Eosinophilic cystitis and haematuria: Case report of a rare disease and common presentation.

Int J Surg Case Rep. 2016 May 6;24:43-45

Authors: Chia D

Abstract
INTRODUCTION: Eosinophilic cystitis is a rare inflammatory condition of the bladder that can cause haematuria. The aetiology is unknown and clinical presentation is difficult to distinguish from other causes of haematuria. Diagnosis is confirmed by biopsy. In this case, a patient with haematuria is diagnosed with eosinohpilic cystitis after presenting to hospital. He was commenced on antibiotics for a presumed urinary tract infection with no resolution of haematuria and symptoms. After diagnosis he was commenced on treatment with resolution of symptoms.
CASE PRESENTATION: A 73-year-old male presents with first episode of haematuria. He was initially diagnosed with a urinary tract infection and commenced on antibiotics with no resolution. After further investigations including a cystoscopy and bladder biopsy, he was diagnosed with eosinophilic cystitis. He was treated with steroids improving his symptoms.
CONCLUSION: Eosinophilic cystitis is a rare disease of the bladder which is difficult to distinguish from other causes of haematuria, and is often misdiagnosed. Bladder biopsy is necessary for diagnosis. Early diagnosis is important, and it is through a combination of non-operative and operative interventions such as biopsy. Natural history is difficult to predict as it is difficult to determine is a patient will have a benign course with resolution with or without treatment, or result in a chronic course which may result in bladder damage and renal failure. This case highlights the importance of investigating haematuria that is unresponsive to initial empiric treatment such as antibiotics. It is important to refer to a Urologist for further investigation to rule out a sinister cause, but to also obtain a diagnosis, leading to definitive treatment.

PMID: 27179336 [PubMed - as supplied by publisher]

Primary extraskeletal Ewing sarcoma of the stomach: a rare disease in an uncommon location.

Clin Imaging. 2016 Apr 5;40(5):843-845

Authors: Maxwell AW, Wood S, Dupuy DE

Abstract
We report the case of a 63-year-old female undergoing evaluation of symptomatic anemia, gastroesophageal reflux disease, and abdominal pain. After a thorough diagnostic workup, a large, ulcerated mass was identified in the patient's stomach, and surgical pathology in combination with molecular analysis yielded a diagnosis of primary extraskeletal Ewing sarcoma. In our report, we discuss the epidemiologic, clinicopathologic, and radiographic features of this rare disease and provide a review of the existing literature.

PMID: 27179157 [PubMed - as supplied by publisher]

Peritoneal lymphomatosis confused with peritoneal carcinomatosis due to the previous history of gastric cancer: a case report.

Clin Imaging. 2016 Mar 29;40(5):837-839

Authors: Choi WY, Kim JH, Choi SJ, Park J, Park YH, Lim JH, Lee MH, Kim CS, Yi HG

Abstract
Peritoneal lymphomatosis is a very rare disease of extranodal involvement of malignant lymphoma that is occasionally confounded with other peritoneal diseases. Herein, we reported the case of a 59-year-old woman who presented with massive ascites with prior history of stomach perforation during endoscopic procedure to treat early gastric cancer. Imaging studies showed massive ascites and tumor infiltration in the omentum and peritoneal wall. Initially, relapsed gastric cancer with peritoneal seeding was suspected based on the patient's history and imaging findings. However, final diagnosis was confirmed by ascites cytology as peritoneal lymphomatosis of diffuse large B-cell lymphoma unlike prior clinical information.

PMID: 27179155 [PubMed - as supplied by publisher]

Rare case of neurinoma of the facial nerve.

Braz J Otorhinolaryngol. 2015 Mar-Apr;81(2):226-7

Authors: Passos IM, Massuda ET, Hyppolito MA, Colli BO, Damico TA

PMID: 25649138 [PubMed - indexed for MEDLINE]

Computational Systems Biology Approach Predicts Regulators and Targets of microRNAs and Their Genomic Hotspots in Apoptosis Process.

