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"systems biology"

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A long range distal enhancer controls temporal fine-tuning of PAX6 expression in neuronal precursors.

Dev Biol. 2018 Feb 24;:

Authors: Lacomme M, Medevielle F, Bourbon HM, Thierion E, Kleinjan DJ, Roussat M, Pituello F, Bel-Vialar S

Abstract
Proper embryonic development relies on a tight control of spatial and temporal gene expression profiles in a highly regulated manner. One good example is the ON/OFF switching of the transcription factor PAX6 that governs important steps of neurogenesis. In the neural tube PAX6 expression is initiated in neural progenitors through the positive action of retinoic acid signaling and downregulated in neuronal precursors by the bHLH transcription factor NEUROG2. How these two regulatory inputs are integrated at the molecular level to properly fine tune temporal PAX6 expression is not known. In this study we identified and characterized a 940-bp long distal cis-regulatory module (CRM), located far away from the PAX6 transcription unit and which conveys positive input from RA signaling pathway and indirect repressive signal(s) from NEUROG2. These opposing regulatory signals are integrated through HOMZ, a 94bp core region within E940 which is evolutionarily conserved in distant organisms such as the zebrafish. We show that within HOMZ, NEUROG2 and RA exert their opposite temporal activities through a short 60bp region containing a functional RA-responsive element (RARE). We propose a model in which retinoic acid receptors (RARs) and NEUROG2 repressive target(s) compete on the same DNA motif to fine tune temporal PAX6 expression during the course of spinal neurogenesis.

PMID: 29486153 [PubMed - as supplied by publisher]

An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy.

EMBO Mol Med. 2018 Feb 26;:

Authors: Mishra A, Mamidi AS, Rajmani RS, Ray A, Roy R, Surolia A

Abstract
The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mtb-infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual-edged sword, by targeting the intracellular bacteria as well as the bacterial pro-survival signaling in the host. PRK is highly effective against in vitro and in vivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis.

PMID: 29483133 [PubMed - as supplied by publisher]

Patient-customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients.

Cancer Res. 2018 Feb 26;:

Authors: He L, Tang J, Andersson EI, Timonen S, Koschmieder S, Wennerberg K, Mustjoki S, Aittokallio T

Abstract
The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10/24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.

PMID: 29483097 [PubMed - as supplied by publisher]

Prevalence of Rare Craniofacial Clefts.

J Craniofac Surg. 2017 Jul;28(5):e467-e470

Authors: Kalantar-Hormozi A, Abbaszadeh-Kasbi A, Goravanchi F, Davai NR

Abstract
BACKGROUND: Craniofacial clefts are extremely rare congenital malformations that have adverse functional, psychosocial, and aesthetic effects on patients' life. Although the exact incidence is unclear, it is estimated between 1.4 and 4.9 per 100,000 live births. Prevalence of the rare craniofacial clefts is imprecise due to the paucity of literature as well as their etiologies.
METHODS: All the patients with rare craniofacial clefts during 10 years in a plastic surgery tertiary referral hospital were included, and Tessier craniofacial clefting classification was used for classifying the clefts.
RESULTS: Of 964 patients with craniofacial clefts, 80 (8.29%) patients were identified with rare craniofacial clefts. There were 39 (48.7%) males and 41 (51.3%) females. Family history was determined positive in 30 (37.5%) patients. Tessier number 0 (58.7%) was the most common cleft in the authors' study. Tessier numbers 8, 13, and 30 were the rarest clefts. There was no patient with Clefts numbers 5, 6, or 9. Maternal smoking during pregnancy was observed in 1 (1.3%) of the women and 3 of the women had used drugs, 1 of them used the dexamethasone tablets and 2 of them could not remember name of the used drug.
CONCLUSIONS: Tessier number 0 was the most common cleft and Tessier numbers 8, 13, and 30 were the rarest types. The precise etiology of rare craniofacial clefts remained undetermined in this study. Women should be educated about the risk factors and subsequent ways of preventing from these risk factors.

PMID: 28678141 [PubMed - indexed for MEDLINE]

Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases.

AAPS PharmSciTech. 2017 May;18(4):1318-1331

Authors: Krupa A, Majda D, Mozgawa W, Szlęk J, Jachowicz R

Abstract
The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70°C and was followed by the chemical degradation with the onset at 290°C. The highest thermal stability was stated for TA, which decomposed at ca. 320°C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190°C. The products of the drug decomposition were identified. FT-FIR was applied to study intra- and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies.

