From 20th Century Metabolic Wall Charts to 21st Century Systems Biology: Database of Mammalian Metabolic Enzymes.

Am J Physiol Renal Physiol. 2016 Dec 14;:ajprenal.00601.2016

Authors: Corcoran CC, Grady CR, Pisitkun T, Parulekar J, Knepper MA

Abstract
The organization of the mammalian genome into gene subsets corresponding to specific functional classes has provided key tools for systems biology research. Here, we have created a web-accessible resource called the Mammalian Metabolic Enzyme Database (https://hpcwebapps.cit.nih.gov/ESBL/Database/MetabolicEnzymes/MetabolicEnzymeDatabase.html) keyed to the biochemical reactions represented on iconic metabolic pathway wall charts created in the previous century. Overall, we have mapped 1647 genes to these pathways, representing approximately 7 percent of the protein-coding genome. To illustrate the use of the database, we apply it to the area of kidney physiology. In so doing, we have created an additional database (Database of Metabolic Enzymes in Kidney Tubule Segments: https://hpcwebapps.cit.nih.gov/ESBL/Database/MetabolicEnzymes/), mapping mRNA abundance measurements (mined from RNA-Seq studies) for all metabolic enzymes to each of 14 renal tubule segments. We carry out bioinformatics analysis of the enzyme expression pattern among renal tubule segments and mine various data sources to identify vasopressin-regulated metabolic enzymes in the renal collecting duct.

PMID: 27974320 [PubMed - as supplied by publisher]

The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing.

Cell Death Dis. 2016 Apr 28;7:e2207

Authors: Mao Y, Tamura T, Yuki Y, Abe D, Tamada Y, Imoto S, Tanaka H, Homma H, Tagawa K, Miyano S, Okazawa H

Abstract
In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis.

PMID: 27124581 [PubMed - indexed for MEDLINE]

Flux Control in Glycolysis Varies Across the Tree of Life.

J Mol Evol. 2016 Mar;82(2-3):146-61

Authors: Orlenko A, Hermansen RA, Liberles DA

Abstract
Biochemical thought posits that rate-limiting steps (defined here as points of flux control) are strongly selected as points of pathway regulation and control and are thus expected to be evolutionarily conserved. Conversely, population genetic thought based upon the concepts of mutation-selection-drift balance at the pathway level might suggest variation in flux controlling steps over evolutionary time. Glycolysis, as one of the most conserved and best characterized pathways, was studied to evaluate its evolutionary conservation. The flux controlling step in glycolysis was found to vary over the tree of life. Further, phylogenetic analysis suggested at least 60 events of gene duplication and additional events of putative positive selection that might alter pathway kinetic properties. Together, these results suggest that even with presumed largely negative selection on pathway output on glycolysis, the co-evolutionary process under the hood is dynamic.

PMID: 26920685 [PubMed - indexed for MEDLINE]

Global prevalence and epidemiological characteristics of congenital cataract: a systematic review and meta-analysis.

Lancet. 2016 Oct;388 Suppl 1:S55

Authors: Wu X, Long E, Lin H, Liu Y

Abstract
BACKGROUND: Congenital cataract is the primary cause of treatable childhood blindness worldwide. The establishment of reliable, epidemiological estimates is an essential first step towards development of causal and management strategies. We therefore undertook an initial systematic review and meta-analysis to estimate the global prevalence and other epidemiological characteristics of congenital cataract.
METHODS: We searched PubMed, Medline, Web of Science, Embase, and Cochrane Library databases with a combination of search terms, including "congenital cataract", "prevalence", "epidemiology", "population", and "survey", up to January, 2015. We did a meta-analysis with a random-effects model based on a proportions approach to determine the population-based prevalence of congenital cataract and to describe the data for the laterality, morphology, associated comorbidities, and cause. We analysed heterogeneity with the meta-regression method, and did subgroup analyses.
FINDINGS: 27 studies were selected from 2610 references. The pooled prevalence estimate was 4·24 per 10 000 people (95% CI 3·16-5·69 per 10 000), making it a rare disease by WHO standards. Most of the variations could be explained by sample size, research period, and age at diagnosis (R(2), amount of heterogeneity accounted for, 65·41%; p=0·0006). Subgroup analyses showed that the highest prevalence of congenital cataract was in Asia, and a trend for increasing prevalence through 2000 in all regions. Other major epidemiological characteristics showed that congenital cataract tended to be bilateral, isolated, hereditary, and in total/nuclear morphology.
INTERPRETATION: This study provides a comprehensive, worldwide estimate of the population-based prevalence of congenital cataract and describes its major epidemiological characteristics. The findings provide suggestions for further studies focused on the cause of congenital cataract, improvements in screening techniques, and the development of public health strategies.
FUNDING: The Ministry of Science and Technology of China Grants (973 programme, 2015CB964600), the Key Research Plan for the National Natural Science Foundation of China (number 91546101), and the Guangdong Provincial Natural Science Foundation for Distinguished Young Scholars of China (number 2014A030306030).

