Publications by authors named "Chris Miller"

125 Publications

Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma.

Hum Vaccin Immunother 2021 Mar 5:1-15. Epub 2021 Mar 5.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

In renal-cell carcinoma (RCC), tumor-reactive T-cell responses can occur spontaneously or in response to systemic immunotherapy with cytokines and immune checkpoint inhibitors. Cancer vaccines and engineered T-cell therapies are designed to selectively augment tumor antigen-specific CD8 T-cell responses with the goal to elicit tumor regression and avoid toxicities associated with nonspecific immunotherapies. In this review, we provide an overview of the central role of T-cell immunity in the treatment of advanced RCC. Clinical outcomes for antigen-targeted vaccines or other T-cell-engaging therapies for RCC are summarized and evaluated, and emerging new strategies to enhance the effectiveness of antigen-specific therapy for RCC are discussed.
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http://dx.doi.org/10.1080/21645515.2020.1870846DOI Listing
March 2021

Q-cubed mutant cues clues to CLC antiport mechanism.

Authors:
Chris Miller

J Gen Physiol 2021 Apr;153(4)

Department of Biochemistry, Brandeis University, Waltham, MA.

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http://dx.doi.org/10.1085/jgp.202112868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894039PMC
April 2021

Chromosome 8 gain is associated with high-grade transformation in MPNST.

JCI Insight 2021 Mar 22;6(6). Epub 2021 Mar 22.

Department of Internal Medicine, Division of Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
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http://dx.doi.org/10.1172/jci.insight.146351DOI Listing
March 2021

First performance report of QIAreach™ Anti-SARS-CoV-2 Total Test, an innovative nanoparticle fluorescence digital detection platform.

J Clin Virol 2020 12 30;133:104681. Epub 2020 Oct 30.

QIAGEN LLC, Germantown, MD, USA.

In 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic. Disease diagnosis, appropriate clinical management and infection control are all important factors in controlling the spread of SARS-CoV-2. The QIAreach™ Anti-SARS-CoV-2 Total Test (Anti-CoV2) is a rapid, qualitative serological test, using proprietary nanoparticle fluorescence technology to detect total antibody (IgA, IgM, and IgG) against SARS-CoV-2. Here we report the results of the US Food and Drug Administration (FDA) clinical agreement study. Thirty positive plasma or serum samples were taken from consenting individuals with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection ≥14 days from symptom onset. Seventy-five samples from before the believed circulation of SARS-CoV-2 (November 1, 2019) were used to assess specificity. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated along with the corresponding exact two-sided 95 % confidence intervals (CI) using an FDA Emergency Use Authorized PCR test as the reference method. Anti-CoV2 was shown to have 100 % sensitivity (PPA; 95 % CI 88.4-100 %) and 100 % specificity (NPA; 95 % CI 95.2-100 %). Against 157 pre-pandemic samples, no cross-reactivity was observed with seasonal coronaviruses or other respiratory pathogens tested. Additionally, no interference was observed when samples were spiked with: conjugated bilirubin 0.4 mg/ml; unconjugated bilirubin 0.4 mg/ml; hemoglobin 5 mg/ml; prednisolone 0.12 mg/ml; triglycerides 15 mg/ml. In conclusion, Anti-CoV2 provides accurate qualitative detection of total antibodies against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jcv.2020.104681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833412PMC
December 2020

Novel de novo intronic variant causes rhizomelic short stature with microretrognathia and developmental delay.

Cold Spring Harb Mol Case Stud 2020 Dec 17;6(6). Epub 2020 Dec 17.

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.

The archain 1 () gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5-yr-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the related syndrome caused by a novel de novo intronic variant. Whole-exome sequencing of the proband and his parents was utilized to determine the genetic origin of the patient's disorder and identified a de novo variant, NM_001655.5:c.654-15A > G, in the gene. Follow-up functional characterization of mRNA from the patient demonstrated that this variant creates a splicing defect of the mRNA. -related syndrome represents an emerging disorder of developmental delay, and this report represents the sixth described patient. Despite the few instances reported in literature, the phenotype is consistent between our patient and previously reported individuals.
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http://dx.doi.org/10.1101/mcs.a005728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784487PMC
December 2020

COVID-19 pandemic personal development plan: A model for maximising higher specialty training.

Future Healthc J 2020 Oct;7(3):e80-e83

Leicester Royal Infirmary, Leicester, UK.

