Editorial: When innovation goes fast. The case of hemophilia.
Curr Opin Pharmacol. 2019 04;45:94
Authors: Williams M
PMID: 31331868 [PubMed - indexed for MEDLINE]
Time-Resolved MRI Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model.
Cancer Res. 2019 09 15;79(18):4776-4786
Authors: Stephen ZR, Chiarelli PA, Revia RA, Wang K, Kievit F, Dayringer C, Jeon M, Ellenbogen R, Zhang M
Abstract
Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. High-resolution T2-weighted, T2*-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTX-mediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. SIGNIFICANCE: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.
PMID: 31331912 [PubMed - indexed for MEDLINE]
Rescue of Rod Synapses by Induction of Cav Alpha 1F in the Mature Cav1.4 Knock-Out Mouse Retina.
Invest Ophthalmol Vis Sci. 2019 07 01;60(8):3150-3161
Authors: Laird JG, Gardner SH, Kopel AJ, Kerov V, Lee A, Baker SA
Abstract
Purpose: Cav1.4 is a voltage-gated calcium channel clustered at the presynaptic active zones of photoreceptors. Cav1.4 functions in communication by mediating the Ca2+ influx that triggers neurotransmitter release. It also aids in development since rod ribbon synapses do not form in Cav1.4 knock-out mice. Here we used a rescue strategy to investigate the ability of Cav1.4 to trigger synaptogenesis in both immature and mature mouse rods.
Methods: In vivo electroporation was used to transiently express Cav α1F or tamoxifen-inducible Cav α1F in a subset of Cav1.4 knock-out mouse rods. Synaptogenesis was assayed using morphologic markers and a vision-guided water maze.
Results: We found that introduction of Cav α1F to knock-out terminals rescued synaptic development as indicated by PSD-95 expression and elongated ribbons. When expression of Cav α1F was induced in mature animals, we again found restoration of PSD-95 and elongated ribbons. However, the induced expression of Cav α1F led to diffuse distribution of Cav α1F in the terminal instead of being clustered beneath the ribbon. Approximately a quarter of treated animals passed the water maze test, suggesting the rescue of retinal signaling in these mice.
Conclusions: These data confirm that Cav α1F expression is necessary for rod synaptic terminal development and demonstrate that rescue is robust even in adult animals with late stages of synaptic disease. The degree of rod synaptic plasticity seen here should be sufficient to support future vision-restoring treatments such as gene or cell replacement that will require photoreceptor synaptic rewiring.
PMID: 31335952 [PubMed - indexed for MEDLINE]
An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.
Cell. 2019 08 08;178(4):835-849.e21
Authors: Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, Richman AR, Silverbush D, Shaw ML, Hebert CM, Dewitt J, Gritsch S, Perez EM, Gonzalez Castro LN, Lan X, Druck N, Rodman C, Dionne D, Kaplan A, Bertalan MS, Small J, Pelton K, Becker S, Bonal D, Nguyen QD, Servis RL, Fung JM, Mylvaganam R, Mayr L, Gojo J, Haberler C, Geyeregger R, Czech T, Slavc I, Nahed BV, Curry WT, Carter BS, Wakimoto H, Brastianos PK, Batchelor TT, Stemmer-Rachamimov A, Martinez-Lage M, Frosch MP, Stamenkovic I, Riggi N, Rheinbay E, Monje M, Rozenblatt-Rosen O, Cahill DP, Patel AP, Hunter T, Verma IM, Ligon KL, Louis DN, Regev A, Bernstein BE, Tirosh I, Suvà ML
Abstract
Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.
PMID: 31327527 [PubMed - indexed for MEDLINE]
Amnion membrane hydrogel and amnion membrane powder accelerate wound healing in a full thickness porcine skin wound model.
