Publications by authors named "Soledad Fernandez"

155 Publications

Prediction of ethanol self-administration in pre-weanling, adolescent, and young adult rats.

Dev Psychobiol 2021 Mar 9;63(2):378-384. Epub 2020 Aug 9.

Instituto de Investigación Médica M. y M. Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.

Alcohol (ethanol) use is almost normative by late adolescence, in most western countries. It is important to identify factors that distinguish those who progress from alcohol initiation to sustained use of the drug, from those that keep a controlled pattern of drinking. The factors precipitating this transition may change across development. This study analyzed associations between behavioral endophenotypes and ethanol intake at three developmental periods. Exp. 1 measured ethanol drinking at postnatal day 18, via an intraoral infusion procedure, in male or female pre-weanling rats screened for anxiety response in the light-dark box test and for distance traveled in a novel open field. Exp. 2 measured, in juvenile/adolescent or young adult rats, the association between shelter seeking, exploratory/risk-taking behaviors, anxiety or hedonic responses, and ethanol intake. Ethanol intake in pre-weanlings was explained by distance traveled in a novel environment, whereas anxiety responses, measured in the multivariate concentric square field apparatus (MSCF), selectively predicted ethanol intake at adolescence, but not at adulthood. Those juvenile/adolescents with lower mean duration of visit to areas of the MSCF that evoke anxiogenic responses exhibited heightened ethanol intake. These findings suggest that the association between anxiety and ethanol intake may be specifically relevant during adolescence.
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http://dx.doi.org/10.1002/dev.22025DOI Listing
March 2021

Thrombin generation in subjects with lupus anticoagulant without prior thrombosis or gestational morbidities.

Thromb Res 2020 12 28;196:425-431. Epub 2020 Sep 28.

Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain; Department of Hematology, Hospitales Quirón públicos, IIS-FJD, Universidad Autónoma de Madrid, Madrid, Spain.

Background: Lupus anticoagulant (LA) can be a cause of thrombosis and/or pregnancy morbidities, producing antiphospholipid syndrome (APS). An increase in thrombin generation (TG) is correlated with prothrombotic status. Several changes in TG-derived parameters have been reported in APS patients.

Objectives: Evaluate whether the TG phenotype of APS can also be described in LA subjects without clinical manifestations of APS, and to investigate the possible influence of both LA potency and antiphospholipid (aPL) profile on it.

Results: TG was analyzed in 153 cases of LA and 41 healthy controls. We have observed prolongation of both lag time (3.7 min vs 2.32 min, p < 0.001) and time to peak (6.48 min vs 5.27 min, p < 0.001), increased peak height (221.7 nM vs 182.7 nM, p < 0.001), slightly higher ETP (221.7 nM·min vs 182.7 nM·min, p = 0.041), and higher velocity index (100.7 nM/min vs 74.53 nM/min, p = 0.001) in LA subjects compared to controls. After adding thrombomodulin (TM), ETP%inh was significantly lower in LA group (37.90% vs 59.90%, p < 0.001) showing resistance to TM/activated protein C (APC). Significant differences were found in lag time, time to peak and ETP%inh according to the potency and aPL profile.

Conclusions: Previously described differences in TG-derived parameters in APS patients have been confirmed in incidental LA subjects: prolonged lag time and time to peak, slightly higher ETP, higher peak height, and less sensitivity to TM/APC. High LA potency and triple-positive aPL profile enhance differences in lag time, time to peak and, especially, increase APC resistance, but no effect in ETP was observed.
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http://dx.doi.org/10.1016/j.thromres.2020.09.025DOI Listing
December 2020

Variance formulae for multiphase stepped wedge cluster randomized trial.

Stat Med 2020 12 17;39(28):4147-4168. Epub 2020 Aug 17.

Department of Biomedical Informatics, Ohio State University, Columbus, Ohio, USA.

