Repurposing Drugs in Oncology: Next Steps.

Trends Cancer. 2017 Aug;3(8):543-546

Authors: Verbaanderd C, Meheus L, Huys I, Pantziarka P

Abstract
The repurposing of existing non-cancer drugs is a potential source of new treatment options for cancer patients with high unmet medical needs. While scientific research is progressing rapidly in the field of drug repurposing, the implementation of drug repurposing still faces important financial and regulatory hurdles that should be addressed to optimise clinical adoption.

PMID: 28780930 [PubMed - in process]

Myotonic dystrophy: candidate small molecule therapeutics.

Drug Discov Today. 2017 Aug 02;:

Authors: Konieczny P, Selma-Soriano E, Rapisarda AS, Fernandez-Costa JM, Perez-Alonso M, Artero R

Abstract
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing and therapeutic gene modulation.

PMID: 28780071 [PubMed - as supplied by publisher]

Measuring Global Disease with Wikipedia: Success, Failure, and a Research Agenda.

Comput Support Coop Work. 2017 Feb-Mar;2017:1812-1834

Authors: Priedhorsky R, Osthus D, Daughton AR, Moran KR, Generous N, Fairchild G, Deshpande A, Del Valle SY

Abstract
Effective disease monitoring provides a foundation for effective public health systems. This has historically been accomplished with patient contact and bureaucratic aggregation, which tends to be slow and expensive. Recent internet-based approaches promise to be real-time and cheap, with few parameters. However, the question of when and how these approaches work remains open. We addressed this question using Wikipedia access logs and category links. Our experiments, replicable and extensible using our open source code and data, test the effect of semantic article filtering, amount of training data, forecast horizon, and model staleness by comparing across 6 diseases and 4 countries using thousands of individual models. We found that our minimal-configuration, language-agnostic article selection process based on semantic relatedness is effective for improving predictions, and that our approach is relatively insensitive to the amount and age of training data. We also found, in contrast to prior work, very little forecasting value, and we argue that this is consistent with theoretical considerations about the nature of forecasting. These mixed results lead us to propose that the currently observational field of internet-based disease surveillance must pivot to include theoretical models of information flow as well as controlled experiments based on simulations of disease.

PMID: 28782059 [PubMed - in process]

Addressing the unmet needs of current antidepressants: does neuroscience help or hinder clinical psychopharmacology research?

Expert Opin Pharmacother. 2017 Aug 07;:

Authors: Goldberg JF, Rush AJ

PMID: 28780896 [PubMed - as supplied by publisher]

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts.

Curr Hypertens Rep. 2017 Sep;19(9):70

Authors: Tiu AC, Bishop MD, Asico LD, Jose PA, Villar VAM

Abstract
The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.

PMID: 28780627 [PubMed - in process]

Validation of a Cystic Fibrosis Medication Knowledge Questionnaire.

Glob Pediatr Health. 2017;4:2333794X17719803

Authors: FitzPatrick B, Hawboldt J, Jane Smith M, Lee T

Abstract
Low adherence to cystic fibrosis (CF) treatment is associated with poor health outcomes, while knowledge of the disease and medication regimen can positively influence adherence. This study's purpose was to develop and validate a questionnaire to help determine CF medication knowledge of pediatric patients and caregivers. Our questionnaire had 37 items: 22 selected-response and 15 open-response questions. We used validation processes from the Standards for Educational and Psychological Testing. CF experts analyzed validity evidence based on content. Then, the questionnaire was field tested with 17 pediatric patients and 18 caregivers. The correlation between age and medication knowledge was medium (r = .33), but was not significant (P = .189). Cronbach's α for the overall test was .84. Participants thought the questionnaire was important and suitable, with a few minor suggestions to improve wording. Strong validity evidence indicates the questionnaire could be used to assess medication knowledge and allow more personalized education to improve adherence.

PMID: 28781991 [PubMed]

Serotypes and antibiotic susceptibility of Streptococcus pneumoniae isolated from hospitalized patients with community-acquired pneumonia in Italy.

