UW Neurological Surgery Recent PubMed Publications

Extracting Thickness Profiles of Anterior Mitral Leaflets in Echocardiography Videos.

Conf Proc IEEE Eng Med Biol Soc. 2018 07;2018:3582-3585

Authors: Pires L, Sultan MS, Martins N, Costa E, Veiga D, Ferreira MJ, Mattos S, Coimbra MT

Abstract
Rheumatic heart disease is the serious consequence of repeated episodes of acute rheumatic fever. It is the major cause of heart valve damage resulting in morbidity and mortality. Its early detection is considered vital to control the disease's progression. The key manifestations that are visible in the early stages of this disease are changes in the thickness, shape and mobility of the mitral valve leaflets. Echocardiography based screening is sensitive enough to identify these changes in early stages of the disease. In this work, an automatic approach is proposed to measure, quantify and analyze the thickness of the anterior mitral leaflet, in an echocardiographic video. The shape of the anterior mitral leaflet is simplified via morphological skeletonization and spline modelling to get the central line of the leaflet. To analyze the overall thickness from the tip to its base, the anterior mitral leaflet is divided into four quartiles. In ach quartile the thickness is measured as the length of the line segment resulting from the intersection of the contour with the normal direction of the central point of each quartile. Finally, the thickness is analyzed by measuring the variance per quartile, divided by leaflet position (open, straight and closed). The comparison between the normal and pathological leaflets are also presented, exhibiting statistical significant differences in all quartiles, especially near the tip of the leaflet.

PMID: 30441152 [PubMed - indexed for MEDLINE]

A machine-learning approach to volitional control of a closed-loop deep brain stimulation system.

J Neural Eng. 2019 02;16(1):016004

Authors: Houston B, Thompson M, Ko A, Chizeck H

Abstract
OBJECTIVE: Deep brain stimulation (DBS) is a well-established treatment for essential tremor, but may not be an optimal therapy, as it is always on, regardless of symptoms. A closed-loop (CL) DBS, which uses a biosignal to determine when stimulation should be given, may be better. Cortical activity is a promising biosignal for use in a closed-loop system because it contains features that are correlated with pathological and normal movements. However, neural signals are different across individuals, making it difficult to create a 'one size fits all' closed-loop system.
APPROACH: We used machine learning to create a patient-specific, CL DBS system. In this system, binary classifiers are used to extract patient-specific features from cortical signals and determine when volitional, tremor-evoking movement is occurring to alter stimulation voltage in real time.
MAIN RESULTS: This system is able to deliver stimulation up to 87%-100% of the time that subjects are moving. Additionally, we show that the therapeutic effect of the system is at least as good as that of current, continuous-stimulation paradigms.
SIGNIFICANCE: These findings demonstrate the promise of CL DBS therapy and highlight the importance of using subject-specific models in these systems.

PMID: 30444218 [PubMed - indexed for MEDLINE]

The Impact of Organizational Culture on Leadership Burnout.

Front Health Serv Manage. 2018;35(2):34-37

Authors: Williams MD

PMID: 30433903 [PubMed - indexed for MEDLINE]

The Endoplasmic Reticulum Chaperone GRP78/BiP Modulates Prion Propagation in vitro and in vivo.

Sci Rep. 2017 03 23;7:44723

Authors: Park KW, Eun Kim G, Morales R, Moda F, Moreno-Gonzalez I, Concha-Marambio L, Lee AS, Hetz C, Soto C

Abstract
Prion diseases are fatal neurodegenerative disorders affecting several mammalian species, characterized by the accumulation of the misfolded form of the prion protein, which is followed by the induction of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). GRP78, also called BiP, is a master regulator of the UPR, reducing ER stress levels and apoptosis due to an enhancement of the cellular folding capacity. Here, we studied the role of GRP78 in prion diseases using several in vivo and in vitro approaches. Our results show that a reduction in the expression of this molecular chaperone accelerates prion pathogenesis in vivo. In addition, we observed that prion replication in cell culture was inversely related to the levels of expression of GRP78 and that both proteins interact in the cellular context. Finally, incubation of PrPSc with recombinant GRP78 led to the dose-dependent reduction of protease-resistant PrPSc in vitro. Our results uncover a novel role of GRP78 in reducing prion pathogenesis, suggesting that modulating its levels/activity may offer a novel opportunity for designing therapeutic approaches for these diseases. These findings may also have implications for other diseases involving the accumulation of misfolded proteins.

