Publications by authors named "Amy Webb"

52 Publications

Fibroblast-Specific Proteo-Transcriptomes Reveal Distinct Fibrotic Signatures of Human Sinoatrial Node in Non-Failing and Failing Hearts.

Circulation 2021 Apr 20. Epub 2021 Apr 20.

Department of Physiology & Cell Biology; Bob and Corrine Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH.

Up to fifty percent of the adult human sinoatrial node (SAN), is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may further increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atria. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment. Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted non-failing (non-HF, n=22; 48.7±3.1y.o,) and HF human hearts (n=16; 54.9±2.6y.o.). Connective tissue content was quantified from Masson's trichrome stained head-center and center-tail SAN sections. Expression of extracellular matrix (ECM) proteins, including Collagens 1, 3A1, cartilage intermediate layer protein 1 (CILP1) and periostin, fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (~10x5x2 mm) and right atria (RA) were isolated, cultured, passaged once, and treated ±transforming growth factor beta-1 (TGFβ1) and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA and proteomic analyses. Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF vs non-HF hearts (57.7±2.6% vs 44.0±1.2% <0.0001). Proliferating phosphorylated histone3/vimentin/CD31 fibroblasts were higher in HF SAN. Vimentin/alpha smooth muscle actin/CD31 myofibroblasts along with increased interstitial periostin expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long non-coding RNA, microRNA and proteomic profiles between non-HF and HF SAN and RA fibroblasts, and TGFβ1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with ECM flexibility, stiffness, focal adhesion and metabolism were altered in HF SAN fibroblasts compared to non-HF SAN. This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1 and periostin-positive interstitial fibrosis only in HF vs non-HF human hearts. Comprehensive proteo-transcriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN ECM in HF hearts. Fibroblast-specific profiles generated by our proteo-transcriptomic analyses of the human SAN, provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051583DOI Listing
April 2021

Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome.

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Glucocorticoid (GC) resistance complicates the treatment of ~10-20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation and after ~7 weeks of GC therapy to identify a 12-gene panel able to differentiate steroid resistant NS (SRNS) from steroid-sensitive NS (SSNS). Among this panel, subsequent validation and analyses of one biologically relevant candidate, sulfatase 2 (SULF2), in up to a total of 66 children, revealed that both SULF2 leukocyte expression and plasma arylsulfatase activity Post/Pre therapy ratios were greater in SSNS vs. SRNS. However, neither plasma SULF2 endosulfatase activity (measured by VEGF binding activity) nor plasma VEGF levels, distinguished SSNS from SRNS, despite VEGF's reported role as a downstream mediator of SULF2's effects in glomeruli. Experimental studies of NS-related injury in both rat glomeruli and cultured podocytes also revealed decreased SULF2 expression, which were partially reversible by GC treatment of podocytes. These findings together suggest that SULF2 levels and activity are associated with GC resistance in NS, and that SULF2 may play a protective role in NS via the modulation of downstream mediators distinct from VEGF.
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http://dx.doi.org/10.3390/jcm10030523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867139PMC
February 2021

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

J Pediatr Hematol Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.
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http://dx.doi.org/10.1097/MPH.0000000000002020DOI Listing
November 2020

Bioinspired One Cell Culture Isolates Highly Tumorigenic and Metastatic Cancer Stem Cells Capable of Multilineage Differentiation.

Adv Sci (Weinh) 2020 Jun 28;7(11):2000259. Epub 2020 Apr 28.

Fischell Department of Bioengineering University of Maryland College Park MD 20742 USA.

