Pharmacogenetics of dipeptidyl peptidase 4 inhibitors in a Taiwanese population with type 2 diabetes.

Oncotarget. 2017 Feb 01;:

Authors: Liao WL, Lee WJ, Chen CC, Lu CH, Chen CH, Chou YC, Lee IT, Sheu WH, Wu JY, Yang CF, Wang CH, Tsai FJ

Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral anti-hyperglycemic drugs enabling effective glycemic control in type 2 diabetes (T2D). Despite DPP-4 inhibitors' advantages, the patients' therapeutic response varies. In this retrospective cohort study, 171 Taiwanese patients with T2D were classified as sensitive or resistant to treatment based on the mean change in HbA1c levels. Using an assumption-free genome-wide association study, 45 single nucleotide polymorphisms (SNPs) involved in the therapeutic response to DPP-4 inhibitors (P < 1 × 10-4) were identified at or near PRKD1, CNTN3, ASK, and LOC10537792. A SNP located within the fourth intron of PRKD1 (rs57803087) was strongly associated with DPP-4 inhibitor response (P = 3.2 × 10-6). This is the first pharmacogenomics study on DPP-4 inhibitor treatment for diabetes in a Taiwanese population. Our data suggest that genes associated with β-cell function and apoptosis are involved in the therapeutic effect of DPP-4 inhibitors, even in the presence of additional oral anti-diabetic drugs. Our findings provide information on how genetic variants influence drug response and may benefit the development of personalized medicine.

PMID: 28160554 [PubMed - as supplied by publisher]

En route to precision medicine through the integration of biological sex into pharmacogenomics.

Clin Sci (Lond). 2017 Feb 01;131(4):329-342

Authors: Gaignebet L, Kararigas G

Abstract
Frequently, pharmacomechanisms are not fully elucidated. Therefore, drug use is linked to an elevated interindividual diversity of effects, whether therapeutic or adverse, and the role of biological sex has as yet unrecognized and underestimated consequences. A pharmacogenomic approach could contribute towards the development of an adapted therapy for each male and female patient, considering also other fundamental features, such as age and ethnicity. This would represent a crucial step towards precision medicine and could be translated into clinical routine. In the present review, we consider recent results from pharmacogenomics and the role of sex in studies that are relevant to cardiovascular therapy. We focus on genome-wide analyses, because they have obvious advantages compared with targeted single-candidate gene studies. For instance, genome-wide approaches do not necessarily depend on prior knowledge of precise molecular mechanisms of drug action. Such studies can lead to findings that can be classified into three categories: first, effects occurring in the pharmacokinetic properties of the drug, e.g. through metabolic and transporter differences; second, a pharmacodynamic or drug target-related effect; and last diverse adverse effects. We conclude that the interaction of sex with genetic determinants of drug response has barely been tested in large, unbiased, pharmacogenomic studies. We put forward the theory that, to contribute towards the realization of precision medicine, it will be necessary to incorporate sex into pharmacogenomics.

PMID: 28159880 [PubMed - in process]

Pharmacogenetics of antidepressant response: A polygenic approach.

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jan 31;:

Authors: García-González J, Tansey KE, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Žagar T, Czerski PM, Jerman B, Buttenschøn HN, Schulze TG, Zobel A, Farmer A, Aitchison KJ, Craig I, McGuffin P, Giupponi M, Perroud N, Bondolfi G, Evans D, O'Donovan M, Peters TJ, Wendland JR, Lewis G, Kapur S, Perlis R, Arolt V, Domschke K, Major Depressive Disorder Working Group of the Psychiatric Genomic Consortium, Breen G, Curtis C, Sang-Hyuk L, Kan C, Newhouse S, Patel H, Baune BT, Uher R, Lewis CM, Fabbri C

Abstract
BACKGROUND: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.
METHODS: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).
RESULTS: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.
DISCUSSION: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.

PMID: 28159590 [PubMed - as supplied by publisher]

Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis.

