Publications by authors named "Kathryn L Pellegrini"

17 Publications

  • Page 1 of 1

Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

Cell 2021 01 10;184(2):460-475.e21. Epub 2020 Nov 10.

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address:

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.cell.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654323PMC
January 2021

Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques.

Cell 2020 11 9;183(5):1354-1366.e13. Epub 2020 Oct 9.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address:

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546181PMC
November 2020

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

bioRxiv 2020 Sep 16. Epub 2020 Sep 16.

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.09.16.300277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523106PMC
September 2020

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans.

Science 2020 09 11;369(6508):1210-1220. Epub 2020 Aug 11.

Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.

Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators-including EN-RAGE, TNFSF14, and oncostatin M-which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.
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http://dx.doi.org/10.1126/science.abc6261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665312PMC
September 2020

Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures.

J Virol 2020 09 15;94(19). Epub 2020 Sep 15.

Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA

The newly emerged human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic of respiratory illness. Current evidence suggests that severe cases of SARS-CoV-2 are associated with a dysregulated immune response. However, little is known about how the innate immune system responds to SARS-CoV-2. In this study, we modeled SARS-CoV-2 infection using primary human airway epithelial (pHAE) cultures, which are maintained in an air-liquid interface. We found that SARS-CoV-2 infects and replicates in pHAE cultures and is directionally released on the apical, but not basolateral, surface. Transcriptional profiling studies found that infected pHAE cultures had a molecular signature dominated by proinflammatory cytokines and chemokine induction, including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and CXCL8, and identified NF-κB and ATF-4 as key drivers of this proinflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III interferon (IFN) response to SARS-CoV-2 infection. However, pretreatment and posttreatment with type I and III IFNs significantly reduced virus replication in pHAE cultures that correlated with upregulation of antiviral effector genes. Combined, our findings demonstrate that SARS-CoV-2 does not trigger an IFN response but is sensitive to the effects of type I and III IFNs. Our studies demonstrate the utility of pHAE cultures to model SARS-CoV-2 infection and that both type I and III IFNs can serve as therapeutic options to treat COVID-19 patients. The current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. Our research identifies an excellent system to model SARS-CoV-2 infection of the human airways that can be used to test various treatments. Analysis of infection in this model system found that human airway epithelial cell cultures induce a strong proinflammatory cytokine response yet block the production of type I and III IFNs to SARS-CoV-2. However, treatment of airway cultures with the immune molecules type I or type III interferon (IFN) was able to inhibit SARS-CoV-2 infection. Thus, our model system identified type I or type III IFN as potential antiviral treatments for COVID-19 patients.
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http://dx.doi.org/10.1128/JVI.00985-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495371PMC
September 2020

A Four-Group Urine Risk Classifier for Predicting Outcome in Prostate Cancer Patients.

BJU Int 2019 May 20. Epub 2019 May 20.

Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK.

Objectives: To develop a risk classifier using urine-derived extracellular vesicle RNA (UEV-RNA) capable of providing diagnostic information of disease status prior to biopsy, and prognostic information for men on active surveillance (AS).

Patients And Methods: Post-digital rectal examination UEV-RNA expression profiles from urine (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based Continuation-Ratio model was built to generate four Prostate-Urine-Risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico Low-risk (PUR-2), Intermediate-risk (PUR-3), and High-risk (PUR-4) PCa. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation.

Results: Each PUR signature was significantly associated with its corresponding clinical category (p<0.001). PUR-4 status predicted the presence of clinically significant Intermediate or High-risk disease, AUC = 0.77 (95% CI: 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n=87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (p<0.001; IQR HR = 2.86, 95% CI:1.83-4.47). PUR-4, when utilised continuously, dichotomised patient groups with differential progression rates of 10% and 60% five years post-urine collection (p<0.001, HR = 8.23, 95% CI:3.26-20.81).