PMID: 27495162 [PubMed - indexed for MEDLINE]

The Alpha-2A Adrenergic Receptor Gene -1291C/G Single Nucleotide Polymorphism is Associated with the Efficacy of Methylphenidate in Treating Taiwanese Children and Adolescents with Attention-Deficit Hyperactivity Disorder.

Psychiatry Investig. 2018 Feb 28;:

Authors: Huang HC, Wu LS, Yu SC, Wu BJ, Lua AC, Lee SM, Liu CZ

Abstract
Objective: The therapeutic effect of methylphenidate (MPH) in treating attention-deficit/hyperactivity disorder (ADHD) has been related to the alpha-2A adrenergic receptor (ADRA2A) gene -1291C/G single nucleotide polymorphism (SNP). We investigated the effect of MPH in treating Taiwanese children and adolescent with ADHD and its relation to the ADRA2A gene -1291C/G SNP.
Methods: The subjects with DSM-IV ADHD diagnosis underwent a titration period to find out the dose of MPH for maintenance treatment. After 4 weeks maintenance treatment, the effect of MPH was evaluated by the Swanson, Nolan and Pelham version IV total scores. The subjects with more than 25% score reduction were referred to responders and those with ≥50% improvement were considered as better responders. The -1291C/G variant of the ADRA2A gene was identified by DNA sequencing and what relevance it has to the MPH response was examined by binary logistic regression analysis.
Results: Of the 59 subjects, 44 (74.6%) were responsive to MPH treatment and the responsiveness was not shown to be associated with the ADRA2A gene -1291C/G SNP. As the responsive subjects were categorized as moderate responders and better responders and subjected to statistical analysis, the GG homozygotes showed a greater chance to have a better response to MPH treatment than CC homozygotes (p=0.02), with an odds ratio of 32.14 (95% CI=1.64-627.80).
Conclusion: The ADRA2A gene -1291C/G SNP is associated with the efficacy of MPH for the treatment of ADHD in Taiwanese children and adolescents. The responsive subjects bearing homozygous -1291G allele are more likely to have a better response to MPH treatment.

PMID: 29486545 [PubMed - as supplied by publisher]

Pharmacogenetics and target identification in diabetes.

Curr Opin Genet Dev. 2018 Feb 24;50:68-73

Authors: Pearson ER

Abstract
In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11. Beyond monogenic diabetes, pharmacogenetic variants have yet to impact on clinical practice, yet the effect sizes (e.g. for metformin intolerance and OCT1 variants; or for metformin action and SLC2A2 variants) are potentially of clinical utility, especially if the genotype is already known at the point of prescribing. Over the next few years, increasing cohort sizes and linkage at scale to electronic medical records will provide considerable potential for stratification and novel target identification in diabetes.

PMID: 29486427 [PubMed - as supplied by publisher]

Genome-wide association studies in Crohn's disease: Past, present and future.

Clin Transl Immunology. 2018;7(1):e1001

Authors: Verstockt B, Smith KG, Lee JC

Abstract
Over the course of the past decade, genome-wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL-17/IL-23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development - a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven 'within-cases' analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.

PMID: 29484179 [PubMed]

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

Oncotarget. 2018 Jan 26;9(7):7631-7643

Authors: Feng PH, Yu CT, Chen KY, Luo CS, Wu SM, Liu CY, Kuo LW, Chan YF, Chen TT, Chang CC, Lee CN, Chuang HC, Lin CF, Han CL, Lee WH, Lee KY

Abstract
Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated.
Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown.
Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway.
Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

PMID: 29484139 [PubMed]

Pharmacogenetics as Personalized Medicine: Association Investigation of SOD2 rs4880, CYP2C19 rs4244285, and FCGR2A rs1801274 Polymorphisms in a Breast Cancer Population in Iraqi Women.

Clin Breast Cancer. 2018 Jan 31;:

Authors: Jabir FA, Hoidy WH

Abstract
BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with targeted therapies.
PATIENTS AND METHODS: In this study, we performed a population-based approach intersecting high-throughput genotype data from Iraqi populations with publicly available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. A total of 50 patients and 25 healthy controls were enrolled in our study. Genotyping of rs4880, rs4244285, and rs1801274 were examined in association with breast cancer in Iraqi women.
RESULTS: We found that individuals carrying the CT genotype of rs4880 manifested an increased risk of breast cancer compared with those carrying the TT genotype (odds ratio [OR], 0.171; 95% confidence interval [CI], 0.053-0.551; P = .002). In the dominant model, we observed that the CT and CC genotype of rs4880 showed an increased risk of breast cancer compared with the TT genotype (OR, 0.248; 95% CI, 0.089-0.690; P = .006). Moreover, subjects with the GA genotype of rs4244285 presented a higher risk of breast cancer than the GG genotype (OR, 0.256; 95% CI, 0.066-0.987; P = .038) and dominant models (OR, 0.025; 95% CI, 0.054-0.775; P = .013).
CONCLUSION: The analysis revealed that rs1801274 showed linkage disequilibrium and decreased risk of breast cancer. In conclusion, our study suggests that rs4880 and rs4244285 polymorphisms play an important role in development of breast cancer in an Iraqi population, and no significant association was found between rs1801274 and the risk of breast cancer.