In a multiphase stepped wedge cluster randomized trial (MSW-CRT), more than one intervention will be initiated on each sequence in a fixed order. Hence, with the MSW-CRT design, the effect of the first intervention can be evaluated when compared to control, as well as the added-on effects of the subsequent interventions. Studies that use MSW-CRT have been proposed, but properties of this design have not been explicitly studied. We derive closed-form variance formulae to test the interventions' effects, which can be readily used for sample size and power calculation. Additionally, we provide relationships between variances to test the interventions' effects and design parameters. Under special conditions, some important properties include: (i) the variances to test different interventions' effects (ie, the first intervention effect and the second intervention effect) may be same; (ii) as the cluster-period mean autocorrelation increases, the variance to test an intervention effect may first increase and then decrease; (iii) as the amount of periods between the initiations of two interventions (ie, lag) increases, the variance to test an intervention effect may remain unchanged. We illustrate the relationships between power and design parameters using the variance formulae. From a few illustrative examples, we observe that the statistical test that uses data only relevant to a specific intervention has inferior power (relative power loss <15%) compared to the test when using all the study data. Also, power is reduced when both the total number of periods and lag are decreased simultaneously (relative power loss <20%).
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http://dx.doi.org/10.1002/sim.8716DOI Listing
December 2020

Power analysis for RNA-Seq differential expression studies using generalized linear mixed effects models.

BMC Bioinformatics 2020 May 19;21(1):198. Epub 2020 May 19.

Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, 1800 Cannon Dr., Columbus, 43210, OH, USA.

Background: Power analysis becomes an inevitable step in experimental design of current biomedical research. Complex designs allowing diverse correlation structures are commonly used in RNA-Seq experiments. However, the field currently lacks statistical methods to calculate sample size and estimate power for RNA-Seq differential expression studies using such designs. To fill the gap, simulation based methods have a great advantage by providing numerical solutions, since theoretical distributions of test statistics are typically unavailable for such designs.

Results: In this paper, we propose a novel simulation based procedure for power estimation of differential expression with the employment of generalized linear mixed effects models for correlated expression data. We also propose a new procedure for power estimation of differential expression with the use of a bivariate negative binomial distribution for paired designs. We compare the performance of both the likelihood ratio test and Wald test under a variety of simulation scenarios with the proposed procedures. The simulated distribution was used to estimate the null distribution of test statistics in order to achieve the desired false positive control and was compared to the asymptotic Chi-square distribution. In addition, we applied the procedure for paired designs to the TCGA breast cancer data set.

Conclusions: In summary, we provide a framework for power estimation of RNA-Seq differential expression under complex experimental designs. Simulation results demonstrate that both the proposed procedures properly control the false positive rate at the nominal level.
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http://dx.doi.org/10.1186/s12859-020-3541-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236949PMC
May 2020

Preclinical Toxicology of rQNestin34.5v.2: An Oncolytic Herpes Virus with Transcriptional Regulation of the ICP34.5 Neurovirulence Gene.

Mol Ther Methods Clin Dev 2020 Jun 30;17:871-893. Epub 2020 Mar 30.

Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210, USA.

rQNestin34.5v.2 is an oncolytic herpes simplex virus 1 (oHSV) that retains expression of the neurovirulent ICP34.5 gene under glioma-selective transcriptional regulation. To prepare an investigational new drug (IND) application, we performed toxicology and efficacy studies of rQNestin34.5v.2 in mice in the presence or absence of the immunomodulating drug cyclophosphamide (CPA). ICP34.5 allows HSV1 to survive interferon and improves viral replication by dephosphorylation of the eIF-2α translation factor. rQNestin34.5v.2 dephosphorylated eIF-2α in human glioma cells, but not in human normal cells, resulting in significantly higher cytotoxicity and viral replication in the former compared to the latter. toxicity of rQNestin34.5v.2 was compared with that of wild-type F strain in immunocompetent BALB/c mice and athymic mice by multiple routes of administration in the presence or absence of CPA. A likely no observed adverse effect level (NOAEL) dose for intracranial rQNestin34.5v.2 was estimated, justifying a phase 1 clinical trial in recurrent glioma patients (ClinicalTrials.gov: NCT03152318), after successful submission of an IND.
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http://dx.doi.org/10.1016/j.omtm.2020.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195500PMC
June 2020

A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer.

BMC Med Genomics 2020 04 3;13(Suppl 5):45. Epub 2020 Apr 3.

Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH, 43210, USA.

Background: Initially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study.

Results: Expression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter- and intra- cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance.