Mol Genet Metab Rep. 2017 Mar;10:84-91

Authors: Tise CG, Anforth LE, Zhou AE, Perry JA, McArdle PF, Streeten EA, Shuldiner AR, Yerges-Armstrong LM

Abstract
CONTEXT: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10(- 20)).
OBJECTIVE: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.
DESIGN: Retrospective cohort study.
SETTING: Academic research.
PATIENTS: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.
MAIN OUTCOME MEASURES: DHEA, DHEA-S, and DHEA-S/DHEA ratio.
RESULTS: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10(- 13) ), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03).
CONCLUSIONS: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

PMID: 28154797 [PubMed - in process]

Measuring adherence to a Choosing Wisely recommendation in a regional oncology clinic.

J Clin Oncol. 2016 Mar;34(7_suppl):196

Authors: Lyman GH, Kreizenbeck KL, Fedorenko CR, Alfiler A, Noble H, Kusnir-Wong T, Mohedano A, Stewart FM, Greer BE, Ramsey SD

Abstract
196 Background: Natural language processing (NLP) has the potential to significantly ease the burden of manual abstraction of unstructured electronic text when measuring adherence to national guidelines. We incorporated NLP into standard data processing techniques such as manual abstraction and database queries in order to more efficiently evaluate a regional oncology clinic's adherence to ASCO's Choosing Wisely colony stimulating factor (CSF) recommendation using clinical, billing, and cancer registry data.
METHODS: Database queries on the clinic's cancer registry yielded the study population of patients with stage II-IV breast, non-small cell lung (NSCL), and colorectal cancer. We manually abstracted chemotherapy regimens from paper prescription records. CSF orders were collected through queries on the clinic's facility billing data, when available; otherwise through a custom NLP program and manual abstraction of the electronic medical record. The NLP program was designed to identify clinical note text containing CSF information, which was then manually abstracted.
RESULTS: Out of 31,725 clinical notes for the eligible population, the NLP program identified 1,487 clinical notes with CSF-related language, effectively reducing the number of notes requiring abstraction by up to 95%. Between 1/1/2012-12/31/2014, adherence to the ASCO CW CSF recommendation at the regional oncology clinic was 89% for a population of 322 patients.
CONCLUSIONS: NLP significantly reduced the burden of manual abstraction by singling out relevant clinical text for abstractors. Abstraction is often necessary due to the complexity of data collection tasks or the use of paper records. However, NLP is a valuable addition to the suite of data processing techniques traditionally used to measure adherence to national guidelines.

PMID: 28152842 [PubMed - in process]

Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-only Crohn's Disease in Treatment-naïve Pediatric Patients.

Gastroenterology. 2017 Jan 26;:

Authors: Rosen MJ, Karns R, Vallance JE, Bezold R, Waddell A, Collins MH, Haberman Y, Minar P, Baldassano RN, Hyams JS, Baker SS, Kellermayer R, Noe JD, Griffiths AM, Rosh JR, Crandall WV, Heyman MB, Mack DR, Kappelman MD, Markowitz J, Moulton DE, Leleiko NS, Walters TD, Kugathasan S, Wilson KT, Hogan SP, Denson LA

Abstract
BACKGROUND & AIMS: There is controversy over the role of the type 2 immune response in pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naïve patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are upregulated in treatment-naïve pediatric patients with UC, compared to patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels associate with clinical outcomes.
METHODS: We used a real-time reverse transcription quantitative PCR array to analyze mRNA expression patterns in rectal mucosal samples from 138 treatment-naïve pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 and 2012. Results were validated in real-time reverse transcription quantitative PCR analyses of rectal RNA from and independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center.
RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin 5 gene [IL5], IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared to patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P=.001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (OR, 6.469; 95% CI, 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12).
CONCLUSION: In an analysis of rectal tissues from treatment-naïve pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.

PMID: 28132889 [PubMed - as supplied by publisher]

Drug repurposing and therapeutic anti-microRNA predictions for inhibition of oxidized low-density lipoprotein-induced vascular smooth muscle cell-associated diseases.

