ABCC1, ABCG2 and FOXP3: Predictive Biomarkers of Toxicity from Methotrexate Treatment in Patients Diagnosed with Moderate-to-Severe Psoriasis.

BACKGROUND: Methotrexate (MTX) is one of the most extensively used drugs in the treatment of moderate-to-severe psoriasis (PS). However, it frequently must be suspended owing to the toxicity in certain patients. OBJECTIVE: To evaluate the influence of ABCC1, ABCG2, and FOXP3 in the development of MTX toxicity in PS. METHODS: Retrospective cohort study with 101 patients. Five single-nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction with TaqMan probes. RESULTS: Patients carrying ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.04; 95% CI = 1.48-46.78; p = 0.015); FOXP3 rs376154-GT and GG genotypes (GT vs. TT/GG: OR = 3.86; 95% CI = 1.17-13.92; p = 0.031) and ABCG2 rs13120400-T allele (T vs. CC: OR = 8.33; 95% CI = 1.24-164.79; p = 0.059) showed a higher risk of developing more than one adverse effect. The toxicity analysis by subtypes showed that the ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.10; 95% CI = 1.69-46.63; p = 0.011) and FOXP3 rs376154-GT genotype (OR = 4.11; 95% CI = 1.22-15.30; p = 0.027) were associated with the appearance of asthenia. No association of the other ABCC1 polymorphisms (rs35592 and rs246240) with MTX toxicity was found. CONCLUSION: ABCC1, ABCG2, and FOXP3 polymorphisms can be considered to be risk biomarkers of toxicities in PS patients treated with MTX.

Impact of Functional Polymorphisms on Drug Survival of Biological Therapies in Patients with Moderate-to-Severe Psoriasis.

Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk.

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41-0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47-1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40-0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12-1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.

Vitamin D-Related Single Nucleotide Polymorphisms as Risk Biomarker of Cardiovascular Disease.

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. In addition to environmental risk factors, genetic predisposition increases the risk; this includes alterations in the vitamin D receptor gene (VDR). These alterations play a key role in modifying vitamin D uptake, being able to modify its function and increasing susceptibility to cardiovascular disorders. The aim of this study was to evaluate the association of polymorphisms in the VDR gene and risk of CVD in a Caucasian population. A retrospective case-control study was conducted comprising 246 CVD patients and 246 controls of Caucasian origin from Southern Spain. The genetic polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570) and Cdx2 (rs11568820) were determined by means of real-time polymerase chain reaction (PCR) for allelic discrimination using TaqMan® probes. The logistic regression analysis adjusted for body mass index and diabetes revealed that the TT genotype was associated with a higher risk of CVD in both the genotypic model (p = 0.0430; OR = 2.30; 95% CI = 1.06-5.37; TT vs. CC) and the recessive model (p = 0.0099; OR = 2.71; 95% CI = 1.31-6.07; TT vs. C). Haplotype analysis revealed that the haplotype GAC (p = 0.047; OR = 0.34; 95% CI = 0.12-0.98) was associated with increased risk of CVD. The VDR polymorphisms FokI (rs2228570) was significantly associated with the development of CVD. No influence was observed of the VDR polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) on the risk of developing CVD in the patients studied.

Genetic polymorphisms on the effectiveness or safety of breast cancer treatment: Clinical relevance and future perspectives.

Breast cancer (BC) is the most frequent neoplasm and one of the main causes of death in women. The pharmacological treatment of BC consists of hormonal therapy, chemotherapeutic agents and targeted therapy. The response to BC therapy is highly variable in clinical practice. This variability can be explained by the presence of genetic polymorphisms in genes involved in the pharmacokinetics, pharmacodynamics or immune response of patients. The abundant evidence of associations between low-activity alleles CYP2D6*3, *4, *5, *6, *10 and *41 and poor results with tamoxifen therapy, and between DPYD gene polymorphisms rs3918290, rs55886062, rs67376798 and rs75017182 and increased risk of toxicity to fluoropyrimidine therapy, justify the existence of clinical pharmacogenetic guidelines. The NQO1 rs1800566 polymorphism is related to poorer results in BC therapy with chemotherapy agents. The polymorphism rs1695 of the GSTP1 gene has been associated with the effectiveness and toxicity of fluorouracil, cyclophosphamide and epirubicin therapy. Finally, the HLA-DQA1*02:01 allele is significantly associated with the occurrence of liver toxicity events in patients receiving lapatinib. There is moderate evidence to support the aforementioned associations and, therefore, a high probability of these being considered as future predictive genetic biomarkers of response. However, further studies are required to reinforce or clarify their clinical relevance.

