Modeling diseases in multiple mouse strains for precision medicine studies.

Physiol Genomics. 2017 Jan 27;:physiolgenomics.00123.2016

Authors: Klein AD

Abstract
The genetic basis of the phenotypic variability observed in patients can be studied in mice by generating disease models through genetic or chemical interventions in many genetic backgrounds where the clinical phenotypes can be assessed and used for Genome-Wide Association Studies (GWAS). This is particularly relevant for rare disorders, where patients sharing identical mutations can present with a wide variety of symptoms, but there are not enough number of patients to ensure statistical power of GWAS. Inbred strains are homozygous for each loci and their Single Nucleotide Polymorphisms (SNPs) catalogues are known and freely available, facilitating the bioinformatics and reducing the costs of the study since it is not required to genotype every mouse. This kind of approach can be applied for pharmacogenomics studies as well.

PMID: 28130429 [PubMed - as supplied by publisher]

Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells.

Elife. 2017 Jan 28;6:

Authors: Mahamed D, Boulle M, Ganga Y, Mc Arthur C, Skroch S, Oom L, Catinas O, Pillay K, Naicker M, Rampersad S, Mathonsi C, Hunter J, Sreejit G, Pym AS, Lustig G, Sigal A

Abstract
A hallmark of pulmonary tuberculosis is formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states.

PMID: 28130921 [PubMed - as supplied by publisher]

Identification of Protein Complexes by Integrating Multiple Alignment of Protein Interaction Networks.

Bioinformatics. 2017 Jan 27;:

Authors: Ma CY, Phoebe Chen YP, Berger B, Liao CS

Abstract
MOTIVATION: Protein complexes are one of the keys to studying the behavior of a cell system. Many biological functions are carried out by protein complexes. During the past decade, the main strategy used to identify protein complexes from high-throughput network data has been to extract near-cliques or highly dense subgraphs from a single protein-protein interaction (PPI) network. Although experimental PPI data has increased significantly over recent years, most PPI networks still have many false positive interactions and false negative edge loss due to the limitations of high-throughput experiments. In particular, the false negative errors restrict the search space of such conventional protein complex identification approaches. Thus, it has become one of the most challenging tasks in systems biology to automatically identify protein complexes.
RESULTS: In this work, we propose a new algorithm, NEOComplex (NECC- and Ortholog-based Complex identification by multiple network alignment), which integrates functional orthology information capable of being obtained by different types of MNA (multiple network alignment) approaches to expand the search space of protein complex detection. As part of our approach, we also define a new edge clustering coefficient to assign weight to interaction edges in PPI networks so that protein complexes can be identified more accurately.The edge clustering coefficient is based on the intuition that there is functional information captured in the common neighbors of the common neighbors as well. Our results show that the algorithm outperforms well-known protein complex identification tools in a balance between precision and recall on three eukaryotic species: human, yeast, and fly. As a result of MNAs of the species, the proposed approach can tolerate the edge loss of PPI networks and even discover sparse protein complexes which have traditionally been a challenge to predict.
AVAILABILITY: http://acolab.ie.nthu.edu.tw/bionetwork/NEOComplex CONTACT: bab@csail.mit.edu, csliao@ie.nthu.edu.tw.

PMID: 28130237 [PubMed - as supplied by publisher]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/01/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"cystic fibrosis"

These pubmed results were generated on 2017/01/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A Systematic Framework for Drug Repositioning from Integrated Omics and Drug Phenotype Profiles Using Pathway-Drug Network.