J Bioinform Comput Biol. 2016 Dec 22;:1650043

Authors: Chen ST, Huang CH, Kok VC, Huang CF, Ciou JS, Tsai JJ, Kurubanjerdjit N, Ng KL

Abstract
Drug repurposing is a new method for disease treatments, which accelerates the identification of new uses for existing drugs with minimal side effects for patients. MicroRNA-based therapeutics are a class of drugs that have been used in gene therapy following the FDA's approval of the first anti-sense therapy. This study examines the effects of oxLDL on vascular smooth muscle cells (VSMCs) and identifies potential drugs and antimiRs for treating VSMC-associated diseases. The Connectivity Map (cMap) database is utilized to identify potential new uses of existing drugs. The success of the identifications was supported by MTT assay, clonogenic assay and clinical trial data. Specifically, 37 drugs, some of which are undergoing clinical trials, were identified. Three of the identified drugs exhibit IC50 activities. Among the 37 drugs' targets, three differentially expressed genes (DEGs) are identified as drug targets by using both the DrugBank and the NCBI PubChem Compound databases. Also, one DEG, DNMT1, which is regulated by 17 miRNAs, where these miRNAs are potential targets for developing antimiR-based miRNA therapy, is found.

PMID: 28150521 [PubMed - as supplied by publisher]

A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities.

Cell Physiol Biochem. 2016;39(3):871-88

Authors: Deng Y, Wang Z, Zhang F, Qiao M, Yan Z, Wei Q, Wang J, Liu H, Fan J, Zou Y, Liao J, Hu X, Chen L, Yu X, Haydon RC, Luu HH, Qi H, He TC, Zhang J

Abstract
BACKGROUND/AIMS: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells.
METHODS: Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity.
RESULTS: We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo.
CONCLUSION: Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer.

PMID: 27497986 [PubMed - indexed for MEDLINE]

Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats.

Cell Physiol Biochem. 2016;39(3):901-7

Authors: Wang G, Fang H, Zhen Y, Xu G, Tian J, Zhang Y, Zhang D, Zhang G, Xu J, Zhang Z, Qiu M, Ma Y, Zhang H, Zhang X

Abstract
BACKGROUND/AIMS: To explore the effects of sulforaphane (SFN) on neuronal apoptosis in hippocampus and memory impairment in diabetic rats.
METHODS: Thirty male rats were randomly divided into normal control, diabetic model and SFN treatment groups (N = 10 in each group). Streptozotocin (STZ) was applied to establish diabetic model. Water Morris maze task was applied to test learning and memory. Tunel assaying was used to detect apoptosis in hippocampus. The expressions of Caspase-3 and myeloid cell leukemia 1(MCL-1) were detected by western blotting. Neurotrophic factor levels and AKT/GSK3β pathway were also detected.
RESULTS: Compared with normal control, learning and memory were apparently impaired, with up-regulation of Caspase-3 and down-regulation of MCL-1 in diabetic rats. Apoptotic neurons were also found in CA1 region after diabetic modeling. By contrast, SFN treatment prevented the memory impairment, decreased the apoptosis of hippocampal neurons. SFN also attenuated the abnormal expression of Caspase-3 and MCL-1 in diabetic model. Mechanically, SFN treatment reversed diabetic modeling-induced decrease of p-Akt, p-GSK3β, NGF and BDNF expressions.
CONCLUSION: SFN could prevent the memory impairment and apoptosis of hippocampal neurons in diabetic rat. The possible mechanism was related to the regulation of neurotropic factors and Akt/GSK3β pathway.

PMID: 27497670 [PubMed - indexed for MEDLINE]

Exploring the usability of EUCERD core indicators for rare diseases.