Secreted Frizzled – Related Protein 4 y el cáncer de mama / Secreted Frizzled – Related Protein 4 and breast cancer

Introducción: el correcto funcionamiento y la supervivencia de la célula vienen mediados por multitud de procesos clave. El delicado equilibrio que se requiere entre dichos fenómenos hace que un error en los mecanismos de control desencadene el inicio de la carcinogénesis. Dentro de las rutas metabólicas encargadas de su regulación se encuentran las vías de señalización del Wnt. De esta forma, aquellas moléculas que intervengan en dichas vías presentarán un papel clave para el estudio de la patología, entre las que destaca secreted Frizzled – Related Protein 4 (sFRP4). Método: se ha llevado a cabo una búsqueda bibliográfica en bases de datos de referencia, como es el caso de Medline, Scopus o Web of Science. Resultados: a sFRP4 se le ha otorgado el papel de modulador negativo de las vías de Wnt debido a su capacidad de competir por los ligandos Wnt y evitar el inicio de dichas rutas. Por lo tanto, sFRP4 será esencial en el control del inicio y desarrollo del cáncer en aquellos tejidos donde se exprese la proteína, dentro de los que se considera el tejido mamario. Conclusiones: los recientes estudios acerca de la implicación de sFRP4 en el desarrollo de diversas patologías, justifican que la proteína haya captado la atención en los últimos años. De esta forma, se puede afirmar que sFRP4 presenta un interesante potencial como biomarcador en el tratamiento, diagnóstico y pronóstico del cáncer de mama, entre otras enfermedades. (AU)

Introduction: cell’s correct functionality and surveillance are brokered by a wide range of essential proceedings. The delicate equilibrium required between those phenomenon means that an error in the control mechanisms pro-voke the carcinogenesis commencement. In those metabolic pathways in charge of controlling the mechanisms are found the Wnt signaling pathways. Therefore, molecules that interact with the pathways mentioned, where secret-ed Frizzled – Related Protein 4 is located, will play a key role in the pathology knowledge. Method: a bibliographic research has been done in referral databases, such as Medline and Scopus. Results: sFRP4 has been identified as a negative modulator of the Wnt signaling pathways. This is due to its capacity of competing for the Wnt ligands and avoiding the commencement of the pathways. Otherwise, sFRP4 is essential for the control of the cancer beginning and development in those tissues where the protein is expressed, being mammary tissues considered into them. Conclusions: recent studies about the implications of sFRP4 in the development of several pathologies justify that the protein had garnered attention in recent years. Furthermore, it can be affirmed that sFRP4 presents an inter-esting potential as biomarker in the breast cancer treatment, diagnosis and prognosis, among other pathologies. (AU)

Impact of Genetic Polymorphisms on the Metabolic Pathway of Vitamin D and Survival in Non-Small Cell Lung Cancer.

Vitamin D has been associated with risk, development, and progression of cancer. However, the genes involved in its metabolism are highly polymorphic, compromising its activity. The aim of this study is to evaluate the association between the gene polymorphisms involved in the metabolic pathway of vitamin D and survival in patients with non-small-cell lung cancer (NSCLC). The study was designed as an observational cohort which included 194 Caucasians patients from southern Spain with NSCLC. Real-time polymerase chain reaction was used to analyze the following polymorphisms: CYP27B1 rs4646536, rs3782130, and rs10877012; CYP24A1 rs6068816 and rs4809957; GC rs7041; CYP2R1 rs10741657; VDR rs1544410 (BsmI), rs11568820 (Cdx-2), rs2228570 (FokI), rs7975232 (ApaI), and rs731236 (TaqI). Progression-free survival (PFS) and overall survival were assessed. Cox regression showed that rs4646536 was associated with PFS in the general population (p = 0.0233) and in the non-resected NSCLC subgroup (p = 0.0233). In the resected NSCLC subgroup, rs11568820 was associated with OS (p = 0.0129) and rs7041 with PFS (p = 0.0447). In the non-resected NSCLC subgroup, rs6068816 was associated with PFS (p = 0.0048) and OS (p = 0.0089) and rs731236 and rs7975232 were associated with OS (p = 0.0005) and PFS (p = 0.0002), respectively. The other polymorphisms showed no effect on the results. The rs4646536, rs6068816, rs7041, rs11568820, rs731236, and rs7975232 polymorphisms are associated with survival in NSCLC and may have a substantial role as prognostic markers of the disease.