SAGE Open Med. 2017;5:2050312117720058

Authors: Di Pasquale M, Aliberti S, Azzari C, Moriondo M, Nieddu F, Blasi F, Mantero M

Abstract
BACKGROUND: Pneumonia remain an important public health problem. The primary objective was to determine the proportion of community-acquired pneumonia that is attributable to Streptococcus pneumoniae infection; secondary objectives were the description of community-acquired pneumonia attributable to Streptococcus pneumoniae according to socio-demographic and clinical variables, the clinical evolution of community-acquired pneumonia and the description of the serotype distribution of vaccine-preventable disease and antibiotic resistance rate of pneumococcal infections.
METHODS: An observational, prospective study was conducted on consecutive patients coming from the community, who were hospitalized with pneumonia. Data on admission, at discharge and 30 days after discharge were collected. Logistic regression models were used to evaluate the risk factors independently associated with pneumococcal pneumonia.
RESULTS: Among the 193 patients enrolled in the study, the etiology of community-acquired pneumonia was identified in 60 patients (33%) and 35 (18%) of evaluable patients had community-acquired pneumonia due to Streptococcus pneumoniae. Of all clinical characteristics, if no previous antibiotic treatment was performed, there was a 13-fold higher risk of presenting community-acquired pneumonia due to Streptococcus pneumoniae (odds ratio, 12.9; 95% confidence interval, 1.42-117.9). Moreover, the most frequent isolated serotypes were 35F, 3 and 24 (29%, 23% and 16%, respectively).
CONCLUSION: The most frequent serotypes in pneumococcal community-acquired pneumonia are 35F, 3, 24, 6 and 7A, and thus almost 50% of Streptococcus pneumoniae strains could be covered by pneumococcal conjugate vaccine 13 in adult patients with risk factors for pneumococcal infections.

PMID: 28781877 [PubMed]

Interpretation of Cystic Fibrosis Centre rankings: Meaningful comparisons or biased statistics?

J Cyst Fibros. 2017 Aug 04;:

Authors: Stanojevic S

PMID: 28781231 [PubMed - as supplied by publisher]

The role of imaging in the diagnosis of bronchiectasis: the key is in the distribution.

Radiologia. 2017 Aug 03;:

Authors: Bueno J, Flors L

Abstract
Diseases that involve the medium caliber airways (segmental and subsegmental bronchi) are common and present clinically with nonspecific respiratory symptoms such as cough, recurrent respiratory infections and occasionally, hemoptysis. The abnormal and irreversible dilation of bronchi is known as "bronchiectasis". The diagnosis can be challenging and the analysis of the regional distribution of the bronchiectasis is the most useful diagnostic guide. The objective of this manuscript is to describe the main imaging findings of bronchiectasis and their classification, review the diseases that most commonly present with this abnormality, and provide an approach to the diagnosis based on their imaging appearance and anatomic distribution. Bronchiectasis is a frequent finding that may result from a broad range of disorders. Imaging plays a paramount role in diagnosis, both in the detection and classification, and in the diagnosis of the underlying pathology.

PMID: 28781148 [PubMed - as supplied by publisher]

The use of pulmonary clearance medications in the acutely ill patient.

Expert Rev Respir Med. 2017 Aug 07;:

Authors: Papacostas MF, Luckett P, Hupp S

Abstract
INTRODUCTION: Retention of airway secretions occurs in disease, leading to airway plugging, atelectasis, and worsened respiratory mechanics, making airway clearance an important therapeutic target. Areas Covered: Many medications designed to enhance clearance of airway secretions are available. We will review the medications available to enhance airway clearance, their mechanisms of action, and the evidence available for their use in acutely ill patients. Expert Commentary: In the cystic fibrosis (CF) population, beneficial effects have been shown in pulmonary function with the use of some of these agents. In the non-CF population, there is limited evidence regarding these medications. While some studies have found benefit, the quality of evidence is low, making it difficult to draw conclusions. While certain patients may derive benefit, the general use of these medications in acutely ill patients without CF cannot be recommended at this time.

PMID: 28780895 [PubMed - as supplied by publisher]

Association between F508 deletion in CFTR and chronic pancreatitis risk.

