Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia.

BMC Neurosci. 2015;16:67

Authors: Luo J, Lee SH, VandeVrede L, Qin Z, Piyankarage S, Tavassoli E, Asghodom RT, Ben Aissa M, Fà M, Arancio O, Yue L, Pepperberg DR, Thatcher GR

Abstract
BACKGROUND: Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property.
RESULTS: The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice.
CONCLUSION: Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.

PMID: 26480871 [PubMed - indexed for MEDLINE]

Repurposing Non-Antimicrobial Drugs and Clinical Molecules to Treat Bacterial Infections.

Curr Pharm Des. 2015;21(28):4106-11

Authors: Younis W, Thangamani S, Seleem MN

Abstract
There is a pressing need to develop novel antimicrobials to circumvent the scourge of antimicrobial resistance. The objective of this study is to identify non-antibiotic drugs with potent antimicrobial activity, within an applicable clinical range. A library, containing 727 FDA approved drugs and small molecules, was screened against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae). Drugs that showed antimicrobial activity in an applicable clinical range were further tested in vitro and in vivo in an infected mouse model. The initial screening identified 24 non-antibiotic drugs and clinical molecules active against Gram-positive pathogens including methicillin- resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) isolates. Two non-antibiotic drugs showed activity against Gram-negative pathogens. Among the active non-antibiotic drugs, only ebselen (EB) and 5-fluoro-2'-deoxyuridine (FdUrd), showed bactericidal activity, in an applicable clinical range, against multi-drug-resistant Staphylococcus isolates including MRSA, vancomycin-resistant S. aureus (VRSA), and vancomycin-intermediate S. aureus (VISA). The minimum inhibitory concentration at which 90% of clinical isolates of S. aureus were inhibited (MIC90) was found to be 0.25 and 0.0039mg/L for EB and FdUrd, respectively. Treatment with EB orally significantly increased mice survival in a lethal model of septicemic MRSA infection by (60%) compared to that of control. FdUrd oral and intraperitoneal treatment significantly enhanced mouse survival by 60% and 100%, respectively. These data encourage screening and repurposing of non-antibiotic drugs and clinical molecules to treat multidrug-resistant bacterial infections.

PMID: 25961308 [PubMed - indexed for MEDLINE]

Pharmacogenomics and the treatment of acute myeloid leukemia.

Pharmacogenomics. 2016 Jul 6;

Authors: Megías-Vericat JE, Montesinos P, Herrero MJ, Bosó V, Martínez-Cuadrón D, Poveda JL, Sanz MÁ, Aliño SF

Abstract
Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous malignancy that is primarily treated with combinations of cytarabine and anthracyclines. Although this scheme remains effective in most of the patients, variability of outcomes in patients has been partly related with their genetic variability. Several pharmacogenetic studies have analyzed the impact of polymorphisms in genes encoding transporters, metabolizers or molecular targets of chemotherapy agents. A systematic review on all eligible studies was carried out in order to estimate the effect of polymorphisms of anthracyclines and cytarabine pathways on efficacy and toxicity of AML treatment. Other emerging genes recently studied in AML, such as DNA repair genes, genes potentially related to chemotherapy response or AML prognosis, have also been included.

PMID: 27381050 [PubMed - as supplied by publisher]

The Role of Pharmacogenomics: The Same Medications Do Not Work the Same on Everyone.

Nurs Clin North Am. 2016 Mar;51(1):ix-x

Authors: Krau SD

PMID: 26897430 [PubMed - indexed for MEDLINE]

A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis.