The coronavirus disease 2019 (COVID-19) pandemic has led to multiple service delivery changes across acute care sectors in the UK. Due to increased responsibility for care of COVID-19 patients, medical trainees across all specialties might experience difficulty in achieving certain competencies for their training curriculum due to changes in learning opportunities. While there might be a tendency to perceive these changes negatively in terms of the impact on training, we think this unprecedented situation might present a unique learning opportunity. A group of geriatric medicine trainees and trainers devised an innovative, forward-thinking specific training plan based on existing Joint Royal Colleges of Physicians Training Board geriatric medicine curricula, encouraging development of a personal development plan (PDP) tailored to the pandemic. This model could be considered for all specialty training curricula, providing a proactive approach to optimising training during the pandemic. By formulating a 'pandemic PDP' early and considering methods to maximise learning, training needs can be met even in these extraordinary times.
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http://dx.doi.org/10.7861/fhj.2020-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571723PMC
October 2020

The structure of depressive symptoms and characteristics and their relation to overall severity in major depressive disorder.

Psychiatry Res 2020 12 11;294:113399. Epub 2020 Sep 11.

Department of Psychology, Stanford University, Stanford, CA 94305, United States; Stanford Neurosciences Institute, Stanford University School of Medicine, Stanford, CA 94305, United States.

Although many investigators have examined symptoms of major depressive disorder (MDD), the multivariate relations among these features of depression and their relative associations with overall severity of depression are not well understood. The present study is the first to examine the underlying factor structure of depression across a broad set of constructs and to model the multivariate association of these factors with the overall severity of depression. We conducted a large-scale factor analysis and multiple regression in a sample of participants diagnosed with MDD (N = 233) and healthy controls (N = 235). We obtained a five-factor solution composed of the following factors: (1) anxiety; (2) behavioral activation; (3) core symptoms; (4) rumination; and (5) emotional intensity. The core symptoms factor, composed primarily of DSM-5 diagnostic criteria for MDD, was the only factor that showed a consistent, significant association with overall severity of depression and functional impairment. Rumination combined with behavioral inhibition and positive and negative affect combined with each other to form coherent constructs that may be useful in examining differences among depressed individuals. These findings provide an important data-driven framework for the multidimensional symptom structure of depression and suggest several actionable ways for improving clinical assessment and treatment for individuals with MDD.
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http://dx.doi.org/10.1016/j.psychres.2020.113399DOI Listing
December 2020

Nox4 regulates InsP receptor-dependent Ca release into mitochondria to promote cell survival.

EMBO J 2020 10 10;39(19):e103530. Epub 2020 Aug 10.

School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre, London, UK.

Cells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post-mitotic cells such as cardiomyocytes and neurons. Here, we show that stress-induced upregulation of the ROS-generating protein Nox4 at the ER-mitochondria contact sites (MAMs) is a pro-survival mechanism that inhibits calcium transfer through InsP receptors (InsP R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP R, thereby inhibiting calcium flux and mPT-dependent necrosis. In hearts subjected to ischemia-reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS-generating protein mediates pro-survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT.
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http://dx.doi.org/10.15252/embj.2019103530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527947PMC
October 2020

The need for improved discharge criteria for hospitalised patients with COVID-19-implications for patients in long-term care facilities.

Age Ageing 2021 01;50(1):16-20

Department of Respiratory Sciences, University of Leicester, Leicester, UK.

In the COVID-19 pandemic, patients who are older and residents of long-term care facilities (LTCF) are at greatest risk of worse clinical outcomes. We reviewed discharge criteria for hospitalised COVID-19 patients from 10 countries with the highest incidence of COVID-19 cases as of 26 July 2020. Five countries (Brazil, Mexico, Peru, Chile and Iran) had no discharge criteria; the remaining five (USA, India, Russia, South Africa and the UK) had discharge guidelines with large inter-country variability. India and Russia recommend discharge for a clinically recovered patient with two negative reverse transcription polymerase chain reaction (RT-PCR) tests 24 h apart; the USA offers either a symptom based strategy-clinical recovery and 10 days after symptom onset, or the same test-based strategy. The UK suggests that patients can be discharged when patients have clinically recovered; South Africa recommends discharge 14 days after symptom onset if clinically stable. We recommend a unified, simpler discharge criteria, based on current studies which suggest that most SARS-CoV-2 loses its infectivity by 10 days post-symptom onset. In asymptomatic cases, this can be taken as 10 days after the first positive PCR result. Additional days of isolation beyond this should be left to the discretion of individual clinician. This represents a practical compromise between unnecessarily prolonged admissions and returning highly infectious patients back to their care facilities, and is of particular importance in older patients discharged to LTCFs, residents of which may be at greatest risk of transmission and worse clinical outcomes.
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http://dx.doi.org/10.1093/ageing/afaa206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543250PMC
January 2021

Guest Editors' Corner.