Influence of Genetic Polymorphisms on Clinical Outcomes of Glatiramer Acetate in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of autoimmune origin, in which inflammation and demyelination lead to neurodegeneration and progressive disability. Treatment is aimed at slowing down the course of the disease and mitigating its symptoms. One of the first-line treatments used in patients with MS is glatiramer acetate (GA). However, in clinical practice, a response rate of between 30% and 55% is observed. This variability in the effectiveness of the medication may be influenced by genetic factors such as polymorphisms in the genes involved in the pathogenesis of MS. Therefore, this review assesses the impact of genetic variants on the response to GA therapy in patients diagnosed with MS. The results suggest that a relationship exists between the effectiveness of the treatment with GA and the presence of polymorphisms in the following genes: CD86, CLEC16A, CTSS, EOMES, MBP, FAS, TRBC1, IL1R1, IL12RB2, IL22RA2, PTPRT, PVT1, ALOX5AP, MAGI2, ZAK, RFPL3, UVRAG, SLC1A4, and HLA-DRB1*1501. Consequently, the identification of polymorphisms in these genes can be used in the future as a predictive marker of the response to GA treatment in patients diagnosed with MS. Nevertheless, there is a lack of evidence for this and more validation studies need to be conducted to apply this information to clinical practice.

Clinical Application of Pharmacogenetic Markers in the Treatment of Dermatologic Pathologies.

Dermatologic pathologies are the fourth most common cause of non-fatal disease worldwide; however, they produce a psychosocial, economic, and occupational impact equal to or greater than other chronic conditions. The most prevalent are actinic keratosis, followed by basal-cell carcinoma, in a lesser proportion acne vulgaris, psoriasis, and hidradenitis suppurativa, among others, and more rarely dermatitis herpetiformis. To treat actinic keratosis and basal-cell carcinoma, 5-fluorouracil (5-FU) 0.5% is administered topically with good results, although in certain patients it produces severe toxicity. On the other hand, dapsone is a drug commonly used in inflammatory skin conditions such as dermatitis herpetiformis; however, it occasionally causes hemolytic anemia. Additionally, biologic drugs indicated for the treatment of moderate-to-severe psoriasis and hidradenitis suppurativa have proved to be effective and safe; nevertheless, a small percentage of patients do not respond to treatment with biologics in the long term or they are ineffective. This interindividual variability in response may be due to alterations in genes that encode proteins involved in the pathologic environment of the disease or the mechanism of action of the medication. Pharmacogenetics studies the relationship between genetic variations and drug response, which is useful for the early identification of non-responsive patients and those with a higher risk of developing toxicity upon treatment. This review describes the pharmacogenetic recommendations with the strongest evidence at present for the treatments used in dermatology, highlighting those included in clinical practice guides. Currently, we could only find pharmacogenetic clinical guidelines for 5-FU. However, the summary of product characteristics for dapsone contains a pharmacogenetic recommendation from the United States Food and Drug Administration. Finally, there is an enormous amount of information from pharmacogenetic studies in patients with dermatologic pathologies (mainly psoriasis) treated with biologic therapies, but they need to be validated in order to be included in clinical practice guides.

Influence of Genetic Polymorphisms on Response to Biologics in Moderate-to-Severe Psoriasis.