Stem Cells Transl Med. 2020 01;9(1):80-92
Authors: Murphy SV, Skardal A, Nelson RA, Sunnon K, Reid T, Clouse C, Kock ND, Jackson J, Soker S, Atala A
Abstract
There is a need for effective wound treatments that retain the bioactivity of a cellular treatment, but without the high costs and complexities associated with manufacturing, storing, and applying living biological products. Previously, we developed an amnion membrane-derived hydrogel and evaluated its wound healing properties using a mouse wound model. In this study, we used a full thickness porcine skin wound model to evaluate the wound-healing efficacy of the amnion hydrogel and a less-processed amnion product comprising a lyophilized amnion membrane powder. These products were compared with commercially available amnion and nonamnion wound healing products. We found that the amnion hydrogel and amnion powder treatments demonstrated significant and rapid wound healing, driven primarily by new epithelialization versus closure by contraction. Histological analysis demonstrated that these treatments promote the formation of a mature epidermis and dermis with similar composition to healthy skin. The positive skin regenerative outcomes using amnion hydrogel and amnion powder treatments in a large animal model further demonstrate their potential translational value for human wound treatments.
PMID: 31328435 [PubMed - indexed for MEDLINE]
The Spectrum of Trigeminal Neuralgia Without Neurovascular Compression.
Neurosurgery. 2019 09 01;85(3):E553-E559
Authors: Magown P, Ko AL, Burchiel KJ
Abstract
BACKGROUND: In trigeminal neuralgia type 1 (TN1), neurovascular compression (NVC) is often assumed to be the pain initiating mechanism. NVC can be surgically addressed by microvascular decompression (MVD). However, some patients with TN1 present without NVC (WONVC).
OBJECTIVE: To characterize and analyze the clinical spectrum of a TN1 patient population WONVC.
METHODS: A retrospective chart review of patients presenting with TN1 between 2007 and 2017 was performed. Patients who were potential candidates for MVD surgery underwent high-resolution imaging with 3-dimensional (3D) reconstruction to address the presence, or absence, of NVC. Demographic data about the populations with NVC (WNVC) and WONVC were collected.
RESULTS: Of 242 patients with TN1, 32% did not have NVC. Patients WONVC were on average 10.6 yr younger than those WNVC. TN1 onset in patients WONVC was more frequent below 48.7 yr, and the opposite was found in patients WNVC. Compared to patients WNVC, those WONVC were predominantly female (odds ratio 4.8), on average were 4 yr younger at symptom onset (34.7 yr) and 7.8 yr younger at first clinic visit, and had a 3.7 yr shorter symptom duration.
CONCLUSION: Patients presenting with TN1 WONVC were predominantly females in their mid-30s with short symptom duration. In the absence of NVC, this subgroup of TN1 patients has limited surgical options, and potentially a longer condition duration that must be managed medically or surgically. This population WONVC might provide insights into the true pathophysiology of TN1.
PMID: 31329945 [PubMed - indexed for MEDLINE]
Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma.
J Neurooncol. 2019 Sep;144(2):403-407
Authors: Kaley TJ, Panageas KS, Mellinghoff IK, Nolan C, Gavrilovic IT, DeAngelis LM, Abrey LE, Holland EC, Lassman AB
Abstract
PURPOSE: Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM).
METHODS: We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort.
RESULTS: Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14).
CONCLUSIONS: PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.
PMID: 31325145 [PubMed - indexed for MEDLINE]
PAG1 limits allergen-induced type 2 inflammation in the murine lung.
Allergy. 2020 02;75(2):336-345
Authors: Ullah MA, Vicente CT, Collinson N, Curren B, Sikder MAA, Sebina I, Simpson J, Varelias A, Lindquist JA, Ferreira MAR, Phipps S
Abstract
BACKGROUND: Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome-wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)-induced allergic sensitization and allergic airway inflammation.
METHODS: Pag1-deficient (Pag1-/- ) and wild-type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti-CD4 antibody) and adoptive transfer studies.
RESULTS: Type 2 inflammation (eosinophilia, eotaxin-2 expression, IL-4/IL-5/IL-13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1-/- mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high-mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte-derived dendritic cell numbers in the mediastinal lymph nodes, and increased T-helper type 2 (TH 2)-cell differentiation. CD4+ T-cell depletion studies or the adoptive transfer of WT OVA-specific CD4+ T cells to WT or Pag1-/- recipients demonstrated that the heightened propensity for TH 2-cell differentiation was both T cell intrinsic and extrinsic.