Drug Des Devel Ther. 2015;9:5433-8

Authors: Jung JA, Kim TE, Lee H, Jeong BH, Park HY, Jeon K, Kwon OJ, Ko JW, Choi R, Woo HI, Koh WJ, Lee SY

Abstract
BACKGROUND/AIM: Isoniazid (INH) is an essential component of first-line anti-tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study.
METHODS: A total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0-6.0 mg/L. This dosing algorithm was then used for newly enrolled 53 patients.
RESULTS: Serum concentrations of INH were significantly lower in the rapid-acetylators than in the slow-acetylators (2.55 mg/L vs 6.78 mg/L, median, P<0.001). A multivariate stepwise linear regression analysis revealed that NAT2 and body weight independently affected INH concentrations: INH concentration (mg/L) = 13.821-0.1× (body weight, kg) -2.273× (number of high activity alleles of NAT2; 0, 1, 2). In 53 newly enrolled patients, the frequency at which they were within the therapeutic range of 3.0-6.0 mg/L was higher in the model-based treatment group compared to the standard treatment group (80.8% vs 59.3%).
CONCLUSION: The use of individualized pharmacogenetic-guided INH dosage regimens that incorporate NAT2 genotype and body weight may help to ensure achievement of therapeutic concentrations of INH in the TB patients.

PMID: 26491254 [PubMed - indexed for MEDLINE]

Personalized medicine, genomics, and pharmacogenomics: a primer for nurses.

Clin J Oncol Nurs. 2014 Aug;18(4):437-41

Authors: Blix A

Abstract
Personalized medicine is the study of patients' unique environmental influences as well as the totality of their genetic code-their genome-to tailor personalized risk assessments, diagnoses, prognoses, and treatments. The study of how patients' genomes affect responses to medications, or pharmacogenomics, is a related field. Personalized medicine and genomics are particularly relevant in oncology because of the genetic basis of cancer. Nurses need to understand related issues such as the role of genetic and genomic counseling, the ethical and legal questions surrounding genomics, and the growing direct-to-consumer genomics industry. As genomics research is incorporated into health care, nurses need to understand the technology to provide advocacy and education for patients and their families.

PMID: 25095297 [PubMed - indexed for MEDLINE]

An integrated systems biology approach identifies positive cofactor 4 as a factor that increases reprogramming efficiency.

Nucleic Acids Res. 2016 Feb 18;44(3):1203-15

Authors: Jo J, Hwang S, Kim HJ, Hong S, Lee JE, Lee SG, Baek A, Han H, Lee JI, Lee I, Lee DR

Abstract
Spermatogonial stem cells (SSCs) can spontaneously dedifferentiate into embryonic stem cell (ESC)-like cells, which are designated as multipotent SSCs (mSSCs), without ectopic expression of reprogramming factors. Interestingly, SSCs express key pluripotency genes such as Oct4, Sox2, Klf4 and Myc. Therefore, molecular dissection of mSSC reprogramming may provide clues about novel endogenous reprogramming or pluripotency regulatory factors. Our comparative transcriptome analysis of mSSCs and induced pluripotent stem cells (iPSCs) suggests that they have similar pluripotency states but are reprogrammed via different transcriptional pathways. We identified 53 genes as putative pluripotency regulatory factors using an integrated systems biology approach. We demonstrated a selected candidate, Positive cofactor 4 (Pc4), can enhance the efficiency of somatic cell reprogramming by promoting and maintaining transcriptional activity of the key reprograming factors. These results suggest that Pc4 has an important role in inducing spontaneous somatic cell reprogramming via up-regulation of key pluripotency genes.

PMID: 26740582 [PubMed - indexed for MEDLINE]

Predicting Dental Caries Outcomes in Children: A "Risky" Concept.