Mol Biotechnol. 2016 May 13;

Authors: Alanazi IO, Ebrahimie E

Abstract
Novel computational systems biology tools such as common targets analysis, common regulators analysis, pathway discovery, and transcriptomic-based hotspot discovery provide new opportunities in understanding of apoptosis molecular mechanisms. In this study, after measuring the global contribution of microRNAs in the course of apoptosis by Affymetrix platform, systems biology tools were utilized to obtain a comprehensive view on the role of microRNAs in apoptosis process. Network analysis and pathway discovery highlighted the crosstalk between transcription factors and microRNAs in apoptosis. Within the transcription factors, PRDM1 showed the highest upregulation during the course of apoptosis, with more than 9-fold expression increase compared to non-apoptotic condition. Within the microRNAs, MIR1208 showed the highest expression in non-apoptotic condition and downregulated by more than 6 fold during apoptosis. Common regulators algorithm showed that TNF receptor is the key upstream regulator with a high number of regulatory interactions with the differentially expressed microRNAs. BCL2 and AKT1 were the key downstream targets of differentially expressed microRNAs. Enrichment analysis of the genomic locations of differentially expressed microRNAs led us to the discovery of chromosome bands which were highly enriched (p < 0.01) with the apoptosis-related microRNAs, such as 13q31.3, 19p13.13, and Xq27.3 This study opens a new avenue in understanding regulatory mechanisms and downstream functions in the course of apoptosis as well as distinguishing genomic-enriched hotspots for apoptosis process.

PMID: 27178576 [PubMed - as supplied by publisher]

A heuristic model for working memory deficit in schizophrenia.

Biochim Biophys Acta. 2016 May 10;

Authors: Qi Z, Yu GP, Tretter F, Pogarell O, Grace AA, Voit EO

Abstract
BACKGROUND: The life of schizophrenia patients is severely affected deficits in working memory. In various brain regions, the reciprocal interactions between excitatory glutamatergic neurons and inhibitory GABAergic neurons are crucial. Other neurotransmitters, in particular dopamine, serotonin, acetylcholine, and norepinephrine, modulate the local balance between glutamate and GABA and therefore regulate the function of brain regions. Persistent alterations in the balances between the neurotransmitters can result in working memory deficits.
METHODS: Here we present a heuristic computational model that accounts for interactions among neurotransmitters across various brain regions. The model is based on the concept of a neurochemical interaction matrix at the biochemical level and combines this matrix with a mobile model representing physiological dynamic balances among neurotransmitter systems associated with working memory.
RESULTS: The comparison of clinical and simulation results demonstrates that the model output is qualitatively very consistent with the available data. In addition, the model captured how perturbations migrated through different neurotransmitters and brain regions. Results showed that chronic administration of ketamine can cause a variety of imbalances, and application of an antagonist of the D2 receptor in PFC can also induce imbalances but in a very different manner.
CONCLUSIONS: The heuristic computational model permits a variety of assessments of genetic, biochemical, and pharmacological perturbations and serves as an intuitive tool for explaining clinical and biological observations.
GENERAL SIGNIFICANCE: The heuristic model is more intuitive than biophysically detailed models. It can serve as an important tool for interdisciplinary communication and even for psychiatric education of patients and relatives. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.

PMID: 27177811 [PubMed - as supplied by publisher]

A novel procedure on next generation sequencing data analysis using text mining algorithm.

BMC Bioinformatics. 2016;17(1):213

Authors: Zhao W, Chen JJ, Perkins R, Wang Y, Liu Z, Hong H, Tong W, Zou W

Abstract
BACKGROUND: Next-generation sequencing (NGS) technologies have provided researchers with vast possibilities in various biological and biomedical research areas. Efficient data mining strategies are in high demand for large scale comparative and evolutional studies to be performed on the large amounts of data derived from NGS projects. Topic modeling is an active research field in machine learning and has been mainly used as an analytical tool to structure large textual corpora for data mining.
METHODS: We report a novel procedure to analyse NGS data using topic modeling. It consists of four major procedures: NGS data retrieval, preprocessing, topic modeling, and data mining using Latent Dirichlet Allocation (LDA) topic outputs. The NGS data set of the Salmonella enterica strains were used as a case study to show the workflow of this procedure. The perplexity measurement of the topic numbers and the convergence efficiencies of Gibbs sampling were calculated and discussed for achieving the best result from the proposed procedure.
RESULTS: The output topics by LDA algorithms could be treated as features of Salmonella strains to accurately describe the genetic diversity of fliC gene in various serotypes. The results of a two-way hierarchical clustering and data matrix analysis on LDA-derived matrices successfully classified Salmonella serotypes based on the NGS data. The implementation of topic modeling in NGS data analysis procedure provides a new way to elucidate genetic information from NGS data, and identify the gene-phenotype relationships and biomarkers, especially in the era of biological and medical big data.
CONCLUSION: The implementation of topic modeling in NGS data analysis provides a new way to elucidate genetic information from NGS data, and identify the gene-phenotype relationships and biomarkers, especially in the era of biological and medical big data.