PMID: 27968871 [PubMed - in process]

Actinomycosis of the abdominal wall after cholecystectomy: transferral theory.

Neth J Med. 2016 Dec;74(10):451-454

Authors: Kooi EJ, de Vries PJ, van Geloven AW, Stel HV, Kingma PJ

Abstract
Abdominal actinomycosis is a rare disease caused by Gram-positive anaerobic Actinomyces bacteria. Here, we present a patient with an intrauterine contraceptive device who developed a long lasting and unexplained recurrent, painful abdominal swelling a few months after a laparoscopic cholecystectomy.

PMID: 27966440 [PubMed - in process]

Stroke as the Sole Manifestation of Takayasu Arteritis in a 15-Year-Old Boy with Latent Tuberculosis.

Case Rep Neurol Med. 2016;2016:8736248

Authors: Benjaminsen E, Reigstad A, Cengija V, Lilleby V, Carlsson M

Abstract
Introduction. Takayasu arteritis is a rare disease affecting the aorta and its main branches, causing arterial claudication and end-organ ischemia, including stroke. The etiology is unknown but is believed to be autoimmune. An association between Takayasu arteritis and tuberculosis has been suggested, but the possible relation is unclear. Case Presentation. A 15-year-old Somali boy was diagnosed with latent tuberculosis. He had a lesion in the right lung, and both the tuberculin skin test by the Mantoux method and Quantiferon GOLD test turned out positive. After he suffered a cerebral infarct in the right hemisphere, childhood Takayasu arteritis was diagnosed. The diagnosis was based on diagnostic imaging showing a high-grade stenosis of the origin of the right common carotid artery, an occluded common carotid artery on the left side, a circumferential thickening of the vessel walls in the right and left common carotid artery, and laboratory findings with elevated C-reactive protein. Conclusion. Takayasu arteritis is an uncommon cause of stroke. It should however be kept in mind as a cause of cerebrovascular disease, especially in the young.

PMID: 27965905 [PubMed - in process]

Rituximab-Associated Inflammatory Progressive Multifocal Leukoencephalopathy.

Case Rep Infect Dis. 2016;2016:8915047

Authors: Punch C, Schofield C, Harris P

Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare disease of the immunosuppression that results from neurotropic invasion of the JC virus which leads to demyelination of oligodendrocytes. Immune reconstitution inflammatory syndrome (IRIS), on the other hand, is a condition of inflammation that develops as the immune system reconstitutes. This case report describes a case of a 35-year-old HIV-negative male who presented with three weeks of right lower extremity paresthesias as well as right upper extremity apraxia. He was diagnosed with PML complicated by IRIS secondary to Rituximab, which he had completed four months prior to presentation. Despite the condition's poor prognosis, the patient recovered with only minor deficits.

PMID: 27965904 [PubMed - in process]

A Rare Disease With Cardiac Involvement.

Am J Crit Care. 2016 Dec;26(1):89-90

Authors: Al-Zaiti SS, Pelter MM, Kozik TM, Carey MG

PMID: 27965234 [PubMed - in process]

Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts.

Biomed Res Int. 2016;2016:6824719

Authors: Nanke Y, Kobashigawa T, Yago T, Kawamoto M, Yamanaka H, Kotake S

Abstract
Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis.

PMID: 27965978 [PubMed - in process]

Synergistic drug combinations from electronic health records and gene expression.

J Am Med Inform Assoc. 2016 Dec 09;:

Authors: Low YS, Daugherty AC, Schroeder EA, Chen W, Seto T, Weber S, Lim M, Hastie T, Mathur M, Desai M, Farrington C, Radin AA, Sirota M, Kenkare P, Thompson CA, Yu PP, Gomez SL, Sledge GW, Kurian AW, Shah NH

Abstract
OBJECTIVE: Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.
METHOD: We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.
RESULTS: From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.
CONCLUSIONS: This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.