J Dent Res. 2016 Mar;95(3):248-54

Authors: Divaris K

Abstract
In recent years, unprecedented gains in the understanding of the biology and mechanisms underlying human health and disease have been made. In the domain of oral health, although much remains to be learned, the complex interactions between different systems in play have begun to unravel: host genome, oral microbiome with its transcriptome, proteome and metabolome, and more distal influences, including relevant behaviors and environmental exposures. A reasonable expectation is that this emerging body of knowledge can help improve the oral health and optimize care for individuals and populations. These goals are articulated by the National Institutes of Health as "precision medicine" and the elimination of health disparities. Key processes in these efforts are the discovery of causal factors or mechanistic pathways and the identification of individuals or population segments that are most likely to develop (any or severe forms of) oral disease. This article critically reviews the fundamental concepts of risk assessment and outcome prediction, as they relate to early childhood caries (ECC)-a common complex disease with significant negative impacts on children, their families, and the health system. The article highlights recent work and advances in methods available to estimate caries risk and derive person-level caries propensities. It further discusses the reasons for their limited utility in predicting individual ECC outcomes and informing clinical decision making. Critical issues identified include the misconception of defining dental caries as a tooth or surface-level condition versus a person-level disease; the fallacy of applying population-level parameters to individuals, termed privatization of risk; and the inadequacy of using frequentist versus Bayesian modeling approaches to derive individual disease propensity estimates. The article concludes with the notion that accurate caries risk assessment at the population level and "precision dentistry" at the person level are both desirable and achievable but must be based on high-quality longitudinal data and rigorous methodology.

PMID: 26647391 [PubMed - indexed for MEDLINE]

Systems-level organization of yeast methylotrophic lifestyle.

BMC Biol. 2015;13:80

Authors: Rußmayer H, Buchetics M, Gruber C, Valli M, Grillitsch K, Modarres G, Guerrasio R, Klavins K, Neubauer S, Drexler H, Steiger M, Troyer C, Al Chalabi A, Krebiehl G, Sonntag D, Zellnig G, Daum G, Graf AB, Altmann F, Koellensperger G, Hann S, Sauer M, Mattanovich D, Gasser B

Abstract
BACKGROUND: Some yeasts have evolved a methylotrophic lifestyle enabling them to utilize the single carbon compound methanol as a carbon and energy source. Among them, Pichia pastoris (syn. Komagataella sp.) is frequently used for the production of heterologous proteins and also serves as a model organism for organelle research. Our current knowledge of methylotrophic lifestyle mainly derives from sophisticated biochemical studies which identified many key methanol utilization enzymes such as alcohol oxidase and dihydroxyacetone synthase and their localization to the peroxisomes. C1 assimilation is supposed to involve the pentose phosphate pathway, but details of these reactions are not known to date.
RESULTS: In this work we analyzed the regulation patterns of 5,354 genes, 575 proteins, 141 metabolites, and fluxes through 39 reactions of P. pastoris comparing growth on glucose and on a methanol/glycerol mixed medium, respectively. Contrary to previous assumptions, we found that the entire methanol assimilation pathway is localized to peroxisomes rather than employing part of the cytosolic pentose phosphate pathway for xylulose-5-phosphate regeneration. For this purpose, P. pastoris (and presumably also other methylotrophic yeasts) have evolved a duplicated methanol inducible enzyme set targeted to peroxisomes. This compartmentalized cyclic C1 assimilation process termed xylose-monophosphate cycle resembles the principle of the Calvin cycle and uses sedoheptulose-1,7-bisphosphate as intermediate. The strong induction of alcohol oxidase, dihydroxyacetone synthase, formaldehyde and formate dehydrogenase, and catalase leads to high demand of their cofactors riboflavin, thiamine, nicotinamide, and heme, respectively, which is reflected in strong up-regulation of the respective synthesis pathways on methanol. Methanol-grown cells have a higher protein but lower free amino acid content, which can be attributed to the high drain towards methanol metabolic enzymes and their cofactors. In context with up-regulation of many amino acid biosynthesis genes or proteins, this visualizes an increased flux towards amino acid and protein synthesis which is reflected also in increased levels of transcripts and/or proteins related to ribosome biogenesis and translation.
CONCLUSIONS: Taken together, our work illustrates how concerted interpretation of multiple levels of systems biology data can contribute to elucidation of yet unknown cellular pathways and revolutionize our understanding of cellular biology.