Cancer stem cells (CSCs) are rare cancer cells that are postulated to be responsible for cancer relapse and metastasis. However, CSCs are difficult to isolate and poorly understood. Here, a bioinspired approach for label-free isolation and culture of CSCs, by microencapsulating one cancer cell in the nanoliter-scale hydrogel core of each prehatching embryo-like core-shell microcapsule, is reported. Only a small percentage of the individually microencapsulated cancer cells can proliferate into a cell colony. Gene and protein expression analyses indicate high stemness of the cells in the colonies. Importantly, the colony cells are capable of cross-tissue multilineage (e.g., endothelial, cardiac, neural, and osteogenic) differentiation, which is not observed for "CSCs" isolated using other contemporary approaches. Further studies demonstrate the colony cells are highly tumorigenic, metastatic, and drug resistant. These data show the colony cells obtained with the bioinspired one-cell-culture approach are truly CSCs. Significantly, multiple pathways are identified to upregulate in the CSCs and enrichment of genes related to the pathways is correlated with significantly decreased survival of breast cancer patients. Collectively, this study may provide a valuable method for isolating and culturing CSCs, to facilitate the understanding of cancer biology and etiology and the development of effective CSC-targeted cancer therapies.
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http://dx.doi.org/10.1002/advs.202000259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284220PMC
June 2020

Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

Clin Cancer Res 2020 07 6;26(13):3117-3125. Epub 2020 Apr 6.

Moffitt Cancer Center, Tampa, Florida.

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and , , and mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).

Patients And Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.

Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.

Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a -mutant selected population.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334091PMC
July 2020

National Healthcare Safety Network Standardized Antimicrobial Administration Ratios (SAARs): A Progress Report and Risk Modeling Update Using 2017 Data.

Clin Infect Dis 2020 Dec;71(10):e702-e709

Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: The Standardized Antimicrobial Administration Ratio (SAAR) is a risk-adjusted metric of antimicrobial use (AU) developed by the Centers for Disease Control and Prevention (CDC) in 2015 as a tool for hospital antimicrobial stewardship programs (ASPs) to track and compare AU with a national benchmark. In 2018, CDC updated the SAAR by expanding the locations and antimicrobial categories for which SAARs can be calculated and by modeling adult and pediatric locations separately.

Methods: We identified eligible patient-care locations and defined SAAR antimicrobial categories. Predictive models were developed for eligible adult and pediatric patient-care locations using negative binomial regression applied to nationally aggregated AU data from locations reporting ≥9 months of 2017 data to the National Healthcare Safety Network (NHSN).

Results: 2017 Baseline SAAR models were developed for 7 adult and 8 pediatric SAAR antimicrobial categories using data reported from 2156 adult and 170 pediatric locations across 457 hospitals. The inclusion of step-down units and general hematology-oncology units in adult 2017 baseline SAAR models and the addition of SAARs for narrow-spectrum B-lactam agents, antifungals predominantly used for invasive candidiasis, antibacterial agents posing the highest risk for Clostridioides difficile infection, and azithromycin (pediatrics only) expand the role SAARs can play in ASP efforts. Final risk-adjusted models are used to calculate predicted antimicrobial days, the denominator of the SAAR, for 40 SAAR types displayed in NHSN.

Conclusions: SAARs can be used as a metric to prompt investigation into potential overuse or underuse of antimicrobials and to evaluate the effectiveness of ASP interventions.
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http://dx.doi.org/10.1093/cid/ciaa326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879497PMC
December 2020

A microRNA-based signature predicts local-regional failure and overall survival after pancreatic cancer resection.

Oncotarget 2020 Mar 10;11(10):913-923. Epub 2020 Mar 10.

The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH, USA.

Resectable pancreatic adenocarcinoma (PC) is generally managed with surgery followed by chemotherapy, but the role of postoperative chemoradiation (pCRT) is controversial. We sought to identify a microRNA (miRNA) expression profile associated with higher risk for local-regional recurrence (LRR), which might help identify patients that may benefit from pCRT. Total RNA was isolated from viable tumor from 88 patients who underwent PC resection with or without chemotherapy, but did not receive radiation. Digital miRNA expression profiling was performed and risk scores were calculated based on the expression levels of the four most significantly correlated miRNAs, and dichotomized about the median to detect correlations between risk group, LRR and overall survival (OS). Two cohorts from The Cancer Genome Atlas (TCGA) and Seoul National University (SNU) were used for validation. Patients with high-risk scores had significantly worse LRR ( 0.001) and worse OS ( 0.034). Two-year OS rates for the high- and low-risk groups were 27.7% and 52.2%, respectively. On multivariable analysis, the risk score remained significantly associated with LRR ( 0.018). When validated on TCGA data, a high-risk score was associated with worse OS on univariate ( 0.03) and multivariable analysis ( 0.017). When validated on the SNU cohort, a high-risk score was likewise associated with worse OS ( 0.042). We have developed a 4-miRNA molecular signature that is associated with risk of LRR and OS after PC resection and validated on two separate cohorts. This signature has the potential to select patients most likely to benefit from pCRT, and should be tested further.
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http://dx.doi.org/10.18632/oncotarget.27496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075466PMC
March 2020