Biomed Res Int. 2016;2016:7147039

Authors: Jadamba E, Shin M

Abstract
Drug repositioning offers new clinical indications for old drugs. Recently, many computational approaches have been developed to repurpose marketed drugs in human diseases by mining various of biological data including disease expression profiles, pathways, drug phenotype expression profiles, and chemical structure data. However, despite encouraging results, a comprehensive and efficient computational drug repositioning approach is needed that includes the high-level integration of available resources. In this study, we propose a systematic framework employing experimental genomic knowledge and pharmaceutical knowledge to reposition drugs for a specific disease. Specifically, we first obtain experimental genomic knowledge from disease gene expression profiles and pharmaceutical knowledge from drug phenotype expression profiles and construct a pathway-drug network representing a priori known associations between drugs and pathways. To discover promising candidates for drug repositioning, we initialize node labels for the pathway-drug network using identified disease pathways and known drugs associated with the phenotype of interest and perform network propagation in a semisupervised manner. To evaluate our method, we conducted some experiments to reposition 1309 drugs based on four different breast cancer datasets and verified the results of promising candidate drugs for breast cancer by a two-step validation procedure. Consequently, our experimental results showed that the proposed framework is quite useful approach to discover promising candidates for breast cancer treatment.

PMID: 28127549 [PubMed - in process]

Improving medicines use for children: A global imperative.

Clin Pharmacol Ther. 2017 Jan 27;:

Authors: MacLeod SM

PMID: 28127760 [PubMed - as supplied by publisher]

Machine learning and systems genomics approaches for multi-omics data.

Biomark Res. 2017;5:2

Authors: Lin E, Lane HY

Abstract
In light of recent advances in biomedical computing, big data science, and precision medicine, there is a mammoth demand for establishing algorithms in machine learning and systems genomics (MLSG), together with multi-omics data, to weigh probable phenotype-genotype relationships. Software frameworks in MLSG are extensively employed to analyze hundreds of thousands of multi-omics data by high-throughput technologies. In this study, we reviewed the MLSG software frameworks and future directions with respect to multi-omics data analysis and integration. Our review was targeted at researching recent approaches and technical solutions for the MLSG software frameworks using multi-omics platforms.

PMID: 28127429 [PubMed]

CETP: Pharmacogenomics-Based Response to the CETP Inhibitor Dalcetrapib.

Arterioscler Thromb Vasc Biol. 2017 Jan 26;:

Authors: Tardif JC, Rhainds D, Rhéaume E, Dubé MP

Abstract
High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease. Dalcetrapib is a CETP modulator in which effects on cardiovascular outcomes were demonstrated in the dal-OUTCOMES trial to be influenced by correlated polymorphisms in the ADCY9 (adenylate cyclase 9) gene (P=2.4×10(-)(8) for rs1967309). Patients with the AA genotype at rs1967309 had a relative reduction of 39% in the risk of presenting a cardiovascular event when treated with dalcetrapib compared with placebo (confidence interval, 0.41-0.92). In contrast, patients with the GG genotype had a 27% increase in risk, whereas heterozygotes (AG) presented a neutral result. Supporting evidence from the dal-PLAQUE-2 study using carotid ultrasonography revealed that the polymorphisms tested in the ADCY9 linkage disequilibrium block were associated with disease regression for patients with the protective genotype, progression for the harmful genotype, and no effect in heterozygotes (P≤0.05 and ≤0.01 for 10 and 3 polymorphisms, respectively) when comparing dalcetrapib to placebo. Strikingly concordant and significant genotype-dependent effects of dalcetrapib were also obtained for changes in high-sensitivity C-reactive protein and cholesterol efflux. The Dal-GenE randomized trial is currently being conducted in patients with a recent acute coronary syndrome bearing the AA genotype at rs1967309 in the ADCY9 gene to confirm the effects of dalcetrapib on hard cardiovascular outcomes.

PMID: 28126828 [PubMed - as supplied by publisher]

Serum Metabolomics of Burkitt Lymphoma Mouse Models.