Conclusions: Our systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.
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http://dx.doi.org/10.1186/s12920-020-0682-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118829PMC
April 2020

Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses.

Sci Rep 2020 03 20;10(1):5095. Epub 2020 Mar 20.

Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA.

The mode of action for oncolytic viruses (OVs) in cancer treatment is thought to depend on a direct initial cytotoxic effect against infected tumor cells and subsequent activation of immune cell responses directed against the neoplasm. To study both of these effects in a mouse model of glioblastoma (GBM), we employed murine GBM cells engineered to constitutively express the type I Herpes Simplex Virus (HSV1) HSV-1 receptor, nectin-1, to allow for more efficient infection and replication by oncolytic HSV (oHSV). These cells were further engineered with a surrogate tumor antigen to facilitate assays of T cell activity. We utilized MRI-based volumetrics to measure GBM responses after injection with the oHSV and bioluminescent imaging (BLI) to determine oHSV replicative kinetics in the injected tumor mass. We found increased infiltration of both surrogate tumor antigen- and oHSV antigen-specific CD8+ T cells within 7 days after oHSV injection. There was no increase in tumor infiltrating CD8+ T cells expressing "exhaustion" markers, yet oHSV infection led to a reduction in PD-1+ CD8+ T cells in injected GBMs and an increase in IFNγ+ CD8+ T cells. There was a significant direct correlation between oHSV-mediated reduction in GBM volume and increased infiltration of both viral and tumor antigen-specific CD8+ T cells, as well as oHSV intratumoral gene activity. These findings imply that CD8+ T cell cytotoxicity against both tumor and viral antigens as well as intratumoral oHSV gene expression are important in oHSV-mediated GBM therapy.
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http://dx.doi.org/10.1038/s41598-020-61736-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083912PMC
March 2020

Fully moderated t-statistic in linear modeling of mixed effects for differential expression analysis.

BMC Bioinformatics 2019 Dec 20;20(Suppl 24):675. Epub 2019 Dec 20.

Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, 1800 Cannon Dr., Columbus, 43210, OH, USA.

Background: Gene expression profiling experiments with few replicates lead to great variability in the estimates of gene variances. Toward this end, several moderated t-test methods have been developed to reduce this variability and to increase power for testing differential expression. Most of these moderated methods are based on linear models with fixed effects where residual variances are smoothed under a hierarchical Bayes framework. However, they are inadequate for designs with complex correlation structures, therefore application of moderated methods to linear models with mixed effects are needed for differential expression analysis.

Results: We demonstrated the implementation of the fully moderated t-statistic method for linear models with mixed effects, where both residual variances and variance estimates of random effects are smoothed under a hierarchical Bayes framework. We compared the proposed method with two current moderated methods and show that the proposed method can control the expected number of false positives at the nominal level, while the two current moderated methods fail.

Conclusions: We proposed an approach for testing differential expression under complex correlation structures while providing variance shrinkage. The proposed method is able to improve power by moderation and controls the expected number of false positives properly at the nominal level.
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http://dx.doi.org/10.1186/s12859-019-3248-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923909PMC
December 2019

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway.

Cancers (Basel) 2019 Dec 14;11(12). Epub 2019 Dec 14.

Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43201, USA.

Hepatocellular carcinoma (HCC) is the most prevalent primary cancer and a highly aggressive liver malignancy. Liver cancer cells reprogram their metabolism to meet their needs for rapid proliferation and tumor growth. In the present study, we investigated the alterations in the expression of the genes involved in glucose metabolic pathways as well as their association with the clinical stage and survival of HCC patients. We found that the expressions of around 30% of genes involved in the glucose metabolic pathway are consistently dysregulated with a predominant down-regulation in HCC tumors. Moreover, the differentially expressed genes are associated with an advanced clinical stage and a poor prognosis. More importantly, unsupervised clustering analysis with the differentially expressed genes that were also associated with overall survival (OS) revealed a subgroup of patients with a worse prognosis including reduced OS, disease specific survival, and recurrence-free survival. This aggressive subtype had significantly increased expression of stemness-related genes and down-regulated metabolic genes, as well as increased immune infiltrates that contribute to a poor prognosis. Collectively, this integrative study indicates that expressions of the glucose metabolic genes could be used as potential prognostic markers and/or therapeutic targets, which might be helpful in developing precise treatment for patients with HCC.
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http://dx.doi.org/10.3390/cancers11122023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966574PMC
December 2019

Practical considerations for the implementation of adaptive designs for oncology Phase I dose-finding trials.