BISR-RNAseq: an efficient and scalable RNAseq analysis workflow with interactive report generation.

BMC Bioinformatics 2019 Dec 20;20(Suppl 24):670. Epub 2019 Dec 20.

Biomedical Informatics, The Ohio State University, Columbus, OH, USA.

Background: RNA sequencing has become an increasingly affordable way to profile gene expression patterns. Here we introduce a workflow implementing several open-source softwares that can be run on a high performance computing environment.

Results: Developed as a tool by the Bioinformatics Shared Resource Group (BISR) at the Ohio State University, we have applied the pipeline to a few publicly available RNAseq datasets downloaded from GEO in order to demonstrate the feasibility of this workflow. Source code is available here: workflow: https://code.bmi.osumc.edu/gadepalli.3/BISR-RNAseq-ICIBM2019 and shiny: https://code.bmi.osumc.edu/gadepalli.3/BISR_RNASeq_ICIBM19. Example dataset is demonstrated here: https://dataportal.bmi.osumc.edu/RNA_Seq/.

Conclusion: The workflow allows for the analysis (alignment, QC, gene-wise counts generation) of raw RNAseq data and seamless integration of quality analysis and differential expression results into a configurable R shiny web application.
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http://dx.doi.org/10.1186/s12859-019-3251-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923898PMC
December 2019

Multiple functional variants in the region are pretransplant markers for risk of GVHD and infection deaths.

Blood Adv 2019 08;3(16):2512-2524

Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH.

Graft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor-recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)-, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and values were corrected for multiple comparisons. Donor risk alleles in rs22441131 ( = .00026) and rs2310241 ( = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 ( = 9.7 × 10), rs13019803 ( = 8.9 × 10), and rs13015714 ( = 5.3 × 10) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.
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http://dx.doi.org/10.1182/bloodadvances.2019000075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712530PMC
August 2019

Modeling Human Cancer-induced Cachexia.

Cell Rep 2019 08;28(6):1612-1622.e4

Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University, Columbus, OH 43210, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia is associated with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models, which fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology as cachectic patients. We envision that the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
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http://dx.doi.org/10.1016/j.celrep.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733019PMC
August 2019

Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer.

Lung Cancer 2019 08 17;134:167-173. Epub 2019 Jun 17.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

Materials And Methods: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis.

Results: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).

Conclusion: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194132PMC
August 2019

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation.

Cell Rep 2019 06 23;27(12):3547-3560.e5. Epub 2019 May 23.

Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

Orchestrating cell-cycle-dependent mRNA oscillations is critical to cell proliferation in multicellular organisms. Even though our understanding of cell-cycle-regulated transcription has improved significantly over the last three decades, the mechanisms remain untested in vivo. Unbiased transcriptomic profiling of G, G-S, and S-G-M sorted cells from FUCCI mouse embryos suggested a central role for E2Fs in the control of cell-cycle-dependent gene expression. The analysis of gene expression and E2F-tagged knockin mice with tissue imaging and deep-learning tools suggested that post-transcriptional mechanisms universally coordinate the nuclear accumulation of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the cell cycle in vivo. In summary, we mapped the spatiotemporal expression of sentinel E2F activators and canonical and atypical repressors at the single-cell level in vivo and propose that two distinct E2F modules relay the control of gene expression in cells actively cycling (E2F3A-8-4) and exiting the cycle (E2F3A-4) during mammalian development.
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http://dx.doi.org/10.1016/j.celrep.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673649PMC
June 2019

Inhibiting BRAF Oncogene-Mediated Radioresistance Effectively Radiosensitizes BRAF-Mutant Thyroid Cancer Cells by Constraining DNA Double-Strand Break Repair.