PLoS One. 2017;12(1):e0170896

Authors: Yang F, Du J, Zhang H, Ruan G, Xiang J, Wang L, Sun H, Guan A, Shen G, Liu Y, Guo X, Li Q, Tang Y

Abstract
Burkitt lymphoma (BL) is a rare and highly aggressive type of non-Hodgkin lymphoma. The mortality rate of BL patients is very high due to the rapid growth rate and frequent systemic spread of the disease. A better understanding of the pathogenesis, more sensitive diagnostic tools and effective treatment methods for BL are essential. Metabolomics, an important aspect of systems biology, allows the comprehensive analysis of global, dynamic and endogenous biological metabolites based on their nuclear magnetic resonance (NMR) and mass spectrometry (MS). It has already been used to investigate the pathogenesis and discover new biomarkers for disease diagnosis and prognosis. In this study, we analyzed differences of serum metabolites in BL mice and normal mice by NMR-based metabolomics. We found that metabolites associated with energy metabolism, amino acid metabolism, fatty acid metabolism and choline phospholipid metabolism were altered in BL mice. The diagnostic potential of the metabolite differences was investigated in this study. Glutamate, glycerol and choline had a high diagnostic accuracy; in contrast, isoleucine, leucine, pyruvate, lysine, α-ketoglutarate, betaine, glycine, creatine, serine, lactate, tyrosine, phenylalanine, histidine and formate enabled the accurate differentiation of BL mice from normal mice. The discovery of abnormal metabolism and relevant differential metabolites may provide useful clues for developing novel, noninvasive approaches for the diagnosis and prognosis of BL based on these potential biomarkers.

PMID: 28129369 [PubMed - in process]

Volar locking plate (VLP) versus non-locking plate (NLP) in the treatment of die-punch fractures of the distal radius, an observational study.

Int J Surg. 2016 Oct;34:142-147

Authors: Zhang X, Hu C, Yu K, Bai J, Tian D, Xu Y, Zhang B

Abstract
PURPOSE: This study aims to evaluate whether volar locking plate was superior over non-locking plate in the treatment of die-punch fractures of the distal radius.
METHODS: A total of 57 patients with closed die-punch fractures of the distal radius were included and analyzed. Of them, 32 were treated by non-locking plate (NLP) and the remaining 25 were treated by volar locking plate (VLP). Preoperative radiographs, computer tomographs and three-dimensional reconstruction, radiographs taken at immediate postoperation and at last follow-up were extracted and evaluated. Patients' electronic medical records were inquired and related demographic and medical data were documented. The documented contents were volar tilt, radial inclination, ulnar variance, grip strength, Disabilities of the Arm, Shoulder, and Hand (DASH) and visual analog scale (VAS) scores and complications.
RESULTS: VLP group demonstrated a significantly reduced radial subsidence of 1.5 mm (0.7 versus 2.2 mm), during the interval of bony union (P < 0.001), compared to NLP group. Larger proportion of patients (88% versus 62.5%) in VLP group gained acceptable joint congruity (step-off <2 mm) at the final follow-up (P = 0.037). No significant differences were observed between the groups in the measurements of volar tilt, radial inclination, DASH, VAS and grip strength recovery at the last follow-up. There was a trend of fewer overall complications (5/25 versus 10/32) and major complications that required surgery interventions (1/25 versus 4/32) in VLP than NLP groups, although the difference did not approach to significance (P = 0.339, 0.372).
CONCLUSIONS: VLP leaded to significantly better results of reduction maintainance and the final joint congruity than NLP, while reducing overall and major complications. However, the results should be treated in the context of limitations and the clinical significance of the difference required further studies to investigate.

PMID: 27593172 [PubMed - indexed for MEDLINE]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"cystic fibrosis"

These pubmed results were generated on 2017/01/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Six psychotropics for pre-symptomatic & early Alzheimer's (MCI), Parkinson's, and Huntington's disease modification.

Neural Regen Res. 2016 Nov;11(11):1712-1726

Authors: Lauterbach EC

Abstract
The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment (MCI) phase of AD: salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data indicate that lithium reduces AD risk. Animal model studies (AMS) reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS findings show promise. Pre-symptomatic PD: lithium and valproate AMS findings are encouraging. Early HD: uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication (valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD) are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.

PMID: 28123400 [PubMed - in process]

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug resistant ALL.