PMID: 29482947 [PubMed - as supplied by publisher]

COL3A1 and SNAP91: novel glioblastoma markers with diagnostic and prognostic value.

Oncotarget. 2016 Oct 25;7(43):70494-70503

Authors: Gao YF, Mao XY, Zhu T, Mao CX, Liu ZX, Wang ZB, Li L, Li X, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
Although patients with glioblastoma (GBM) have grave prognosis, significant variability in patient outcome is observed. This study aims to identify novel targets for GBM diagnosis and therapy. Microarray data (GSE4290, GSE7696, and GSE4412) obtained from the Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) by significant analysis of microarray (SAM). Intersection of the identified DEGs for each profile revealed 46 DEGs in GBM. A subset of common DEGs were validated by real-time reverse transcription quantitative PCR (qPCR). The prognostic value of some of the markers was also studied. We determined that RRM2 and COL3A1 were increased and directly correlated with glioma grade, while SH3GL2 and SNAP91 were decreased in GBM and inversely correlated with glioma grade. Kaplan-Meir analysis of GSE7696 revealed that COL3A1 and SNAP91 correlated with survival, suggesting that COL3A1 and SNAP91 may be suitable biomarkers for diagnostic or therapeutic strategies for GBM.

PMID: 27655637 [PubMed - indexed for MEDLINE]

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.

Neurobiol Dis. 2016 Oct;94:55-62

Authors: Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, Rosenthal LS, Pantelyat A, Gibbs JR, Albert MS, Hernandez DG, Hillis AE, Stone DJ, Singleton AB, North American Brain Expression Consortium, Hardy JA, Troncoso JC, Scholz SW

Abstract
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.

PMID: 27312774 [PubMed - indexed for MEDLINE]

An overview of clinical management of cyclic vomiting syndrome in childhood.

Curr Med Res Opin. 2018 Feb 27;:1-16

Authors: Romano C, Dipasquale V, Rybak A, Comito D, Borrelli O

Abstract
This narrative review provides an update of cyclic vomiting syndrome pathogenesis, diagnosis and management, based upon studies published after the 2008 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) official recommendations. The review began with a comprehensive PubMed/Medline, search for "cyclic vomiting syndrome", "periodic syndromes" and "pediatrics" from 2000 up to October 2017. Additional papers were identified by reviewing the reference lists of retrieved publications. Cyclic vomiting syndrome is a severe, debilitating disorder of the brain-gut axis with unclear pathogenesis, that significantly effects long-term quality of life of effected children and their family. The 2008 NASPGHAN recommendations defined the major clinical, diagnostic and therapeutic peculiarities. Over the last 10 years, advancements in pathogenesis and diagnostic criteria have been made, and new prophylactic and therapeutic strategies have been proposed. These aspects are discussed in this manuscript. For the pediatrician, the major aim is to have early clinical suspicion to avoid diagnostic delay and to start adequate, phase-related, symptoms-tailored management.

PMID: 29484898 [PubMed - as supplied by publisher]

Inflammatory serum markers up to 5 years after comprehensive periodontal therapy of aggressive and chronic periodontitis.

Clin Oral Investig. 2018 Feb 27;:

Authors: Ramich T, Asendorf A, Nickles K, Oremek GM, Schubert R, Nibali L, Wohlfeil M, Eickholz P