PMID: 27177941 [PubMed - as supplied by publisher]

Naked-eye fingerprinting of single nucleotide polymorphisms on psoriasis patients.

Nanoscale. 2016 May 13;

Authors: Valentini P, Marsella A, Tarantino P, Mauro S, Baglietto S, Congedo M, Paolo Pompa P

Abstract
We report a low-cost test, based on gold nanoparticles, for the colorimetric (naked-eye) fingerprinting of a panel of single nucleotide polymorphisms (SNPs), relevant for the personalized therapy of psoriasis. Such pharmacogenomic tests are not routinely performed on psoriasis patients, due to the high cost of standard technologies. We demonstrated high sensitivity and specificity of our colorimetric test by validating it on a cohort of 30 patients, through a double-blind comparison with two state-of-the-art instrumental techniques, namely reverse dot blotting and sequencing, finding 100% agreement. This test offers high parallelization capabilities and can be easily generalized to other SNPs of clinical relevance, finding broad utility in diagnostics and pharmacogenomics.

PMID: 27174795 [PubMed - as supplied by publisher]

Ciliary neurotrophic factor upregulates follistatin and Pak1, causes overexpression of muscle differentiation related genes and downregulation of established atrophy mediators in skeletal muscle.

Metabolism. 2016 Jun;65(6):915-25

Authors: Tsompanidis A, Vafiadaki E, Blüher S, Kalozoumi G, Sanoudou D, Mantzoros CS

Abstract
INTRODUCTION: The Ciliary Neurotrophic Factor (CNTF) is a pluripotent cytokine with anorexigenic actions in the hypothalamus that improves insulin sensitivity, increases energy expenditure and induces weight loss. Since CNTF also has an established myotrophic role, we sought to examine whether skeletal muscle contributes to the CNTF-induced metabolic improvement and identify the molecular mechanisms mediating these effects.
METHODS: We used a mouse model of diet-induced obesity, to which high or low CNTF doses were administered for 7days. Whole transcriptome expression levels were analyzed in dissected soleus muscles using microarrays and data were then confirmed using qRT-PCR.
RESULTS: We demonstrate that CNTF administration significantly downregulates leptin, while it upregulates follistatin and Pak1; a molecule associated with insulin sensitization in skeletal muscle. A significant overexpression of muscle differentiation related genes and downregulation of established atrophy mediators was observed.
CONCLUSIONS: The overall gene expression changes suggest an indirect, beneficial effect of CNTF on metabolism, energy expenditure and insulin sensitivity, exerted by the pronounced stimulation of muscle growth, with similarities to the described effect of follistatin and the activation of the Akt pathway in skeletal muscle.

PMID: 27173470 [PubMed - in process]

Combinatorial pharmacogenomic guidance for psychiatric medications reduces overall pharmacy costs in a 1 year prospective evaluation.

Curr Med Res Opin. 2015;31(9):1633-43

Authors: Winner JG, Carhart JM, Altar CA, Goldfarb S, Allen JD, Lavezzari G, Parsons KK, Marshak AG, Garavaglia S, Dechairo BM

Abstract
OBJECTIVES: The objective of this project was to determine pharmacy cost savings and improvement in adherence based on a combinatorial pharmacogenomic test (CPGx ) in patients who had switched or added a new psychiatric medication after having failed monotherapy for their psychiatric disorder.
RESEARCH DESIGN AND METHODS: The prospective project compared 1 year pharmacy claims between a GeneSight CPGx guided cohort and a propensity-matched control group. Patients were project eligible if they augmented or switched to a different antidepressant or antipsychotic medication within the previous 90 days. Following the medication switch or augmentation, pharmacogenomic (PGx) testing was offered to each patient's treating clinician. Pharmacy claims were extracted from the Medco pharmacy claims database for each patient (n = 2168) for 1 year following testing and compared to a 5-to-1 propensity-matched treatment as usual (TAU), standard of care control group (n = 10,880).
MAIN OUTCOME MEASURES: Total pharmacy spend per member per year; adherence.
RESULTS: Patients who received PGx testing saved $1035.60 in total medication costs (both CNS and non-CNS medications) over 1 year compared to the non-tested standard of care cohort (p = 0.007). PGx testing improved adherence compared to standard of care (ΔPDCCPGx = 0.11 vs ΔPDCTAU = -0.01; p < 0.0001). Pharmacy cost savings averaged $2774.53 for patients who were changed to a CPGx congruent medication regimen, compared to those who were not (p < 0.0001).
CONCLUSIONS: PGx testing provides significant 'real world' cost savings, while simultaneously improving adherence in a difficult to treat psychiatric population. Limitations of this study include the lack of therapeutic efficacy follow-up data and possible confounding due to matching only on demographic and psychiatric variables.