PMID: 28333162 [PubMed - indexed for MEDLINE]

Hepatitis B Virus Therapeutic Agent ARB-1740 Has Inhibitory Effect on Hepatitis Delta Virus in a New Dually-Infected Humanized Mouse Model.

ACS Infect Dis. 2019 05 10;5(5):738-749

Authors: Ye X, Tateno C, Thi EP, Kakuni M, Snead NM, Ishida Y, Barnard TR, Sofia MJ, Shimada T, Lee ACH

Abstract
Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts, and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually infected humanized mice. Treatment with ARB-1740, a clinical stage HBV-targeting siRNA agent delivered using lipid nanoparticle (LNP) technology, effectively reduced HBV viremia by 2.3 log10 and serum HBsAg by 2.6 log10, leading to 1.6 log10 reduction of HDV viremia. In contrast, HDV-targeting siRNA inhibited HDV in both blood and liver compartments without affecting HBV and PEGylated interferon-alpha reduced HBV viremia by 2.0 log10 but had no effect on HDV viremia under these study conditions. These results illustrate the inhibitory effects of siRNAs against these two viral infections and suggest that ARB-1740 may be of therapeutic benefit for hepatitis delta patients, a subpopulation with high unmet medical need.

PMID: 30408957 [PubMed - indexed for MEDLINE]

Synthesis and Evaluation of Baylis-Hillman Reaction Derived Imidazole and Triazole Cinnamates as Antifungal Agents.

Int J Med Chem. 2018;2018:5758076

Authors: Nelson GL, Williams MJ, Jonnalagadda S, Alam MA, Mereddy G, Johnson JL, Jonnalagadda SK

Abstract
Allylic acetates derived from Baylis-Hillman reaction undergo efficient nucleophilic isomerization with imidazoles and triazoles to provide imidazolylmethyl and triazolylmethyl cinnamates stereoselectively. Antifungal evaluation of these derivatives against Cryptococcus neoformans exhibits good minimum inhibitory concentration values. These compounds exhibit low toxicity in proliferating MCF-7 breast cancer cell line. Structure activity relationship studies indicate that halogenated aromatic derivatives provide better antifungal activity.

PMID: 30410798 [PubMed]

Comparative functional genomic screens of three yeast deletion collections reveal unexpected effects of genotype in response to diverse stress.

Open Biol. 2017 06;7(6):

Authors: Acton E, Lee AH, Zhao PJ, Flibotte S, Neira M, Sinha S, Chiang J, Flaherty P, Nislow C, Giaever G

Abstract
The Yeast Knockout (YKO) collection has provided a wealth of functional annotations from genome-wide screens. An unintended consequence is that 76% of gene annotations derive from one genotype. The nutritional auxotrophies in the YKO, in particular, have phenotypic consequences. To address this issue, 'prototrophic' versions of the YKO collection have been constructed, either by introducing a plasmid carrying wild-type copies of the auxotrophic markers (Plasmid-Borne, PBprot) or by backcrossing (Backcrossed, BCprot) to a wild-type strain. To systematically assess the impact of the auxotrophies, genome-wide fitness profiles of prototrophic and auxotrophic collections were compared across diverse drug and environmental conditions in 250 experiments. Our quantitative profiles uncovered broad impacts of genotype on phenotype for three deletion collections, and revealed genotypic and strain-construction-specific phenotypes. The PBprot collection exhibited fitness defects associated with plasmid maintenance, while BCprot fitness profiles were compromised due to strain loss from nutrient selection steps during strain construction. The repaired prototrophic versions of the YKO collection did not restore wild-type behaviour nor did they clarify gaps in gene annotation resulting from the auxotrophic background. To remove marker bias and expand the experimental scope of deletion libraries, construction of a bona fide prototrophic collection from a wild-type strain will be required.

PMID: 28592509 [PubMed - indexed for MEDLINE]

Simultaneous Quantification of Plasmodium Antigens and Host Factor C-Reactive Protein in Asymptomatic Individuals with Confirmed Malaria by Use of a Novel Multiplex Immunoassay.