PMID: 26400155 [PubMed - indexed for MEDLINE]

The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder.

Transplantation. 2016 Mar;100(3):497-505

Authors: Seifert ME, Hruska KA

Abstract
The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease (CKD)-mineral bone disorder (MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.

PMID: 26356179 [PubMed - indexed for MEDLINE]

Analytical methods in sphingolipidomics: Quantitative and profiling approaches in food analysis.

J Chromatogr A. 2016 Jan 8;1428:16-38

Authors: Canela N, Herrero P, Mariné S, Nadal P, Ras MR, Rodríguez MÁ, Arola L

Abstract
In recent years, sphingolipidomics has emerged as an interesting omic science that encompasses the study of the full sphingolipidome characterization, content, structure and activity in cells, tissues or organisms. Like other omics, it has the potential to impact biomarker discovery, drug development and systems biology knowledge. Concretely, dietary food sphingolipids have gained considerable importance due to their extensively reported bioactivity. Because of the complexity of this lipid family and their diversity among foods, powerful analytical methodologies are needed for their study. The analytical tools developed in the past have been improved with the enormous advances made in recent years in mass spectrometry (MS) and chromatography, which allow the convenient and sensitive identification and quantitation of sphingolipid classes and form the basis of current sphingolipidomics methodologies. In addition, novel hyphenated nuclear magnetic resonance (NMR) strategies, new ionization strategies, and MS imaging are outlined as promising technologies to shape the future of sphingolipid analyses. This review traces the analytical methods of sphingolipidomics in food analysis concerning sample extraction, chromatographic separation, the identification and quantification of sphingolipids by MS and their structural elucidation by NMR.

PMID: 26275862 [PubMed - indexed for MEDLINE]

Text Mining the History of Medicine.

PLoS One. 2016;11(1):e0144717

Authors: Thompson P, Batista-Navarro RT, Kontonatsios G, Carter J, Toon E, McNaught J, Timmermann C, Worboys M, Ananiadou S

Abstract
Historical text archives constitute a rich and diverse source of information, which is becoming increasingly readily accessible, due to large-scale digitisation efforts. However, it can be difficult for researchers to explore and search such large volumes of data in an efficient manner. Text mining (TM) methods can help, through their ability to recognise various types of semantic information automatically, e.g., instances of concepts (places, medical conditions, drugs, etc.), synonyms/variant forms of concepts, and relationships holding between concepts (which drugs are used to treat which medical conditions, etc.). TM analysis allows search systems to incorporate functionality such as automatic suggestions of synonyms of user-entered query terms, exploration of different concepts mentioned within search results or isolation of documents in which concepts are related in specific ways. However, applying TM methods to historical text can be challenging, according to differences and evolutions in vocabulary, terminology, language structure and style, compared to more modern text. In this article, we present our efforts to overcome the various challenges faced in the semantic analysis of published historical medical text dating back to the mid 19th century. Firstly, we used evidence from diverse historical medical documents from different periods to develop new resources that provide accounts of the multiple, evolving ways in which concepts, their variants and relationships amongst them may be expressed. These resources were employed to support the development of a modular processing pipeline of TM tools for the robust detection of semantic information in historical medical documents with varying characteristics. We applied the pipeline to two large-scale medical document archives covering wide temporal ranges as the basis for the development of a publicly accessible semantically-oriented search system. The novel resources are available for research purposes, while the processing pipeline and its modules may be used and configured within the Argo TM platform.

PMID: 26734936 [PubMed - indexed for MEDLINE]

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning.

Crit Rev Oncol Hematol. 2016 Jun 18;

Authors: Gadducci A, Biglia N, Tana R, Cosio S, Gallo M

Abstract
Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell. AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway. Moreover, metformin decreases the production of insulin, insulin-like growth factor, inflammatory cytokines and vascular endothelial growth factor, and therefore it exerts anti-mitotic, anti-inflammatory and anti-angiogenetic effects. Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells, and acts together with chemotherapy to block tumor growth in different cancers. Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies. The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers. The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies. Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers.

