The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain.

Eur Arch Psychiatry Clin Neurosci. 2017 Jun 17;:

Authors: Kanji S, Fonseka TM, Marshe VS, Sriretnakumar V, Hahn MK, Müller DJ

Abstract
With the emergence of knowledge implicating the human gut microbiome in the development and regulation of several physiological systems, evidence has accumulated to suggest a role for the gut microbiome in psychiatric conditions and drug response. A complex relationship between the enteric nervous system, the gut microbiota and the central nervous system has been described which allows for the microbiota to influence and respond to a variety of behaviors and psychiatric conditions. Additionally, the use of pharmaceuticals may interact with and alter the microbiota to potentially contribute to adverse effects of the drug. The gut microbiota has been described in several psychiatric disorders including depression and anxiety, but only a few reports have discussed the role of the microbiome in schizophrenia. The following review examines the evidence surrounding the gut microbiota in behavior and psychiatric illness, the role of the microbiota in schizophrenia and the potential for antipsychotics to alter the gut microbiota and promote adverse metabolic events.

PMID: 28624847 [PubMed - as supplied by publisher]

KCNQ1 gene polymorphism is associated with glycaemic response to treatment with DPP-4 inhibitors.

Diabetes Res Clin Pract. 2017 May 19;130:142-147

Authors: Gotthardová I, Javorský M, Klimčáková L, Kvapil M, Schroner Z, Kozárová M, Malachovská Z, Ürgeová A, Židzik J, Tkáč I

Abstract
AIMS: Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I.
METHODS: We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR-HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (ΔHbA1c) after 6-month DPP4I treatment.
RESULTS: KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (β=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes.
CONCLUSIONS: KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies.

PMID: 28624668 [PubMed - as supplied by publisher]

Evaluation of a biomimetic 3D substrate based on the Human Elastin-like Polypeptides (HELPs) model system for elastolytic activity detection.

J Biotechnol. 2017 Jun 14;:

Authors: Corich L, Busetti M, Petix V, Passamonti S, Bandiera A

Abstract
Elastin is a fibrous protein that confers elasticity to tissues such as skin, arteries and lung. It is extensively cross-linked, highly hydrophobic and insoluble. Nevertheless, elastin can be hydrolysed by bacterial proteases in infectious diseases, resulting in more or less severe tissue damage. Thus, development of substrates able to reliably and specifically detect pathogen-secreted elastolytic activity is needed to improve the in vitro evaluation of the injury that bacterial proteases may provoke. In this work, two human biomimetic elastin polypeptides, HELP and HELP1, as well as the matrices derived from HELP, have been probed as substrates for elastolytic activity detection. Thirty strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients were analyzed in parallel with standard substrates, to detect proteolytic and elastolytic activity. Results point to the HELP-based 3D matrix as an interesting biomimetic model of elastin to assess bacterial elastolytic activity in vitro. Moreover, this model substrate enables to further elucidate the mechanism underlying elastin degradation at molecular level, as well as to develop biomimetic material-based devices responsive to external stimuli.

PMID: 28624377 [PubMed - as supplied by publisher]

CRISPR/Cas9-Mediated Three Nucleotide Insertion Corrects a Deletion Mutation in MRP1/ABCC1 and Restores Its Proper Folding and Function.

Mol Ther Nucleic Acids. 2017 Jun 16;7:429-438

Authors: Xu Q, Hou YX, Chang XB

Abstract
A three-nucleotide deletion in cystic fibrosis transmembrane conductance regulator/ATP-binding cassette transporter C7 (CFTR/ABCC7) resulting in the absence of phenylalanine at 508 leads to mis-fold of the mutated protein and causes cystic fibrosis. We have used a comparable three-nucleotide deletion mutant in another ABCC family member, multidrug resistance-associated protein (MRP1)/ABCC1, to determine whether CRISPR-Cas9-mediated recombination can safely and efficiently knock in three-nucleotide to correct the mutation. We have found that the rate of homology-directed recombination mediated by guideRNA (gRNA) complementary to the deletion mutant is significantly higher than the one mediated by gRNA complementary to the wild-type (WT) donor. In addition, the rate of homology-directed recombination mediated by gRNA complementary to the WT donor is significantly higher than that of gRNAs complementary to the 5' or 3' side of the deletion mutant. Interestingly, the frequency of mutations introduced by gRNA complementary to the deletion mutant is significantly higher than with gRNA complementary to WT donor. However, combination of gRNAs complementary to both WT donor and deletion mutant decreased the rate of homology-directed recombination, but did not significantly decrease the mutation rate introduced by this system. Thus, the data presented here provide guidance for designing of gRNA and donor DNA to do genome editing, especially to correct the mutations with three mismatched nucleotides, such as three-nucleotide deletion or insertion.