J Clin Microbiol. 2019 01;57(1):

Authors: Jang IK, Tyler A, Lyman C, Kahn M, Kalnoky M, Rek JC, Arinaitwe E, Adrama H, Murphy M, Imwong M, Ling CL, Proux S, Haohankhunnatham W, Rist M, Seilie AM, Hanron A, Daza G, Chang M, Das S, Barney R, Rashid A, Landier J, Boyle DS, Murphy SC, McCarthy JS, Nosten F, Greenhouse B, Domingo GJ

Abstract
Malaria rapid diagnostic tests (RDTs) primarily detect Plasmodium falciparum antigen histidine-rich protein 2 (HRP2) and the malaria-conserved antigen lactate dehydrogenase (LDH) for P. vivax and other malaria species. The performance of RDTs and their utility is dependent on circulating antigen concentration distributions in infected individuals in a population in which malaria is endemic and on the limit of detection of the RDT for the antigens. A multiplexed immunoassay for the quantification of HRP2, P. vivax LDH, and all-malaria LDH (pan LDH) was developed to accurately measure circulating antigen concentration and antigen distribution in a population with endemic malaria. The assay also measures C-reactive protein (CRP) levels as an indicator of inflammation. Validation was conducted with clinical specimens from 397 asymptomatic donors from Myanmar and Uganda, confirmed by PCR for infection, and from participants in induced blood-stage malaria challenge studies. The assay lower limits of detection for HRP2, pan LDH, P. vivax LDH, and CRP were 0.2 pg/ml, 9.3 pg/ml, 1.5 pg/ml, and 26.6 ng/ml, respectively. At thresholds for HRP2, pan LDH, and P. vivax LDH of 2.3 pg/ml, 47.8 pg/ml, and 75.1 pg/ml, respectively, and a specificity ≥98.5%, the sensitivities for ultrasensitive PCR-confirmed infections were 93.4%, 84.9%, and 48.9%, respectively. Plasmodium LDH (pLDH) concentration, in contrast to that of HRP2, correlated closely with parasite density. CRP levels were moderately higher in P. falciparum infections with confirmed antigenemia versus those in clinical specimens with no antigen. The 4-plex array is a sensitive tool for quantifying diagnostic antigens in malaria infections and supporting the evaluation of new ultrasensitive RDTs.

PMID: 30404944 [PubMed - indexed for MEDLINE]

Microsurgical Clipping of a Ruptured Basilar Apex Aneurysm: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 Nov 08;:

Authors: Cheng CY, Qazi Z, Hallam DK, Ghodke BV, Sekhar LN

Abstract
A 59-yr-old woman presented with a sudden onset of headache with neck pain and stiffness, Hunt and Hess grade 2. Brain computed tomography (CT) showed subarachnoid hemorrhage, Fisher Grade 2. Intra-arterial digital subtraction angiography (IADSA) showed a basilar artery apex aneurysm, dome size 9 mm and neck 3 mm, leaning towards the right, and a dominant right artery of Percheron. Endovascular treatment and microsurgical clipping were both explained to the patient, but she decided to undergo microsurgery due to the durability of treatment.She underwent a right frontotemporal craniotomy and orbital osteotomy. We performed optic nerve decompression and intradural anterior clinoidectomy to enhance the exposure. Working through the carotid-oculomotor space, the posterior communicating artery was traced back to the posterior cerebral artery. The basilar artery was temporarily occluded for aneurysm dissection after burst suppression to protect the brain. The aneurysm was irregular, multilobulated, and projecting upward. The dominant thalamoperforate artery (artery of Percheron) was arising from the right P1, and densely adherent to the sac of the aneurysm. After dissection of the artery of Percheron away from the aneurysm, it was completely occluded by a side-curved titanium clip. The patient had right oculomotor nerve paresis and headache postoperatively, but at discharge 2 wk later the headache and paresis had completely resolved. The postoperative IADSA showed total occlusion of the aneurysm with patency of the artery of Percheron.This 3-dimensional video shows the technical nuances of microsurgical clipping of a ruptured basilar apex aneurysm and intraoperative dissection of the artery of Percheron.Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 30407554 [PubMed - as supplied by publisher]

Disseminated Tuberculosis Presenting as Chronic Orchiepididymitis in a Military Trainee: A Case Report and Review of the Literature.