Future Drug Discov 2019 Oct 11;1(2):FDD18. Epub 2019 Oct 11.

Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, 1800 Cannon Dr. Columbus, OH 43210, USA.

The traditional 3 + 3 design continues to be commonly used for Phase I dose-finding oncology trials, despite increasing criticisms and development of innovative methods. Unfortunately, it is a challenge to convince principal investigators to use novel designs. The goal of this paper is to persuade researchers to break away from 3 + 3 design and provide potential solutions to better designs and implementation strategy. We reviewed the statistical methods for adaptive Phase I designs. The barriers among all the major components of the implementation team have been emphasized and potential solutions have been discussed. Institutional support to the principal investigators and statistician, as well as to other team members is essential to design and implement adaptive trials in academic medical institutions.
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http://dx.doi.org/10.4155/fdd-2019-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811732PMC
October 2019

Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth.

Life Sci Alliance 2018 Oct 26;1(5):e201800190. Epub 2018 Oct 26.

Hollings Cancer Center and Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.

The contribution of the tumor microenvironment to pancreatic ductal adenocarcinoma (PDAC) development is currently unclear. We therefore examined the consequences of disrupting paracrine Hedgehog (HH) signaling in PDAC stroma. Herein, we show that ablation of the key HH signaling gene () in stromal fibroblasts led to increased proliferation of pancreatic tumor cells. Furthermore, deletion resulted in proteasomal degradation of the tumor suppressor PTEN and activation of oncogenic protein kinase B (AKT) in fibroblasts. An unbiased proteomic screen identified RNF5 as a novel E3 ubiquitin ligase responsible for degradation of phosphatase and tensin homolog (PTEN) in -null fibroblasts. () knockdown or pharmacological inhibition of glycogen synthase kinase 3β (GSKβ), the kinase that marks PTEN for ubiquitination, rescued PTEN levels and reversed the oncogenic phenotype, identifying a new node of PTEN regulation. In PDAC patients, low stromal PTEN correlated with reduced overall survival. Mechanistically, PTEN loss decreased hydraulic permeability of the extracellular matrix, which was reversed by hyaluronidase treatment. These results define non-cell autonomous tumor-promoting mechanisms activated by disruption of the HH/PTEN axis and identifies new targets for restoring stromal tumor-suppressive functions.
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http://dx.doi.org/10.26508/lsa.201800190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238420PMC
October 2018

Pharmacokinetic-Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High-Dose Melphalan for Autologous Stem Cell Transplant.

CPT Pharmacometrics Syst Pharmacol 2018 11 20;7(11):748-758. Epub 2018 Oct 20.

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.

High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphalan varies, and many patients experience severe toxicities. Prolonged severe neutropenia is one of the most severe toxicities and contributes to potentially life-threatening infections and failure of ASCT. Granulocyte-colony stimulating factor (G-CSF) is given to stimulate neutrophil proliferation after melphalan administration. The aim of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model capable of predicting neutrophil kinetics in individual patients with MM undergoing ASCT with high-dose melphalan and G-CSF administration. The extended PK/PD model incorporated several covariates, including G-CSF regimen, stem cell dose, hematocrit, sex, creatinine clearance, p53 fold change, and race. The resulting model explained portions of interindividual variability in melphalan exposure, therapeutic effect, and feedback regulation of G-CSF on neutrophils, thus enabling simulation of various doses and prediction of neutropenia duration.
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http://dx.doi.org/10.1002/psp4.12345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263666PMC
November 2018

Arming an Oncolytic Herpes Simplex Virus Type 1 with a Single-chain Fragment Variable Antibody against PD-1 for Experimental Glioblastoma Therapy.

Clin Cancer Res 2019 01 2;25(1):290-299. Epub 2018 Oct 2.

Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: Glioblastoma (GBM) is resistant to standard of care. Immune checkpoints inhibitors (such as anti-PD-1 mAbs) efficiently restore antitumor T-cell activity. We engineered a new oncolytic herpes simplex virus (oHSV) expressing a single-chain antibody against PD-1 (scFvPD-1) to evaluate its efficacy in mouse models of GBM.