Conclusion: UEV-RNA can provide diagnostic information of aggressive PCa prior to biopsy, and prognostic information for men on AS. PUR represents a new & versatile biomarker that could result in substantial alterations to current treatment of PCa patients. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/bju.14811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851983PMC
May 2019

epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer.

JCO Precis Oncol 2019 14;2019. Epub 2019 Jan 14.

University College Dublin.

Purpose: Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa. We investigated the accuracy of a six-gene DNA methylation panel (Epigenetic Cancer of the Prostate Test in Urine [epiCaPture]) at detecting PCa, high-grade (Gleason score greater than or equal to 8) and high-risk (D'Amico and Cancer of the Prostate Risk Assessment] PCa from urine.

Patients And Methods: Prognostic utility of epiCaPture genes was first validated in two independent prostate tissue cohorts. epiCaPture was assessed in a multicenter prospective study of 463 men undergoing prostate biopsy. epiCaPture was performed by quantitative methylation-specific polymerase chain reaction in DNA isolated from prebiopsy urine sediments and evaluated by receiver operating characteristic and decision curves (clinical benefit). The epiCaPture score was developed and validated on a two thirds training set to one third test set.

Results: Higher methylation of epiCaPture genes was significantly associated with increasing aggressiveness in PCa tissues. In urine, area under the receiver operating characteristic curve was 0.64, 0.86, and 0.83 for detecting PCa, high-grade PCa, and high-risk PCa, respectively. Decision curves revealed a net benefit across relevant threshold probabilities. Independent analysis of two epiCaPture genes in the same clinical cohort provided analytical validation. Parallel epiCaPture analysis in urine and matched biopsy cores showed added value of a liquid biopsy.

Conclusion: epiCaPture is a urine DNA methylation test for high-risk PCa. Its tumor specificity out-performs that of prostate-specific antigen (greater than 3 ng/mL). Used as an adjunct to prostate-specific antigen, epiCaPture could aid patient stratification to determine need for biopsy.
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http://dx.doi.org/10.1200/PO.18.00134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383793PMC
January 2019

Identification of the Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer.

Cancers (Basel) 2018 Oct 11;10(10). Epub 2018 Oct 11.

Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta 30322, Georgia.

Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis.

Results: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost the AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between the high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting a refinement of critical TFCGs in prostate cancer progression.

Conclusions: We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent the development of CRPC following ADT.
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http://dx.doi.org/10.3390/cancers10100379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210624PMC
October 2018

Detection of prostate cancer-specific transcripts in extracellular vesicles isolated from post-DRE urine.

Prostate 2017 Jun 17;77(9):990-999. Epub 2017 Apr 17.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Background: The measurement of gene expression in post-digital rectal examination (DRE) urine specimens provides a non-invasive method to determine a patient's risk of prostate cancer. Many currently available assays use whole urine or cell pellets for the analysis of prostate cancer-associated genes, although the use of extracellular vesicles (EVs) has also recently been of interest. We investigated the expression of prostate-, kidney-, and bladder-specific transcripts and known prostate cancer biomarkers in urine EVs.

Methods: Cell pellets and EVs were recovered from post-DRE urine specimens, with the total RNA yield and quality determined by Bioanalyzer. The levels of prostate, kidney, and bladder-associated transcripts in EVs were assessed by TaqMan qPCR and targeted sequencing.

Results: RNA was more consistently recovered from the urine EV specimens, with over 80% of the patients demonstrating higher RNA yields in the EV fraction as compared to urine cell pellets. The median EV RNA yield of 36.4 ng was significantly higher than the median urine cell pellet RNA yield of 4.8 ng. Analysis of the post-DRE urine EVs indicated that prostate-specific transcripts were more abundant than kidney- or bladder-specific transcripts. Additionally, patients with prostate cancer had significantly higher levels of the prostate cancer-associated genes PCA3 and ERG.

