A Narrative Review on Pharmacogenomics in Psychiatry: Scientific Definitions, Principles, and Practical Resources.

PURPOSE/BACKGROUND: Pharmacogenetics (PGx) studies the genetic factors underlying interindividual variability in drug response. Only a few countries around the world are already using PGx testing in psychiatric clinical practice, whereas others are still far from adopting it. The main barrier to the clinical adoption of PGx testing seems to be the limited knowledge among psychiatrists regarding the clinical relevance of specific genetic variants to personalize therapies and the accessibility of PGx data. This review aims at further highlighting the importance of PGx-driven clinical decision making for psychotropic medications and raising psychiatrists' awareness of the value of PGx testing in psychiatry. METHODS/PROCEDURES: We summarize the genes for which substantial evidence exists about the clinical utility of integrating their PGx testing in psychiatry. Specifically, we systematically describe the functional role of clinically relevant allelic variants, their frequency across different ethnic groups, and how they contribute to classify patients in relation to their capability in metabolizing psychotropic drugs. FINDINGS/RESULTS: Briefly, clinical guidelines recommend considering PGx testing of the cytochrome class 2 C9 (CYP2C9), C19 (CYP2C19), and D6 (CYP2D6) genes and the human leukocyte antigen (HLA)-A and -B genes for several psychotropic drugs. IMPLICATIONS/CONCLUSIONS: Extensive studies have been carried out to provide a solid rationale for the inclusion of PGx testing in psychiatry. Comprehensive clinical guidelines are readily accessible to support health care providers in tailoring the prescription of psychotropic drugs based on patient's genotype information. This approach presents a tangible opportunity to significantly improve individual responses to psychiatric medications.

Deficits in emotion recognition and processing in children with high callous-unemotional traits: the role of the MAOA gene.

Children with high Callous-Unemotional (CU) traits show deficits in recognizing and processing facial expressions. Alterations in emotion recognition have been linked to a higher synaptic concentration of monoaminergic neurotransmitters. The current study investigated the relationship between the MAOA-Low-activity alleles and the ability to recognize and process facial expressions in 97 male children (8-12 years old) diagnosed with disruptive behavior disorder. Participants completed a computerized emotion-recognition task while an eye-tracking system recorded the number (Fixation Count, FC) and length (Fixation Duration, FD) of fixations to the eye region of the emotional stimuli. Children with high CU traits exhibited lower scores in recognition of sadness and anger, and lower FC and FD for sadness and fear than children with low CU traits. Children carrying the MAOA-Low-activity alleles displayed lower FD for sadness, and FD and FC for fear than those carrying the MAOA-High-activity alleles. These genetic effects appeared even stronger in children with CU traits. Moderation analysis revealed that CU traits were associated with lower FC and FD for fear, and lower FD for sadness, probably due to the MAOA-Low-activity alleles. Our findings, although to be replicated, suggest MAOA-Low-activity alleles as potential genetic biomarkers to identify CU children in need of training focused on emotion processing.

Emerging immunotherapeutic strategies for the treatment of breast cancer.

Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.

Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.

BACKGROUND: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. PATIENTS AND METHODS: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. RESULTS: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. CONCLUSIONS: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.

In-Hospital Mortality and Post-Transplantation Complications in Elderly Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Population-Based Study.