PMID: 28624219 [PubMed - in process]

Whole-exome sequencing identified compound heterozygous variants in MMKS in a Chinese pedigree with Bardet-Biedl syndrome.

Sci China Life Sci. 2017 Jun 14;:

Authors: Qi Z, Shen Y, Fu Q, Li W, Yang W, Xu W, Chu P, Zhang Y, Wang H

Abstract
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. At least 21 candidate BBS-associated genes (BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants (c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant (c.2029G>C, p.E677Q) in NPHP1 and a missense variant (c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.

PMID: 28624958 [PubMed - as supplied by publisher]

Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains.

Neuromuscul Disord. 2017 May 04;:

Authors: Harris E, Burki U, Marini-Bettolo C, Neri M, Scotton C, Hudson J, Bertoli M, Evangelista T, Vroling B, Polvikoski T, Roberts M, Töpf A, Bushby K, McArthur D, Lochmüller H, Ferlini A, Straub V, Barresi R

Abstract
Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.

PMID: 28624464 [PubMed - as supplied by publisher]

Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward?

Mol Diagn Ther. 2017 Jun 17;:

Authors: Langley RJ, Wong HR

Abstract
Sepsis remains one of the leading causes of death in the USA and it is expected to get worse as the population ages. Moreover, the standard of care, which recommends aggressive treatment with appropriate antibiotics, has led to an increase in multiple drug-resistant organisms. There is a dire need for the development of new antibiotics, improved antibiotic stewardship, and therapies that treat the host response. Development of new sepsis therapeutics has been a disappointment as no drugs are currently approved to treat the various complications from sepsis. Much of the failure has been blamed on animal models that do not accurately reflect the course of the disease. However, recent improvements in metabolomic, transcriptomic, genomic, and proteomic platforms have allowed for a broad-spectrum look at molecular changes in the host response using clinical samples. Integration of these multi-omic datasets allows researchers to perform systems biology approaches to identify novel pathophysiology of the disease. In this review, we highlight what is currently known about sepsis and how integrative omics has identified new diagnostic and predictive models of sepsis as well as novel mechanisms. These changes may improve patient care as well as guide future preclinical analysis of sepsis.

PMID: 28624903 [PubMed - as supplied by publisher]

High-throughput screening technologies for enzyme engineering.

Curr Opin Biotechnol. 2017 Jun 15;48:196-202

Authors: Longwell CK, Labanieh L, Cochran JR

Abstract
Emerging technologies are enabling ultra-high-throughput screening of combinatorial enzyme libraries to identify variants with improved properties such as increased activity, altered substrate specificity, and increased stability. Each of these enzyme engineering platforms relies on compartmentalization of reaction components, similar to microtiter plate-based assays which have been commonly used for testing the activity of enzyme variants. The technologies can be broadly divided into three categories according to their spatial segregation strategy: (1) cells as reaction compartments, (2) in vitro compartmentalization via synthetic droplets, and (3) microchambers. Here, we discuss these emerging platforms, which in some cases enable the screening of greater than 10 million enzyme variants, and highlight benefits and limitations of each technology.

PMID: 28624724 [PubMed - as supplied by publisher]

Drought responsive microRNAs in two barley cultivars differing in their level of sensitivity to drought stress.