Experimental Design: NG34scFvPD-1 expresses the human gene transcriptionally controlled by the Nestin promoter to allow replication in GBM cells and a scFvPD-1 cDNA transcriptionally controlled by the CMV promoter. ELISA assays were performed to detect binding of scFvPD-1 to mouse and human PD-1. cytotoxicity and replication assays were performed to measure NG34scFvPD-1 oncolysis, and scFvPD-1 expression and secretion were determined. survival studies using orthotopic mouse GBM models were performed to evaluate the therapeutic potency of NG34scFvPD-1.

Results: NG34scFvPD-1-infected GBM cells express and secrete scFvPD-1 that binds mouse PD-1. The introduction of the scFvPD-1 sequence in the viral backbone does not alter the oncolytic properties of NG34scFvPD-1. NG34scFvPD-1 treatment improved the survival with a tail of durable survivorship in 2 syngeneic immunocompetent mouse models of GBM. Mice that survived the first GBM challenge rejected the second challenge of GBM when implanted in the contralateral hemisphere. However, this was not true when athymic mice were employed as the recipients of the second challenge, consistent with the need for an intact immune system to obtain a memory response.

Conclusions: NG34scFvPD-1 treatment induces a durable antitumor response in 2 preclinical mouse models of GBM with evidence for antitumor memory.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800097PMC
January 2019

Stromal PTEN determines mammary epithelial response to radiotherapy.

Nat Commun 2018 07 17;9(1):2783. Epub 2018 Jul 17.

Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.

The importance of the tumor-associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.
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http://dx.doi.org/10.1038/s41467-018-05266-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050339PMC
July 2018

Modeling tumor immunity of mouse glioblastoma by exhausted CD8 T cells.

Sci Rep 2018 01 9;8(1):208. Epub 2018 Jan 9.

Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA.

T cell exhaustion occurs during chronic infection and cancers. Programmed cell death protein-1 (PD-1) is a major inhibitory checkpoint receptor involved in T cell exhaustion. Blocking antibodies (Abs) against PD-1 or its ligand, PD-L1, have been shown to reverse T cell exhaustion during chronic infection and cancers, leading to improved control of persistent antigen. However, modeling tumor-specific T cell responses in mouse has been difficult due to the lack of reagents to detect and phenotype tumor-specific immune responses. We developed a novel mouse glioma model expressing a viral epitope derived from lymphocytic choriomeningitis virus (LCMV), which allowed monitoring of tumor-specific CD8 T-cell responses. These CD8 T cells express high levels of PD-1 and are unable to reject tumors, but this can be reversed by anti-PD-1 treatment. These results suggest the efficacy of PD-1 blockade as a treatment for glioblastoma, an aggressive tumor that results in a uniformly lethal outcome. Importantly, this new syngeneic tumor model may also provide further opportunities to characterize anti-tumor T cell exhaustion and develop novel cancer immunotherapies.
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http://dx.doi.org/10.1038/s41598-017-18540-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760520PMC
January 2018

In Reply.

Oncologist 2018 01 13;23(1):136. Epub 2017 Nov 13.

Department of Biomedical Informatics, Ohio State University Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.

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http://dx.doi.org/10.1634/theoncologist.2017-0542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759828PMC
January 2018

Carbon Monoxide Alarm and Smoke Alarm Use Among Parents Recruited From a Pediatric Emergency Department.

J Prim Prev 2018 02;39(1):1-15

Center for Injury Research and Policy, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.

Although the proper installation and maintenance of carbon monoxide (CO) and smoke alarms can protect individuals from residential CO-related and fire-related injuries, these devices are underutilized. We describe characteristics associated with self-reported CO and smoke alarm use of parents recruited from a pediatric emergency department to improve CO alarm use. Parents of children ≤ 18 years (N = 299) reported socio-demographic characteristics and CO and smoke alarm ownership and practices. We assigned participants to a behavioral profile and a Precaution Adoption Process Model stage based on their self-reported CO and smoke alarm use. Most participants (71%) did not have CO alarms in their homes, but reported owning at least one working smoke alarm (98%). Participants who reported "perfect" CO alarm behavior (defined as having a working CO alarm, one near a sleeping area, with batteries replaced every 6 months; 9%) were more likely to earn a higher income, own their home, and have lived at their current residence for at least 2 years. Participants who reported "perfect" smoke alarm behavior (defined as having a working smoke alarm on every level, with batteries replaced every 6 months; 49%) were more likely to rent their home, receive federal assistance, and have lived at their current residence for at least 2 years. Interventions to increase correct CO alarm use are necessary.
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http://dx.doi.org/10.1007/s10935-017-0493-4DOI Listing
February 2018