Case Rep Infect Dis. 2018;2018:7316097

Authors: Williams MU, Burris A, Zingalis A, Lindholm DA, White BK

Abstract
Orchiepididymitis is a clinical diagnosis. The acute form secondary to sexually transmitted or enteric pathogens is well known to primary care providers. However, chronic orchiepididymitis may be secondary to genitourinary tuberculosis (TB), and physicians in countries with a low prevalence of TB might not consider it in their differential diagnosis. Indeed, cognitive errors, such as anchoring or availability bias, may contribute to a delayed diagnosis of genitourinary TB. We present a case of chronic orchiepididymitis as a result of disseminated TB in a Cameroonian male who was visiting the United States for military training. He experienced diagnostic delay and was ultimately diagnosed by orchiectomy. Early consideration of a diagnosis of TB for chronic or recurrent orchiepididymitis in a patient with epidemiologic risk factors is of utmost importance because delayed diagnosis could lead to organ loss.

PMID: 30402306 [PubMed]

ARB-1740, a RNA Interference Therapeutic for Chronic Hepatitis B Infection.

ACS Infect Dis. 2019 05 10;5(5):725-737

Authors: Thi EP, Dhillon AP, Ardzinski A, Bidirici-Ertekin L, Cobarrubias KD, Cuconati A, Kondratowicz AS, Kwak K, Li AHL, Miller A, Pasetka C, Pei L, Phelps JR, Snead NM, Wang X, Ye X, Sofia MJ, Lee ACH

Abstract
Current approved nucleoside analogue treatments for chronic hepatitis B virus (HBV) infection are effective at controlling viral titer but are not curative and have minimal impact on the production of viral proteins such as surface antigen (HBsAg), the HBV envelope protein believed to play a role in maintaining the immune tolerant state required for viral persistence. Novel agents are needed to effect HBV cure, and reduction of HBV antigenemia may potentiate activation of effective and long-lasting host immune control. ARB-1740 is a clinical stage RNA interference agent composed of three siRNAs delivered using lipid nanoparticle technology. In a number of cell and animal models of HBV, ARB-1740 caused HBV RNA reduction, leading to inhibition of multiple elements of the viral life cycle including HBsAg, HBeAg, and HBcAg viral proteins as well as replication marker HBV DNA. ARB-1740 demonstrated pan-genotypic activity in vitro and in vivo, targeting three distinct highly conserved regions of the HBV genome, and effectively inhibited replication of nucleoside analogue-resistant HBV variants. Combination of ARB-1740 with a capsid inhibitor and pegylated interferon-alpha led to greater liver HBsAg reduction which correlated with more robust induction of innate immune responses in a human chimeric mouse model of HBV. The preclinical profile of ARB-1740 demonstrates the promise of RNA interference and HBV antigen reduction in treatment strategies driving toward a cure for HBV.

PMID: 30403127 [PubMed - indexed for MEDLINE]

Acute Post-Traumatic Sleep May Define Vulnerability to a Second Traumatic Brain Injury in Mice.

J Neurotrauma. 2019 04 15;36(8):1318-1334

Authors: Rowe RK, Harrison JL, Morrison HW, Subbian V, Murphy SM, Lifshitz J

Abstract
Chronic neurological impairments can manifest from repetitive traumatic brain injury (rTBI), particularly when subsequent injuries occur before the initial injury completely heals. Herein, we apply post-traumatic sleep as a physiological biomarker of vulnerability, hypothesizing that a second TBI during post-traumatic sleep worsens neurological and histological outcomes compared to one TBI or a second TBI after post-traumatic sleep subsides. Mice received sham or diffuse TBI by midline fluid percussion injury; brain-injured mice received one TBI or rTBIs at 3- or 9-h intervals. Over 40 h post-injury, injured mice slept more than shams. Functional assessments indicated lower latencies on rotarod and increased Neurological Severity Scores for mice with rTBIs within 3 h. Anxiety-like behaviors in the open field task were increased for mice with rTBIs at 3 h. Based on pixel density of silver accumulation, neuropathology was greater at 28 days post-injury (DPI) in rTBI groups than sham and single TBI. Cortical microglia morphology was quantified and mice receiving rTBI were de-ramified at 14 DPI compared to shams and mice receiving a single TBI, suggesting robust microglial response in rTBI groups. Orexin-A-positive cells were sustained in the lateral hypothalamus with no loss detected, indicating that loss of wake-promoting neurons did not contribute to post-traumatic sleep. Thus, duration of post-traumatic sleep is a period of vulnerability that results in exacerbated injury from rTBI. Monitoring individual post-traumatic sleep is a potential clinical tool for personalized TBI management, where regular sleep patterns may inform rehabilitative strategies and return-to-activity guidelines.