Orbis 2020 1;64(3):371-373. Epub 2020 Jul 1.

Guest Editors.

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http://dx.doi.org/10.1016/j.orbis.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329279PMC
July 2020

Urethral involvement is associated with higher mortality and local recurrence in vulvar melanoma: a single institutional experience.

Hum Pathol 2020 10 20;104:1-8. Epub 2020 Jul 20.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Vulvar malignant melanoma (VMM), although uncommon, comprises 5-10% of all vulvar malignancies. Local control is notoriously poor in VMM with recurrence rates of 30-50% compared with approximately 3% in cutaneous melanomas. We studied clinicopathologic features of 37 women with VMM, after reviewing three decades of clinical follow-up data in our institutional databases. Most patients were Caucasian (n = 35) with an average age at diagnosis of 60.6 years (range 23-83). The most common subtype was mucosal lentiginous melanoma (n = 25). We compared Kaplan-Meier survival curves of 31 patients defined by clinical and microscopic attributes using exact log-rank tests. Younger patients at diagnosis (23-64 years), those with thin melanomas (≤1 mm), and those with Clark's level II or III tumors had better 5-year survival rates than older patients (65-83 years) and those with thick melanomas (>1 mm) and those with Clark's level IV or V (P ≤ 0.05), respectively, by exact log-rank test. Local recurrence of melanoma occurred in 15 patients. Nine patients (24%) had eventual urethral involvement by malignant melanoma, and this feature was associated with significantly shorter survival (P = 0.036). Patients with urethral involvement had shorter median time to death and worse 5-year survival rates. Given that spread to the urethra is common in VMM and urethral recurrence is also associated with mortality, pathology excision specimens should be carefully reviewed with attention to urethral involvement as a potentially important prognostic factor.
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http://dx.doi.org/10.1016/j.humpath.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669565PMC
October 2020

Vestibular and Cardiovascular Responses After Long-Duration Spaceflight.

Aerosp Med Hum Perform 2020 Aug;91(8):621-627

The vestibulo-sympathetic reflex operates during orthostatically challenging movements to initiate cardiovascular responses in advance of a baroreceptor-mediated response. The objective of this study was to determine whether there was an association between changes in vestibular function and cardiovascular responses during a prone-to-stand movement in astronauts after return from long-duration spaceflight. Thirteen crewmembers who participated in International Space Station missions were tested before spaceflight and 1 d after landing. Vestibular function was evaluated by computerized dynamic posturography while their head was erect and while they performed dynamic head tilts. Heart rate and mean arterial blood pressure were measured while the subjects were in prone and standing positions. The 21.4% increase in the astronauts' heart rate during the prone to stand maneuver after spaceflight correlated significantly with their spaceflight-induced 48.7% decrease in postural stability during dynamic head tilts. The larger mean arterial pressure in the prone position after spaceflight compared to preflight (+7%) also correlated with the postflight decrease in postural stability during dynamic head tilts. These results indicate that an appropriate vestibular function is important to evoke optimum vestibulo-sympathetic response during orthostatically challenging voluntary movements performed after spaceflight. They also suggest that there may be a greater need to generate an anticipatory cardiovascular response after spaceflight.
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http://dx.doi.org/10.3357/AMHP.5502.2020DOI Listing
August 2020

Engineering Microphysiological Immune System Responses on Chips.

Trends Biotechnol 2020 08 18;38(8):857-872. Epub 2020 Feb 18.

Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Tissues- and organs-on-chips are microphysiological systems (MPSs) that model the architectural and functional complexity of human tissues and organs that is lacking in conventional cell monolayer cultures. While substantial progress has been made in a variety of tissues and organs, chips recapitulating immune responses have not advanced as rapidly. This review discusses recent progress in MPSs for the investigation of immune responses. To illustrate recent developments, we focus on two cases in point: immunocompetent tumor microenvironment-on-a-chip devices that incorporate stromal and immune cell components and pathomimetic modeling of human mucosal immunity and inflammatory crosstalk. More broadly, we discuss the development of systems immunology-on-a-chip devices that integrate microfluidic engineering approaches with high-throughput omics measurements and emerging immunological applications of MPSs.
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http://dx.doi.org/10.1016/j.tibtech.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368088PMC
August 2020

Functional Imaging of the Outer Retinal Complex using High Fidelity Imaging Retinal Densitometry.