Penetrance of a rare familial mutation predisposing to papillary thyroid cancer.

Fam Cancer 2018 07;17(3):431-434

Senior Medical Science Liaison, Guardant Health, Redwood City, CA, USA.

Familial non-medullary thyroid cancer (FNMTC) is clinically defined as two or more first-degree relatives with NMTC and appears to follow an autosomal dominant inheritance pattern. Approximately 5-7% of NMTC is hereditary and affects multiple generations with a young age of onset. The primary aim of this study was to determine the age-specific penetrance of NMTC in individuals from a large family with FNMTC with a previously identified private mutation at 4q32, with a secondary aim to determine the penetrance for benign thyroid disease in this family. We present a large family with NMTC in which we had previously described a culpable mutation. Participants provided their personal medical history and family history. The germline 4q32 A > C mutation was detected in 34 of 68 tested individuals. Age-specific penetrance of thyroid cancer and benign thyroid disease was determined using the inverted Kaplan-Meier method of segregation analysis. Individuals who tested positive for the 4q32 mutation have a 68.9% (95% CI 46.5-88.7) risk of developing thyroid cancer by age 70 and a 65.3% (95% CI 46.0-83.8) risk of developing benign thyroid disease by age 70. The 4q32 A > C mutation significantly increases the risk to develop thyroid cancer but not benign thyroid disease in members of this family. The female:male sex ratio of 1.33 that we observed in affected mutation carriers differs greatly from the ratio of approximately 3:1 observed in PTC, supporting a central role of the mutation. Early thyroid surveillance with annual ultrasound is recommended to individuals testing positive for this private familial mutation.
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http://dx.doi.org/10.1007/s10689-017-0048-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897192PMC
July 2018

Generation of a pancreatic cancer model using a Pdx1-Flp recombinase knock-in allele.

PLoS One 2017 21;12(9):e0184984. Epub 2017 Sep 21.

Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.

The contribution of the tumor microenvironment to the development of pancreatic adenocarcinoma (PDAC) is unclear. The LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre (KPC) tumor model, which is widely utilized to faithfully recapitulate human pancreatic cancer, depends on Cre-mediated recombination in the epithelial lineage to drive tumorigenesis. Therefore, specific Cre-loxP recombination in stromal cells cannot be applied in this model, limiting the in vivo investigation of stromal genetics in tumor initiation and progression. To address this issue, we generated a new Pdx1FlpO knock-in mouse line, which represents the first mouse model to physiologically express FlpO recombinase in pancreatic epithelial cells. This mouse specifically recombines Frt loci in pancreatic epithelial cells, including acinar, ductal, and islet cells. When combined with the Frt-STOP-Frt KrasG12D and p53Frt mouse lines, simultaneous Pdx1FlpO activation of mutant Kras and deletion of p53 results in the spectrum of pathologic changes seen in PDAC, including PanIN lesions and ductal carcinoma. Combination of this KPF mouse model with any stroma-specific Cre can be used to conditionally modify target genes of interest. This will provide an excellent in vivo tool to study the roles of genes in different cell types and multiple cell compartments within the pancreatic tumor microenvironment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184984PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608307PMC
October 2017

3-(Benzyloxy)-1-(5-[F]fluoropentyl)-5-nitro-1H-indazole: a PET radiotracer to measure acetylcholinesterase in brain.

Future Med Chem 2017 06 20;9(10):983-994. Epub 2017 Jun 20.

Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.

Aim: Noninvasive studies of the acetylcholinesterase (AChE) level in Alzheimer's disease (AD) patients can contribute to a better understanding of the disease and its therapeutic. We propose 3-(benzyloxy)-1-(5-[F]fluoropentyl)-5-nitro-1H-indazole, [F]-IND1, structurally related to the AChE-inhibitor CP126,998, as a new positron emission tomography-radiotracer.