PMID: 30398389 [PubMed - indexed for MEDLINE]

Endovascular Treatment of Acute Ischemic Stroke Under General Anesthesia: Predictors of Good Outcome.

J Neurosurg Anesthesiol. 2018 Jul;30(3):223-230

Authors: Athiraman U, Sultan-Qurraie A, Nair B, Tirschwell DL, Ghodke B, Havenon AD, Hallam DK, Kim LJ, Becker KJ, Sharma D

Abstract
BACKGROUND: The choice of anesthetic technique, general anesthesia (GA) versus Monitored Anesthesia Care, may impact the outcome of patients undergoing endovascular treatment of acute ischemic stroke (AIS). The aim of this study was to identify the factors associated with good discharge outcome in patients receiving GA for AIS.
MATERIALS AND METHODS: Electronic medical records of patients above 18 years old who underwent endovascular treatment of AIS under GA at a Comprehensive Stroke Center from 2010 to 2014 were reviewed. Good outcome was defined as discharge modified Rankin Score 0 to 2 and poor outcome as modified Rankin Score 3 to 6; logistic regression analysis was performed to examine the association between the clinical characteristics and the outcome.
RESULTS: In total, 88 patients (56 males), aged 63±15 years with median National Institute of Health Stroke Scale (NIHSS) score 16 (range, 4 to 38) were included. Nineteen (22%) patients had good outcome and 78 (88%) had systolic blood pressure below the guideline recommended 140 mm Hg under GA. After adjusting for age and NIHSS score, the independent predictors of good discharge outcomes were higher maximum end-tidal carbon dioxide (odds ratio [OR], 1.14; confidence interval [CI], 1.02-1.28; P=0.02) and extubation after endovascular treatment (OR, 26.31; CI, 4.80-144.12; P<0.0001). A secondary analysis was performed after excluding 25 patients emergently intubated in the Emergency Department for airway protection. In the logistic regression analysis controlling for age and NIHSS score, postprocedure extubation was still associated with higher odds of good outcomes (OR, 13.35; CI, 2.58-68.90; P=0.002).
CONCLUSIONS: These findings indicate the importance of ventilation management and extubation after endovascular intervention under GA in patients with AIS.

PMID: 28763432 [PubMed - indexed for MEDLINE]

h-Channels Contribute to Divergent Intrinsic Membrane Properties of Supragranular Pyramidal Neurons in Human versus Mouse Cerebral Cortex.

Neuron. 2018 12 05;100(5):1194-1208.e5

Authors: Kalmbach BE, Buchin A, Long B, Close J, Nandi A, Miller JA, Bakken TE, Hodge RD, Chong P, de Frates R, Dai K, Maltzer Z, Nicovich PR, Keene CD, Silbergeld DL, Gwinn RP, Cobbs C, Ko AL, Ojemann JG, Koch C, Anastassiou CA, Lein ES, Ting JT

Abstract
Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single-cell/nucleus RNA sequencing revealed ubiquitous HCN1-subunit expression in excitatory neurons in human, but not mouse, supragranular layers. Using patch-clamp recordings, we found stronger h-channel-related membrane properties in supragranular pyramidal neurons in human temporal cortex, compared to mouse supragranular pyramidal neurons in temporal association area. The magnitude of these differences depended upon cortical depth and was largest in pyramidal neurons in deep L3. Additionally, pharmacologically blocking h-channels produced a larger change in membrane properties in human compared to mouse neurons. Finally, using biophysical modeling, we provide evidence that h-channels promote the transfer of theta frequencies from dendrite-to-soma in human L3 pyramidal neurons. Thus, h-channels contribute to between-species differences in a fundamental neuronal property.

PMID: 30392798 [PubMed - indexed for MEDLINE]

Effects of Acute Deltamethrin Exposure in Adult and Developing Sprague Dawley Rats on Acoustic Startle Response in Relation to Deltamethrin Brain and Plasma Concentrations.