Clin Cancer Res 2019 08 16;25(15):4749-4760. Epub 2019 May 16.

Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio.

Purpose: Activating BRAF mutations, most commonly BRAF, are a major oncogenic driver of many cancers. We explored whether BRAF promotes radiation resistance and whether selectively targeting BRAF with a BRAF inhibitor (vemurafenib, BRAFi) sensitizes BRAF thyroid cancer cells to radiotherapy.

Experimental Design: Immunoblotting, neutral comet, immunocytochemistry, functional reporter, and clonogenic assays were used to analyze the outcome and molecular characteristics following radiotherapy with or without BRAF or vemurafenib in thyroid cancer cells.

Results: BRAF thyroid cancer cell lines were associated with resistance to ionizing radiation (IR), and expression of BRAF into wild-type BRAF thyroid cancer cells led to IR resistance. BRAFi inhibited ERK signaling in BRAF mutants, but not BRAF wild-type thyroid cancer cell lines. BRAFi selectively radiosensitized and delayed resolution of IR-induced γH2AX nuclear foci in BRAF cells. Moreover, BRAFi impaired global DNA repair and altered the resolution of 53BP1 and RAD51 nuclear foci in BRAF cells following IR. BRAF mutants displayed enhanced nonhomologous end-joining (NHEJ) repair activity, which was abolished by BRAFi. Intriguingly, BRAF mutation led to upregulation of XLF, a component of NHEJ, which was prevented by BRAFi. Importantly, BRAFi in combination with radiotherapy resulted in marked and sustained tumor regression of BRAF thyroid tumor xenografts.

Conclusions: BRAF mutation promotes NHEJ activity leading to radioresistance and BRAFi selectively radiosensitizes BRAF thyroid cancer cells through inhibiting NHEJ. Our findings suggest that combining BRAFi and radiation may improve the therapeutic outcome of patients with BRAF-mutant thyroid cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677585PMC
August 2019

KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer.

J Natl Compr Canc Netw 2019 05;17(5):409-413

Division of Medical Oncology.

BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine-refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V-activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.
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http://dx.doi.org/10.6004/jnccn.2019.7292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673655PMC
May 2019

Using NHSN's Antimicrobial Use Option to Monitor and Improve Antibiotic Stewardship in Neonates.

Hosp Pediatr 2019 05;9(5):340-347

Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: The Antimicrobial Use (AU) Option of the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN) is a surveillance resource that can provide actionable data for antibiotic stewardship programs. Such data are used to enable measurements of AU across hospitals and before, during, and after stewardship interventions.

Methods: We used monthly AU data and annual facility survey data submitted to the NHSN to describe hospitals and neonatal patient care locations reporting to the AU Option in 2017, examine frequencies of most commonly reported agents, and analyze variability in AU rates across hospitals and levels of care. We used results from these analyses in a collaborative project with Vermont Oxford Network to develop neonatal-specific Standardized Antimicrobial Administration Ratio (SAAR) agent categories and neonatal-specific NHSN Annual Hospital Survey questions.

Results: As of April 1, 2018, 351 US hospitals had submitted data to the AU Option from at least 1 neonatal unit. In 2017, ampicillin and gentamicin were the most frequently reported antimicrobial agents. On average, total rates of AU were highest in level III NICUs, followed by special care nurseries, level II-III NICUs, and well newborn nurseries. Seven antimicrobial categories for neonatal SAARs were created, and 6 annual hospital survey questions were developed.

Conclusions: A small but growing percentage of US hospitals have submitted AU data from neonatal patient care locations to NHSN, enabling the use of AU data aggregated by NHSN as benchmarks for neonatal antimicrobial stewardship programs and further development of the SAAR summary measure for neonatal AU.
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http://dx.doi.org/10.1542/hpeds.2018-0265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869145PMC
May 2019

MicroRNA molecular profiling identifies potential signaling pathways conferring resistance to chemoradiation in locally-advanced rectal adenocarcinoma.