Autologous hematopoietic stem cell transplantation (auto-HSCT) has improved survival in patients with multiple myeloma (MM) and is increasingly used in elderly patients. The aim of this study was to characterize and compare in-hospital complications and mortality after auto-HSCT in younger (< age 65) versus elderly (> age 65) MM patients utilizing the Nationwide Inpatient Sample. Over a 3-year period (2008 to 2010), 2209 patients with MM were admitted to US hospitals for auto-HSCT. The median age was 59 years, with 1650 patients (74.7%) younger than age 65 and 559 patients (25.3%) 65 or older. Overall, in-hospital mortality in MM patients after auto-HSCT was rare (1.5%) and there was no significant difference in mortality between elderly and younger patients. Elderly patients did have a significantly increased mean length of stay (18.6 days + 10.8 days [SD] versus 16.8 days + 7.2 days [SD], P < .001) and mean total hospital charges ($161,117 + $105,008 [SD] versus $151,192 + $78,342 [SD] , P = .018) compared with younger patients. Elderly patients were significantly more likely than younger patients to develop major in-hospital post-transplantation complications such as severe sepsis (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.40 to 5.21; P = .003), septic shock (OR, 3.10; 95% CI, 1.43 to 6.71; P = .004), pneumonia (OR, 1.62; 95% CI, 1.06 to 2.46; P = .024), acute respiratory failure (OR, 3.44; 95% CI, 1.70 to 6.96; P = .001), endotracheal intubation requiring prolonged mechanical ventilation (OR, 2.19; 95% CI, 1.06 to 4.55; P = .035), acute renal failure (OR, 2.14; 95% CI, 1.38 to 3.33; P = .001), and cardiac arrhythmias (OR, 2.06; 95% CI, 1.52 to 2.79; P <.001). These data may help guide informed consent discussions and provide a focus for future studies to reduce treatment-related morbidity in elderly MM patients undergoing auto-HSCT.

Mesenchymal stromal/stem cells in drug therapy: New perspective.

Mesenchymal stromal/stem cells (MSC) have emerged as a class of cells suitable for cellular delivery of nanoparticles, drugs and micro-RNA cargo for targeted treatments such as tumor and other protective mechanisms. The special properties of MSC underscore the current use for various clinical applications. Examples of applications include but are not limited to regenerative medicine, immune disorders and anti-cancer therapies. In recent years, there has been intense research in modifying MSC to achieve targeted and efficient clinical outcomes. This review discusses effects of MSC in an inflammatory microenvironment and then explains how these properties could be important to the overall application of MSC in cell therapy. The article also advises caution in the application of these cells because of their role in tumorigenesis. The review stresses the use of MSC as vehicles for drug delivery and discusses the accompanying challenges, based on the influence of the microenvironment on MSC.

Interpreting the gene expression microarray results: a user-based experience.

In recent years many tools have been developed to cope with the interpretation of gene expression results from microarray experiments. The effectiveness of these tools largely depends on their ease of use by biomedical researchers. Tools based on effective computational methods, indeed, cannot be fully exploited by users if they are not supported by an intuitive interface, a large set of utilities and effective outputs. In this paper, 10 tools for the interpretation of gene expression microarray results have been tested on 11 microarray datasets and evaluated according to eight assessment criteria: 1. interface design and usability, 2. easiness of input submission, 3. effectiveness of output representation and 4. of the downloaded outputs, 5. possibility to submit multiple gene IDs, 6. sources of information, 7. provision of different statistical tests and 8. of multiple test correction methods. Strengths and weaknesses of each tool are highlighted to: a. provide useful tips to users dealing with the biological interpretation of microarray results; b. draw the attention of software developers on the usability of their tools.

Increased expression of musashi 1 on breast cancer cells has implication to understand dormancy and survival in bone marrow.

Breast cancer (BC) stem cells (CSCs) resist treatment and can exist as dormant cells in tissues such as the bone marrow (BM). Years before clinical diagnosis, BC cells (BCCs) could migrate from the primary site where the BM niche cells facilitate dedifferentiation into CSCs. Additionally, dedifferentiation could occur by cell autonomous methods. Here we studied the role of Msi 1, a RNA-binding protein, Musashi I (Msi 1). We also analyzed its relationship with the T-cell inhibitory molecule programmed death-ligand 1 (PD-L1) in CSCs. PD-L1 is an immune checkpoint that is a target in immune therapy for cancers. Msi 1 can support BCC growth through stabilization of oncogenic transcripts and modulation of stem cell-related gene expression. We reported on a role for Msi 1 to maintain CSCs. This seemed to occur by the differentiation of CSCs to more matured BCCs. This correlated with increased transition from cycling quiescence and reduced expression of stem cell-linked genes. CSCs co-expressed Msi 1 and PD-L1. Msi 1 knockdown led to a significant decrease in CSCs with undetectable PD-L1. This study has implications for Msi 1 as a therapeutic target, in combination with immune checkpoint inhibitor. Such treatment could also prevent dedifferentiation of breast cancer to CSCs, and to reverse tumor dormancy. The proposed combined treatment might be appropriate for other solid tumors.