Psoriasis is a chronic inflammatory skin pathology of autoimmune origin and unknown etiology. There are various therapies for treating it, including a wide range of biopharmaceuticals indicated in moderate-to-severe psoriasis. Depending on their therapeutic target, they are classified as tumor necrosis factor inhibitors (anti-TNF) or cytokine inhibitors (interleukin-12, 23, and 17 antagonists). Although they have proved effective and safe, in clinical practice, many patients show a short- and long-term suboptimal response and even varying degrees of toxicity. This variability in response may be influenced by genetic factors, such as polymorphisms in the genes involved in the pathological environment, metabolism or mechanism of action of the drug that could affect the effectiveness and toxicity of biological therapies. This review assesses pharmacogenetic studies of the impact of genetic factors on response to biopharmaceuticals and toxicity in patients diagnosed with moderate-to-severe psoriasis. The results suggest that polymorphisms detected in the HLA genes, in genes that encode cytokines (TNF, IL genes, TNFAIP3), transporters (PDE3A-SLCO1C1, SLC12A8), receptors (TNFRSF1B, CD84, FCGR2A and FCGR3A, IL17RA, IL23R, TLR genes, PGLYRP4) and associated proteins (TNFAIP3, LY96, TIRAP, FBXL19), as well as other genes implicated in the pathogenesis of psoriasis (CDKAL1, CARD14, PTTG1, MAP3K1, ZNF816A, GBP6, CTNNA2, HTR2A, CTLA4, TAP1) can be used in the future as predictive markers of treatment response and/or toxicity with biological therapies in patients diagnosed with moderate-to-severe psoriasis, tailoring treatment to the individual patient.

Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis.

The introduction of new therapies for the treatment of multiple sclerosis (MS) is a very recent phenomenon and little is known of their mechanism of action. Moreover, the response is subject to interindividual variability and may be affected by genetic factors, such as polymorphisms in the genes implicated in the pathologic environment, pharmacodynamics, and metabolism of the disease or in the mechanism of action of the medications, influencing the effectiveness of these therapies. This review evaluates the impact of pharmacogenetics on the response to treatment with new therapies in patients diagnosed with MS. The results suggest that polymorphisms detected in the GSTP1, ITGA4, NQO1, AKT1, and GP6 genes, for treatment with natalizumab, ZMIZ1, for fingolimod and dimethyl fumarate, ADA, for cladribine, and NOX3, for dimethyl fumarate, may be used in the future as predictive markers of treatment response to new therapies in MS patients. However, there are few existing studies and their samples are small, making it difficult to generalize the role of these genes in treatment with new therapies. Studies with larger sample sizes and longer follow-up are therefore needed to confirm the results of these studies.

Changes in Brassica oleracea Leaves Infected With Xanthomonas campestris pv. campestris by Proteomics Analysis.

Understanding plant's response mechanisms against pathogenesis is fundamental for the development of resistant crop varieties and more productive agriculture. In this regard, "omic" approaches are heralded as valuable technologies. In this work, combining isobaric tags for relative and absolute quantification (iTRAQ) technology with mass spectrometry, the proteomes from leaves of Brassica oleracea plants infected with Xanthomonas campestris pv. campestris (Xcc), and control plants at two different post-infection times were compared. Stronger proteomic changes were obtained at 12 days post-infection in comparison with 3 days. The responses observed involved different cell processes, from primary metabolism, such as photosynthesis or photorespiration, to other complex processes such as redox homeostasis, hormone signaling, or defense mechanisms. Most of the proteins decreased in the earlier response were involved in energetic metabolism, whereas later response was characterized by a recovery of primary metabolism. Furthermore, our results indicated that proteolysis machinery and reactive oxygen species (ROS) homeostasis could be key processes during this plant-pathogen interaction. Current data provide new insights into molecular mechanisms that may be involved in defense responses of B. oleracea to Xcc.