Sci Rep 2020 03 11;10(1):4494. Epub 2020 Mar 11.

School of Optometry and Vision Sciences, Maindy Road, Cardiff University, Cardiff, Wales, CF24 4HQ, UK.

We describe a new technique, high fidelity Imaging Retinal Densitometry (IRD), which probes the functional integrity of the outer retinal complex. We demonstrate the ability of the technique to map visual pigment optical density and synthesis rates in eyes with and without macular disease. A multispectral retinal imaging device obtained precise measurements of retinal reflectance over space and time. Data obtained from healthy controls and 5 patients with intermediate AMD, before and after photopigment bleaching, were used to quantify visual pigment metrics. Heat maps were plotted to summarise the topography of rod and cone pigment kinetics and descriptive statistics conducted to highlight differences between those with and without AMD. Rod and cone visual pigment synthesis rates in those with AMD (v = 0.043 SD 0.019 min and v = 0.119 SD 0.046 min, respectively) were approximately half those observed in healthy controls (v = 0.079 SD 0.024 min for rods and v = 0.206 SD 0.069 min for cones). By mapping visual pigment kinetics across the central retina, high fidelity IRD provides a unique insight into outer retinal complex function. This new technique will improve the phenotypic characterisation, diagnosis and treatment monitoring of various ocular pathologies, including AMD.
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http://dx.doi.org/10.1038/s41598-020-60660-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066170PMC
March 2020

Discovery and Development of Gaseous Nitric Oxide Under Increased Atmospheric Pressure as an Antimicrobial: In Vitro and In Vivo Testing of Nitric Oxide Against Multidrug-Resistant Organisms.

Clin Podiatr Med Surg 2020 Apr 30;37(2):231-246. Epub 2020 Jan 30.

Hansen Pharmaceutical, LLC, 7000 SW 62nd Avenue, Suite 405, South Miami, FL 33143, USA.

Gaseous nitric oxide under increased atmospheric pressure (gNOp) has shown ability to kill multidrug-resistant bacteria in an in vitro model and in a live mammalian (porcine) model. Factors impacting the kill rate of the multidrug-resistant bacteria include atmospheric pressures, concentration of gaseous NO, flow rate, and duration of application. Using successful in vitro parameters, gNOp showed multilog reduction of bacteria in a live mammalian (porcine) model. The in vitro testing system, using the EpiDerm-FT skin model (stem cell grown skin), was used to develop an infected wound model for Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant S aureus.
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http://dx.doi.org/10.1016/j.cpm.2019.11.001DOI Listing
April 2020

Ascorbic Acid 2-Glucoside Pretreatment Protects Cells from Ionizing Radiation, UVC, and Short Wavelength of UVB.

Genes (Basel) 2020 02 25;11(3). Epub 2020 Feb 25.

Department of Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.

Ascorbic acid 2-glucoside (AA2G), glucosylated ascorbic acid (AA), has superior properties for bioavailability and stability compared to AA. Although AA2G has shown radioprotective properties similar to AA, effects for UV light, especially UVC and UVB, are not studied. AA2G was tested for cytotoxicity and protective effects against ionizing radiation, UVC, and broadband and narrowband UVB in Chinese hamster ovary (CHO) cells and compared to AA and dimethyl sulfoxide (DMSO). Pretreatment with DMSO, AA, and AA2G showed comparative protective effects in CHO wild type and radiosensitive xrs5 cells for cell death against ionizing radiation with reducing the number of radiation-induced DNA damages. Pretreatment with AA and AA2G protected CHO wild type and UV sensitive UV135 cells from UVC and broadband UV, but not from narrowband UVB. DMSO showed no protective effects against tested UV. The UV filtration effects of AA and AA2G were analyzed with a spectrometer and spectroradiometer. AA and AA2G blocked UVC and reduced short wavelengths of UVB, but had no effect on wavelengths above 300nm. These results suggest that AA2G protects cells from radiation by acting as a radical scavenger to reduce initial DNA damage, as well as protecting cells from certain UVB wavelengths by filtration.
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http://dx.doi.org/10.3390/genes11030238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140853PMC
February 2020

Co-induction of anaesthesia with alfaxalone and midazolam in dogs: a randomized, blinded clinical trial.