Plant Physiol Biochem. 2017 Jun 07;118:121-129

Authors: Fard EM, Bakhshi B, Keshavarznia R, Nikpay N, Shahbazi M, Salekdeh GH

Abstract
MicroRNAs (miRNAs) are known to be involved in the regulation of gene expression, including that of genes involved in the response to stress. Here, a comparison has been drawn between the miRNA profiles of a drought susceptible, 'Morocco 9-75', and a drought tolerant, 'Yousef', barley cultivars. Leaf water content, shoot dry matter and chlorophyll content decreased in 'Morocco 9-75' more considerably compared with 'Yousef' under drought stress. Furthermore, lower stomatal conductance and higher leaf temperature were observed in 'Morocco 9-75' compared with 'Yousef'. Based on the criteria set for differential abundance, 118 of conserved and novel miRNAs were identified as being responsive to soil water status. Although drought stress resulted in an altered abundance of more miRNAs in 'Morocco 9-75' than in 'Yousef', drought stress was generally associated with an increased miRNA abundance in 'Yousef' and a decreased abundance in 'Morocco 9-75'. An in silico analysis identified 645 genes as putative targets for the drought-responsive miRNAs in 'Yousef' and 3735 in 'Morocco 9-75'. Gene ontology analysis showed that drought stress was associated with the altered abundance of miRNAs targeting growth, development, the juvenile to adult transition and hormone signaling. Some miRNAs which became more abundant in 'Yousef' are thought to target genes intimately involved in development and stress adaptation. In 'Morocco 9-75', drought stress induced changes in the abundance of miRNAs associated with genes affecting growth, development, the juvenile to adult transition and ABA signaling. The data imply that miRNAs may affect the tolerance/sensitivity of barley to drought stress by modulating the expression of a wide set of genes and induction of some physiological changes.

PMID: 28624683 [PubMed - as supplied by publisher]

Alternative Polyadenylation Patterns for Novel Gene Discovery and Classification in Cancer.

Neoplasia. 2017 Jun 15;19(7):574-582

Authors: Begik O, Oyken M, Cinkilli Alican T, Can T, Erson-Bensan AE

Abstract
Certain aspects of diagnosis, prognosis, and treatment of cancer patients are still important challenges to be addressed. Therefore, we propose a pipeline to uncover patterns of alternative polyadenylation (APA), a hidden complexity in cancer transcriptomes, to further accelerate efforts to discover novel cancer genes and pathways. Here, we analyzed expression data for 1045 cancer patients and found a significant shift in usage of poly(A) signals in common tumor types (breast, colon, lung, prostate, gastric, and ovarian) compared to normal tissues. Using machine-learning techniques, we further defined specific subsets of APA events to efficiently classify cancer types. Furthermore, APA patterns were associated with altered protein levels in patients, revealed by antibody-based profiling data, suggesting functional significance. Overall, our study offers a computational approach for use of APA in novel gene discovery and classification in common tumor types, with important implications in basic research, biomarker discovery, and precision medicine approaches.

PMID: 28624626 [PubMed - as supplied by publisher]

Cell-Size-Dependent Transcription of FLC and Its Antisense Long Non-coding RNA COOLAIR Explain Cell-to-Cell Expression Variation.

Cell Syst. 2017 Jun 08;:

Authors: Ietswaart R, Rosa S, Wu Z, Dean C, Howard M

Abstract
Single-cell quantification of transcription kinetics and variability promotes a mechanistic understanding of gene regulation. Here, using single-molecule RNA fluorescence in situ hybridization and mathematical modeling, we dissect cellular RNA dynamics for Arabidopsis FLOWERING LOCUS C (FLC). FLC expression quantitatively determines flowering time and is regulated by antisense (COOLAIR) transcription. In cells without observable COOLAIR expression, we quantify FLC transcription initiation, elongation, intron processing, and lariat degradation, as well as mRNA release from the locus and degradation. In these heterogeneously sized cells, FLC mRNA number increases linearly with cell size, resulting in a large cell-to-cell variability in transcript level. This variation is accounted for by cell-size-dependent, Poissonian FLC mRNA production, but not by large transcriptional bursts. In COOLAIR-expressing cells, however, antisense transcription increases with cell size and contributes to FLC transcription decreasing with cell size. Our analysis therefore reveals an unexpected role for antisense transcription in modulating the scaling of transcription with cell size.

PMID: 28624615 [PubMed - as supplied by publisher]

Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen.