Conclusions: Post-DRE urine EVs are a viable source of prostate-derived RNAs for biomarker discovery and prostate cancer status can be distinguished from analysis of these specimens. Continued analysis of urine EVs offers the potential discovery of novel biomarkers for pre-biopsy prostate cancer detection.
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http://dx.doi.org/10.1002/pros.23355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907935PMC
June 2017

Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality.

BJU Int 2017 06 11;119(6):961-967. Epub 2017 Feb 11.

Winship Cancer Institute, Atlanta, GA, USA.

Objectives: To determine the prognostic potential of a 24-gene signature, Sig24, for identifying patients with prostate cancer who are at risk of developing metastases or of prostate cancer-specific mortality (PCSM) after radical prostatectomy (RP).

Patients And Methods: Sig24 scores were calculated from previously collected gene expression microarray data from the Cleveland Clinic and Mayo Clinic (I and II). The performance of Sig24 was determined using time-dependent c-index analysis, Cox proportional hazards regression and Kaplan-Meier survival analysis.

Results: Higher Sig24 scores were significantly associated with higher pathological Gleason scores in all three cohorts. Analysis of the Mayo Clinic II cohort, which included time-to-event information, indicated that patients with high Sig24 scores also had a higher risk of developing metastasis (hazard ratio [HR] 3.78, 95% confidence interval [CI]: 1.96-7.29; P < 0.001) or of PCSM (HR 6.54, 95% CI: 2.16-19.83; P < 0.001).

Conclusions: The findings of the present study show the applicability of Sig24 for the prognosis of metastasis or PCSM after RP. Future studies investigating the combination of Sig24 with available prognostic tests may provide new approaches to improve risk stratification for patients with prostate cancer.
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http://dx.doi.org/10.1111/bju.13779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444982PMC
June 2017

Application of small RNA sequencing to identify microRNAs in acute kidney injury and fibrosis.

Toxicol Appl Pharmacol 2016 Dec 17;312:42-52. Epub 2015 Dec 17.

Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA. Electronic address:

Establishing a microRNA (miRNA) expression profile in affected tissues provides an important foundation for the discovery of miRNAs involved in the development or progression of pathologic conditions. We conducted small RNA sequencing to generate a temporal profile of miRNA expression in the kidneys using a mouse model of folic acid-induced (250mg/kgi.p.) kidney injury and fibrosis. From the 103 miRNAs that were differentially expressed over the time course (>2-fold, p<0.05), we chose to further investigate miR-18a-5p, which is expressed during the acute stage of the injury; miR-132-3p, which is upregulated during transition between acute and fibrotic injury; and miR-146b-5p, which is highly expressed at the peak of fibrosis. Using qRT-PCR, we confirmed the increased expression of these candidate miRNAs in the folic acid model as well as in other established mouse models of acute injury (ischemia/reperfusion injury) and fibrosis (unilateral ureteral obstruction). In situ hybridization confirmed high expression of miR-18a-5p, miR-132-3p and miR-146b-5p throughout the kidney cortex in mice and humans with severe kidney injury or fibrosis. When primary human proximal tubular epithelial cells were treated with model nephrotoxicants such as cadmium chloride (CdCl), arsenic trioxide, aristolochic acid (AA), potassium dichromate (KCrO) and cisplatin, miRNA-132-3p was upregulated 4.3-fold after AA treatment and 1.5-fold after KCrO and CdCl treatment. These results demonstrate the application of temporal small RNA sequencing to identify miR-18a, miR-132 and miR-146b as differentially expressed miRNAs during distinct phases of kidney injury and fibrosis progression.
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http://dx.doi.org/10.1016/j.taap.2015.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912473PMC
December 2016

The transcription factor ERG increases expression of neurotransmitter receptors on prostate cancer cells.

BMC Cancer 2015 Aug 27;15:604. Epub 2015 Aug 27.

Department of Surgery, Urology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, E/CLS-446, Boston, MA, 02215, USA.

Background: The TMPRSS2-ERG gene fusion occurs in about half of prostate cancer (PCa) cases and results in overexpression of the transcription factor ERG. Overexpression of ERG has many effects on cellular function. However, how these changes enhance cell growth and promote tumor development is unclear.