Toxicol Sci. 2019 03 01;168(1):61-69

Authors: Williams MT, Gutierrez A, Vorhees CV

Abstract
Deltamethrin (DLM) is a commonly used pesticide that helps to control crop destruction, disease, and nuisance insects. In rodents DLM can produce choreoathetosis, salivation, and decreased acoustic startle responses (ASR). Herein, adult Sprague Dawley rats were assessed for ASR 2 h after DLM delivered in 5 ml/kg corn oil, however no decrease was observed. Therefore, a test-retest protocol was used to reduce variability, and the effects on ASR on postnatal day 15 (P15) and adult rats were assessed 2, 4, 6, and 8 h after DLM administration (0, 1, 2, or 4 mg/kg for P15 rats and 0, 2, 8, or 25 mg/kg for adults). In a separate set of rats identically treated, DLM levels were determined in blood and brain. DLM (8 or 25 mg/kg) in adult rats decreased ASR up to 4 h, whereas in P15 rats decreases were observed between 2 and 8 h. The adult 25 mg/kg group showed consistent signs of salivation and tremor, whereas in P15 rats salivation was observed in the 2 and 4 mg/kg groups and tremor was observed at all doses over the 8-h period. Mortality was observed in all P15 dose groups but not in adults. Dose-dependent increases of DLM in blood and brain regardless of age were observed. At approximately equivalent whole brain concentrations, effects were more pronounced in P15 rats than in adult rats. Comparable brain levels of DLM do not explain differences in ASR and tremor between the P15 and adult rats. These data indicate age-dependent differences in sensitivity to DLM.

PMID: 30395337 [PubMed - indexed for MEDLINE]

Stroke: Basic and Clinical.

Adv Neurobiol. 2017;15:281-293

Authors: Singh TP, Weinstein JR, Murphy SP

Abstract
Tissue plasminogen activator (tPA) was first approved in the USA 25 years ago for those who had experienced a recent occlusion (<3 h) of a cerebral vessel. Now, advances in clot retrieval (stentriever), in concert with tPA, heralds new optimism for ischemic stroke victims, but adds more pressure to identify therapies that will minimize hypoxic damage, protect compromised cells, and promote rehabilitation. In the past preclinical investigations have been poor at predicting potential clinical therapy, but they have contributed enormously to understanding post-stroke pathology. Current clinical trials ( www.strokecenter.org/trials ) anticipate a broad range of approaches: from hypothermia, to cell therapy, to neuroprotection.

PMID: 28674985 [PubMed - indexed for MEDLINE]

Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity.

iScience. 2018 Oct 16;9:71-83

Authors: Wallmann T, Zhang XM, Wallerius M, Bolin S, Joly AL, Sobocki C, Leiss L, Jiang Y, Bergh J, Holland EC, Enger PØ, Andersson J, Swartling FJ, Miletic H, Uhrbom L, Harris RA, Rolny C

Abstract
High-grade gliomas (HGGs) are the most aggressive and invasive primary brain tumors. The platelet-derived growth factor (PDGF) signaling pathway drives HGG progression, and enhanced expression of PDGF receptors (PDGFRs) is a well-established aberration in a subset of glioblastomas (GBMs). PDGFRA is expressed in glioma cells, whereas PDGFRB is mostly restricted to the glioma-associated stroma. Here we show that the spatial location of TAMMs correlates with the expansion of a subset of tumor cells that have acquired expression of PDGFRB in both mouse and human low-grade glioma and HCGs. Furthermore, M2-polarized microglia but not bone marrow (BM)-derived macrophages (BMDMs) induced PDGFRB expression in glioma cells and stimulated their migratory capacity. These findings illustrate a heterotypic cross-talk between microglia and glioma cells that may enhance the migratory and invasive capacity of the latter by inducing PDGFRB.

PMID: 30384135 [PubMed - as supplied by publisher]

Epigenetic and Transcriptome Profiling Identifies a Population of Visceral Adipose-Derived Progenitor Cells with the Potential to Differentiate into an Endocrine Pancreatic Lineage.