Cell Syst. 2017 Jun 14;:

Authors: Québatte M, Christen M, Harms A, Körner J, Christen B, Dehio C

Abstract
The Bartonella gene transfer agent (BaGTA) is an archetypical example for domestication of a phage-derived element to permit high-frequency genetic exchange in bacterial populations. Here we used multiplexed transposon sequencing (TnSeq) and single-cell reporters to globally define the core components and transfer dynamics of BaGTA. Our systems-level analysis has identified inner- and outer-circle components of the BaGTA system, including 55 regulatory components, as well as an additional 74 and 107 components mediating donor transfer and recipient uptake functions. We show that the stringent response signal guanosine-tetraphosphate (ppGpp) restricts BaGTA induction to a subset of fast-growing cells, whereas BaGTA particle uptake depends on a functional Tol-Pal trans-envelope complex that mediates outer-membrane invagination upon cell division. Our findings suggest that Bartonella evolved an efficient strategy to promote genetic exchange within the fittest subpopulation while disfavoring exchange of deleterious genetic information, thereby facilitating genome integrity and rapid host adaptation.

PMID: 28624614 [PubMed - as supplied by publisher]

Intestinal Fungal Dysbiosis Associates With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

Gastroenterology. 2017 Jun 14;:

Authors: Botschuijver S, Roeselers G, Levin E, Jonkers DM, Welting O, Heinsbroek SE, de Weerd HH, Boekhout T, Fornai M, Masclee AA, Schuren FHJ, de Jonge WJ, Seppen J, van den Wijngaard RM

Abstract
BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity.
METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble β-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1.
RESULTS: α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble β-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate β-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine.
CONCLUSIONS: In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble β-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.

PMID: 28624575 [PubMed - as supplied by publisher]

Dissecting the chloroplast proteome of chickpea (Cicer arietinum L.) provides new insights into classical and non-classical functions.

J Proteomics. 2017 Jun 14;:

Authors: Lande NV, Subba P, Barua P, Gayen D, Keshava Prasad TS, Chakraborty S, Chakraborty N

Abstract
Chloroplast, the energy organelle unique to plant cells, is a dynamic entity which integrates an array of metabolic pathways and serves as first level for energy conversion for the entire ecological hierarchy. Increasing amount of sequence data and evolution of mass spectrometric approaches has opened up new avenues for opportune exploration of the global proteome of this organelle. In our study, we aimed at generation of a comprehensive catalogue of chloroplast proteins in a grain legume, chickpea and provided a reference proteome map. To accurately assign the identified proteins, purity of chloroplast-enriched fraction was stringently monitored by multiple chemical and immunological indexes, besides pigment and enzyme analyses. The proteome analysis led to the identification of 2451 proteins, including 27 isoforms, which include predicted and novel chloroplast constituents. The identified proteins were validated through their sequence analysis. Extensive sequence based localization prediction revealed more than 50% proteins to be chloroplast resident by at least two different algorithms. Chromosomal distribution of identified proteins across nuclear and chloroplast genome unveiled the presence of 55 chloroplast encoded gene. In depth comparison of our dataset with the non-redundant set of chloroplast proteins identified so far across other species revealed novel as well as overlapping candidates.
BIOLOGICAL SIGNIFICANCE: Pulses add large amount of nitrogen to the soil and has very low water footprint and therefore, contributes to fortification of sustainable agriculture. Chickpea is one of the earliest cultivated legumes and serves as an energy and protein source for humans and animals. Chloroplasts are the unique organelles which conduct photosynthesis. Investigation on chloroplast proteome is of particular significance, especially to plant biologists, as it would allow a better understanding of chloroplast function in plants. Generation of a saturated proteome map would not only validate the proteome inventory from its genome sequencing, but also serve as a comprehensive catalogue for future studies. We identified 2451 proteins, encoded by both the nuclear as well as chloroplast genomes, presumably involved in multivariate metabolic processes. The chloroplast deduced proteome and putative chloroplast proteins identified in this study would provide a foundation for future investigation of the expression and function of the chloroplast proteins of chickpea in specific and other crops species in general.

PMID: 28624520 [PubMed - as supplied by publisher]

Evaluation of whole exome sequencing by targeted gene sequencing and Sanger sequencing.