Oncotarget 2018 Jun 22;9(48):28951-28964. Epub 2018 Jun 22.

The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210, USA.

Purpose: There has been growing interest in using chemoradiation (CRT) for non-operative management of rectal cancer, and identifying patients who might benefit most from this approach is crucial. This study identified miRNAs (miRs) associated with clinical outcomes and treatment resistance by evaluating both pre- and post-CRT expression profiles.

Methods: Forty patients, 9 with pathologic complete response (pCR) and 31 with pathologic incomplete response (pIR) were included. MicroRNA was extracted from 40 pre-therapy tumor samples and 31 post-chemoradiation surgical samples with pathologic incomplete response (pIR). A generalized linear model was used to identify miRs associated with pCR. A linear mixed effects model was used to identify miRs differentially expressed before and after treatment. miR expression was dichotomized at the mean and clinical outcomes were evaluated using Cox proportional hazard modeling.

Results: Nine miRs were associated with pCR (p<0.05), but none were significant after false discovery rate correction. Among patients with pIR, 68 miRs were differentially expressed between the pre and post-CRT groups (FDR p<0.05). Ingenuity pathway analysis (IPA) demonstrated multiple signaling networks associated with pIR, including p38MAPK, TP53, AKT, IL-6, and RAS. Increased let-7b was correlated with increased distant metastasis (DM), worse relapse-free survival (RFS), and worse overall survival (OS) (p<0.05).

Conclusions: No miRs were significantly correlated with pCR. We identified miRs that were differentially expressed between pre- and post-CRT tumor samples, and these miRs implicated multiple signaling pathways that may confer resistance to CRT. In addition, we identified an association between increased let-7b and worse clinical outcomes (DM, DFS, OS).
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http://dx.doi.org/10.18632/oncotarget.25652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034754PMC
June 2018

Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies.

BMC Med Genomics 2018 Jun 20;11(1):55. Epub 2018 Jun 20.

Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, P.O.Box 100484, Gainesville, FL, 32610-0486, USA.

Background: Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics.

Methods: We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone.

Results: FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value < 2.0 × 10), and responders to HCTZ or chlorthalidone presented up-regulated transcripts. Rs11065987 in chromosome 12, a trans-eQTL for expression of FOS, PPP1R15A and other genes, is also associated with BP response to HCTZ in PEAR whites (SBP: β = - 2.1; p = 1.7 × 10; DBP: β = - 1.4; p = 2.9 × 10).

Conclusions: These findings suggest FOS, DUSP1 and PPP1R15A as potential molecular determinants of antihypertensive response to thiazide diuretics.

Trial Registration: NCT00246519 , NCT01203852 www.clinicaltrials.gov.
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http://dx.doi.org/10.1186/s12920-018-0370-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011347PMC
June 2018

Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).

Circ Genom Precis Med 2018 04;11(4):e001854

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics (C.W.M., O.M., A.C.C.S., N.M.E.R., M.K.-S., M.S., J.G.G., R.M.C.-D., Y.G., J.A.J.), Department of Pharmaceutical Outcomes and Policy (C.D.), Department of Pharmaceutics, College of Pharmacy (A.N.D., R.S.P.S.), Genetics & Genomics Graduate Program, Genetics Institute (A.C.C.S., Y.S.), Department of Biology, College of Liberal Arts and Sciences (W.M.), Department of Community Health and Family Medicine, College of Medicine (J.G.G.), and Division of Cardiovascular Medicine, Department of Medicine (R.M.C.-D., J.A.J.), University of Florida, Gainesville; School of Pharmacy, College of Health Professions, Pacific University, Hillsboro, OR (M.K.-S.); Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt (M.S.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Medicine (S.T.T.), Mayo Clinic, Rochester, MN; Human Genetics Center, Institute of Molecular Medicine, University of Texas Health Science Center, Houston (E.B.); Section of Nephrology, Department of Medicine, University of Chicago, IL (A.B.C.); Department of Biomedical Informatics, Center for Pharmacogenomics (A.W.) and Department of Cancer Biology and Genetics, College of Medicine (W.S.), Ohio State University, Columbus; and Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (S.E.S.).