Ann Ist Super Sanita. 2015;51(4):342-5

Authors: Ferrelli RM, De Santis M, Gentile AE, Taruscio D

Abstract
In the context of the Community Programme in the field of Health, the European Commission financed a series of initiatives to support the development and use of indicators for planning health services for Rare Diseases (RDs). The European Project for Rare Disease National Plans Development (EUROPLAN) elaborated a set of 59 process and outcome indicators, for monitoring the implementation and for evaluating the impact of the National Plans on RDs. Due to the high number and difficulty in handling the indicators, the subsequent Joint Action "Working for RDs" planned to derive a selection of 21 core indicators that were adopted by the European Union Committee of Experts on RDs in June 2013. The descriptive study carried out in the framework of the Joint Action to select the key indicators to orient policies for RDs shows that core indicators represent an excellent opportunity to share knowledge and comparability among Member States.

PMID: 26783222 [PubMed - indexed for MEDLINE]

Mobile Technology in the Perioperative Arena: Rapid Evolution and Future Disruption.

Anesth Analg. 2017 Feb 01;:

Authors: Rothman BS, Gupta RK, McEvoy MD

Abstract
Throughout the history of medicine, physicians have relied upon disruptive innovations and technologies to improve the quality of care delivered, patient outcomes, and patient satisfaction. The implementation of mobile technology in health care is quickly becoming the next disruptive technology. We first review the history of mobile technology over the past 3 decades, discuss the impact of hardware and software, explore the rapid expansion of applications (apps), and evaluate the adoption of mobile technology in health care. Next, we discuss how technology serves as the vehicle that can transform traditional didactic learning into one that adapts to the learning behavior of the student by using concepts such as the flipped classroom, just-in-time learning, social media, and Web 2.0/3.0. The focus in this modern education paradigm is shifting from teacher-centric to learner-centric, including providers and patients, and is being delivered as context-sensitive, or semantic, learning. Finally, we present the methods by which connected health systems via mobile devices increase information collection and analysis from patients in both clinical care and research environments. This enhanced patient and provider connection has demonstrated benefits including reducing unnecessary hospital readmissions, improved perioperative health maintenance coordination, and improved care in remote and underserved areas. A significant portion of the future of health care, and specifically perioperative medicine, revolves around mobile technology, nimble learners, patient-specific information and decision-making, and continuous connectivity between patients and health care systems. As such, an understanding of developing or evaluating mobile technology likely will be important for anesthesiologists, particularly with an ever-expanding scope of practice in perioperative medicine.

PMID: 28151816 [PubMed - as supplied by publisher]

Genes2GO: A web application for querying gene sets for specific GO terms.

Bioinformation. 2016;12(3):231-232

Authors: Chawla K, Kuiper M

Abstract
Gene ontology annotations have become an essential resource for biological interpretations of experimental findings. The process of gathering basic annotation information in tables that link gene sets with specific gene ontology terms can be cumbersome, in particular if it requires above average computer skills or bioinformatics expertise. We have therefore developed Genes2GO, an intuitive R-based web application. Genes2GO uses the biomaRt package of Bioconductor in order to retrieve custom sets of gene ontology annotations for any list of genes from organisms covered by the Ensembl database. Genes2GO produces a binary matrix file, indicating for each gene the presence or absence of specific annotations for a gene. It should be noted that other GO tools do not offer this user-friendly access to annotations.
AVAILABILITY: Genes2GO is freely available and listed under http://www.semantic-systems-biology.org/tools/externaltools/.

PMID: 28149059 [PubMed]

SAFE: SPARQL Federation over RDF Data Cubes with Access Control.