Association between polymorphisms in the vitamin D receptor and susceptibility to multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a neurodegenerative chronic inflammatory. Mutations in the vitamin D receptor (VDR) gene can substantially affect serum vitamin D levels or alter its functionality, and can consequently increase susceptibility to developing MS. The objective of this study was to evaluate the association between polymorphisms in the VDR gene and risk of MS in a (Spanish) Caucasian population. PATIENTS AND METHODS: We conducted a retrospective case-control study comprising 209 patients with relapsing-remitting multiple sclerosis (RRMS) and 836 controls of Caucasian origin from southern Spain. The ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms were determined by allelic discrimination real-time PCR using TaqMan probes. RESULTS: The recessive logical regression model, adjusted for age and sex, revealed that the TT genotype for VDR FokI (rs2228570) polymorphism was associated with higher risk of MS (P = 0.0150; OR = 1.82; 95% CI = 1.12-2.94; TT vs. CT + CC). No association between the other polymorphisms and development of MS was found in any of the models analyzed. The haplotype analysis, adjusted for age, smoking, and sex, did not find any statistically significant association between the haplotypes analyzed and risk of MS. CONCLUSIONS: The VDR FokI (rs2228570) polymorphism was significantly associated with developing MS. We found no influence of the ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms on the risk of developing MS in our patients.

Impact of Single-Nucleotide Polymorphisms of CTLA-4, CD80 and CD86 on the Effectiveness of Abatacept in Patients with Rheumatoid Arthritis.

Abatacept (ABA) is used as a first-line treatment in patients diagnosed with moderate and severe rheumatoid arthritis (RA). The interindividual response to ABA therapy is very variable in these patients. The objective of our study was therefore to investigate the role of polymorphisms of the CTLA-4, CD80 and CD86 genes, as well as that of clinical factors of the disease, in the response to ABA in patients with RA. A retrospective cohort study was carried out in 109 patients receiving treatment with ABA and diagnosed with RA. The genetic variables were analyzed using real-time PCR with TaqMan® probes. The patients were classified according to the European League Against Rheumatism (EULAR) criteria at 6 and 12 months from start of treatment. The independent variables associated with higher EULAR response were lower duration of previous biologic disease-modifying anti-rheumatic drugs and lower baseline values of the disease activity score 28 after 6 months of ABA treatment; and lower baseline patient's visual analogue scale (PVAS) after 12 months. In addition, a significant association was found between duration of ABA treatment, non-administration of concomitant glucocorticoids and lower baseline values of the number of inflamed joints and erythrocyte sedimentation rate clinical variables, with remission of the disease after 6 months' treatment with ABA. Finally, remission of the disease after 12 months' treatment with ABA was associated with earlier age at start of ABA therapy and lower number of previous biologic therapies (BTs). The CTLA-4rs5742909-T allele and the CTLA-4rs231775-G allele were found to be associated with satisfactory EULAR response and low disease activity (LDA) after 12 months' treatment with ABA (CTLA-4rs5742909 T vs. CC; OR = 5.88; CI95% = 1.48-23.29 and OR = 4.75; CI95% = 1.35-17.94, respectively, and CTLA-4rs231775 G vs. AA, OR = 3.48; CI95% = 1.20-10.09 and OR = 4.68; CI95% = 1.49-17.94, respectively). In conclusion, patients with RA treated with ABA showed better EULAR response and LDA rate when they had the CTLA-4 rs5742909-T or CTLA-4 rs231775-G polymorphisms; furthermore, this remission rate increased in patients that began ABA treatment earlier, those with a lower number of previous BTs and those with a lower PVAS value.

Effect of genetic polymorphisms on therapeutic response in multiple sclerosis relapsing-remitting patients treated with interferon-beta.

Treatment with interferon beta (IFNß) is one of the first-line treatments for multiple sclerosis. In clinical practice, however, many patients present suboptimal response to IFNß, with the proportion of non-responders ranging from 20 to 50%. This variable response can be affected by genetic factors, such as polymorphisms in the genes involved in the disease state, pharmacodynamics, metabolism or in the action mechanism of IFNß, which can affect the efficacy of this drug. This review assesses the impact of pharmacogenetics studies on response to IFNß treatment among patients diagnosed with relapsing-remitting multiple sclerosis (RRMS). The results suggest that the detection of polymorphisms in several genes (CD46, CD58, FHIT, IRF5, GAPVD1, GPC5, GRBRB3, MxA, PELI3 and ZNF697) could be used in the future as predictive markers of response to IFNß treatment in patients diagnosed with RRMS. However, few studies have been carried out and they have been performed on small sample sizes, which makes it difficult to generalize the role of these genes in IFNß treatment. Studies on large sample sizes with longer term follow-up are therefore required to confirm these results.