Abstract
AIM: The aim of the study is to assess the long-term effect of active periodontal therapy on serum inflammatory parameters in patients with aggressive (AgP) and chronic (ChP) periodontitis in a non-randomised clinical study.
METHODS: Twenty-five ChP and 17 AgP were examined clinically prior to (baseline), 12 weeks and 60 months after subgingival debridement of all pockets within 2 days. Systemic antibiotics were prescribed if Aggregatibacter actinomycetemcomitans was detected (10 AgP, 8 ChP), flap surgery was rendered if required. Neutrophil elastase (NE), C-reactive protein (CRP), lipopolysaccharide binding protein, interleukin 6, 8, and leukocyte counts were assessed at baseline, 12 weeks and 60 months.
RESULTS: Clinical parameters improved significantly in both groups from 12 weeks to 60 months. Eleven AgP and 18 ChP patients received surgical treatment after the 12 weeks examination. Only 3 patients in each group attended ≥ 2 supportive maintenance visits per year. NE and CRP were significantly higher in AgP than ChP at baseline and 60 months (p < 0.01). For leukocyte counts in ChP, significant changes were observed (baseline: 6.11 ± 1.44 nl-1; 12 weeks: 5.34 ± 1.40 nl-1; 60 months: 7.73 ± 2.89 nl-1; p < 0.05). Multiple regression analysis identified African origin, surgical treatment and female sex to correlate with better clinical improvement.
CONCLUSION: Despite comprehensive periodontal treatment, AgP patients exhibit higher NE and CRP levels than ChP patients up to 5 years after therapy.
CLINICAL RELEVANCE: Systemic inflammatory burden in AgP patients is higher than in ChP patients even 5 years after periodontal treatment.

PMID: 29484548 [PubMed - as supplied by publisher]

Comparison of facemask and mouthpiece interfaces for multiple breath washout measurements.

J Cyst Fibros. 2018 Feb 23;:

Authors: Robinson PD, Lum S, Moore C, Hardaker KM, Benseler N, Aurora P, Cooper P, Fitzgerald D, Jensen R, McDonald R, Selvadurai H, Ratjen F, Stanojevic S

Abstract
BACKGROUND: Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children.
METHODS: We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children.
RESULTS: In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age.
CONCLUSION: Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur.

PMID: 29483003 [PubMed - as supplied by publisher]

Loss of Chromatin Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times.

Gastroenterology. 2018 Feb 24;:

Authors: Roy S, LaFramboise WA, Liu TC, Cao D, Luvison A, Miller C, Lyons MA, O'Sullivan RJ, Zureikat AH, Hogg ME, Tsung A, Lee KK, Bahary N, Brand RE, Chennat JS, Fasanella KE, McGrath K, Nikiforova MN, Papachristou GI, Slivka A, Zeh HJ, Singhi AD

Abstract
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and ATRX chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single non-syndrome, non-functional PanNET. We found distant metastases contained alterations in MEN1 (n=8), ATRX (n=5), DAXX (n=5), TSC2 (n=3), and DEPDC5 (n=3). We found copy number loss of CDKN2A in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling including SETD2 (n=4), ARID1A (n=2), CHD8 (n=2), and DNMT1 (n=2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3K36me3), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3K36me3, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin remodeling genes and CDKN2A contribute to metastasis of PanNETs.

PMID: 29486199 [PubMed - as supplied by publisher]

Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

Dig Dis Sci. 2018 Feb 26;:

Authors: Vardi I, Barel O, Sperber M, Schvimer M, Nunberg M, Field M, Ouahed J, Marek-Yagel D, Werner L, Haberman Y, Lahad A, Anikster Y, Rechavi G, Barshack I, McElwee JJ, Maranville J, Somech R, Snapper SB, Weiss B, Shouval DS

Abstract
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.
AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis.
METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function.
RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface.
CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

PMID: 29484573 [PubMed - as supplied by publisher]

Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.

Hypertension. 2018 Feb 26;:

Authors: Warejko JK, Schueler M, Vivante A, Tan W, Daga A, Lawson JA, Braun DA, Shril S, Amann K, Somers MJG, Rodig NM, Baum MA, Daouk G, Traum AZ, Kim HB, Vakili K, Porras D, Lock J, Rivkin MJ, Chaudry G, Smoot LB, Singh MN, Smith ER, Mane SM, Lifton RP, Stein DR, Ferguson MA, Hildebrandt F

Abstract
Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (NF1, JAG1, ELN, GATA6, and RNF213). Ten of the 15 mutations have not previously been reported. This is the first report of ELN, RNF213, or GATA6 mutations in individuals with MAS. Mutations were detected in NF1 (6/15 families), JAG1 (4/15 families), ELN (3/15 families), and one family each for GATA6 and RNF213 Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

PMID: 29483232 [PubMed - as supplied by publisher]

Genomic and functional fidelity of small cell lung cancer patient-derived xenografts.

Cancer Discov. 2018 Feb 26;:

Authors: Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zhong J, Igo P, Hazar-Rethinam MH, LiCausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Büttner R, Haas S, Sequist LV, Shaw AT, Wong KK, Hata AN, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, Farago AF

Abstract
Small cell lung cancer (SCLC) patient-derived xenografts (PDXs) can be generated from biopsies or circulating tumor cells (CTCs), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a two-year timeframe, at 89% and 38% efficiency, respectively. Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and cisplatin (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.

PMID: 29483136 [PubMed - as supplied by publisher]