of developing psychiatric and mood disorders in adult age. OBJECTIVE: While many studies are accessible on KS in adult individuals, the neuroinflammatory condition in adolescent and prepubertal KS individuals is not fully known. METHODS: Our study aims to evaluate in prepubertal and adolescent KS individuals, for the first time, the levels of the serum of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), cytokines having subtle roles in oxidative processes, and neuroinflammation with respect to the levels of TNF-α, TGF-ß, MCP-1, IL-1α, IL-2, IL-6, IL-10, and IL-12 and oxidative stress by employing free oxygen radicals defense and free oxygen radicals test. RESULTS: We found no changes in NGF and oxidative stress parameters, but BDNF decreased compared to healthy children. Quite interestingly, our data showed reduced levels of IL-2, IL-1α, IL- 12, IL-10, and IL-6 in prepubertal KS children. CONCLUSION: The present study discloses disrupted immune system and neurotrophin pathways in KS children.

Cardiovascular risk factors in patients on long-term treatment with nevirapine- or efavirenz-based regimens.

OBJECTIVES: The aim of this study was to evaluate the cardiovascular risk among patients treated for more than 5 years with regimens based on nevirapine or efavirenz. PATIENTS AND METHODS: A total of 276 patients were retrospectively evaluated, 156 of whom were treated with nevirapine and 120 with efavirenz, by examining traditional risk factors and detecting the presence of subclinical carotid lesions with colour-Doppler ultrasonography. RESULTS: When comparing the data at baseline and follow-up in the nevirapine group, total cholesterol, low-density lipoprotein cholesterol (LDLc) and triglycerides showed a significant decrease, while high-density lipoprotein cholesterol increased. Ultrasound data, obtained in a subgroup of 67 patients, did not show significant changes for those treated with nevirapine. In the efavirenz group, total cholesterol, LDLc, triglycerides, glycaemia, body mass index and the number of patients with a pathological ultrasound significantly increased. When comparing the two groups at baseline and follow-up, nevirapine patients had significantly higher values of total cholesterol, LDLc and triglycerides at baseline, while total cholesterol and LDLc differed non-significantly at follow-up; triglycerides became significantly lower in the nevirapine arm with respect to the efavirenz group. Glycaemia was comparable between the two groups at baseline, while it was significantly lower in the nevirapine group at follow-up. The number of pathological ultrasound findings was significantly higher in the efavirenz group at follow-up. CONCLUSIONS: Patients treated with nevirapine demonstrated a better lipid and glucose profile and a lower tendency to develop subclinical atherosclerotic lesions.

Nerve Growth Factor in Alcohol Use Disorders.

The nerve growth factor (NGF) belongs to the family of neurotrophic factors. Initially discovered as a signaling molecule involved in the survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons, it also participates in the regulation of the immune system and endocrine system. NGF biological activity is due to the binding of two classes of receptors: the tropomyosin-related kinase A (TrkA) and the low-affinity NGF pan-neurotrophin receptor p75. Alcohol Use Disorders (AUD) are one of the most frequent mental disorders in developed countries, characterized by heavy drinking, despite the negative effects of alcohol on brain development and cognitive functions that cause individual's work, medical, legal, educational, and social life problems. In addition, alcohol consumption during pregnancy disrupts the development of the fetal brain causing a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). The rationale of this review is to describe crucial findings on the role of NGF in humans and animals, when exposed to prenatal, chronic alcohol consumption, and on binge drinking.

Neuroinflammatory Markers in the Serum of Prepubertal Children with Down Syndrome.

Down Syndrome (DS) is the most common chromosomal disorder. Although DS individuals are mostly perceived as characterized by some distinct physical features, cognitive disabilities, and cardiac defects, they also show important dysregulations of immune functions. While critical information is available for adults with DS, little literature is available on the neuroinflammation in prepubertal DS children. We aimed to evaluate in prepubertal DS children the serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), oxidative stress as free oxygen radicals defense (FORD), free oxygen radicals test (FORT), and cytokines playing key roles in neuroinflammation and oxidative processes as TNF-α, TGF-ß, MCP-1, IL-1α, IL-2, IL-6, IL-10, and IL-12. No differences were found in NGF between DS children and controls. However, BDNF was higher in DS subjects compared to controls. We also did not reveal changes in FORD and FORT. Quite interestingly, the serum of DS children disclosed a marked decrease in all analyzed cytokines with evident differences in serum cytokine presence between male and female DS children. In conclusion, the present study evidences in DS prepubertal children a disruption in the neurotrophins and immune system pathways.