Long-Chain Polyunsaturated Fatty Acids, Homocysteine at Birth and Fatty Acid Desaturase Gene Cluster Polymorphisms are Associated with Children's Processing Speed up to Age 9 Years.

Both pre- and early postnatal supplementation with docosahexaenoic acid (DHA), arachidonic acid (AA) and folate have been related to neural development, but their long-term effects on later neural function remain unclear. We evaluated the long-term effects of maternal prenatal supplementation with fish-oil (FO), 5-methyltetrahydrofolate (5-MTHF), placebo or FO + 5-MTHF, as well as the role of fatty acid desaturase (FADS) gene cluster polymorphisms, on their offspring's processing speed at later school age. This study was conducted in NUHEAL children at 7.5 (n = 143) and 9 years of age (n = 127). Processing speed tasks were assessed using Symbol Digit Modalities Test (SDMT), Children Color Trails Test (CCTT) and Stroop Color and Word Test (SCWT). Long-chain polyunsaturated fatty acids, folate and total homocysteine (tHcy) levels were determined at delivery from maternal and cord blood samples. FADS and methylenetetrahydrofolate reductase (MTHFR) 677 C > T genetic polymorphisms were analyzed. Mixed models (linear and logistic) were performed. There were significant differences in processing speed performance among children at different ages (p < 0.001). The type of prenatal supplementation had no effect on processing speed in children up to 9 years. Secondary exploratory analyses indicated that children born to mothers with higher AA/DHA ratio at delivery (p < 0.001) and heterozygotes for FADS1 rs174556 (p < 0.05) showed better performance in processing speed at 9 years. Negative associations between processing speed scores and maternal tHcy levels at delivery were found. Our findings suggest speed processing development in children up to 9 years could be related to maternal factors, including AA/DHA and tHcy levels, and their genetic background, mainly FADS polymorphism. These considerations support that maternal prenatal supplementation should be quantitatively adequate and individualized to obtain better brain development and mental performance in the offspring.

Calcium-signaling proteins mediate the plant transcriptomic response during a well-established Xanthomonas campestris pv. campestris infection.

The plant immune system is divided into two branches; one branch is based on the recognition of pathogen-associated molecular patterns (PAMP-triggered immunity), and the other relies on pathogenic effector detection (effector-triggered immunity). Despite each branch being involved in different complex mechanisms, both lead to transcription reprogramming and, thus, changes in plant metabolism. To study the defense mechanisms involved in the Brassica oleracea-Xanthomonas campestris pv. campestris (Xcc) interaction, we analyzed the plant transcriptome dynamics at 3 and 12 days postinoculation (dpi) by using massive analysis of 3'-cDNA ends. We identified more induced than repressed transcripts at both 3 and 12 dpi, although the response was greater at 12 dpi. Changes in the expression of genes related to the early infection stages were only detected at 12 dpi, suggesting that the timing of triggered defenses is crucial to plant survival. qPCR analyses in susceptible and resistant plants allowed us to highlight the potential role of two calcium-signaling proteins, CBP60g and SARD1, in the resistance against Xcc. This role was subsequently confirmed using Arabidopsis knockout mutants.