Methods: To investigate the role of ERG, LNCaP and PC3 cells were transfected with ERG and gene expression and metabolic profile were analyzed.

Results: Our data show that expression of ERG induces overexpression of many nicotinicacetylcholine receptors (nAChRs). In addition, metabolic profiling by LC-MS/MS revealed elevated production of several neurotransmitters in cells expressing ERG. Consistently, treatment of ERG-expressing cells with nicotine induced elevated calcium influx, GSK3β (Ser9) phosphorylation and cell proliferation. Finally, we show that PCa patientswho are smokers have larger tumors if their tumors are TMPRSS2-ERG gene fusion positive.

Conclusion: Collectively, our data suggest that ERG sensitizes prostate tumor cells to neurotransmitter receptor agonists like nicotine.
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http://dx.doi.org/10.1186/s12885-015-1612-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549934PMC
August 2015

Nanoparticle Detection of Urinary Markers for Point-of-Care Diagnosis of Kidney Injury.

PLoS One 2015 17;10(7):e0133417. Epub 2015 Jul 17.

Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts, United States of America; Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, Massachusetts, United States of America.

The high incidence of acute and chronic kidney injury due to various environmental factors such as heavy metals or chemicals has been a major problem in developing countries. However, the diagnosis of kidney injury in these areas can be more challenging due to the lack of highly sensitive and specific techniques that can be applied in point-of-care settings. To address this, we have developed a technique called 'micro-urine nanoparticle detection (μUNPD)', that allows the detection of trace amounts of molecular markers in urine. Specifically, this technique utilizes an automated on-chip assay followed by detection with a hand-held device for the read-out. Using the μUNPD technology, the kidney injury markers KIM-1 and Cystatin C were detected down to concentrations of 0.1 ng/ml and 20 ng/ml respectively, which meets the cut-off range required to identify patients with acute or chronic kidney injury. Thus, we show that the μUNPD technology enables point of care and non-invasive detection of kidney injury, and has potential for applications in diagnosing kidney injury with high sensitivity in resource-limited settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133417PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506142PMC
May 2016

RNA biomarkers to facilitate the identification of aggressive prostate cancer.

Mol Aspects Med 2015 Nov 27;45:37-46. Epub 2015 May 27.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Winship Cancer Institute at Emory University, Atlanta, GA 30322, USA. Electronic address:

A large number of men are diagnosed with prostate cancer each year, but many will not experience morbidity or mortality as a result of their cancers. Therefore, biomarkers for prostate cancer are necessary to carefully select patients for initial diagnostic biopsy or to facilitate care decisions for men who have already been diagnosed with prostate cancer. RNA-based approaches to biomarker discovery allow the investigation of non-coding RNAs, gene fusion transcripts, splice variants, and multi-gene expression panels in tissue, urine, or blood as opportunities to improve care decisions. This review focuses on RNA biomarkers that are available as commercial assays, and therefore already available for potential clinical use, as well as providing an overview of newer RNA biomarkers that are in earlier stages of clinical development.
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http://dx.doi.org/10.1016/j.mam.2015.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637232PMC
November 2015

MicroRNA-155 deficient mice experience heightened kidney toxicity when dosed with cisplatin.

Toxicol Sci 2014 Oct 11;141(2):484-92. Epub 2014 Jul 11.

Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, Massachusetts Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts

The development of nephrotoxicity limits the maximum achievable dosage and treatment intervals for cisplatin chemotherapy. Therefore, identifying mechanisms that regulate this toxicity could offer novel methods to optimize cisplatin delivery. MicroRNAs are capable of regulating many different genes, and can influence diverse cellular processes, including cell death and apoptosis. We previously observed miR-155 to be highly increased following ischemic or toxic injury to the kidneys and, therefore, sought to determine whether mice deficient in miR-155 would respond differently to kidney injury. We treated C57BL/6 and miR-155(-/-) mice with 20 mg/kg of cisplatin and found a significantly higher level of kidney injury in the miR-155(-/-) mice. Genome-wide expression profiling and bioinformatic analysis indicated the activation of a number of canonical signaling pathways relating to apoptosis and oxidative stress over the course of the injury, and identified potential upstream regulators of these effects. One predicted upstream regulator was c-Fos, which has two confirmed miR-155 binding sites in its 3' UTR and, therefore, can be directly regulated by miR-155. We established that the miR-155(-/-) mice had significantly higher levels of c-Fos mRNA and protein than the C57BL/6 mice at 72 h after cisplatin exposure. These data indicate a role for miR-155 in the cisplatin response and suggest that targeting of c-Fos could be investigated to reduce cisplatin-induced nephrotoxicity.
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http://dx.doi.org/10.1093/toxsci/kfu143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200048PMC
October 2014

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation.

Proc Natl Acad Sci U S A 2014 Jul 23;111(27):9887-92. Epub 2014 Jun 23.

Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;

The hormonal milieu influences immune tolerance and the immune response against viruses and cancer, but the direct effect of androgens on cellular immunity remains largely uncharacterized. We therefore sought to evaluate the effect of androgens on murine and human T cells in vivo and in vitro. We found that murine androgen deprivation in vivo elicited RNA expression patterns conducive to IFN signaling and T-cell differentiation. Interrogation of mechanism showed that testosterone regulates T-helper 1 (Th1) differentiation by inhibiting IL-12-induced Stat4 phosphorylation: in murine models, we determined that androgen receptor binds a conserved region within the phosphatase, Ptpn1, and consequent up-regulation of Ptpn1 then inhibits IL-12 signaling in CD4 T cells. The clinical relevance of this mechanism, whereby the androgen milieu modulates CD4 T-cell differentiation, was ascertained as we found that androgen deprivation reduced expression of Ptpn1 in CD4 cells from patients undergoing androgen deprivation therapy for prostate cancer. Our findings, which demonstrate a clinically relevant mechanism by which androgens inhibit Th1 differentiation of CD4 T cells, provide rationale for targeting androgens to enhance CD4-mediated immune responses in cancer or, conversely, for modulating androgens to mitigate CD4 responses in disorders of autoimmunity.
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http://dx.doi.org/10.1073/pnas.1402468111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103356PMC
July 2014

The survival of myoblasts after intramuscular transplantation is improved when fewer cells are injected.

Transplantation 2011 Mar;91(5):522-6

Discipline of Microbiology and Immunology, School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Australia.

Background: Myoblast transplantation has long been studied as a potential therapy for Duchenne muscular dystrophy as the incorporation of donor myoblasts into host muscle allows the production of functional dystrophin protein. However, the clinical feasibility of this approach is limited by the poor survival of the donor cells in the weeks after transplantation. It has recently been determined that the intramuscular transplantation of large numbers of cells can lead to the formation of ischemic necrosis in the center of these cell masses. For this reason, the relationship between donor cell survival and the number of cells transplanted was investigated.

Methods: Myoblasts were prepared from the hind limb muscles of male C57BL/10Sn mice and transplanted into the tibialis anterior muscles of female mdx mice at one of the following amounts: 10, 10, 10, or 10 cells. The survival of the transplanted cells was analyzed using a Y chromosome-specific qPCR.

Results: It was found that donor cell survival was improved 1 week after transplantation when fewer myoblasts were transplanted, including the observation of donor cell proliferation after the transplantation of 10 myoblasts. However, concentration effects and long-term survival complicate the interpretation of these results.

Conclusions: These results indicate that early donor myoblast survival was dependent on the number of cells transplanted and the volume of liquid used to deliver them into the muscle. We believe that this finding has implications for the design and interpretation of future experimentation relating to intramuscular cell therapies.
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http://dx.doi.org/10.1097/TP.0b013e318208a8c0DOI Listing
March 2011