Oxidative stress inhibition by resveratrol in alcohol-dependent mice.

OBJECTIVES: Uncontrolled ingestion of alcohol has dramatic consequences on the entire organism that are also associated with the oxidation process induced by alcohol and elevate radical oxygen species. Resveratrol, a nonflavonoid phenol, shows well-documented antioxidant properties. We investigated the potential antioxidant ability of this natural compound in a mouse model of alcohol addiction. METHODS: We administered (per os) for 60 d 10 mg · kg-1 · d-1 of resveratrol in alcoholic adult male mice. Oxidative stress was evaluated by measuring serum-free oxygen radicals defense and free oxygen radical levels. Resveratrol metabolites were measured in the serum of mice that were administered with resveratrol. Finally, the effect of resveratrol on the alcohol-induced alteration of brain-derived neurotrophic factors (BDNF) in the liver was investigated. RESULTS: Prolonged consumption of resveratrol strongly counteracts serum radical oxygen species formation caused by chronic alcohol intake without effects on natural, free oxygen radical defense. The presence of resveratrol metabolites in the serum only of animals supplemented with resveratrol potentiates the evidence that the antioxidant effect observed is due to the ingestion of the natural compound. Moreover, resveratrol supplementation can counteract alcohol-induced BDNF elevation in the liver, which is the main target of organ alcohol-induced damage. CONCLUSIONS: The consumption of resveratrol through metabolite formation may play a protective role by decreasing free radical formation and modulating the BDNF involved in hepatic disruption induced by chronic alcohol consumption. Further investigation into the mechanism underlying the protective effect could reinforce the potential use of resveratrol as a dietary supplement to prevent damage associated with chronic alcohol abuse.

Nerve growth factor in the psychiatric brain.

The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.

Surveillance of toxoplasmosis in pregnant women in Albania.

This study presents the initial results derived from a collaborative project aimed at the surveillance of the toxoplasma infection in a population of 496 Albanian pregnant women. From October 2004 to March 2005, serum samples were tested to detect IgG, IgM and IgG avidity for toxoplasmosis. Of the 496 pregnant women examined, 241 (48.6% [range 44-53]; IC 95%). resulted positive for IgG, three of whom (1.3%) were also positive for IgM. As the preliminary results of our survey disclose the absence of an efficient pre-gravidic screening and counseling for the prevention of toxoplasmosis in Albania, we propose a health education program for all pregnant women, together with serological testing (screening) for those exposed to predictors of toxoplasmosis infection as an epidemiological support and financially sustainable alternative.

NGF and BDNF Alterations by Prenatal Alcohol Exposure.

BACKGROUND: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention. OBJECTIVE: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure. METHODS: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways. RESULTS: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns. CONCLUSION: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce a potential prevention of the harmful effects of the paternal and/or maternal alcohol exposure.

Nerve Growth Factor Role on Retinal Ganglion Cell Survival and Axon Regrowth: Effects of Ocular Administration in Experimental Model of Optic Nerve Injury.

Retinal ganglion cell (RGC) degeneration occurs within 2 weeks following optic nerve crush (ONC) as a consequence of reduced retro-transport of growth factors including nerve growth factor (NGF). The hypothesis that intravitreal (ivt) and eye drop (ed) administration of recombinant human NGF (rhNGF) might counteract ONC in adult rats is explored in this study. We found that both ivt- and ed-rhNGF reduced RGC loss and stimulated axonal regrowth. Chiefly, survival and regenerative effects of rhNGF were associated with a reduction of cells co-expressing Nogo-A/p75NTR at crush site borders, which contribute to glia scar formation following nerve injury, and induce further degeneration. We also found that ocular application of rhNGF reduced p75NTR and proNGF and enhanced phosphorylation of TrkA and its intracellular signals at retina level. Nogo-R and Rock2 expression was also normalized by ed-rhNGF treatment in both ONC and contralateral retina. Our findings that ocular applied NGF reaches and exerts biological actions on posterior segment of the eye give a further insight into the neurotrophin diffusion/transport through eye structures and/or their trafficking in optic nerve. In addition, the use of a highly purified NGF form in injury condition in which proNGF/p75NTR binding is favored indicates that increased availability of mature NGF restores the balance between TrkA and p75NGF, thus resulting in RGC survival and axonal growth. In conclusion, ocular applied NGF is confirmed as a good experimental paradigm to study mechanisms of neurodegeneration and regeneration, disclose biomarkers, and time windows for efficacy treatment following cell or nerve injury.

Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins.

Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient's prognosis in both TrkA- dependent and independent cancers.