J Biomed Semantics. 2017 Feb 01;8(1):5

Authors: Khan Y, Saleem M, Mehdi M, Hogan A, Mehmood Q, Rebholz-Schuhmann D, Sahay R

Abstract
BACKGROUND: Several query federation engines have been proposed for accessing public Linked Open Data sources. However, in many domains, resources are sensitive and access to these resources is tightly controlled by stakeholders; consequently, privacy is a major concern when federating queries over such datasets. In the Healthcare and Life Sciences (HCLS) domain real-world datasets contain sensitive statistical information: strict ownership is granted to individuals working in hospitals, research labs, clinical trial organisers, etc. Therefore, the legal and ethical concerns on (i) preserving the anonymity of patients (or clinical subjects); and (ii) respecting data ownership through access control; are key challenges faced by the data analytics community working within the HCLS domain. Likewise statistical data play a key role in the domain, where the RDF Data Cube Vocabulary has been proposed as a standard format to enable the exchange of such data. However, to the best of our knowledge, no existing approach has looked to optimise federated queries over such statistical data.
RESULTS: We present SAFE: a query federation engine that enables policy-aware access to sensitive statistical datasets represented as RDF data cubes. SAFE is designed specifically to query statistical RDF data cubes in a distributed setting, where access control is coupled with source selection, user profiles and their access rights. SAFE proposes a join-aware source selection method that avoids wasteful requests to irrelevant and unauthorised data sources. In order to preserve anonymity and enforce stricter access control, SAFE's indexing system does not hold any data instances-it stores only predicates and endpoints. The resulting data summary has a significantly lower index generation time and size compared to existing engines, which allows for faster updates when sources change.
CONCLUSIONS: We validate the performance of the system with experiments over real-world datasets provided by three clinical organisations as well as legacy linked datasets. We show that SAFE enables granular graph-level access control over distributed clinical RDF data cubes and efficiently reduces the source selection and overall query execution time when compared with general-purpose SPARQL query federation engines in the targeted setting.

PMID: 28148277 [PubMed - in process]

Cancer patients' and physicians' preferences for decision making regarding pharmacogenomic testing (PGT).

J Clin Oncol. 2012 Dec;30(34_suppl):13

Authors: Hon H, Qiu X, Masroor S, De Souza B, McFarlane G, Wong CA, Tobros K, Azad AK, Hasani E, Rozanec N, Leighl NB, Atehortua NA, Alibhai SM, Xu W, Issa AM, Liu G

Abstract
13 Background: Pharmacogenomics is increasingly utilized in oncology; however, there is little knowledge concerning cancer patients' or oncologists' attitudes toward PGT decision-making in clinical practice.
METHODS: A broad cross-section of cancer patients were interviewed regarding their attitudes toward PGT using hypothetical time, efficacy and toxicity trade-off and willingness-to-pay scenarios (N=278) and/or quantitative choice-based conjoint analysis surveys (N=264); 64 cancer specialists/physicians in training were surveyed similarly.
RESULTS: Of patients participating in the trade-off scenario phase of study, >94% accepted chemotherapy, and of these, >98% wanted PGT that identifies a subset of patients either benefiting from chemotheraphy or who were at risk of severe toxicity. Patients were willing to pay between CAD $1,000-$1,900 for PGT and accept wait times for results of 2-3 weeks. Similar findings were observed in the conjoint phase of the study, with preferences for PGT starting to decline when the out-of-pocket costs reached CAD $500-$1,500, wait time for results exceeded 14 days, and when the prevalence of the genetic variant fell below 25%. Adjuvant patients' acceptance of PGT was most influenced by cost (decision weight [DW]=41%) and prevalence of the genetic variant associated with lack of benefit from chemo (DW=26%). Metastatic patients were most influenced by cost (DW=49%) and wait times (DW=31%). More patients reported difficulty understanding conjoint surveys (14%) than trade-off scenarios (7%; p=0.01). 81% of patients wanted to be involved in decision-making regarding PGT; while 30% of physicians felt it should be a physician-only decision (p=0.006). However, 21% of patients and 5% of physicians admitted to not understanding PGT, while just 14% of physicians rated themselves as very knowledgeable regarding PGT.
CONCLUSIONS: Cancer patients overwhelmingly accept and want to be involved in decision-making regarding PGT, to a greater extent than what physicians prefer. However, communication of PGT information was a potential barrier, as a considerable minority lacked the necessary knowledge to facilitate informed decision-making. Improved patient and physician education is necessary.