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression.

PURPOSE: For patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression. METHODS: We examined a multicenter retrospective cohort of patients with ESR1-MUT MBC who received abemaciclib after disease progression on ET plus palbociclib. We generated a panel of CDK4/6i resistance genes and compared abemaciclib progression-free survival (PFS) in patients without versus with mutations in this panel (CDKi-R[-] v CDKi-R[+]). We studied how ESR1-MUT and CDKi-R mutations affect abemaciclib sensitivity of immortalized breast cancer cells and patient-derived circulating tumor cell lines in culture. RESULTS: In ESR1-MUT MBC with disease progression on ET plus palbociclib, the median PFS was 7.0 months for CDKi-R(-) (n = 17) versus 3.5 months for CDKi-R(+) (n = 11), with a hazard ratio of 2.8 (P = .03). In vitro, CDKi-R alterations but not ESR1-MUT induced abemaciclib resistance in immortalized breast cancer cells and were associated with resistance in circulating tumor cells. CONCLUSION: For ESR1-MUT MBC with resistance to ET and palbociclib, PFS on abemaciclib is longer for patients with CDKi-R(-) than CDKi-R(+). Although a small and retrospective data set, this is the first demonstration of a genomic panel associated with abemaciclib sensitivity in the postpalbociclib setting. Future directions include testing and improving this panel in additional data sets, to guide therapy selection for patients with HR+/HER2- MBC.

Effects on human transcriptome of mutated BRCA1 BRCT domain: a microarray study.

BACKGROUND: BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer. METHODS: We compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain. RESULTS: 201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair. CONCLUSIONS: Our results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity.

HTR1B genotype and psychopathy: Main effect and interaction with paternal maltreatment.

Psychopathy is a condition characterized by atypical emotions and socially maladaptive behavioral patterns. Among incarcerated people, psychopathy has been associated with higher rates of crimes, recidivism, and resistance to treatment. Many studies have indicated significant heritability of psychopathic traits, but little is known about the specific contribution of genes and their interaction with adverse experiences in life. Considering the primary role that serotonin plays in cognition and emotion, we investigated TPH2-rs4570625, 5-HTTLPR, MAOA-uVNTR, HTR1B-rs13212041 and HTR2A-rs6314 as risk factors for psychopathy in the largest sample of institutionalized individuals studied so far, consisting of 793 US White male incarcerated adults, and in a replication sample of 168 US White male incarcerated adolescents. In a subgroup of the adult sample, the interaction between genetics and parenting style, assessed by the Measure of Parental Style (MOPS) questionnaire, was also evaluated. The HTR1B-rs13212041-T/T genotype, as compared to HTR1B-rs13212041-C allele, predicted higher psychopathy scores in both the adult and the adolescent samples. The interaction between HTR1B-rs13212041-T/T genotype and paternal MOPS scores, investigated in a subgroup of the adult sample, was an even stronger predictor of higher levels of psychopathy than either the genetics or the environment taken individually. Overall, these data, obtained in two independent samples, shed new light on neurobiological correlates of psychopathy with promising implications both at a clinical and forensic level.

ANKK1 and TH gene variants in combination with paternal maltreatment increase susceptibility to both cognitive and attentive impulsivity.

Recent scientific findings suggest that dopamine exerts a central role on impulsivity, as well as that aversive life experiences may promote the high levels of impulsivity that often underlie violent behavior. To deepen our understanding of the complex gene by environment interplay on impulsive behavior, we genotyped six dopaminergic allelic variants (ANKK1-rs1800497, TH-rs6356, DRD4-rs1800955, DRD4-exonIII-VNTR, SLC6A3-VNTR and COMT-rs4680) in 655 US White male inmates convicted for violent crimes, whose impulsivity was assessed by BIS-11 (Barratt Impulsiveness Scale). Furthermore, in a subsample of 216 inmates from the whole group, we also explored the potential interplay between the genotyped dopaminergic variants and parental maltreatment measured by MOPS (Measure of Parental Style) in promoting impulsivity. We found a significant interaction among paternal MOPS scores, ANKK1-rs1800497-T allele and TH-rs6356-A allele, which increased the variance of BIS-11 cognitive/attentive scores explained by paternal maltreatment from 1.8 up to 20.5%. No direct association between any of the individual genetic variants and impulsivity was observed. Our data suggest that paternal maltreatment increases the risk of attentive/cognitive impulsivity and that this risk is higher in carriers of specific dopaminergic alleles that potentiate the dopaminergic neurotransmission. These findings add further evidence to the mutual role that genetics and early environmental factors exert in modulating human behavior and highlight the importance of childhood care interventions.