Blood. 2017 Jan 25;:

Authors: Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, Richter-Pechanska P, Marovca B, Pail O, Jenni S, Diaz-Flores E, Chang BH, Brown TJ, Collins RH, Uhrig S, Balasubramanian GP, Bandapalli OR, Higi S, Eugster S, Voegeli P, Delorenzi M, Cario G, Loh ML, Schrappe M, Stanulla M, Kulozik AE, Muckenthaler MU, Saha V, Irving JA, Meisel R, Radimerski T, Von Stackelberg A, Eckert C, Tyner JW, Horvath P, Bornhauser BC, Bourquin JP

Abstract
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in co-cultures on bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal co-culture did not prevent leukemia cell cycle activity, while a specific sensitivity profile to cell cycle related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In cases with refractory relapses, individual patterns of marked drug resistance, but also exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in BCP-ALL subsets including MLL-AF4 and TCF3-HLF ALL, and in some T-ALLs, predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with IC50 values below 20 nM was detected in two independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC Inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib based on drug profiling information and achieved a five-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials in order to develop drug repurposing strategies for patients with urgent medical needs.

PMID: 28122742 [PubMed - as supplied by publisher]

Zoosexuality: an unusual cause of colorectal injury.

Acta Chir Belg. 2016 Oct;116(5):316-318

Authors: Virgilio E, Franzese E, Caterino S

Abstract
Zoosexuality (the sexual intercourse between humans and animals) represents an extremely rare but potentially fatal cause of colorectal trauma and sepsis. A case of penetrating rectal injury associated with a rapidly progressive sepsis following sexual intercourse with a Maremma Sheepdog is presented.

PMID: 27426668 [PubMed - indexed for MEDLINE]

Surgical treatment of megaduodenum in familial visceral myopathy - report of a case and review of the literature.

Acta Chir Belg. 2016 Oct;116(5):305-308

Authors: Papis D, Marangoni G

Abstract
INTRODUCTION: Familial visceral myopathy (VM) is a rare genetic disease that affects intestinal motility and results in pseudo-obstruction. Medical treatments can provide supportive measures but no curative treatment.
CASE REPORT: A 20-year-old male with known diagnosis of VM was referred to our Unit in May 2013 with recurrent episodes of vomiting and hospital admissions not responding to medical treatment. Pre-operative imaging showed megaduodenum with marked delayed transit and normal small and large bowel transit. He underwent an elective Roux-en-Y duodeno-jejunostomy. The post-operative course was uneventful with complete resolution of the symptoms with a 2 years follow-up.
DISCUSSION: Due to the early age of presentation, VM affects patient both psychologically and physically. Surgical treatment of megaduodenum in visceral myopathy in the absence of motility disorder of the small bowel seems to achieve satisfactory symptomatic relief and could be considered in this rare cohort of patients.

PMID: 27410460 [PubMed - indexed for MEDLINE]

Traumatic herniation of the lung.

Acta Chir Belg. 2016 Oct;116(5):322-324

Authors: Corten BJ, Dijk WA, Bilderbeek-Beckers M, Janzing HM

Abstract
We present a relatively rare clinical presentation of herniation of lung parenchyma. In our case, the patient suffered multiple rib fractures, with an intercostal herniation of lung tissue after a trauma. We opted for a conservative treatment, given the clinical presentation, and the absence of incarceration or strangulation of the pulmonary tissue. In the absence of clear guidelines for this rare presentation, current treatment can be conservative or surgical, depending on the clinical presentation.

PMID: 27397036 [PubMed - indexed for MEDLINE]

Three cases of triple A syndrome (Allgrove syndrome) in pediatric surgeons' view.