PMID: 28146908 [PubMed - in process]

New tissue aquisition tools for molecular biology.

J Clin Oncol. 2012 Oct 20;30(30_suppl):102

Authors:

Abstract
102 Background: Histological and biomolecular examinations are a prerequisite to understand diseases, determine optimal individualized care, and identify targets for potential novel therapies. Despite this key role of tissue-based research the act of biopsy still remains troublesome. New direct and frontal biopsy technologies are emerging with the aim to alleviate the bottleneck of inappropriate minimal invasive interventions. Recent clinical trials evaluated the use of macrobiopsies in providing the necessary tissues for molecular biology.
METHODS: The new instruments for minimal-invasive procedures were evaluated in different single and multicenter clinical trials to generate data on providing enough high-quality tissue for biomolecular research in comparison to diagnostic surgery for various soft tissues and bone lesions throughout the body. In addition, patient comfort and costs data were taken up in the survey.
RESULTS: Direct and frontal type macrobiopsy systems give tissue samples between 150 mg and 300 mg of highly specified parts of the diseased area in a way very similar to open surgery. In addition, biopsy procedures are increasingly more patient friendly with appropriate comfort and safety. The new macrobiopsies are less expensive, making molecular biology at reach for every oncological patient, company, and health care provider.
CONCLUSIONS: Direct and frontal macrobiopsies open new avenues for future bio-banking, pharmacogenomics, biomolecular research, and personalized medicine. It is anticipated that drug discovery and clinical implementation of targeted therapies will be highly facilitated, and that clinical research time for multicenter trials will be significantly shortened.

PMID: 28142432 [PubMed - in process]

The effect of the affordable care act dependent coverage provision on patients with cystic fibrosis.

Pediatr Pulmonol. 2017 Feb 02;:

Authors: Tumin D, Li SS, Kopp BT, Kirkby SE, Tobias JD, Morgan WJ, Hayes D

Abstract
BACKGROUND: The Patient Protection and Affordable Care Act (ACA), enacted in 2010, expanded private insurance coverage of young adults through the dependent coverage provision. This policy's implications for patients with cystic fibrosis (CF) are unknown.
METHODS: The CF Foundation Patient Registry was used to identify patients seen at CF centers, 3 years before and after ACA implementation. Patients were grouped according to eligibility for the dependent care provision (18-25 years old in 2010) or ineligibility (26-35 years old). Year-level difference-in-difference logistic regressions evaluated the association between ACA enactment and insurance status (private, public, or no insurance). Routine annual care consistent with CF Foundation guidelines (≥4 clinic visits, ≥4 respiratory cultures, and ≥2 pulmonary function tests/year) was a secondary outcome.
RESULTS: The analysis included 4,024 and 3,132 patients in the eligible and ineligible groups, respectively (35,353 patient-years). In the eligible group, 62% had private insurance before and after ACA; 18% had public insurance before and after ACA; and 5% switched from public to private insurance. In the eligible group, lack of insurance coverage became more common in the post-ACA period (relative risk ratio vs. private insurance [RRR] = 1.95; 95%CI: 1.57, 2.43; P < 0.001). Public insurance coverage also became more common (RRR = 1.50; 95%CI: 1.39, 1.62; P < 0.001). Use of routine care increased post-ACA, but more strongly in the ineligible group than in the eligible group.
CONCLUSIONS: The ACA dependent coverage provision did not increase private insurance coverage or use of routine care among CF patients who were potentially affected by this policy. Pediatr Pulmonol. 2016; 9999:XX-XX. © 2016 Wiley Periodicals, Inc.

PMID: 28152283 [PubMed - as supplied by publisher]

Make Precision Medicine Work for Chronic Kidney Disease.