Background: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses).

Methods: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2).

Results: Our top SNP rs3784921 was in the gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; =2.09×10) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided =0.006). In addition, expression differed by rs3784921 genotype (=0.007), and rs1802409, a proxy SNP for rs3784921 (=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided =0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes and CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.
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http://dx.doi.org/10.1161/CIRCGEN.117.001854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901893PMC
April 2018

The Standardized Antimicrobial Administration Ratio: A New Metric for Measuring and Comparing Antibiotic Use.

Clin Infect Dis 2018 07;67(2):179-185

Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: To provide a standardized, risk-adjusted method for summarizing antibiotic use (AU), enable hospitals to track their AU over time and compare their AU data to national benchmarks, the Centers for Disease Control and Prevention developed the Standardized Antimicrobial Administration Ratio (SAAR).

Methods: Hospitals reporting to the National Healthcare Safety Network (NHSN) AU Option collect and submit aggregated AU data electronically as antimicrobial days of therapy per patient days present. SAARs were developed for specific NHSN adult and pediatric patient care locations and cover five antimicrobial agent categories: (1) broad-spectrum agents predominantly used for hospital-onset/multi-drug resistant bacteria; (2) broad-spectrum agents predominantly used for community-acquired infections; (3) anti-methicillin-resistant Staphylococcus aureus agents; (4) agents predominantly used for surgical site infection prophylaxis; and (5) all antibiotic agents. The SAAR is an observed-to-predicted use ratio where predicted use is estimated from a statistical model; a SAAR of 1 indicates that observed use and predicted use are equal.

Results: Most location-level SAARs were statistically significantly different than 1: adult locations up to 52% lower than 1 and up to 41% higher than 1. Median SAARs in adult and pediatric ICUs had a range of 0.667-1.119. SAAR distributions serve as an external comparison to national SAARs.

Conclusions: This is the first aggregate AU metric that uses point-of-care, antimicrobial administration data electronically reported to a national surveillance system to enable risk-adjusted, AU comparisons across multiple hospitals. Endorsed by the National Quality Forum, SAARs provide AU benchmarks that stewardship programs can use to help drive improvements.
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http://dx.doi.org/10.1093/cid/ciy075DOI Listing
July 2018

Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics.

Sci Rep 2017 11 22;7(1):16068. Epub 2017 Nov 22.

Center for Pharmacogenomics and Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.

Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10) and TSC22D3 (p = 1.9 × 10) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.
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http://dx.doi.org/10.1038/s41598-017-16343-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700078PMC
November 2017

Uptake of Antibiotic Stewardship Programs in US Acute Care Hospitals: Findings From the 2015 National Healthcare Safety Network Annual Hospital Survey.

Clin Infect Dis 2017 Oct;65(10):1748-1750

Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia.

To assess uptake of the Centers for Disease Control and Prevention's Core Elements of Hospital Antibiotic Stewardship Programs, we analyzed stewardship practices as reported in the 2015 National Healthcare Safety Network's Annual Hospital Survey. Hospital uptake of all 7 core elements increased from 40.9% in 2014 to 48.1% in 2015.
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http://dx.doi.org/10.1093/cid/cix651DOI Listing
October 2017

Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant.

Blood 2017 09 15;130(13):1585-1596. Epub 2017 Aug 15.

College of Pharmacy, The Ohio State University, Columbus, OH.

Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes.
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http://dx.doi.org/10.1182/blood-2017-05-784637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620418PMC
September 2017

Molecular profiling of locally-advanced rectal adenocarcinoma using microRNA expression (Review).

Int J Oncol 2017 Aug 14;51(2):393-404. Epub 2017 Jun 14.

The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210, USA.