Vet Anaesth Analg 2019 Sep 8;46(5):613-619. Epub 2019 Jun 8.

Northwest Veterinary Specialists, Sutton Weaver, Cheshire, United Kingdom.

Objective: To qualitatively assess the co-induction of anaesthesia with midazolam and alfaxalone and to determine cardiovascular or respiratory alterations compared with alfaxalone alone.

Study Design: A randomized, blinded, clinical trial.

Animals: A total of 29 American Society of Anesthesiologists grade I or II, client-owned dogs undergoing elective orthopaedic or soft tissue surgery.

Methods: All dogs received 0.02 mg kg acepromazine and 0.3 mg kg methadone intramuscularly 30 minutes prior to anaesthesia. Measurements of heart rate (HR), respiratory frequency and blood pressure (BP) were assessed pre-induction and at 0, 2 and 5 minutes post-induction. Anaesthesia was induced with 0.5 mg kg alfaxalone followed by either 0.4 mg kg midazolam intravenously (group M) or an equal volume of saline (group S). Conditions were assessed for intubation and further boluses of 0.25 mg kg alfaxalone were given as required. Response to co-induction, ease of intubation and quality of induction were scored, and total dose of alfaxalone required for intubation was recorded. Repeated measures one-way analysis of variance with post hoc Tukey's test was used to assess within group changes over time and Student t tests were used to compare between groups. Incidence of apnoea was assessed using a Fisher's exact test. Data are shown as mean ± standard deviation.

Results: Group M included 14 dogs and group S 15 dogs. There was a significant difference in the total dose of alfaxalone required for intubation, 0.65 ± 0.20 mg kg group M and 0.94 ± 0.26 mg kg group S (p = 0.002). Apnoea occurred significantly more frequently in group M (p = 0.007). There were no clinically significant differences in HR or BP at the measured time points between groups.

Conclusions And Clinical Relevance: Co-induction with midazolam had significant alfaxalone-sparing effects with no clinically detectable cardiovascular changes. Apnoea is common after co-induction.
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http://dx.doi.org/10.1016/j.vaa.2019.03.009DOI Listing
September 2019

Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study.

BMC Cancer 2019 04 18;19(1):366. Epub 2019 Apr 18.

Universitätsklinikum Schleswig-Holstein, Schittenhelmstr, 7, D-24 105, Kiel, Germany.

Following publication of the original article [1], it was reported that the legend for Fig. 1 was incomplete. The complete figure legend is.
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http://dx.doi.org/10.1186/s12885-019-5568-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474043PMC
April 2019

Integrated epigenomic profiling reveals endogenous retrovirus reactivation in renal cell carcinoma.

EBioMedicine 2019 Mar 1;41:427-442. Epub 2019 Mar 1.

Department of Pathology, University of Washington, Seattle, WA 98195, United States; Kidney Research Institute, Seattle, WA 98104, United States. Electronic address:

Background: Transcriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. Renal cell carcinoma (RCC) is the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. Despite intensive study, novel therapeutic strategies to target RCC have been difficult to develop. Since the RCC epigenome is relatively understudied, we sought to elucidate key mechanisms underpinning the tumor phenotype and its clinical behavior.

Methods: We performed genome-wide chromatin accessibility (DNase-seq) and transcriptome profiling (RNA-seq) on paired tumor/normal samples from 3 patients undergoing nephrectomy for removal of RCC. We incorporated publicly available data on HIF binding (ChIP-seq) in a RCC cell line. We performed integrated analyses of these high-resolution, genome-scale datasets together with larger transcriptomic data available through The Cancer Genome Atlas (TCGA).

Findings: Though HIF transcription factors play a cardinal role in RCC oncogenesis, we found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding near their gene body. Examination of chromatin accessibility profiles revealed that some of these transcription factors influenced the tumor's regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Elevated POU5F1 transcript levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Unexpectedly, we discovered a HIF-pathway-responsive promoter embedded within a endogenous retroviral long terminal repeat (LTR) element at the transcriptional start site of the PSOR1C3 long non-coding RNA gene upstream of POU5F1. RNA transcripts are induced from this promoter and read through PSOR1C3 into POU5F1 producing a novel POU5F1 transcript isoform. Rather than being unique to the POU5F1 locus, we found that HIF binds to several other transcriptionally active LTR elements genome-wide correlating with broad gene expression changes in RCC.