PMID: 27378194 [PubMed - as supplied by publisher]

Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.

JAMA Neurol. 2016 Jul 5;

Authors: Cortés-Vicente E, Gallardo E, Martínez MÁ, Díaz-Manera J, Querol L, Rojas-García R, Illa I

Abstract
Importance: Double-seronegative myasthenia gravis (dSNMG) includes patients with myasthenia gravis (MG) without detectable antibodies to the nicotinic acetylcholine receptor (AChR) or to muscle-specific tyrosine kinase (MuSK). The lack of a biomarker hinders the diagnosis and clinical management in these patients. Cortactin, a protein acting downstream from agrin/low-density lipoprotein receptor-related protein 4 (LRP4)/MuSK, has been described as an antigen in dSNMG.
Objective: To describe the frequency and clinical features of patients with dSNMG who have cortactin antibodies.
Design, Setting, and Participants: A retrospective cross-sectional study was conducted at Hospital de la Santa Creu i Sant Pau, an institutional practice referral center in Barcelona, Spain, between May 1, 2015, and November 30, 2015. We included 250 patients with a definitive diagnosis of MG with available serum samples at the time of diagnosis. Descriptive and comparative data analyses were performed.
Exposures: Cortactin antibodies were measured by enzyme-linked immunosorbent assay and Western blot; AChR, MuSK, and anti-striated muscle antibodies were detected using a standard method; and LRP4 antibodies were tested using a cell-based assay.
Main Outcomes and Measures: The primary outcome was the frequency of patients with dSNMG who have cortactin antibodies. Secondary outcomes were demographic, clinical, neurophysiological, and laboratory data.
Results: Of 250 patients (mean [SD] age at onset, 49.7 [21.2] years; 56% female), 38 (15.2%) had dSNMG, 201 (80.4%) had MG with AChR antibodies, and 11 (4.4%) had MG with MuSK antibodies. Cortactin antibodies were identified in 28 patients with MG: 9 of 38 (23.7%) who had dSNMG, 19 of 201 (9.5%) who had MG with AChR antibodies (significantly lower than those with dSNMG: 9.5% vs 23.7%; P = .02), and 0 of 11 who had MG with MuSK antibodies; 0 of 29 controls had cortactin antibodies. At onset, among the 9 patients with dSNMG and cortactin antibodies, 6 had ocular MG and 3 had Myasthenia Gravis Foundation of America clinical classification IIA. Two patients with ocular MG developed generalized MG. The group with dSNMG and cortactin antibodies, compared with those who had MG with AChR antibodies, more frequently had mild forms at onset (100.0% vs 62.7%; P = .03), had fewer bulbar signs at maximal worsening (0% vs 41.3%; P = .01), and were younger at onset (median [interquartile range], 34.9 [9.5] vs 53.9 [38.5] years; P = .03); the group with dSNMG and cortactin antibodies also more frequently had ocular MG at onset than those with MG and AChR antibodies, although the difference was not statistically significant (66.7% vs 40.8%; P = .17). Of 17 patients with ocular dSNMG, 4 (23.5%) had antibodies to cortactin.
Conclusions and Relevance: In this study, patients with cortactin antibodies and dSNMG had an ocular or mild generalized phenotype of MG. Including the detection of cortactin antibodies in the routine diagnosis of dSNMG may be helpful in ocular MG.

PMID: 27379450 [PubMed - as supplied by publisher]

[Spanish patients with central hypoventilation syndrome included in the European Registry. The 2015 data].