Med Princ Pract. 2016 Dec 14;:

Authors: Sun L, Zou LX, Chen MJ

Abstract
Precision medicine is based on accurate diagnosis and tailored intervention through the use of omics and clinical data together with epidemiology and environmental exposures. Precision medicine should be achieved with minimum adverse events and maximum efficacy in patients with chronic kidney disease (CKD). In this review, the breakthroughs of omics in CKD and the application of systems biology are reviewed. The potential role of transforming growth factor-β1 in the targeted intervention of renal fibrosis is discussed as an example of how to make precision medicine work for CKD.

PMID: 28152529 [PubMed - as supplied by publisher]

Bioinformatics Analysis of Functional Associations of PTMs.

Methods Mol Biol. 2017;1558:303-320

Authors: Minguez P, Bork P

Abstract
Post-translational modifications (PTMs) are an important source of protein regulation; they fine-tune the function, localization, and interaction with other molecules of the majority of proteins and are partially responsible for their multifunctionality. Usually, proteins have several potential modification sites, and their patterns of occupancy are associated with certain functional states. These patterns imply cross talk among PTMs within and between proteins, the majority of which are still to be discovered. Several methods detect associations between PTMs; these have recently combined into a global resource, the PTMcode database, which contains already known and predicted functional associations between pairs of PTMs from more than 45,000 proteins in 19 eukaryotic species.

PMID: 28150244 [PubMed - in process]

Prediction of Protein Interactions by Structural Matching: Prediction of PPI Networks and the Effects of Mutations on PPIs that Combines Sequence and Structural Information.

Methods Mol Biol. 2017;1558:255-270

Authors: Tuncbag N, Keskin O, Nussinov R, Gursoy A

Abstract
Structural details of protein interactions are invaluable to the understanding of cellular processes. However, the identification of interactions at atomic resolution is a continuing challenge in the systems biology era. Although the number of structurally resolved complexes in the Protein Databank increases exponentially, the complexes only cover a small portion of the known structural interactome. In this chapter, we review the PRISM system that is a protein-protein interaction (PPI) prediction tool-its rationale, principles, and applications. We further discuss its extensions to discover the effect of single residue mutations, to model large protein assemblies, to improve its performance by exploiting conformational protein ensembles, and to reconstruct large PPI networks or pathway maps.

PMID: 28150242 [PubMed - in process]

Bioinformatics Analysis of Protein Phosphorylation in Plant Systems Biology Using P3DB.

Methods Mol Biol. 2017;1558:127-138

Authors: Yao Q, Xu D

Abstract
Protein phosphorylation is one of the most pervasive protein post-translational modification events in plant cells. It is involved in many plant biological processes, such as plant growth, organ development, and plant immunology, by regulating or switching signaling and metabolic pathways. High-throughput experimental methods like mass spectrometry can easily characterize hundreds to thousands of phosphorylation events in a single experiment. With the increasing volume of the data sets, Plant Protein Phosphorylation DataBase (P3DB, http://p3db.org ) provides a comprehensive, systematic, and interactive online platform to deposit, query, analyze, and visualize these phosphorylation events in many plant species. It stores the protein phosphorylation sites in the context of identified mass spectra, phosphopeptides, and phosphoproteins contributed from various plant proteome studies. In addition, P3DB associates these plant phosphorylation sites to protein physicochemical information in the protein charts and tertiary structures, while various protein annotations from hierarchical kinase phosphatase families, protein domains, and gene ontology are also added into the database. P3DB not only provides rich information, but also interconnects and provides visualization of the data in networks, in systems biology context. Currently, P3DB includes the KiC (Kinase Client) assay network, the protein-protein interaction network, the kinase-substrate network, the phosphatase-substrate network, and the protein domain co-occurrence network. All of these are available to query for and visualize existing phosphorylation events. Although P3DB only hosts experimentally identified phosphorylation data, it provides a plant phosphorylation prediction model for any unknown queries on the fly. P3DB is an entry point to the plant phosphorylation community to deposit and visualize any customized data sets within this systems biology framework. Nowadays, P3DB has become one of the major bioinformatics platforms of protein phosphorylation in plant biology.

PMID: 28150236 [PubMed - in process]