Interpretation: Integrated transcriptomic and epigenomic analysis of matched tumor and normal tissues from even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes. Several transcription factors appear to act downstream of HIF including the potent stem cell transcription factor POU5F1. Dysregulated expression of POU5F1 is part of a larger pattern of gene expression changes in RCC that may be induced by HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441874PMC
March 2019

Towards cardiac MRI based risk stratification in idiopathic dilated cardiomyopathy.

Heart 2019 02 30;105(4):270-275. Epub 2018 Oct 30.

Cardiac MRI Department, North West Heart Centre, Manchester University Foundation Trust-Wythenshawe Site, Manchester, UK.

Sudden cardiac death (SCD) secondary to arrhythmia remains a risk in those with dilated cardiomyopathy (DCM), an implantable cardiac defibrillator (ICD) is an effective strategy to prevent SCD. Current guidelines recommend selection for ICD based on ejection fraction (EF) less than 35%, however, most SCD occurs in those with EF>35%. Although meta-analysis has demonstrated a survival benefit for primary prevention ICD in DCM, no randomised trial has shown a significant reduction in overall mortality including the most recent 'Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality' study. Clearly, a more sophisticated selection strategy is required. Cardiac MRI (CMR) is an ideal non-invasive imaging technique which allows calculation of EF as well as tissue characterisation with gadolinium contrast, parametric mapping and feature tracking. Late gadolinium enhancement detects mid-wall fibrosis in approximately 30% of those with DCM, three meta-analyses have demonstrated an association between fibrosis in DCM and SCD, and those without fibrosis are at low risk of SCD. T1 mapping and extracellular volume (ECV) calculation are methods of demonstrating diffuse fibrosis in the myocardium. Raised ECV and native T1 have been associated with worse outcomes but the relationship to SCD has not been well studied. Undoubtedly, more research is required but CMR has several tools which offer incremental value above EF to improve risk stratification and consequent outcomes and resource utilisation in those with DCM.
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http://dx.doi.org/10.1136/heartjnl-2018-313767DOI Listing
February 2019

A mighty stream of membrane proteins.

Authors:
Chris Miller

Nat Struct Mol Biol 2018 09;25(9):751-753

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA.

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http://dx.doi.org/10.1038/s41594-018-0121-xDOI Listing
September 2018

Functional Task and Balance Performance in Bed Rest Subjects and Astronauts.

Aerosp Med Hum Perform 2018 Sep;89(9):805-815

Introduction: The purpose of this study was to determine how short- and long-duration spaceflight affects astronauts' performance on functional tests that challenge the balance control system (Seated Egress and Walk; Object Translation; Recovery from Fall/Stand; and Jump Down) and on clinical tests of balance function (Computerized Dynamic Posturography and Tandem Walk). In addition, we examined how exercise affects functional performance after long-term axial body unloading during 70 d of bed rest at 6° head-down tilt.

Methods: Data were collected twice during the 2-mo period before spaceflight or during the 2-wk period before bed rest, and four times after flight or bed rest: on the day of landing or the day bed rest ended, 1 d and 6 d later, and a final session 12 d after bed rest or 30 d after spaceflight.

Results: For bed rest subjects, long-term axial unloading alone caused functional performance deficits immediately after bed rest. However, the addition of an exercise regimen did not significantly improve median functional performance immediately after this axial unloading. For spaceflight subjects, the length of the space mission was directly related to the severity of functional performance deficits within 1 d of landing and during the subsequent recovery period after flight.

Discussion: The performance data suggest that an additional sensorimotor-based countermeasure may be necessary to maintain functional performance at preflight levels immediately after spaceflight.Miller CA, Kofman IS, Brady RR, May-Phillips TR, Batson CD, Lawrence EL, Taylor LC, Peters BT, Mulavara AP, Feiveson AH, Reschke MF, Bloomberg JJ. Functional task and balance performance in bed rest subjects and astronauts. Aerosp Med Hum Perform. 2018; 89(9):805-815.
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http://dx.doi.org/10.3357/AMHP.5039.2018DOI Listing
September 2018

Protecting against electrode insertion trauma using dexamethasone.

Cochlear Implants Int 2019 01 20;20(1):1-11. Epub 2018 Aug 20.

a The HEARing CRC , Carlton , Australia.