Dig Liver Dis. 2017 Jul 01;:

Authors: Zhao D, Xu Y, Li J, Fu S, Xiao F, Song X, Xie Z, Jiang M, He Y, Liu C, Wen Q, Yang X

Abstract
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) has been reported to influence individual susceptibility to chronic pancreatitis (CP), but the results of previous studies are controversial.
AIMS: We performed a study to demonstrate the relationship between CFTR and CP.
METHODS: We searched PubMed, Scopus, and Embase for studies of patients with CP. Seven studies from 1995 to 2016 were identified, and included 64,832 patients. Pooled prevalence and 95% confidence intervals (CIs) were calculated.
RESULTS: F508 deletion in CFTR was significantly positively associated with CP risk in the overall analysis (odds ratio [OR]=3.20, 95% CI: 2.30-4.44, I(2)=31.7%). In subgroup analysis stratified by ethnicity, F508 deletion was significantly associated with CP risk in Indian populations, using a fixed effects model (ORs=5.45, 95% CI: 2.52-11.79, I(2)=0.0%), and in non-Indian populations, using a random effects model (ORs=3.59, 95% CI: 1.73-7.48, I(2)=60.9%). At the same time, we found that Indians with F508 deletion had much higher CP prevalence than non-Indians. Interestingly, F508 deletion was also associated with CP and idiopathic CP risk in subgroup analysis stratified by aeitiology, using the fixed effects model.
CONCLUSIONS: Based on current evidence, F508 deletion is a risk factor for CP, and Indians with F508 deletion have much higher CP morbidity.

PMID: 28780053 [PubMed - as supplied by publisher]

Commentary on: "Comprehensive molecular characterization of papillary renal-cell carcinoma." Cancer Genome Atlas Research Network.: N Engl J Med. 2016 Jan 14;374(2):135-45.

Urol Oncol. 2017 Aug 02;:

Authors: Lee BH

Abstract
BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15%-20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation, and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.
METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.
RESULTS: Types 1 and 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into 3 individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase.
CONCLUSIONS: Types 1 and 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CpG island methylator phenotype in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least 3 subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

PMID: 28780132 [PubMed - as supplied by publisher]

Biosynthesis of the antimicrobial cyclic lipopeptides nunamycin and nunapeptin by Pseudomonas fluorescens strain In5 is regulated by the LuxR-type transcriptional regulator NunF.

Microbiologyopen. 2017 Aug 06;:

Authors: Hennessy RC, Phippen CBW, Nielsen KF, Olsson S, Stougaard P

Abstract
Nunamycin and nunapeptin are two antimicrobial cyclic lipopeptides (CLPs) produced by Pseudomonas fluorescens In5 and synthesized by nonribosomal synthetases (NRPS) located on two gene clusters designated the nun-nup regulon. Organization of the regulon is similar to clusters found in other CLP-producing pseudomonads except for the border regions where putative LuxR-type regulators are located. This study focuses on understanding the regulatory role of the LuxR-type-encoding gene nunF in CLP production of P. fluorescens In5. Functional analysis of nunF coupled with liquid chromatography-high-resolution mass spectrometry (LC-HRMS) showed that CLP biosynthesis is regulated by nunF. Quantitative real-time PCR analysis indicated that transcription of the NRPS genes catalyzing CLP production is strongly reduced when nunF is mutated indicating that nunF is part of the nun-nup regulon. Swarming and biofilm formation was reduced in a nunF knockout mutant suggesting that these CLPs may also play a role in these phenomena as observed in other pseudomonads. Fusion of the nunF promoter region to mCherry showed that nunF is strongly upregulated in response to carbon sources indicating the presence of a fungus suggesting that environmental elicitors may also influence nunF expression which upon activation regulates nunamycin and nunapeptin production required for the growth inhibition of phytopathogens.

PMID: 28782279 [PubMed - as supplied by publisher]

Integration of Genome Scale Metabolic Networks and gene regulation of metabolic enzymes with Physiologically Based Pharmacokinetics.

CPT Pharmacometrics Syst Pharmacol. 2017 Aug 07;:

Authors: Maldonado EM, Leoncikas V, Fisher CP, Moore JB, Plant NJ, Kierzek AM

Abstract
The scope of Physiologically Based Pharmacokinetic (PBPK) modelling can be expanded by assimilation of the mechanistic models of intracellular processes from Systems Biology field. Genome Scale Metabolic Networks (GSMNs) represent a whole set of metabolic enzymes expressed in human tissues. Dynamic models of the gene regulation of key drug metabolism enzymes are available. Here, we introduce GSMNs and review ongoing work on integration of PBPK, GSMNs and metabolic gene regulation. We demonstrate example models. This article is protected by copyright. All rights reserved.