PMID: 27940607 [PubMed - as supplied by publisher]

Repurposing the anticancer drug mitomycin C for the treatment of persistent Acinetobacter baumannii infections.

Int J Antimicrob Agents. 2016 Oct 07;:

Authors: Cruz-Muñiz MY, López-Jacome LE, Hernández-Durán M, Franco-Cendejas R, Licona-Limón P, Ramos-Balderas JL, Martinéz-Vázquez M, Belmont-Díaz JA, Wood TK, García-Contreras R

Abstract
Acinetobacter baumannii is an emergent opportunistic bacterial pathogen responsible for recalcitrant infections owing to its high intrinsic tolerance to most antibiotics; therefore, suitable strategies to treat these infections are needed. One plausible approach is the repurposing of drugs that are already in use. Among them, anticancer drugs may be especially useful due their cytotoxic activities and ample similarities between bacterial infections and growing tumours. In this work, the effectiveness of four anticancer drugs on the growth of A. baumannii ATTC BAA-747 was evaluated, including the antimetabolite 5-fluorouracil and three DNA crosslinkers, namely cisplatin, mitomycin C (MMC) and merphalan. MMC was the most effective drug, having a minimum inhibitory concentration for 50% of growth in Luria-Bertani medium at ca. 7 µg/mL and completely inhibiting growth at 25 µg/mL. Hence, MMC was tested against a panel of 21 clinical isolates, including 18 multidrug-resistant (MDR) isolates, 3 of which were sensitive only to colistin. The minimum inhibitory concentrations and minimum bactericidal concentrations of MMC in all tested strains were found to be similar to those of A. baumannii ATCC BAA-747, and MMC also effectively killed stationary-phase, persister and biofilm cells. Moreover, MMC was able to increase survival of the insect larvae Galleria mellonella against an otherwise lethal A. baumannii infection from 0% to ≥53% for the antibiotic-sensitive A. baumannii ATCC BAA-747 strain and the MDR strains A560 and A578. Therefore, MMC is highly effective at killing the emergent opportunistic pathogen A. baumannii.

PMID: 27939675 [PubMed - as supplied by publisher]

Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma.

Biochem Biophys Res Commun. 2016 Dec 05;:

Authors: Dai D, Chen H, Tang J, Tang Y

Abstract
Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells. Importantly, the in vivo efficacy of ribavirin and its synergism with paclitaxel is confirmed by two independent OTSCC xenograft mouse models. Mechanistically, ribavirin significantly decreases mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E. Overexpression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the nonphosphorylatable form (eIF4E S209A) reverses the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells. In addition, eIF4E depletion significantly enhances the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel. Our work is the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in vitro and in vivo. Our findings also demonstrate the therapeutic value of inhibiting eIF4E in OTSCC treatment.

PMID: 27932243 [PubMed - as supplied by publisher]

Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models.

Oncotarget. 2016 Dec 01;:

Authors: Rico M, Baglioni M, Bondarenko M, Laluce NC, Rozados V, André N, Carré M, Scharovsky OG, Márquez MM

Abstract
Discovery of new drugs for cancer treatment is an expensive and time-consuming process and the percentage of drugs reaching the clinic remains quite low.Drug repositioning refers to the identification and development of new uses for existing drugs and represents an alternative drug development strategy.In this work, we evaluated the antitumor effect of metronomic treatment with a combination of two repositioned drugs, metformin and propranolol, in triple negative breast cancer models.By in vitro studies with five different breast cancer derived cells, we observed that combined treatment decreased proliferation (P < 0.001), mitochondrial activity (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). In vivo studies in immunocompetent mice confirmed the potential of this combination in reducing tumor growth (P < 0.001) and preventing metastasis (P < 0.05).Taken together our results suggest that metformin plus propranolol combined treatment might be beneficial for triple negative breast cancer control, with no symptoms of toxicity.

PMID: 27926515 [PubMed - as supplied by publisher]

Clinical impact of vitamin D treatment in cystic fibrosis: a pilot randomized, controlled trial.