Treatment for locally-advanced rectal cancer (LARC) typically consists of neoadjuvant chemoradiation followed by total mesorectal excision. Recently, there has been growing interest in non-operative management for patients who are medically-inoperable or wish to avoid surgical morbidity and permanent colostomy. Approximately 50% of patients who receive pre-operative neoadjuvant chemoradiation develop some degree of pathologic response. Approximately 10-20% of patients are found to have a complete pathologic response, a finding which has frequently been shown to predict better clinical outcomes, including local-regional control, distant metastasis and survival. Many recent studies have evaluated the role of molecular biomarkers in predicting response to neoadjuvant therapy. MicroRNAs (miRNAs) are an emerging class of biomarkers that have the potential to predict which patients are most likely to benefit from pre-operative therapy and from a selective surgical approach. Here, we review the published literature on microRNAs as prognostic and predictive biomarkers in rectal cancer after pre-operative therapy. In the future, the development of prospectively validated miRNA signatures will allow clinical implementation of miRNAs as prognostic and predictive signatures in LARC.
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http://dx.doi.org/10.3892/ijo.2017.4045DOI Listing
August 2017

Expression and splicing of ABC and SLC transporters in the human blood-brain barrier measured with RNAseq.

Eur J Pharm Sci 2017 May 7;103:47-51. Epub 2017 Feb 7.

College of Medicine, Center for Pharmacogenomics, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA. Electronic address:

The blood-brain barrier (BBB) expresses numerous membrane transporters that supply needed nutrients to the central nervous system (CNS), consisting mostly of solute carriers (SLC transporters), or remove unwanted substrates via extrusion pumps through the action of ATP binding cassette (ABC) transporters. Previous work has identified many BBB transporters using hybridization arrays or qRT-PCR, using targeted probes. Here we have performed next-generation sequencing of the transcriptome (RNAseq) extracted from cerebral cortex tissues and brain microvessel endothelial cells (BMEC) obtained from two donors. The same RNA samples had previously been measured for transporter expression using qRT-PCR (Geier et al., 2013), yielding similar expression levels for overlapping mRNAs (R=0.66, p<0.001). RNAseq confirms a number of transporters highly enriched in BMECs (e.g., ABCB1, ABCG2, SLCO2B1, and SLC47A1), but also detects novel BMEC transporters. Multiple splice isoforms detected by RNAseq are either robustly enriched or depleted in BMECs, indicating differential RNA processing in the BBB. The Complete RNAseq data are publically available (GSE94064).
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http://dx.doi.org/10.1016/j.ejps.2017.02.010DOI Listing
May 2017

Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response.

Circ Cardiovasc Genet 2017 Jan;10(1)

Background: Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response.

Methods And Results: Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (Δ systolic BP/Δ diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mm Hg, respectively, Δ systolic BP P=3×10, Δ diastolic BP P=5×10). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression.

Conclusions: This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298887PMC
January 2017

Antimicrobial-Resistant Pathogens Associated With Healthcare-Associated Infections: Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011-2014.

Infect Control Hosp Epidemiol 2016 11 30;37(11):1288-1301. Epub 2016 Aug 30.

Division of Healthcare Quality Promotion,National Center for Emerging and Zoonotic Infectious Diseases,Centers for Disease Control and Prevention,Atlanta,Georgia.

OBJECTIVE To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) that occurred in 2011-2014 and were reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network. METHODS Data from central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonias, and surgical site infections were analyzed. These HAIs were reported from acute care hospitals, long-term acute care hospitals, and inpatient rehabilitation facilities. Pooled mean proportions of pathogens that tested resistant (or nonsusceptible) to selected antimicrobials were calculated by year and HAI type. RESULTS Overall, 4,515 hospitals reported that at least 1 HAI occurred in 2011-2014. There were 408,151 pathogens from 365,490 HAIs reported to the National Healthcare Safety Network, most of which were reported from acute care hospitals with greater than 200 beds. Fifteen pathogen groups accounted for 87% of reported pathogens; the most common included Escherichia coli (15%), Staphylococcus aureus (12%), Klebsiella species (8%), and coagulase-negative staphylococci (8%). In general, the proportion of isolates with common resistance phenotypes was higher among device-associated HAIs compared with surgical site infections. Although the percent resistance for most phenotypes was similar to earlier reports, an increase in the magnitude of the resistance percentages among E. coli pathogens was noted, especially related to fluoroquinolone resistance. CONCLUSION This report represents a national summary of antimicrobial resistance among select HAIs and phenotypes. The distribution of frequent pathogens and some resistance patterns appear to have changed from 2009-2010, highlighting the need for continual, careful monitoring of these data across the spectrum of HAI types. Infect Control Hosp Epidemiol 2016;1-14.
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http://dx.doi.org/10.1017/ice.2016.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857725PMC
November 2016

Policies for Controlling Multidrug-Resistant Organisms in US Healthcare Facilities Reporting to the National Healthcare Safety Network, 2014.