Effect of Taxane Chemotherapy With or Without Indoximod in Metastatic Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. OBJECTIVE: To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. INTERVENTIONS: A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and ß = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. RESULTS: Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01792050.

Strategies to Combat Human Epidermal Growth Factor Receptor 2 (HER2) Resistance in HER2-Positive Breast Cancer.

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in breast cancer led to the development of the first targeted antibody treatment for HER2-positive breast cancer. This treatment breakthrough led to remarkable improvements in both early and late survival. Unfortunately, not all patients with HER2 breast cancer responded positively; some have innate resistance to treatment and others develop resistance over time. In this review, we discuss some research that is currently underway to understand HER2 resistance and strategies in overcoming it.

A genetic profile of oxytocin receptor improves moral acceptability of outcome-maximizing harm in male insurance brokers.

In recent years, conflicting findings have been reported in the scientific literature about the influence of dopaminergic, serotonergic and oxytocinergic gene variants on moral behavior. Here, we utilized a moral judgment paradigm to test the potential effects on moral choices of three polymorphisms of the Oxytocin receptor (OXTR): rs53576, rs2268498 and rs1042770. We analyzed the influence of each single polymorphism and of genetic profiles obtained by different combinations of their genotypes in a sample of male insurance brokers (n = 129), as compared to control males (n = 109). Insurance brokers resulted significantly more oriented to maximize outcomes than control males, thus they expressed more than controls the utilitarian attitude phenotype. When analyzed individually, none of the selected variants influenced the responses to moral dilemmas. In contrast, a composite genetic profile that potentially increases OXTR activity was associated with higher moral acceptability in brokers. We hypothesize that this genetic profile promotes outcome-maximizing behavior in brokers by focusing their attention on what represents a greater good, that is, saving the highest number of people, even though at the cost of sacrificing one individual. Our data suggest that investigations in a sample that most expresses the phenotype of interest, combined with the analysis of composite genetic profiles rather than individual variants, represent a promising strategy to find out weak genetic influences on complex phenotypes, such as moral behavior.

The feeling of anger: From brain networks to linguistic expressions.

This review of the neuroscience of anger is part of The Human Affectome Project, where we attempt to map anger and its components (i.e., physiological, cognitive, experiential) to the neuroscience literature (i.e., genetic markers, functional imaging of human brain networks) and to linguistic expressions used to describe anger feelings. Given the ubiquity of anger in both its normative and chronic states, specific language is used in humans to express states of anger. Following a review of the neuroscience literature, we explore the language that is used to convey angry feelings, as well as metaphors reflecting inner states of anger experience. We then discuss whether these linguistic expressions can be mapped on to the neural circuits during anger experience and to distinct components of anger. We also identify relationships between anger components, brain networks, and other affective research relevant to motivational states of dominance and basic needs for safety.

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia.

Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a "real-life" setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were "resistant;" after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a "low" up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a "high" gene over-expression (p = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a "low" up-regulation were event-free vs. 33% of those who presented a "high" gene expression (p = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.

SNPs in neurotrophin system genes and Alzheimer's disease in an Italian population.