Acta Chir Belg. 2016 Apr;116(2):119-21

Authors: Erginel B, Gün F, Kocaman H, Çelik A, Salman T

Abstract
Triple A syndrome, also known as Allgrove syndrome, is a rare disease, and presents mainly in children. Its cardinal symptoms are achalasia, alacrima, and adrenocorticotropic hormone (ACTH) insensitivity. We report three cases of Triple A syndrome. Our aim is to inform pediatric surgeons about the existence of this rare syndrome and to highlight the need for suspicion of alacrima and ACTH insensitivity in cases of pediatric achalasia. Triple A syndrome should be considered in patients presenting with achalasia. Alacrima should be investigated by a Schirmer test, and adrenal dysfunction should be tested in cases of suspected triple A.

PMID: 27385299 [PubMed - indexed for MEDLINE]

Superior mesenteric artery (Wilkie's) syndrome: a rare cause of upper gastrointestinal system obstruction.

Acta Chir Belg. 2016 Apr;116(2):81-8

Authors: Oguz A, Uslukaya O, Ülger BV, Turkoglu A, Bahadır MV, Bozdag Z, Böyük A, Göya C

Abstract
Background Superior mesenteric artery syndrome (SMAS) results from the compression of the third part of the duodenum between the aorta and the proximal part of the superior mesenteric artery (SMA). Clinical presentation of SMAS is characterized by the dilatation of the proximal part of the third part of the duodenum. SMAS is a rare cause of the upper gastrointestinal system (UGS) obstruction. In this study, we aimed to present our clinical experience in the treatment of five patients with SMAS, which is a rare clinical condition requiring surgery. Patients and methods The retrospective study included five patients who were treated due to SMAS at our clinic between January 2010 and January 2014. Results All the patients were underweight, with a mean BMI of 15.73 (14-16). The clinical symptoms included epigastric pain after food intake, large volume bilious emesis, early satiety, failure to gain weight, indigestion, esophageal reflux, sense of fullness, and persistent weight loss. SMAS was diagnosed using barium meal studies, upper gastrointestinal endoscopy, abdominal ultrasonography, and CT angiography. Four patients underwent duodenojejunostomy and one patient was managed with gastrojejunostomy. No complication was observed during the postoperative period, and all the patients achieved significant improvement in symptoms. Conclusion SMAS is a rare cause of UGS obstruction, and the diagnosis of SMAS is often delayed. SMAS should be suspected in the differential diagnosis of the patients with unsubstantiated symptoms of persistent nausea, emesis, and significant weight loss.

PMID: 27385294 [PubMed - indexed for MEDLINE]

Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients.

Arch Virol. 2016 Nov;161(11):3161-9

Authors: Mehta M, Hetta HF, Abdel-Hameed EA, Rouster SD, Hossain M, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, El-Mokhtar MA, Abdelwahab SF, Medhat A, Sherman KE, Shata MT

Abstract
The IL28B gene is associated with spontaneous or treatment-induced HCV viral clearance. However, the mechanism by which the IL28B single nucleotide polymorphism (SNP) affects the extra-hepatic HCV immune responses and its relationship to HCV pathogenesis have not been thoroughly investigated. To examine the mechanism by which IL28B affects HCV clearance. Forty Egyptian patients with chronic HCV infection receiving an Interferon/ribavirin treatment regimen were enrolled into this study. There were two groups: non-responders (NR; n = 20) and sustained virologic responders (SVR; n = 20). The initial plasma HCV viral loads prior to treatment and IL28B genotypes were determined by quantitative RT-PCR and sequencing, respectively. Liver biopsies were examined to determine the inflammatory score and the stage of fibrosis. Colonic regulatory T cell (Treg) frequency was estimated by immunohistochemistry. No significant association between IL28B genotypes and response to therapy was identified, despite an odds ratio of 3.4 to have the TT genotype in NR compared to SVR (95 % confidence interval 0.3-35.3, p = 0.3). Patients with the TT-IL28Brs12979860 genotype (unfavorable genotype) have significantly higher frequencies of colonic Treg compared to the CT (p = 0.04) and CC (p = 0.03) genotypes. The frequency of colonic Treg cells in HCV-infected patients had a strong association with the IL-28B genotype and may have a significant impact on HCV clearance.

PMID: 27544760 [PubMed - indexed for MEDLINE]