Deshabituación rápida de opioides / Fast opioid detoxification

Introducción: En estos últimos 15 años, el incremento del uso de analgésicos opioides ha sido progresivo y elevado. La percepción de la existencia de cuadros de dolor mal tratados ha provocado que muchos sistemas de salud incentiven a los profesionales en el uso de opioides, para evitar episodios de sufrimiento inútiles y estériles. Dicha incentivación, el uso de receta electrónica, la facilitación y simpleza de prescripción tras la desaparición de receta de estupefacientes tradicional, supuso una liberalización significativa y uso de opioides progresivo entre todas las especialidades médicas que habitualmente no los prescribían. Además, la aparición de nuevos opioides sintéticos, con aparentemente menores efectos secundarios, fáciles de usar y con buen perfil farmacocinético, quizás ha suscitado una confianza irreal en la inocuidad de dichos fármacos. Estos últimos años han sido años de alta prescripción y de hallazgo de efectos no deseados por los elevados consumos y prescripciones un tanto quizá alejadas de la idoneidad y poco control sobre los pacientes. Nosotros detectamos en nuestro departamento de salud varios casos de pacientes con problemas reales derivados del consumo de opioides, de origen iatrogénico, siempre por prescripción médica legal y con gravísimos efectos secundarios, que conllevaban riesgo vital. Objetivo: Realizar una deshabituación rápida del consumo de opioides, sin poner en riesgo la salud y vida del paciente, de un modo rigurosamente monitorizado y controlado. Material y métodos: Nuestra comunicación científica se basa en la descripción del trabajo realizado sobre un grupo de pacientes afectados por un elevado consumo de opioides. Nuestro método de deshabituación a los opioides consiste en el ingreso de los pacientes en la Unidad de Cuidados Intensivos del Servicio de Anestesiología de nuestro hospital para la retirada absoluta de los mismos. Se realiza en primer lugar una valoración basal clínica, psicológica, social y biológica, y tras solicitar un consentimiento informado, se procede a una retirada de los opioides, con monitorización avanzada e inicio de sedación profunda multimodal, hasta el nivel que sea necesario para cada paciente, incluso con previsión de posible intubación orotraqueal y asistencia ventilatoria. Realizamos mantenimiento vital convencional de cuidados intensivos, con fluidoterapia, profilaxis antitrombótica, protección digestiva, fisioterapia, control de diuresis y control bioquímico, metabólico y nutricional durante 96 horas. Posteriormente, el paciente, tras asegurar su estabilidad y seguridad, pasa a una planta de hospitalización convencional durante unas 48 horas, con tratamiento de perfil psiquiátrico manejado por la Unidad de Conductas Adictivas. Tras ser dado de alta hospitalaria, se continúa tratamiento y control por Unidad de Conductas Adictivas, Unidad de Dolor y Unidad de Rehabilitación Física. Resultados: Describimos los resultados obtenidos con el uso de dos pautas en las que se combinan distintos grupos farmacológicos usados para la deshabituación: midazolam, propofol, ketamina, dexmedetomidina, clonidina y naloxona, en la consecución del mantenimiento del paciente libre de opioides garantizando la estabilidad hemodinámica, respiratoria y la seguridad biológica del paciente. Conclusiones: La desconexión rápida de opioides es un tratamiento eficaz, que recupera al paciente de un infierno vital grave del que difícilmente se puede salir sin una ayuda externa. Lo consideramos un método seguro, ya que no se nos ha presentado ninguna complicación severa, aunque son pacientes que precisan de unos cuidados médicos de vigilancia intensiva. El posterior seguimiento y ayuda es imprescindible, aunque como pacientes de dolor, precisan de un buen entorno social y familiar, para conseguir el apoyo necesario y no volver a recaer. Por todo ello, y en base a los resultados obtenidos en nuestro estudio, consideramos que es un método adecuado y eficaz, aunque caro en recursos