Cell Transplant. 2019 01;28(1):89-104

Authors: Williams MD, Joglekar MV, Satoor SN, Wong W, Keramidaris E, Rixon A, O'Connell P, Hawthorne WJ, Mitchell GM, Hardikar AA

Abstract
Type 1 diabetes (T1D) is characterized by the loss of insulin-producing β-cells in the pancreas. T1D can be treated using cadaveric islet transplantation, but this therapy is severely limited by a lack of pancreas donors. To develop an alternative cell source for transplantation therapy, we carried out the epigenetic characterization in nine different adult mouse tissues and identified visceral adipose-derived progenitors as a candidate cell population. Chromatin conformation, assessed using chromatin immunoprecipitation (ChIP) sequencing and validated by ChIP-polymerase chain reaction (PCR) at key endocrine pancreatic gene promoters, revealed similarities between visceral fat and endocrine pancreas. Multiple techniques involving quantitative PCR, in-situ PCR, confocal microscopy, and flow cytometry confirmed the presence of measurable (2-1000-fold over detectable limits) pancreatic gene transcripts and mesenchymal progenitor cell markers (CD73, CD90 and CD105; >98%) in visceral adipose tissue-derived mesenchymal cells (AMCs). The differentiation potential of AMCs was explored in transgenic reporter mice expressing green fluorescent protein (GFP) under the regulation of the Pdx1 (pancreatic and duodenal homeobox-1) gene promoter. GFP expression was measured as an index of Pdx1 promoter activity to optimize culture conditions for endocrine pancreatic differentiation. Differentiated AMCs demonstrated their capacity to induce pancreatic endocrine genes as evidenced by increased GFP expression and validated using TaqMan real-time PCR (at least 2-200-fold relative to undifferentiated AMCs). Human AMCs differentiated using optimized protocols continued to produce insulin following transplantation in NOD/SCID mice. Our studies provide a systematic analysis of potential islet progenitor populations using genome-wide profiling studies and characterize visceral adipose-derived cells for replacement therapy in diabetes.

PMID: 30376726 [PubMed - indexed for MEDLINE]

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma.

Oncoimmunology. 2018;7(11):e1507668

Authors: Moyes KW, Davis A, Hoglund V, Haberthur K, Lieberman NA, Kreuser SA, Deutsch GH, Franco S, Locke D, Carleton MO, Gilbertson DG, Simmons R, Winter C, Silber J, Gonzalez-Cuyar LF, Ellenbogen RG, Crane CA

Abstract
Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue. Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

PMID: 30377570 [PubMed]

Is postoperative Doppler ultrasonography useful for the early detection of asymptomatic pseudoaneurysm and prevention of haemorrhagic complications after partial nephrectomy?

BJU Int. 2018 11;122 Suppl 5:15-21

Authors: Nouhaud FX, Williams M, Arnfield E, Perera ML, Cho J, Esler R, Coughlin G

Abstract
OBJECTIVE: To assess the clinical utility of systematic Doppler ultrasonography (DUS) after robot-assisted partial nephrectomy (PN) for the detection of renal artery pseudoaneurysm (PA) and to allow pre-emptive arterial embolization to reduce the postoperative bleeding risk.
MATERIALS AND METHODS: A retrospective study was conducted including all consecutive patients treated with robot-assisted PN for renal tumours between 2015 and 2017. Every patient underwent renal DUS in the early postoperative period. The presence of PA, arteriovenous malformation or collection on the DUS, as well as the incidence of haemorrhagic complications and need for transfusion/embolization were assessed.
RESULTS: Eighty-three patients were included, with a median (range) age of 58 (19-80) years. The median (range) follow-up was 5 (1-30) months. The mean (±sd) tumour size was 31 (±13.1) mm, the median (range) RENAL nephrometry score was 6 (4-11), and the mean (±sd) warm ischaemia time was 22 (±7) min. A haemostatic agent was used in 12 patients (14.5%). No patient encountered haemorrhagic complications postoperatively, and no patient required transfusion. The median (interquartile range) time to DUS postoperatively was 7 (6-8) days. DUS revealed one asymptomatic PA (1.2%), which was treated with pre-emptive embolization. This was the only patient who encountered a Clavien grade III complication, while 20 patients (24%) had a complication grade I/II.
CONCLUSIONS: No haemorrhagic complications occurred in the present study population, although one asymptomatic PA was found. It was diagnosed early with DUS, allowing pre-emptive management with embolization. These results suggest the potential clinical utility of early postoperative DUS in order to screen for PA to reduce the risk of post-PN haemorrhagic complications.

PMID: 30370984 [PubMed - indexed for MEDLINE]