Experimental: Radiosynthesis, with 18F, stability, lipophilicity and protein binding of [18F]-IND1 were studied. In vivo behavior, in normal mice and on AD mice models, were also analyzed.

Results: [F]-IND1 was obtained in good radiochemical yield, was stable for at least 2 h in different conditions, and had adequate lipophilicity for blood-brain barrier penetration. Biodistribution studies, in normal mice, showed that [F]-IND1 was retained in the brain after 1 h. In vivo tacrine-blocking experiments indicated this uptake could be specifically due to AChE interaction. Studies in transgenic AD mice showed differential, compared with normal mice, binding in many brain regions.

Conclusion: [F]-IND1 can be used to detect AChE changes in AD patients.
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http://dx.doi.org/10.4155/fmc-2017-0023DOI Listing
June 2017

The Evolution of Clinical Trials in Oncology: Defining Who Benefits from New Drugs Using Innovative Study Designs.

Oncologist 2017 09 15;22(9):1015-1019. Epub 2017 Jun 15.

Department of Biomedical Informatics, Ohio State University Center for Biostatistics, Ohio State University, Columbus, Ohio, USA.

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http://dx.doi.org/10.1634/theoncologist.2017-0153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599203PMC
September 2017

Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation.

Dev Cell 2017 05;41(4):392-407.e6

Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular Genetics, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA; Department of Cancer Biology and Genetics, McGill University, Montreal, QC H3A 1A1, Canada; Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center 124J, 86 Jonathan Lucas Street, Charleston, SC 29425, USA. Electronic address:

Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation. Stromal fibroblast-specific deletion of mouse orthologs of several candidates resulted in the hyper-proliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients, and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth-suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.
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http://dx.doi.org/10.1016/j.devcel.2017.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508591PMC
May 2017

Power analysis for RNA-Seq differential expression studies.

BMC Bioinformatics 2017 May 3;18(1):234. Epub 2017 May 3.

Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, 1800 Cannon Dr., Columbus, 43210, OH, USA.

Background: Sample size calculation and power estimation are essential components of experimental designs in biomedical research. It is very challenging to estimate power for RNA-Seq differential expression under complex experimental designs. Moreover, the dependency among genes should be taken into account in order to obtain accurate results.

Results: In this paper, we propose a simulation based procedure for power estimation using the negative binomial distribution and assuming a generalized linear model (at the gene level) that considers the dependence between gene expression level and its variance (dispersion) and also allows equal or unequal dispersion across conditions. We compared the performance of both Wald test and likelihood ratio test under different scenarios. The null distribution of the test statistics was simulated for the desired false positive control to avoid excess false positives with the usage of an asymptotic chi-square distribution. We applied this method to the TCGA breast cancer data set.

Conclusions: We provide a framework for power estimation of RNA-Seq data. The proposed procedure is able to properly control the false positive error rate at the nominal level.
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http://dx.doi.org/10.1186/s12859-017-1648-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415728PMC
May 2017

RCAN1-4 is a thyroid cancer growth and metastasis suppressor.

JCI Insight 2017 03 9;2(5):e90651. Epub 2017 Mar 9.

Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.

Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells. Subcutaneous xenograft models demonstrated that RCAN1-4 knockdown promotes tumor growth. Intravenous metastasis models demonstrated that RCAN1-4 loss promotes tumor metastases to the lungs and their subsequent growth. Finally, stable induction of RCAN1-4 expression reduced thyroid cancer cell growth and invasion. Microarray analysis predicted that nuclear factor, erythroid 2-like 3 (NFE2L3) was a pivotal downstream effector of RCAN1-4. NFE2L3 overexpression was shown to be necessary for RCAN1-4-mediated enhanced growth and invasiveness and NEF2L3 overexpression independently increased cell invasion. In human samples, NFE2L3 was overexpressed in TCGA thyroid cancer samples versus normal tissues and NFE2L3 overexpression was demonstrated in distant metastasis samples from thyroid cancer patients. In conclusion, we provide the first evidence to our knowledge that RCAN1-4 is a growth and metastasis suppressor in vivo and that it functions in part through NFE2L3.
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http://dx.doi.org/10.1172/jci.insight.90651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333959PMC
March 2017

Identification of somatic and germ-line DICER1 mutations in pleuropulmonary blastoma, cystic nephroma and rhabdomyosarcoma tumors within a DICER1 syndrome pedigree.