PMID: 26086890 [PubMed - indexed for MEDLINE]

[Pharmacogenomics of severe drug hypersensitivity reactions--from bench to bedside].

Przegl Lek. 2015;72(12):779-82

Authors: Porębski G, Dyga W, Stobiecki M, Czarnobilska E

Abstract
Recent remarkable findings of pharmacogenomics and basic scientific research provided insights in the pathogenesis of severe drug hypersensitivity reactions such as drug rush with eosinophilia and systemic symptoms (DRESS), abacavir hypersensitivity syndrome or blistering reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis). There is increasing evidence for the strong associations of certain human leukocyte antigen (HLA) alleles with hypersensitivity to particular drugs. HLA genes may serve as genomic biomarkers of predisposition to severe adverse drug reactions and enable to prevent them. In this paper we review essentials and advances in this area.

PMID: 27024960 [PubMed - indexed for MEDLINE]

Systems Medicine approaches to improving understanding, treatment, and clinical management of Neuroendocrine Prostate Cancer.

Curr Pharm Des. 2016 May 13;

Authors: Yadav KK, Khader S, Readhead B, Yadav SS, Li L, Kasarksis A, Tewari AK, Dudley JT

Abstract
BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in men. More than 200,000 new cases are added each year in the US, translating to a lifetime risk of 1 in 7 men. Neuroendocrine prostate cancer (NEPC) is an aggressive and treatment-resistant form of prostate cancer. A subset of patients treated with aggressive androgen deprivation therapy (ADT) present with NEPC. Patients with NEPC have a reduced 5-year overall survival rate of 12.6%. Knowledge integration from genetic, epigenetic, biochemical and therapeutic studies suggests NEPC as an indicative mechanism of resistance development to various forms of therapy.
METHODS: In this perspective, we discuss various experimental, computational and risk prediction methodologies that can be utilized to identify novel therapies against NEPC. We reviewed literature from PubMed using key terms, and computationally analyzed publicly available genomics data to present different possibilities for developing systems medicine based therapeutic and curative models to understand and target prostate cancer and specifically NEPC.
RESULTS: Our study includes gene-set analyses, network analyses, genomics and phenomics aided drug development, microRNA and peptide-based therapeutics, pathway modeling, drug repositioning and cancer immunotherapies. We also discuss the application of cancer risk estimations and mining of electronic medical records to develop personalized risk predictions models for NEPC. Preemptive stratification of patients who are at risk of evolving NEPC phenotypes using predictive models could also help to design and deliver better therapies.
CONCLUSIONS: Collectively, understanding the mechanism of NEPC evolution from prostate cancer using systems biology approaches would help in devising better treatment strategies and is critical and unmet clinical need.

PMID: 27174811 [PubMed - as supplied by publisher]

Editorial overview: Systems biology-the intersection of experiments and computation, underpinning biotechnology.

Curr Opin Biotechnol. 2016 May 9;

Authors: Styczynski MP, Theis FJ

PMID: 27173375 [PubMed - as supplied by publisher]

MicroRNAs in the Evaluation and Potential Treatment of Liver Diseases.

J Clin Med. 2016;5(5)

Authors: Mahgoub A, Steer CJ

Abstract
Acute and chronic liver disease continue to result in significant morbidity and mortality of patients, along with increasing burden on their families, society and the health care system. This in part is due to increased incidence of liver disease associated factors such as metabolic syndrome; improved survival of patients with chronic predisposing conditions such as HIV; as well as advances in the field of transplantation and associated care leading to improved survival. The fact that one disease can result in different manifestations and outcomes highlights the need for improved understanding of not just genetic phenomenon predisposing to a condition, but additionally the role of epigenetic and environmental factors leading to the phenotype of the disease. It is not surprising that providers continue to face daily challenges pertaining to diagnostic accuracy, prognostication of disease severity, progression, and response to therapies. A number of these challenges can be addressed by incorporating a personalized approach of management to the current paradigm of care. Recent advances in the fields of molecular biology and genetics have paved the way to more accurate, individualized and precise approach to caring for liver disease. The study of microRNAs and their role in both healthy and diseased livers is one example of such advances. As these small, non-coding RNAs work on fine-tuning of cellular activities and organ function in a dynamic and precise fashion, they provide us a golden opportunity to advance the field of hepatology. The study of microRNAs in liver disease promises tremendous improvement in hepatology and is likely to lay the foundation towards a personalized approach in liver disease.