Objective: To compare the benefits of a dexamethasone-eluting array for hearing preservation and cochlear histopathology in low trauma (soft-surgery) and high trauma models of cochlear implant surgery.

Methods: Adult guinea pigs were implanted with an intra-cochlear array using two different surgical procedures: either a soft-surgery approach or following generation of electrode insertion trauma (high trauma). Two methods of dexamethasone delivery were evaluated: elution from an electrode array alone, and elution from a cochlear implant electrode array in combination with a pre-operative systemic injection. All electrode arrays were implanted for a period of 4 weeks. Outcome measures at 4 weeks post-implantation included auditory brainstem response (ABR) thresholds, histological analysis of spiral ganglion neuron density, fibrotic tissue, new bone growth, and cochlear damage.

Results: Animals exposed to high surgical trauma showed greater hearing loss than those in the low trauma model, irrespective of the presence of dexamethasone. Whilst the area of intra-cochlear fibrotic tissue growth post-implantation was also independent of dexamethasone administration, new bone growth was significantly reduced in its presence. Our high trauma model effectively obliterated the organ of Corti and significantly reduced spiral ganglion neuron densities in the lower basal turn. This trauma-induced reduction in spiral ganglion neuron survival decreased with the inclusion of a dexamethasone-eluting array. A pre-operative systemic injection of dexamethasone did not significantly improve any outcome measures beyond those provided with a dexamethasone-eluting array alone.

Conclusion: Dexamethasone-eluting intra-cochlear arrays may inhibit osteoneogenesis, and reduce spiral ganglion neuron loss following traumatic cochlear implantation.
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http://dx.doi.org/10.1080/14670100.2018.1509531DOI Listing
January 2019

A 3D Human Renal Cell Carcinoma-on-a-Chip for the Study of Tumor Angiogenesis.

Neoplasia 2018 06 7;20(6):610-620. Epub 2018 May 7.

Kidney Research Institute, University of Washington, Box 359606, 325 Ninth Avenue, Seattle, WA 98104; Fred Hutchinson Cancer Research Center / University of Washington Cancer Consortium, 1100 Fairview Ave N, Seattle, WA 98109; Department of Pathology, University of Washington, Box 356100, 1959 NE Pacific Street, Seattle, WA 98195. Electronic address:

Tractable human tissue-engineered 3D models of cancer that enable fine control of tumor growth, metabolism, and reciprocal interactions between different cell types in the tumor microenvironment promise to accelerate cancer research and pharmacologic testing. Progress to date mostly reflects the use of immortalized cancer cell lines, and progression to primary patient-derived tumor cells is needed to realize the full potential of these platforms. For the first time, we report endothelial sprouting induced by primary patient tumor cells in a 3D microfluidic system. Specifically, we have combined primary human clear cell renal cell carcinoma (ccRCC) cells from six independent donors with human endothelial cells in a vascularized, flow-directed, 3D culture system ("ccRCC-on-a-chip"). The upregulation of key angiogenic factors in primary human ccRCC cells, which exhibited unique patterns of donor variation, was further enhanced when they were cultured in 3D clusters. When embedded in the matrix surrounding engineered human vessels, these ccRCC tumor clusters drove potent endothelial cell sprouting under continuous flow, thus recapitulating the critical angiogenic signaling axis between human ccRCC cells and endothelial cells. Importantly, this phenotype was driven by a primary tumor cell-derived biochemical gradient of angiogenic growth factor accumulation that was subject to pharmacological blockade. Our novel 3D system represents a vascularized tumor model that is easy to image and quantify and is fully tunable in terms of input cells, perfusate, and matrices. We envision that this ccRCC-on-a-chip will be valuable for mechanistic studies, for studying tumor-vascular cell interactions, and for developing novel and personalized antitumor therapies.
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http://dx.doi.org/10.1016/j.neo.2018.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994779PMC
June 2018

Physiological and Functional Alterations after Spaceflight and Bed Rest.

Med Sci Sports Exerc 2018 09;50(9):1961-1980

Neurosciences Laboratory, NASA-Johnson Space Center, Houston, TX.

Introduction: Exposure to microgravity causes alterations in multiple physiological systems, potentially impacting the ability of astronauts to perform critical mission tasks. The goal of this study was to determine the effects of spaceflight on functional task performance and to identify the key physiological factors contributing to their deficits.