BMC Cancer 2017 02 21;17(1):146. Epub 2017 Feb 21.

Laboratorio de Oncología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain.

Background: DICER1 syndrome is a pediatric cancer predisposition condition causing a variety of tumor types in children and young adults. In this report we studied a family with two relatives presenting a variety of neoplastic conditions at childhood.

Methods: Germ-line mutation screening of the complete coding region of the DICER1 gene in genomic DNA from the proband was performed. The presence of somatic DICER1 mutation and further alterations in driver genes was investigated in genomic DNA obtained from available tumor samples.

Results: A nonsense germ-line mutation in DICER1 causing a truncated protein at the IIIb domain level was identified segregating within a family including two affected relatives who developed in one case cystic nephroma and pleuropulmonary blastoma, and rhabdomyosarcoma and multinodular goiter in the other. Additional in trans DICER1 missense somatic mutations in the IIIb DICER1 domain were found both in the cystic nephroma and in the rhabdomyosarcoma, suggesting that neoplasms in this family might arise from the unusual two-hit mechanism for DICER-derived tumorigenesis in which after the presence of a truncated constitutive protein, a neomorphic DICER1 activity is somatically adquired. Additional genetic alterations, such as TP53 mutations, were identified in the rhabdomyosarcoma.

Conclusions: Besides DICER1 loss of standard activity, oncogenic cooperation of other genes, as mutated TP53, may involve developing higher grade tumors within this syndrome. Given the broad clinical spectrum that may arise, genetic counseling and close surveillance must be offered to all family members at risk of DICER1 syndrome.
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http://dx.doi.org/10.1186/s12885-017-3136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320664PMC
February 2017

Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

J Clin Invest 2017 Mar 30;127(3):830-842. Epub 2017 Jan 30.

Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.
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http://dx.doi.org/10.1172/JCI87583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330731PMC
March 2017

Paediatric emergency department-based carbon monoxide detector intervention: a randomised trial.

Inj Prev 2017 10 22;23(5):314-320. Epub 2016 Dec 22.

Emergency Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Background: Although non-fire-related carbon monoxide (CO) poisoning is almost entirely preventable, over 400 people die and 20 000 people are injured each year in the USA from unintentional CO poisoning. Thus, there is a critical need for evidence-based interventions for preventing CO poisoning and increasing the proper use and installation of CO detectors.

Methods: A randomised, controlled trial (Project CODE, a Carbon Monoxide Detector Education intervention) with 2-week and 6-month follow-up home observations was conducted in 299 parents of children aged ≤18 years recruited in the emergency department of a level 1 paediatric trauma centre. The intervention group received an educational tool, a spiral-bound, laminated booklet that resembled a CO detector containing theory-based safety messages based on the precaution adoption process model, a plug-in CO detector and 9 V battery. The control group received a one page flyer on CO poisoning prevention.

Results: Although the difference was not statistically significant, mean CO knowledge score increased at a greater rate for the intervention group than the control group. Intervention group parents were more likely to exhibit 'safe' CO detector use than control group parents at the 2-week follow-up (RR: 2.75; 95% CI 2.06 to 3.69) and 6-month follow-up (RR: 2.78; 95% CI 2.06 to 3.76), after adjusting for self-reported CO detector use behaviour at enrolment and annual per capita income.

Conclusions: An emergency department-delivered intervention containing a theory-based educational tool paired with a CO detector can be an effective method for increasing knowledge about CO poisoning, for prevention and for appropriate use of a CO detector.

Trial Registration Number: NCT00959478.
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http://dx.doi.org/10.1136/injuryprev-2016-042039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644346PMC
October 2017

Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia.

Neoplasia 2016 09;18(9):541-52

Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a Kras(G12D)-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2-deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic Kras(G12D) signaling during the initial stages of tumor development.
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http://dx.doi.org/10.1016/j.neo.2016.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031867PMC
September 2016