Eur J Clin Nutr. 2016 Dec 14;:

Authors: Pincikova T, Paquin-Proulx D, Sandberg JK, Flodström-Tullberg M, Hjelte L

Abstract
BACKGROUND/OBJECTIVES: Vitamin D insufficiency in cystic fibrosis is common. Vitamin D3 is currently preferred over D2. We aimed to study the efficacy of vitamin D2 and D3 at increasing serum 25-hydroxyvitamin D (s25OHD) concentrations and their effect on respiratory health in cystic fibrosis.
SUBJECTS/METHODS: Sixteen CF patients were randomized to receive vitamin D2 or D3 or to serve as controls. The starting dose of 5000 IU (<16 years old) or 7143 IU/day (⩾16 years old) was further individually adjusted. Three months of intervention were followed by two of washout (ClinicalTrials.gov NCT01321905).
RESULTS: To increase s25OHD, the mean daily dose of vitamin D2 and D3 had to be increased up to 15650 and 8184 IU, respectively. The combined group of vitamin D2 and D3 treated patients decreased plasma IL-8 (P<0.05). Patients provided vitamin D3 improved FVC at the end of the trial (P<0.05). Change in s25OHD was positively correlated with changes in the adult Quality-of-Life respiratory score at the end of supplementation (P=0.006, r=0.90), and with changes in FEV1 (P=0.042, r=0.62) and FVC (P=0.036, r=0.63) at one month of washout.
CONCLUSIONS: Vitamin D supplementation may contribute to reduced inflammation and improved lung function in CF.European Journal of Clinical Nutrition advance online publication, 14 December 2016; doi:10.1038/ejcn.2016.259.

PMID: 27966575 [PubMed - as supplied by publisher]

Beyond bronchitis: a review of the congenital and acquired abnormalities of the bronchus.

Insights Imaging. 2016 Dec 13;

Authors: Marini T, Hobbs SK, Chaturvedi A, Kaproth-Joslin K

Abstract
Anomalies of the bronchus can be both congenital and acquired. Several different congenital aberrations of the bronchial anatomy are commonly encountered including tracheal bronchus, accessory cardiac bronchus, and bronchial agenesis/aplasia/hypoplasia. In addition, Williams-Campbell syndrome and cystic fibrosis are two other congenital conditions that result in bronchial pathology. Acquired pathology affecting the bronchi can typically be divided into three broad categories of bronchial disease: bronchial wall thickening, dilatation/bronchiectasis, and obstruction/stenosis. Bronchial wall thickening is the common final response of the airways to irritants, which cause the bronchi to become swollen and inflamed. Bronchiectasis/bronchial dilatation can develop in response to many aetiologies, including acquired conditions such as infection, pulmonary fibrosis, recurrent or chronic aspiration, as well as because of congenital conditions such as cystic fibrosis. The causes of obstruction and stenosis are varied and include foreign body aspiration, acute aspiration, tracheobronchomalacia, excessive dynamic airway collapse, neoplasm, granulomatous disease, broncholithiasis, and asthma. Knowledge of normal bronchial anatomy and its congenital variants is essential for any practicing radiologist. It is the role of the radiologist to identify common imaging patterns associated with the various categories of bronchial disease and provide the ordering clinician a useful differential diagnosis tailored to the patient's clinical history and imaging findings. Teaching Points • Bronchial disorders are both congenital and acquired in aetiology.• Bronchial disease can be divided by imaging appearance: wall thickening, dilatation, or obstruction.• Bronchial wall thickening is the common final response of the airways to irritants.• Imaging patterns must be recognised and the differential diagnosis tailored for patient management.

PMID: 27966195 [PubMed - as supplied by publisher]

Commentary: Blood Eosinophilia Is Associated with Unfavorable Hospitalization Outcomes in Children with Bronchiolitis.

Front Pediatr. 2016;4:123

Authors: Dosanjh A

PMID: 27965947 [PubMed - in process]

Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells.

Front Cell Infect Microbiol. 2016;6:167

Authors: Öz HH, Zhou B, Voss P, Carevic M, Schroth C, Frey N, Rieber N, Hector A, Hartl D

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, P. aeruginosa is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway in vivo infection model, that P. aeruginosa recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which P. aeruginosa airway infection undermines host immunity by modulating neutrophilic MDSCs in vivo.

PMID: 27965936 [PubMed - in process]

Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease.

Paediatr Respir Rev. 2016 Nov 05;:

Authors: Perry LA, Penny-Dimri JC, Aslam AA, Lee TW, Southern KW

PMID: 27964951 [PubMed - as supplied by publisher]

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