Methods: A test battery comprised of seven functional tests and 15 physiological measures was used to investigate the sensorimotor, cardiovascular, and neuromuscular adaptations to spaceflight. Astronauts were tested before and after 6-month spaceflights. Subjects were also tested before and after 70 d of 6° head-down bed rest, a spaceflight analog, to examine the role of axial body unloading on the spaceflight results. These subjects included control and exercise groups to examine the effects of exercise during bed rest.

Results: Spaceflight subjects showed the greatest decrement in performance during functional tasks that required the greatest demand for dynamic control of postural equilibrium which was paralleled by similar decrements in sensorimotor tests that assessed postural and dynamic gait control. Other changes included reduced lower limb muscle performance and increased HR to maintain blood pressure. Exercise performed during bed rest prevented detrimental change in neuromuscular and cardiovascular function; however, both bed rest groups experienced functional and balance deficits similar to spaceflight subjects.

Conclusion: Bed rest data indicate that body support unloading experienced during spaceflight contributes to postflight postural control dysfunction. Further, the bed rest results in the exercise group of subjects confirm that resistance and aerobic exercises performed during spaceflight can play an integral role in maintaining neuromuscular and cardiovascular functions, which can help in reducing decrements in functional performance. These results indicate that a countermeasure to mitigate postflight postural control dysfunction is required to maintain functional performance.
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http://dx.doi.org/10.1249/MSS.0000000000001615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133205PMC
September 2018

The effect on liveweight gain of using anthelmintics with incomplete efficacy against resistant Cooperia oncophora in cattle.

Vet Parasitol 2018 Feb 2;251:56-62. Epub 2018 Jan 2.

AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston North, 4442, New Zealand. Electronic address:

A replicated field trial was conducted to measure the effect on liveweight gain of failing to adequately control anthelmintic resistant populations of Cooperia oncophora and to determine whether populations, and hence production losses, increased with time. Eight mobs of 10 Friesian-Hereford calves were run on independent farmlets from January to December, over each of two years. All mobs were routinely treated with a pour-on formulation of eprinomectin every six weeks, which controlled parasites other than Cooperia. Four mobs also received six weekly treatments with an oral levamisole plus albendazole combination anthelmintic to control Cooperia. Liveweights, condition scores, faecal egg counts and larval numbers on pasture were measured throughout. In the first year animals treated with eprinomectin alone were 12.9 kg lighter in November than those treated with eprinomectin plus albendazole and levamisole, however, in the second year there was no difference between the treatment groups. The data, therefore, support the view that while C. oncophora is less pathogenic than other cattle parasite species it can still cause production losses when present in sufficient numbers. In the first year of the study, parasite load, as measured by faecal nematode egg count and larval numbers on herbage, tended to be higher and calf growth rates lower than in the second year. In both years, counts of infective larvae on herbage declined over winter-spring to be at low levels before mid-summer. This suggests that the carry-over of infection from one crop of calves to the next was relatively small and hence that the level of challenge to the young calves at the start of each year was largely due to the effectiveness of the quarantine treatments administered when the animals arrived on the trial site. Low survival of larvae on pasture between grazing seasons, resulting in small larval populations on pasture when drenching programmes start each summer, might help to explain the widespread development of anthelmintic resistance in this parasite under New Zealand grazing systems.
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http://dx.doi.org/10.1016/j.vetpar.2017.12.023DOI Listing
February 2018

A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia.

Nat Commun 2018 01 3;9(1):42. Epub 2018 Jan 3.

Center for Cancer Innovation, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA.

Cancers that appear pathologically similar often respond differently to the same drug regimens. Methods to better match patients to drugs are in high demand. We demonstrate a promising approach to identify robust molecular markers for targeted treatment of acute myeloid leukemia (AML) by introducing: data from 30 AML patients including genome-wide gene expression profiles and in vitro sensitivity to 160 chemotherapy drugs, a computational method to identify reliable gene expression markers for drug sensitivity by incorporating multi-omic prior information relevant to each gene's potential to drive cancer. We show that our method outperforms several state-of-the-art approaches in identifying molecular markers replicated in validation data and predicting drug sensitivity accurately. Finally, we identify SMARCA4 as a marker and driver of sensitivity to topoisomerase II inhibitors, mitoxantrone, and etoposide, in AML by showing that cell lines transduced to have high SMARCA4 expression reveal dramatically increased sensitivity to these agents.
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http://dx.doi.org/10.1038/s41467-017-02465-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752671PMC
January 2018