Clin Chim Acta. 2017 Jun 14;:

Authors: Chang YS, Huang HD, Yeh KT, Chang JG

Abstract
BACKGROUND: Targeted gene sequencing (TGS) and whole exome sequencing (WES) are being used in clinical testing in laboratories. We compared the performances of TGS and WES using the same DNA samples.
METHODS: DNA was extracted from 10 endometrial tumor tissue specimens. Sequencing were performed with an Illumina HiSeq 2000. We randomly selected variants to confirm through Sanger sequencing or mutant-enriched PCR with Sanger sequencing.
RESULTS: We found that the variants identified in both TGS and WES were true positives (47/47), regardless of the sequencing depth. Most variants found in TGS only were true positives (34/40), and most of the variants found by WES only were false positives (8/18). From these results, we suggest that the sequencing depth may not play important role in the accuracy of NGS-based methods. After analysis, we found that WES had a sensitivity of 72.70%, specificity of 96.27%, precision of 99.44%, and accuracy of 75.03%.
CONCLUSIONS: The results of NGS-based methods must currently be validated, especially for important reported variants regardless of the methods used, and for the use of WES in cancers a higher false negative rate must be considered. More sensitive methods should be used to confirm the NGS results in uneven cancer tissues.

PMID: 28624499 [PubMed - as supplied by publisher]

Letter to the Editor: A response to Horne and Lucey (2017).

J Dairy Sci. 2017 Jul;100(7):5121-5124

Authors: Carver JA, Thorn DC, Ecroyd H, Holt C

PMID: 28624068 [PubMed - in process]

First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours.

Eur J Cancer. 2017 Jun 15;81:142-150

Authors: Rodon J, Postel-Vinay S, Hollebecque A, Nuciforo P, Azaro A, Cattan V, Marfai L, Sudey I, Brendel K, Delmas A, Malasse S, Soria JC

Abstract
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule.
MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria.
RESULTS: A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR.
CONCLUSION: S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies.
TRIAL REGISTRATION NUMBER: ISRCTN00759419.

PMID: 28624695 [PubMed - as supplied by publisher]

Drug repurposing for aging research using model organisms.

Aging Cell. 2017 Jun 16;:

Authors: Ziehm M, Kaur S, Ivanov DK, Ballester PJ, Marcus D, Partridge L, Thornton JM

Abstract
Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging.

PMID: 28620943 [PubMed - as supplied by publisher]

'You should at least ask'. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research.

Eur J Hum Genet. 2016 Oct;24(10):1403-8

Authors: McCormack P, Kole A, Gainotti S, Mascalzoni D, Molster C, Lochmüller H, Woods S

Abstract
Within the myriad articles about participants' opinions of genomics research, the views of a distinct group - people with a rare disease (RD) - are unknown. It is important to understand if their opinions differ from the general public by dint of having a rare disease and vulnerabilities inherent in this. Here we document RD patients' attitudes to participation in genomics research, particularly around large-scale, international data and biosample sharing. This work is unique in exploring the views of people with a range of rare disorders from many different countries. The authors work within an international, multidisciplinary consortium, RD-Connect, which has developed an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for RD research. Focus groups were conducted with 52 RD patients from 16 countries. Using a scenario-based approach, participants were encouraged to raise topics relevant to their own experiences, rather than these being determined by the researcher. Issues include wide data sharing, and consent for new uses of historic samples and for children. Focus group members are positively disposed towards research and towards allowing data and biosamples to be shared internationally. Expressions of trust and attitudes to risk are often affected by the nature of the RD which they have experience of, as well as regulatory and cultural practices in their home country. Participants are concerned about data security and misuse. There is an acute recognition of the vulnerability inherent in having a RD and the possibility that open knowledge of this could lead to discrimination.

PMID: 27049302 [PubMed - indexed for MEDLINE]

Clinically Promising Biomarkers in Cystic Fibrosis Pulmonary Exacerbations.

Lung. 2017 Jun 16;:

Authors: Scott LK, Toner R

Abstract
Cystic fibrosis is a complex genetic disease hallmarked by repetitive infectious exacerbations that leads to destruction of airway architecture, acute on chronic inflammatory changes, and deterioration in lung function. Predicting an exacerbation may help preempt some of these changes by the initiation of swift antibiotic and anti-inflammatory therapy. A search for biomarkers that could predict exacerbations or help guide duration of antibiotic therapy is being aggressively sought. In this review, we discuss the most recent and promising biomarkers that hopefully will assist in the future management of the CF patient.

PMID: 28623538 [PubMed - as supplied by publisher]