CONCLUSION: PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH 2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.
PMID: 31321783 [PubMed - indexed for MEDLINE]
Reversible, Position-Dependent Midbrain Compression in a Patient with Spontaneous Intracranial Hypotension.
World Neurosurg. 2019 Oct;130:293-297
Authors: Williams JR, Buckley R, Oushy S, Ruzevick J, Chesnut RM
Abstract
BACKGROUND: Intracranial hypotension is an underrecognized cause of spontaneous subdural hematoma. Failure to identify this entity and treat the underlying etiology can result in profoundly dangerous clinical consequences, prolonged and costly hospitalization, and caregiver fatigue, as seen in the case presented here.
CASE DESCRIPTION: We present a case of intracranial hypotension associated with a spontaneous cerebrospinal fluid (CSF) leak in the cervical spine leading to consistently reproducible herniation syndrome with head of bed elevation, and bilateral subdural hematomas as a result of a pressure gradient favoring downward migration of intracranial contents resulting in traction on bridging veins. This gradient promoted transtentorial herniation with resultant brainstem compression, leading to a prolonged intensive care unit stay, recurrent respiratory failure, and severe deconditioning. An exhaustive diagnostic workup uncovered a cervical root CSF leak with a nuclear medicine CSF flow study, which was successfully treated with nerve root ligation and dural closure. The patient recovered well postprocedurally and was able to return to baseline level of function.
CONCLUSIONS: This case demonstrates the importance of considering intracranial hypotension in cases of positional herniation syndrome and the necessity for early and aggressive attempts at identifying and treating the underlying cause to prevent unnecessary neurologic dysfunction and protracted medical care.
PMID: 31323415 [PubMed - indexed for MEDLINE]
Advances in whole body MRI for musculoskeletal imaging: Diffusion-weighted imaging.
J Clin Orthop Trauma. 2019 Jul-Aug;10(4):680-686
Authors: Lee K, Park HY, Kim KW, Lee AJ, Yoon MA, Chae EJ, Lee JH, Chung HW
Abstract
Recent advances in imaging technology have enabled the acquisition of anatomical and functional imaging from head to toe in a reasonably short scan time. Accordingly, whole body magnetic resonance imaging (WB-MRI) and diffusion-weighted imaging (WB-DWI) have gained recent attention for the management of musculoskeletal problems such as bone tumors and rheumatologic diseases. WB-MRI is especially useful in diagnosing systemic or widespread disease requiring whole body evaluation, such as bone metastases, multiple myeloma, lymphoma, neurofibromatosis, and spondyloarthropathies. Among WB-MRI sequences, the WB-DWI technique greatly increases the value of WB-MRI in the evaluation of disease extent and characterization as well as treatment monitoring. In support of the utilization of WB-MRI and WB-DWI in orthopedic clinics for various musculoskeletal diseases, we provide an overview of the technical aspects of WB-MRI and WB-DWI and their clinical applications in musculoskeletal tumors and rheumatic diseases.
PMID: 31316239 [PubMed]
Acute Myeloid Leukemia Acquiring Promyelocytic Leukemia-Retinoic Acid Receptor Alpha at Relapse.
World J Oncol. 2019 Jun;10(3):153-156
Authors: Gupta V, Shariff M, Bajwa R, Patel I, Ayyad HA, Levitt MJ, Mencel PJ, Hossain MA
Abstract
Acute promyelocytic leukemia (APL) is identified as the M3 subtype of acute myeloid leukemia (AML). APL is presently one of the most curable leukemias. We describe here a rare case of APL who presented as a relapsed disease after 1 year of chemotherapy for AML. The patient lacked t(15;17) at the initial presentation but was present later at the time of relapse. The patient attained a complete remission following treatment with all-trans retinoic acid (ATRA) and arsenic trioxide-based therapy. We discuss the possible mechanism behind secondary acquisition of promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) at relapse of AML. We also briefly discuss the clinical features, diagnosis and treatment of APL.