Infect Control Hosp Epidemiol 2016 09 28;37(9):1105-8. Epub 2016 Jun 28.

Division of Healthcare Quality Promotion,National Center for Emerging and Zoonotic Infectious Diseases,Centers for Disease Control and Prevention,Atlanta,Georgia.

We examined reported policies for the control of common multidrug-resistant organisms (MDROs) in US healthcare facilities using data from the National Healthcare Safety Network Annual Facility Survey. Policies for the use of Contact Precautions were commonly reported. Chlorhexidine bathing for preventing MDRO transmission was also common among acute care hospitals. Infect Control Hosp Epidemiol 2016:1-4.
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http://dx.doi.org/10.1017/ice.2016.139DOI Listing
September 2016

Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.

Ann Intern Med 2016 Sep 21;165(5):305-15. Epub 2016 Jun 21.

Background: The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited.

Objective: To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM.

Design: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682).

Setting: University hospital.

Participants: Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics.

Intervention: All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment.

Measurements: The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters.

Results: Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo).

Limitation: Single-center study.

Conclusion: Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH.

Primary Funding Source: Burroughs Wellcome Fund and American Diabetes Association.
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http://dx.doi.org/10.7326/M15-1774DOI Listing
September 2016

RNA sequencing of transcriptomes in human brain regions: protein-coding and non-coding RNAs, isoforms and alleles.

BMC Genomics 2015 Nov 23;16:990. Epub 2015 Nov 23.

Center for Pharmacogenomics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.

Background: We used RNA sequencing to analyze transcript profiles of ten autopsy brain regions from ten subjects. RNA sequencing techniques were designed to detect both coding and non-coding RNA, splice isoform composition, and allelic expression. Brain regions were selected from five subjects with a documented history of smoking and five non-smokers. Paired-end RNA sequencing was performed on SOLiD instruments to a depth of >40 million reads, using linearly amplified, ribosomally depleted RNA. Sequencing libraries were prepared with both poly-dT and random hexamer primers to detect all RNA classes, including long non-coding (lncRNA), intronic and intergenic transcripts, and transcripts lacking poly-A tails, providing additional data not previously available. The study was designed to generate a database of the complete transcriptomes in brain region for gene network analyses and discovery of regulatory variants.

Results: Of 20,318 protein coding and 18,080 lncRNA genes annotated from GENCODE and lncipedia, 12 thousand protein coding and 2 thousand lncRNA transcripts were detectable at a conservative threshold. Of the aligned reads, 52 % were exonic, 34 % intronic and 14 % intergenic. A majority of protein coding genes (65 %) was expressed in all regions, whereas ncRNAs displayed a more restricted distribution. Profiles of RNA isoforms varied across brain regions and subjects at multiple gene loci, with neurexin 3 (NRXN3) a prominent example. Allelic RNA ratios deviating from unity were identified in > 400 genes, detectable in both protein-coding and non-coding genes, indicating the presence of cis-acting regulatory variants. Mathematical modeling was used to identify RNAs stably expressed in all brain regions (serving as potential markers for normalizing expression levels), linked to basic cellular functions. An initial analysis of differential expression analysis between smokers and nonsmokers implicated a number of genes, several previously associated with nicotine exposure.

Conclusions: RNA sequencing identifies distinct and consistent differences in gene expression between brain regions, with non-coding RNA displaying greater diversity between brain regions than mRNAs. Numerous RNAs exhibit robust allele selective expression, proving a means for discovery of cis-acting regulatory factors with potential clinical relevance.
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http://dx.doi.org/10.1186/s12864-015-2207-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657279PMC
November 2015