An Pediatr (Barc). 2016 Jul 1;

Authors: García Teresa MA, Porto Abal R, Rodríguez Torres S, García Urabayen D, García Martínez S, Trang H, Campos Barros A, Grupo Español de Trabajo del SHCC, Llorente de la Fuente A, Hernández González A, Bustinza Arriortua A, de la Cruz Moreno J, Pons Odena M, Ventura Faci P, Rubio Ortega L, Pérez Ruiz E, Aguilar Fernández A, Pérez Ocón A, Osona B, Delgado Pecellin I, Arroyo Carrera I, Sayas Catalán J, González Salas E, de Vicente CM

Abstract
INTRODUCTION: Congenital Central Hypoventilation Syndrome (CCHS) is a very rare genetic disease. In 2012 the European Central Hypoventilation Syndrome (EuCHS) Consortium created an online patient registry in order to improve care.
AIM: To determine the characteristics and outcomes of Spanish patients with CCHS, and detect clinical areas for improvement.
MATERIALS AND METHOD: An assessment was made on the data from Spanish patients in the European Registry, updated on December 2015.
RESULTS: The Registry contained 38 patients, born between 1987 and 2013, in 18 hospitals. Thirteen (34.2%) were older than 18 years. Three patients had died. Genetic analysis identified PHOX2B mutations in 32 (86.5%) out of 37 patients assessed. The 20/25, 20/26 and 20/27 polyalanine repeat mutations (PARMs) represented 84.3% of all mutations. Longer PARMs had more, as well as more severe, autonomic dysfunctions. Eye diseases were present in 47%, with 16% having Hirschsprung disease, 13% with hypoglycaemia, and 5% with tumours. Thirty patients (79%) required ventilation from the neonatal period onwards, and 8 (21%) later on in life (late onset/presentation). Eight children (21%) were using mask ventilation at the first home discharge. Five of them were infants with neonatal onset, two of them, both having a severe mutation, were switched to tracheostomy after cardiorespiratory arrest at home. Approximately one-third (34.3%) of patients were de-cannulated and switched to mask ventilation at a mean age of 13.7 years. Educational reinforcement was required in 29.4% of children attending school.
CONCLUSION: The implementation of the EuCHS Registry in Spain has identified some relevant issues for optimising healthcare, such as the importance of genetic study for diagnosis and assessment of severity, the high frequency of eye disease and educational reinforcement, as well as some limitations in ventilatory techniques.

PMID: 27377324 [PubMed - as supplied by publisher]

Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype.

Pharmacogenomics J. 2016 Jul 5;

Authors: Vanhove T, Annaert P, Lambrechts D, Kuypers DR

Abstract
The relevance of most genetic polymorphisms beyond CYP3A5*1 on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies. Of these, ABCB1, ABCC2, OATP1B1, COMT, FMO, PPARA and APOA5 were analyzed as (functional) diplotype groups. Predictors of C0/dose were CYP3A5*1, hematocrit, age, CYP3A4*22, use of concomitant CYP3A4 inhibitor or inducer, ALT, estimated glomerular filtration rate, tacrolimus formulation (once vs twice daily), ABCB1 diplotype and time after transplantation. The effect of ABCB1 diplotype was small but strongly accentuated in CYP3A4*22 carriers and non-existent in CYP3A5 expressors. ABCC2 diplotype had a limited effect on C0/dose that was only statistically significant in CYP3A5 non-expressors.The Pharmacogenomics Journal advance online publication, 5 July 2016; doi:10.1038/tpj.2016.49.

PMID: 27378609 [PubMed - as supplied by publisher]

Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Pharmacogenomics J. 2016 Jul 5;

Authors: Musolino A, Naldi N, Dieci MV, Zanoni D, Rimanti A, Boggiani D, Sgargi P, Generali DG, Piacentini F, Ambroggi M, Cagossi K, Gianni L, Sarti S, Bisagni G, Ardizzoni A, Conte PF, Guarneri V

Abstract
Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.The Pharmacogenomics Journal advance online publication, 5 July 2016; doi:10.1038/tpj.2016.51.