PMID: 31312283 [PubMed]
Commentary: Gamma Knife Radiosurgery for Multiple Sclerosis-Associated Trigeminal Neuralgia.
Neurosurgery. 2019 11 01;85(5):E941-E942
Authors: Song A, Shi W, Lo SS, Ellenbogen R, Ko AL
PMID: 31313810 [PubMed - indexed for MEDLINE]
Predictors of preoperative endovascular embolization of meningiomas: subanalysis of anatomic location and arterial supply.
J Neurointerv Surg. 2020 Feb;12(2):204-208
Authors: Barros G, Feroze AH, Sen R, Kelly CM, Barber J, Hallam DK, Ghodke B, Osbun JW, Kim LJ, Levitt MR
Abstract
INTRODUCTION: Endovascular embolization of intracranial meningiomas is commonly used as an adjunct to surgical resection. We sought to describe the anatomic locations and vascular supplies of meningiomas to identify characteristics predictive of successful preoperative endovascular embolization.
METHODS: We conducted a retrospective review of 139 meningioma cases receiving cerebral angiograms for possible preoperative endovascular embolization at our institution between December 2000 and March 2017. The extent of embolization, arterial supply, anatomic location, and procedural complications were recorded for each case. Univariate and multivariate analyses were performed to identify tumor characteristics that predicted successful embolization.
RESULTS: Of the total meningioma patients undergoing preoperative angiography, 78% (108/139) were successfully embolized, with a 2.8% periprocedural complication rate (3/108). Within the subset of patients with successful embolization, 31% (33/108) achieved complete angiographic embolization. Significant multivariate predictors of embolization (either partial or complete) were convexity/parasagittal locations (OR 5.15, 95% CI 0.93 to 28.54, p=0.060), meningohypophyseal trunk (MHT, OR 4.65, 95% CI 1.63 to 13.23, p=0.004), middle meningeal artery (MMA, OR 10.89, 95% CI 3.43 to 34.64, p<0.001), and ascending pharyngeal artery supply (APA, OR 9.96, 95% CI 1.88 to 52.73, p=0.007). Significant predictors for complete embolization were convexity/parasagittal locations (OR 4.79, 95% CI 1.66 to 13.84, p=0.004) and embolized APA supply (OR 6.94, 95% CI 1.90 to 25.39, p=0.003). Multiple arterial supply was a negative predictor of complete embolization (OR 0.38, 95% CI 0.15 to 0.98, p=0.05).
CONCLUSIONS: Tumor characteristics can be used to predict the likelihood of preoperative meningioma embolization. Parasagittal and convexity meningiomas, and those with APA supply, are most likely to achieve complete angiographic embolization.
PMID: 31308198 [PubMed - indexed for MEDLINE]
Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy.
J Allergy Clin Immunol. 2018 03;141(3):991-1001
Authors: Asai Y, Eslami A, van Ginkel CD, Akhabir L, Wan M, Ellis G, Ben-Shoshan M, Martino D, Ferreira MA, Allen K, Mazer B, de Groot H, de Jong NW, Gerth van Wijk RN, Dubois AEJ, Chin R, Cheuk S, Hoffman J, Jorgensen E, Witte JS, Melles RB, Hong X, Wang X, Hui J, Musk AWB, Hunter M, James AL, Koppelman GH, Sandford AJ, Clarke AE, Daley D
Abstract
BACKGROUND: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis.
OBJECTIVE: We sought to investigate genetic susceptibility to PA.
METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations.
RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30.
CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
PMID: 29030101 [PubMed - indexed for MEDLINE]
Harlequin Syndrome in Acute Thalamic Hemorrhage.
J Stroke Cerebrovasc Dis. 2019 Sep;28(9):e127-e128
Authors: McKenna MC, Menon P, Smyth S, Murphy S
Abstract
Harlequin syndrome is a disorder of the autonomic nervous system. It clinically presents as a distinct line of hemifacial sympathetic denervation. We describe a case of Harlequin syndrome with co-existing central first-order Horner syndrome in the setting of a large thalamic hemorrhage with intraventricular extension.