PMID: 27171116 [PubMed]

Brain Radiation Information Data Exchange (BRIDE): integration of experimental data from low-dose ionising radiation research for pathway discovery.

BMC Bioinformatics. 2016;17(1):212

Authors: Karapiperis C, Kempf SJ, Quintens R, Azimzadeh O, Vidal VL, Pazzaglia S, Bazyka D, Mastroberardino PG, Scouras ZG, Tapio S, Benotmane MA, Ouzounis CA

Abstract
BACKGROUND: The underlying molecular processes representing stress responses to low-dose ionising radiation (LDIR) in mammals are just beginning to be understood. In particular, LDIR effects on the brain and their possible association with neurodegenerative disease are currently being explored using omics technologies.
RESULTS: We describe a light-weight approach for the storage, analysis and distribution of relevant LDIR omics datasets. The data integration platform, called BRIDE, contains information from the literature as well as experimental information from transcriptomics and proteomics studies. It deploys a hybrid, distributed solution using both local storage and cloud technology.
CONCLUSIONS: BRIDE can act as a knowledge broker for LDIR researchers, to facilitate molecular research on the systems biology of LDIR response in mammals. Its flexible design can capture a range of experimental information for genomics, epigenomics, transcriptomics, and proteomics. The data collection is available at: <bride.azurewebsites.net>.

PMID: 27170263 [PubMed - in process]

Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network.

Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):110-5

Authors: Potoyan DA, Zheng W, Komives EA, Wolynes PG

Abstract
Genetic switches based on the [Formula: see text] system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that [Formula: see text] can actively remove NF-κB bound to its genetic sites via a process called "molecular stripping." This allows the [Formula: see text] switch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse-grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factor [Formula: see text] and its various binary and ternary complexes with DNA and the inhibitor IκB. These studies show that the function of the [Formula: see text] genetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding of [Formula: see text] that occurs through conformational selection. Free energy calculations for DNA binding show that the binding of [Formula: see text] not only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.

PMID: 26699500 [PubMed - indexed for MEDLINE]

Generating Systems Biology Markup Language Models from the Synthetic Biology Open Language.

ACS Synth Biol. 2015 Aug 21;4(8):873-9

Authors: Roehner N, Zhang Z, Nguyen T, Myers CJ

Abstract
In the context of synthetic biology, model generation is the automated process of constructing biochemical models based on genetic designs. This paper discusses the use cases for model generation in genetic design automation (GDA) software tools and introduces the foundational concepts of standards and model annotation that make this process useful. Finally, this paper presents an implementation of model generation in the GDA software tool iBioSim and provides an example of generating a Systems Biology Markup Language (SBML) model from a design of a 4-input AND sensor written in the Synthetic Biology Open Language (SBOL).

PMID: 25822671 [PubMed - indexed for MEDLINE]

Quo vadis? The challenges of recombinant protein folding and secretion in Pichia pastoris.

Appl Microbiol Biotechnol. 2015 Apr;99(7):2925-38

Authors: Puxbaum V, Mattanovich D, Gasser B

Abstract
The development of Pichia pastoris as a production platform for recombinant proteins has been a remarkable success story over the last three decades. Stable cheap production processes and the good protein secretion abilities were pacemakers of this development. However, limitations of protein folding, glycosylation or secretion have been identified quite early on. With the availability of genome sequences and the development of systems biology characterization in the last 5 years, remarkable success in strain improvement was achieved. Here, we focus on recent developments of characterization and improvement of P. pastoris production strains regarding protein folding, intracellular trafficking, glycosylation and proteolytic degradation.

PMID: 25722021 [PubMed - indexed for MEDLINE]

The proteomic response of cheliped myofibril tissue in the eurythermal porcelain crab Petrolisthes cinctipes to heat shock following acclimation to daily temperature fluctuations.