PMID: 27378608 [PubMed - as supplied by publisher]

Pharmacogenomic and personalized approaches to tackle the nonalcoholic fatty liver disease.

Pharmacogenomics. 2016 Jul 5;

Authors: Lorbek G, Urlep Ž, Rozman D

Abstract
Nonalcoholic fatty liver disease (NAFLD) is a raising liver disease with increasing prevalence due to the epidemics of obesity and diabetes, with end points in cirrhosis or hepatocellular carcinoma. A multitude of genetic and metabolic perturbations, together with environmental factors, likely drive the disease. However, to date only a few genes, primarily PNPLA3 and TM6SF2, associate with NAFLD and there is no specific treatment. In this review we focus on the therapeutical aspects of NAFLD, taking into account drugs and lifestyle interventions. Sex also influences disease progression and treatment outcomes. Lastly, we discuss the present and potential future of personalized approaches to tackle NAFLD and how the known polymorphisms of NAFLD associated genes influence the choice and success of therapy.

PMID: 27377717 [PubMed - as supplied by publisher]

Developing Treatments for Stimulant Abuse: A Brief Overview.

East Asian Arch Psychiatry. 2016 Jun;26(2):52-9

Authors: Davidson C

Abstract
The abuse of stimulants such as cocaine, amphetamine, and methamphetamine is a huge problem in many parts of the world. Abuse of these drugs does not ruin just the user's life, but also adversely affects those around them. Despite many years of research, there are no approved medications for stimulant dependence, and treatment is focused on psychotherapy and abstinence. Over the last 10 to 20 years, there have been some major changes in approach to medication development for stimulant dependence. These include assessing ligands for non-dopaminergic sites, atypical dopamine transporter ligands, blocking long-term potentiation and / or memory reconsolidation, vaccines against the stimulant, and molecular approaches including pharmacogenomics and gene silencing. Also included in this overview are non-drug treatments such as deep brain stimulation and psychosurgery. This overview highlights recent preclinical and clinical studies of treatment development for stimulant dependence.

PMID: 27377486 [PubMed - as supplied by publisher]

Synthetic Cystic Fibrosis Sputum Medium Regulates Flagellar Biosynthesis through the flhF Gene in Burkholderia cenocepacia.

Front Cell Infect Microbiol. 2016;6:65

Authors: Kumar B, Cardona ST

Abstract
Burkholderia cenocepacia belongs to the Burkholderia cepacia complex (Bcc), a group of at least 18 distinct species that establish chronic infections in the lung of people with the genetic disease cystic fibrosis (CF). The sputum of CF patients is rich in amino acids and was previously shown to increase flagellar gene expression in B. cenocepacia. We examined flagellin expression and flagellar morphology of B. cenocepacia grown in synthetic cystic fibrosis sputum medium (SCFM) compared to minimal medium. We found that CF nutritional conditions induce increased motility and flagellin expression. Individual amino acids added at the same concentrations as found in SCFM also increased motility but not flagellin expression, suggesting a chemotactic effect of amino acids. Electron microscopy and flagella staining demonstrated that the increase in flagellin corresponds to a change in the number of flagella per cell. In minimal medium, the ratio of multiple: single: aflagellated cells was 2:3.5:4.5; while under SCFM conditions, the ratio was 7:2:1. We created a deletion mutant, ΔflhF, to study whether this putative GTPase regulates the flagellation pattern of B. cenocepacia K56-2 during growth in CF conditions. The ΔflhF mutant exhibited 80% aflagellated, 14% single and 6% multiple flagellated bacterial subpopulations. Moreover, the ratio of multiple to single flagella in WT and ΔflhF was 3.5 and 0.43, respectively in CF conditions. The observed differences suggest that FlhF positively regulates flagellin expression and the flagellation pattern in B. cenocepacia K56-2 during CF nutritional conditions.

PMID: 27379216 [PubMed - as supplied by publisher]