PMID: 31301985 [PubMed - indexed for MEDLINE]
The COOH-Terminal Proline-Rich Region of GRP78 Is a Key Regulator of Its Cell Surface Expression and Viability of Tamoxifen-Resistant Breast Cancer Cells.
Neoplasia. 2019 08;21(8):837-848
Authors: Tseng CC, Zhang P, Lee AS
Abstract
Translocation of 78-kDa glucose-regulated protein (GRP78) from endoplasmic reticulum (ER) to plasma membrane represents a paradigm shift beyond its traditional function as an ER chaperone protein. Cell surface GRP78 (csGRP78) exerts novel signaling functions, and mechanisms underlying its cell surface expression are just emerging. Acquired tamoxifen resistance of breast cancer cells is accompanied with elevated level of csGRP78. Therefore, the tamoxifen-resistant MCF7 breast cancer cells (MCF7-LR) represents a clinically relevant model to study mechanisms of csGRP78 expression. We discovered that a proline-rich region (PRR) containing three consecutive prolines close to the COOH-terminus of GRP78 is important for its ability to form a complex with the partner protein, CD44v, as demonstrated by in vitro glutathione S-transferase pull-down assay. Proline to alanine mutations at the PRR compromised GRP78 expression level on the cell surface as evidenced by purification of biotinylated cell surface proteins. Reconstitution of MCF7-LR cells with the PRR mutant after knockdown of endogenous GRP78 diminished the capacity of GRP78 to stimulate STAT3 activation. The enforced expression of a short peptide bearing the PRR region of GRP78 led to reduction of CD44v and Cyclin D1 protein levels as well as cell viability, accompanied with increase in apoptotic signaling including cleaved Caspase-3 and PARP. These findings suggest that the COOH-terminal PRR of GRP78 is critical for its interaction with CD44v as well as its cell surface expression, and enforced expression of the short peptide bearing the PRR region may provide a new approach to lower the viability of tamoxifen-resistant breast cancer cells.
PMID: 31306849 [PubMed - indexed for MEDLINE]
A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage.
J Neurosurg. 2019 Jul 12;:1-9
Authors: Ironside N, Christophe B, Bruce S, Carpenter AM, Robison T, Yoh N, Cremers S, Landry D, Frey HP, Chen CJ, Hoh BL, Kim LJ, Claassen J, Connolly ES
Abstract
OBJECTIVE: Delayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH.
METHODS: In this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH.
RESULTS: Of the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm.
CONCLUSIONS: The power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov).
PMID: 31299655 [PubMed - as supplied by publisher]
Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma.
JCI Insight. 2019 07 11;4(13):
Authors: Wirsching HG, Zhang H, Szulzewsky F, Arora S, Grandi P, Cimino PJ, Amankulor N, Campbell JS, McFerrin L, Pattwell SS, Ene C, Hicks A, Ball M, Yan J, Zhang J, Kumasaka D, Pierce RH, Weller M, Finer M, Quéva C, Glorioso JC, Houghton AM, Holland EC
Abstract
Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSVULBP3 with anti-programmed cell death 1 (anti-PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti-PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti-PD-1-sensitive abscopal effect of oHSVULBP3 warrants further investigation in patients with IDH wild-type glioblastoma.
PMID: 31292299 [PubMed - indexed for MEDLINE]
Acute reperfusion for ST-elevation myocardial infarction in New Zealand (2015-2017): patient and system delay (ANZACS-QI 29).
N Z Med J. 2019 07 12;132(1498):41-59
Authors: Kerr A, Lee M, Grey C, Pegg T, Fisher N, White H, Nunn C, Williams M, Smyth D, Scott T, Chen R, Zhao J, Tun TR, Harwood M, Devlin G
Abstract
AIM: Prompt access to cardiac defibrillation and reperfusion therapy improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). The study aim was to describe the 'patient' and 'system' delay in patients who receive acute reperfusion therapy for ST-elevation myocardial infarction (STEMI) in New Zealand.