Increasing evidence suggests a role for nerve growth factor (NGFB), brain-derived neurotrophic factor (BDNF), and their receptors, nerve growth factor receptor (NGFR), and neurotrophin tyrosine kinase receptors 1 and 2 (NTRK1 and NTRK2), in Alzheimer's disease (AD). However, genetic association between the neurotrophin system genes and AD has been poorly investigated. We genotyped 21 single nucleotide polymorphisms (SNPs) within these genes in a population of Italian AD patients and healthy controls. We found an allele-wise association of rs2072446 on NGFR with familial AD (fAD, p = 0.047), and a genotype-wise association of rs2289656 on NTRK2 with sporadic AD (sAD, p = 0.0036). rs6336 on NTRK1 resulted associated to early-onset sAD in both allele-wise (p = 0.028) and genotype-wise (p = 0.014) analysis, while rs1048218 on BDNF showed allele-wise association with late-onset sAD (p = 0.047). A trend to association with sAD and/or fAD was observed for other SNPs. Our results suggest that genetic variants of neurotrophin system genes might confer susceptibility to AD.

Genes and Aggressive Behavior: Epigenetic Mechanisms Underlying Individual Susceptibility to Aversive Environments.

Over the last two decades, the study of the relationship between nature and nurture in shaping human behavior has encountered a renewed interest. Behavioral genetics showed that distinct polymorphisms of genes that code for proteins that control neurotransmitter metabolic and synaptic function are associated with individual vulnerability to aversive experiences, such as stressful and traumatic life events, and may result in an increased risk of developing psychopathologies associated with violence. On the other hand, recent studies indicate that experiencing aversive events modulates gene expression by introducing stable changes to DNA without modifying its sequence, a mechanism known as "epigenetics". For example, experiencing adversities during periods of maximal sensitivity to the environment, such as prenatal life, infancy and early adolescence, may introduce lasting epigenetic marks in genes that affect maturational processes in brain, thus favoring the emergence of dysfunctional behaviors, including exaggerate aggression in adulthood. The present review discusses data from recent research, both in humans and animals, concerning the epigenetic regulation of four genes belonging to the neuroendocrine, serotonergic and oxytocinergic pathways-Nuclear receptor subfamily 3-group C-member 1 (NR3C1), oxytocin receptor (OXTR), solute carrier-family 6 member 4 (SLC6A4) and monoamine oxidase A (MAOA)-and their role in modulating vulnerability to proactive and reactive aggressive behavior. Behavioral genetics and epigenetics are shedding a new light on the fine interaction between genes and environment, by providing a novel tool to understand the molecular events that underlie aggression. Overall, the findings from these studies carry important implications not only for neuroscience, but also for social sciences, including ethics, philosophy and law.

TAMGeS: a Three-array Method for Genotyping of SNPs by a dual-colour approach.

BACKGROUND: Many of the most effective high-throughput protocols for SNP genotyping employ microarrays. Genotypes are assessed by comparing the signal intensities that derive from the hybridization of different allele-specific probes labelled either by using four fluorescent dyes, one for each base, or by using only two dyes and investigating the polymorphic alleles two by two on separate arrays. The employment of only two dyes makes it possible to use a dual-laser scanner, which has the advantage of being present in every microarray laboratory. However, this protocol may present some drawbacks. To infer all the six possible genotypes it is necessary to compare signals from two arrays, but this comparison not always is successful. A number of systematic errors in the experimental protocol, in fact, may differently affect signal intensities on separate arrays. Here we present TAMGeS (Three-Array Method for Genotyping of SNPs), an exhaustive method for SNP genotyping through SBE (Single Base Extension) and dual-colour microarrays, which makes the comparison of signals on distinct arrays reliable by using a third array and a data handling method for signal normalization based on bilinear regression theory. RESULTS: We tested the effectiveness of the proposed method by evaluating the results obtained from the direct comparison of the two arrays or by applying TAMGeS, both on experimental and synthetic data. With synthetic data, TAMGeS reduced the frequency of errors by an order of magnitude, when the incidence of systematic errors was not negligible. With the experimental data, produced by genotyping 25 SNPs in 437 subjects, TAMGeS reduced the percentage of missing genotypes from 54% (Two-Array Method) to 14.5%. Allelic and genotypic call rates were 99.3% and 99.5%, respectively. The normalization procedure takes into account also systematic errors, which can be generated by a time-delayed assay, thus making the protocol more flexible. CONCLUSION: TAMGeS represents an innovative method, which proved to be very effective in producing reliable SNP genotyping data by dual-colour microarrays. The requirement of a third array is well balanced by the strong enhancement in data quality and by the greater flexibility of the experimental protocol.