J Exp Biol. 2015 Feb 1;218(Pt 3):388-403

Authors: Garland MA, Stillman JH, Tomanek L

Abstract
The porcelain crab Petrolisthes cinctipes lives under rocks and in mussel beds in the mid-intertidal zone where it experiences immersion during high tide and saturating humid conditions in air during low tide, which can increase habitat temperature by up to 20°C. To identify the biochemical changes affected by increasing temperature fluctuations and subsequent heat shock, we acclimated P. cinctipes for 30 days to one of three temperature regimes: (1) constant 10°C, (2) daily temperature fluctuations between 10 and 20°C (5 h up-ramp to 20°C, 1 h down-ramp to 10°C) and (3) 10-30°C (up-ramp to 30°C). After acclimation, animals were exposed to either 10°C or a 30°C heat shock to analyze the proteomic changes in claw muscle tissue. Following acclimation to 10-30°C (measured at 10°C), enolase and ATP synthase increased in abundance. Following heat shock, isoforms of arginine kinase and glycolytic enzymes such as aldolase, triose phosphate isomerase and glyceraldehyde 3-phosphate dehydrogenase increased across all acclimation regimes. Full-length isoforms of hemocyanin increased abundance following acclimation to 10-30°C, but hemocyanin fragments increased after heat shock following constant 10°C and fluctuating 10-20°C, possibly playing a role as antimicrobial peptides. Following constant 10°C and fluctuating 10-20°C, paramyosin and myosin heavy chain type-B increased in abundance, respectively, whereas myosin light and heavy chain decreased with heat shock. Actin-binding proteins, which stabilize actin filaments (filamin and tropomyosin), increased during heat shock following 10-30°C; however, actin severing and depolymerization proteins (gelsolin and cofilin) increased during heat shock following 10-20°C, possibly promoting muscle fiber restructuring. RAF kinase inhibitor protein and prostaglandin reductase increased during heat shock following constant 10°C and fluctuating 10-20°C, possibly inhibiting an immune response during heat shock. The results suggest that ATP supply, muscle fiber restructuring and immune responses are all affected by temperature fluctuations and subsequent acute heat shock in muscle tissue. Furthermore, although heat shock after acclimation to constant 10°C and fluctuating 10-30°C showed the greatest effects on the proteome, moderately fluctuating temperatures (10-20°C) broadened the temperature range over which claw muscle was able to respond to an acute heat shock with limited changes in the muscle proteome.

PMID: 25653421 [PubMed - indexed for MEDLINE]

Systems Medicine approaches to improving understanding, treatment, and clinical management of Neuroendocrine Prostate Cancer.

Curr Pharm Des. 2016 May 13;

Authors: Yadav KK, Khader S, Readhead B, Yadav SS, Li L, Kasarksis A, Tewari AK, Dudley JT

Abstract
BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in men. More than 200,000 new cases are added each year in the US, translating to a lifetime risk of 1 in 7 men. Neuroendocrine prostate cancer (NEPC) is an aggressive and treatment-resistant form of prostate cancer. A subset of patients treated with aggressive androgen deprivation therapy (ADT) present with NEPC. Patients with NEPC have a reduced 5-year overall survival rate of 12.6%. Knowledge integration from genetic, epigenetic, biochemical and therapeutic studies suggests NEPC as an indicative mechanism of resistance development to various forms of therapy.
METHODS: In this perspective, we discuss various experimental, computational and risk prediction methodologies that can be utilized to identify novel therapies against NEPC. We reviewed literature from PubMed using key terms, and computationally analyzed publicly available genomics data to present different possibilities for developing systems medicine based therapeutic and curative models to understand and target prostate cancer and specifically NEPC.
RESULTS: Our study includes gene-set analyses, network analyses, genomics and phenomics aided drug development, microRNA and peptide-based therapeutics, pathway modeling, drug repositioning and cancer immunotherapies. We also discuss the application of cancer risk estimations and mining of electronic medical records to develop personalized risk predictions models for NEPC. Preemptive stratification of patients who are at risk of evolving NEPC phenotypes using predictive models could also help to design and deliver better therapies.
CONCLUSIONS: Collectively, understanding the mechanism of NEPC evolution from prostate cancer using systems biology approaches would help in devising better treatment strategies and is critical and unmet clinical need.

PMID: 27174811 [PubMed - as supplied by publisher]