METHODS: In 2015-17, 3,857 patients who received acute reperfusion therapy were captured in the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry. 'Patient delay' is the time from symptom onset to first medical contact (FMC), and 'system delay' the time from FMC until reperfusion therapy (primary percutaneous coronary intervention (PCI) or fibrinolysis).
RESULTS: Seventy percent of patients received primary PCI and 30% fibrinolysis. Of those receiving fibrinolysis, 122 (10.5%) received pre-hospital fibrinolysis. Seventy-seven percent were transported to hospital by ambulance. After adjustment, people who were older, male and presented to a hospital without a routine primary PCI service were less likely to travel by ambulance. Patient delay: The median delay was 45 minutes for ambulance-transported patients and 97 minutes for those self-transported to hospital, with a quarter delayed by >2 hours and >3 hours, respectively. Delay >1 hour was more common in older patients, Māori and Indian patients and those self-transported to hospital. System delay: For ambulance-transported patients who received primary PCI, the median time was 119 minutes. For ambulance-transported patients who received fibrinolysis, the median system delay was 86 minutes, with Māori patients more often delayed than European/Other patients. For patients who received pre-hospital fibrinolysis the median delay was 46 minutes shorter. For the quarter of patients treated with rescue PCI after fibrinolysis, the median needle-to-rescue time was prolonged-four hours.
CONCLUSIONS: Nationwide implementation of the NZ STEMI pathway is needed to reduce system delays in delivery of primary PCI, fibrinolysis and rescue PCI. Ongoing initiatives are required to reduce barriers to calling the ambulance early after symptom onset.
PMID: 31295237 [PubMed - indexed for MEDLINE]
A Method of Managing Severe Traumatic Brain Injury in the Absence of Intracranial Pressure Monitoring: The Imaging and Clinical Examination Protocol.
J Neurotrauma. 2018 01 01;35(1):54-63
Authors: Chesnut RM, Temkin N, Dikmen S, Rondina C, Videtta W, Petroni G, Lujan S, Alanis V, Falcao A, de la Fuenta G, Gonzalez L, Jibaja M, Lavarden A, Sandi F, Mérida R, Romero R, Pridgeon J, Barber J, Machamer J, Chaddock K
Abstract
The imaging and clinical examination (ICE) algorithm used in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST TRIP) randomized controlled trial is the only prospectively investigated clinical protocol for traumatic brain injury management without intracranial pressure (ICP) monitoring. As the default literature standard, it warrants careful evaluation. We present the ICE protocol in detail and analyze the demographics, outcome, treatment intensity, frequency of intervention usage, and related adverse events in the ICE-protocol cohort. The 167 ICE protocol patients were young (median 29 years) with a median Glasgow Coma Scale motor score of 4 but with anisocoria or abnormal pupillary reactivity in 40%. This protocol produced outcomes not significantly different from those randomized to the monitor-based protocol (favorable 6-month extended Glasgow Outcome Score in 39%; 41% mortality rate). Agents commonly employed to treat suspected intracranial hypertension included low-/moderate-dose hypertonic saline (72%) and mannitol (57%), mild hyperventilation (adjusted partial pressure of carbon dioxide 30-35 mm Hg in 73%), and pressors to maintain cerebral perfusion (62%). High-dose hyperosmotics or barbiturates were uncommonly used. Adverse event incidence was low and comparable to the BEST TRIP monitored group. Although this protocol should produce similar/acceptable results under circumstances comparable to those in the trial, influences such as longer pre-hospital times and non-specialist transport personnel, plus an intensive care unit model of aggressive physician-intensive care by small groups of neurotrauma-focused intensivists, which differs from most high-resource models, support caution in expecting the same results in dissimilar settings. Finally, this protocol's ICP-titration approach to suspected intracranial hypertension (vs. crisis management for monitored ICP) warrants further study.
PMID: 28726590 [PubMed - indexed for MEDLINE]