PMID: 28782239 [PubMed - as supplied by publisher]

Evolution of complex adaptations in molecular systems.

Nat Ecol Evol. 2017 Aug;1(8):1084-1092

Authors: Pál C, Papp B

Abstract
A central challenge in evolutionary biology concerns the mechanisms by which complex adaptations arise. Such adaptations depend on the fixation of multiple, highly specific mutations, where intermediate stages of evolution seemingly provide little or no benefit. It is generally assumed that the establishment of complex adaptations is very slow in nature, as evolution of such traits demands special population genetic or environmental circumstances. However, blueprints of complex adaptations in molecular systems are pervasive, indicating that they can readily evolve. We discuss the prospects and limitations of non-adaptive scenarios, which assume multiple neutral or deleterious steps in the evolution of complex adaptations. Next, we examine how complex adaptations can evolve by natural selection in changing environment. Finally, we argue that molecular 'springboards', such as phenotypic heterogeneity and promiscuous interactions facilitate this process by providing access to new adaptive paths.

PMID: 28782044 [PubMed]

A modular yeast biosensor for low-cost point-of-care pathogen detection.

Sci Adv. 2017 Jun;3(6):e1603221

Authors: Ostrov N, Jimenez M, Billerbeck S, Brisbois J, Matragrano J, Ager A, Cornish VW

Abstract
The availability of simple, specific, and inexpensive on-site detection methods is of key importance for deployment of pathogen surveillance networks. We developed a nontechnical and highly specific colorimetric assay for detection of pathogen-derived peptides based on Saccharomyces cerevisiae-a genetically tractable model organism and household product. Integrating G protein-coupled receptors with a visible, reagent-free lycopene readout, we demonstrate differential detection of major human, plant, and food fungal pathogens with nanomolar sensitivity. We further optimized a one-step rapid dipstick prototype that can be used in complex samples, including blood, urine, and soil. This modular biosensor can be economically produced at large scale, is not reliant on cold-chain storage, can be detected without additional equipment, and is thus a compelling platform scalable to global surveillance of pathogens.

PMID: 28782007 [PubMed - in process]

Functional proteomic characterization of cancer cell lines.

Oncoscience. 2017 May;4(5-6):41-42

Authors: Zhao W, Li J, Mills GB

PMID: 28781984 [PubMed]

New frontiers in metabolomics: from measurement to insight.

F1000Res. 2017;6:1148

Authors: Riekeberg E, Powers R

Abstract
Metabolomics is the newest addition to the "omics" disciplines and has shown rapid growth in its application to human health research because of fundamental advancements in measurement and analysis techniques. Metabolomics has unique and proven advantages in systems biology and biomarker discovery. The next generation of analysis techniques promises even richer and more complete analysis capabilities that will enable earlier clinical diagnosis, drug refinement, and personalized medicine. A review of current advancements in methodologies and statistical analysis that are enhancing and improving the performance of metabolomics is presented along with highlights of some recent successful applications.

PMID: 28781759 [PubMed]

Heterogeneity of Stop Codon Readthrough in Single Bacterial Cells and Implications for Population Fitness.

Mol Cell. 2017 Aug 01;:

Authors: Fan Y, Evans CR, Barber KW, Banerjee K, Weiss KJ, Margolin W, Igoshin OA, Rinehart J, Ling J

Abstract
Gene expression noise (heterogeneity) leads to phenotypic diversity among isogenic individual cells. Our current understanding of gene expression noise is mostly limited to transcription, as separating translational noise from transcriptional noise has been challenging. It also remains unclear how translational heterogeneity originates. Using a transcription-normalized reporter system, we discovered that stop codon readthrough is heterogeneous among single cells, and individual cells with higher UGA readthrough grow faster from stationary phase. Our work also revealed that individual cells with lower protein synthesis levels exhibited higher UGA readthrough, which was confirmed with ribosome-targeting antibiotics (e.g., chloramphenicol). Further experiments and mathematical modeling suggest that varied competition between ternary complexes and release factors perturbs the UGA readthrough level. Our results indicate that fluctuations in the concentrations of translational components lead to UGA readthrough heterogeneity among single cells, which enhances phenotypic diversity of the genetically identical population and facilitates its adaptation to changing environments.

PMID: 28781237 [PubMed - as supplied by publisher]