Introduction: For the last 15 years we have witnessed a steady increase in opioid consumption. Being aware of an undertreatment in certain pain situations, many health care providers have encouraged their physicians to prescribe opioids to avoid unnecessary suffering. Such encouragement, also by means of switching from the traditional paper prescription to the current electronic one, has led to a wide spread in opioid prescription even among those medical specialities which never did before. Besides, new synthetic opioids with apparently less side effects, favourable kinetics and easer to take, might have arosen a wrong impression of unreal harmlessness. Therefore, the increased prescription and its obvious consequence of consumption has led to an alarming increase in the number of side effects, proving our patients not to be so well controlled. We have perceived in our Health Department several different patients with opioid consumption abuse derived from medical prescription with potential life threatening side effects, that's why we have conducted a medical path for their detoxification. Aim: To perform a safe fast opioid detoxification (FOD) in our fully monitored patients. Method and materials: To perform our FOD path we previously admit the patients in our ICU unit. After a careful clinical, psychological, social and biological assessment, and having requested their informed consent, we monitor all their vital constants in bed and we start a deep polymodal sedation up to the required level for each patient, getting even ready for oral intubation and mechanical ventilation if needed. Our regular vital maintenance is based on fluids, deep vein thrombosis prophylaxis, digestive prophylaxis, physiotherapy, urine output and blood tests for 96 hours. Having achieved our goal, regarding the patients are stable, they are discharged to the ward for an additional 48 hours period, with psyquiatric treatment and under the care of the Addictive Conducts Unit. The patients are fi nally discharged from hospital with a multimodal supervision and treatment conducted by our Pain Unit, Addictive Conducts Unit and Physical Rehabilitation. Results: We describe the results achieved with two different drug approaches which combine different pharmacological groups frequently used for detoxification: midazolam, propofol, ketamine, clonidine and naloxone, for our aim of succeeding in keeping the patients opioid-free without endangering their haemodynamic, breathe or biology. Conclusions: FOD has proved to be a successful treatment in rescuing the patients from a living hell out of which they would have found it impossible to leave without qualified help. We deem it safe with the right ICU surveillance, since no major complications have occurred, but a thereafter following and help is mandatory, since, like any other patient attended at a Pain Clinic, they require a favouring social and familiar environment to avoid any relapse. Finally, and given our results, we consider this detoxifi cation method right and safe but highly costly in resources

Current Challenges in Plant Eco-Metabolomics.

The relatively new research discipline of Eco-Metabolomics is the application of metabolomics techniques to ecology with the aim to characterise biochemical interactions of organisms across different spatial and temporal scales. Metabolomics is an untargeted biochemical approach to measure many thousands of metabolites in different species, including plants and animals. Changes in metabolite concentrations can provide mechanistic evidence for biochemical processes that are relevant at ecological scales. These include physiological, phenotypic and morphological responses of plants and communities to environmental changes and also interactions with other organisms. Traditionally, research in biochemistry and ecology comes from two different directions and is performed at distinct spatiotemporal scales. Biochemical studies most often focus on intrinsic processes in individuals at physiological and cellular scales. Generally, they take a bottom-up approach scaling up cellular processes from spatiotemporally fine to coarser scales. Ecological studies usually focus on extrinsic processes acting upon organisms at population and community scales and typically study top-down and bottom-up processes in combination. Eco-Metabolomics is a transdisciplinary research discipline that links biochemistry and ecology and connects the distinct spatiotemporal scales. In this review, we focus on approaches to study chemical and biochemical interactions of plants at various ecological levels, mainly plant⁻organismal interactions, and discuss related examples from other domains. We present recent developments and highlight advancements in Eco-Metabolomics over the last decade from various angles. We further address the five key challenges: (1) complex experimental designs and large variation of metabolite profiles; (2) feature extraction; (3) metabolite identification; (4) statistical analyses; and (5) bioinformatics software tools and workflows. The presented solutions to these challenges will advance connecting the distinct spatiotemporal scales and bridging biochemistry and ecology.

Unraveling the metabolic response of Brassica oleracea exposed to Xanthomonas campestris pv. campestris.

BACKGROUND: Brassica crops together with cereals represent the basis of world supplies. Due to their importance, the production losses caused by Xanthomonas campestris pv. campestris (Xcc) infection represent a high economic impact. Understanding molecular and biochemical mechanisms of plants is essential to develop resistant crops with durable protection against diseases. In this regard, metabolomics has emerged as a valuable technology to provide an overview of the biological status of a plant exposed to a disease. This study investigated the dynamic changes in the metabolic profile of Brassica oleracea plants during an Xcc infection from leaves collected at five different days post infection using a mass spectrometry approach. RESULTS: Results showed that Xcc infection causes dynamic changes in the metabolome of B. oleracea. Moreover, induction/repression pattern of the metabolites implicated in the response follows a complex dynamics during infection progression, indicating a complex temporal response. Specific metabolic pathways such as alkaloids, coumarins or sphingolipids are postulated as promising key role candidates in the infection response. CONCLUSION: This work tries to decipher the changes produced on Brassica crops metabolome under Xcc infection and represents a step forward in the understanding of B. oleracea-Xcc interaction. © 2018 Society of Chemical Industry.