UW Neurological Surgery Recent PubMed Publications

A Humanized Mouse Model for Plasmodium vivax to Test Interventions that Block Liver Stage to Blood Stage Transition and Blood Stage Infection.

iScience. 2020 Jul 18;23(8):101381

Authors: Schäfer C, Roobsoong W, Kangwanrangsan N, Bardelli M, Rawlinson TA, Dambrauskas N, Trakhimets O, Parthiban C, Goswami D, Reynolds LM, Kennedy SY, Flannery EL, Murphy SC, Sather DN, Draper SJ, Sattabongkot J, Mikolajczak SA, Kappe SHI

Abstract
The human malaria parasite Plasmodium vivax remains vastly understudied, mainly due to the lack of suitable laboratory models. Here, we report a humanized mouse model to test interventions that block P. vivax parasite transition from liver stage infection to blood stage infection. Human liver-chimeric FRGN huHep mice infected with P. vivax sporozoites were infused with human reticulocytes, allowing transition of exo-erythrocytic merozoites to reticulocyte infection and development into all erythrocytic forms, including gametocytes, in vivo. In order to test the utility of this model for preclinical assessment of interventions, the invasion blocking potential of a monoclonal antibody targeting the essential interaction of the P. vivax Duffy Binding Protein with the Duffy antigen receptor was tested by passive immunization. This antibody inhibited invasion by over 95%, providing unprecedented in vivo evidence that PvDBP constitutes a promising blood stage vaccine candidate and proving our model highly suitable to test blood stage interventions.

PMID: 32739836 [PubMed - as supplied by publisher]

Transient Administration of Dopaminergic Precursor Causes Inheritable Overfeeding Behavior in Young Drosophila melanogaster Adults.

Brain Sci. 2020 Jul 28;10(8):

Authors: Moulin TC, Ferro F, Berkins S, Hoyer A, Williams MJ, Schiöth HB

Abstract
Imbalances in dopaminergic signaling during development have been indicated as part of the underlying neurobiology of several psychiatric illnesses, including schizophrenia, major depression, bipolar disorder, and food addiction. Yet, how transient manipulation of dopaminergic signaling influences long-lasting behavioral consequences, or if these modifications can induce inheritable traits, it is still not understood. In this study, we used the Drosophila melanogaster model to test if transient pharmacological activation of the dopaminergic system leads to modulations of feeding and locomotion in adult flies. We observed that transient administration of a dopaminergic precursor, levodopa, at 6 h, 3 days or 5 days post-eclosion, induced overfeeding behavior, while we did not find significant effects on locomotion. Moreover, this phenotype was inherited by the offspring of flies treated 6 h or 3 days post-eclosion, but not the offspring of those treated 5 days post-eclosion. These results indicate that transient alterations in dopaminergic signaling can produce behavioral alterations in adults, which can then be carried to descendants. These findings provide novel insights into the conditions in which environmental factors can produce transgenerational eating disorders.

PMID: 32731370 [PubMed]

Dural venous sinus stenting for treatment of pediatric idiopathic intracranial hypertension.

J Neurointerv Surg. 2020 Jul 30;:

Authors: Lee KE, Zehri A, Soldozy S, Syed H, Catapano JS, Maurer R, Albuquerque FC, Liu KC, Wolfe SQ, Brown S, Levitt MR, Fargen KM

Abstract
BACKGROUND: Dural venous sinus stenting (VSS) is an effective treatment for idiopathic intracranial hypertension (IIH) in adult patients. There are no published series to date evaluating safety and efficacy of VSS in pediatric patients.
OBJECTIVE: To report on procedural device selection and technique as well as safety and efficacy of VSS for pediatric patients with medically refractory IIH due to underlying venous sinus stenosis.
METHODS: A multi-institutional retrospective case series identified patients with medically refractory IIH aged less than 18 years who underwent VSS.
RESULTS: 14 patients were identified at four participating centers. Patient ages ranged from 10 to 17 years, and 10 patients (71.4%) were female. Mean body mass index was 25.7 kg/m2 (range 15.8-34.6 kg/m2). Stenting was performed under general endotracheal anesthesia in all except two patients. The average trans-stenotic gradient during diagnostic venography was 10.6 mm Hg. Patients had stents placed in the superior sagittal sinus, transverse sinus, sigmoid sinus, occipital sinus, and a combination. Average follow-up was 1.7 years after stenting. Six patients out of 10 (60%) had reduced medication dosing, 12 of 14 patients (85.7%) had improvements in headaches, two patients (100%) with pre-stent tinnitus had resolution of symptoms, and four (80%) of five patients with papilledema had improvement on follow-up ophthalmological examinations. Two patients (14.3%) developed postprocedural groin hematomas, one patient (7.1%) developed a groin pseudoaneurysm, and one patient (7.1%) had postprocedural groin bleeding. No other procedural complications occurred. Four patients (28.6%) required further surgical treatment (cerebrospinal shunting and/or stenting) after their first stenting procedure.
CONCLUSIONS: This series suggests that VSS is feasible in a pediatric population with IIH and has a low complication rate and good clinical outcomes.

PMID: 32732257 [PubMed - as supplied by publisher]

Trends in Australian inguinal hernia repair rates: a 15-year population study.

ANZ J Surg. 2020 Jul 31;:

Authors: Williams ML, Hutchinson AG, Oh DD, Young CJ

Abstract
BACKGROUND: An inguinal hernia is one of the most common surgical pathologies, and therefore the repair of an inguinal hernia is one of the most common general surgical procedures. The aim of this study was to assess the trend in inguinal hernia repair (IHR) rates in Australia between 2000/2001 and 2014/2015 using population data from public and private hospitals.
METHODS: ICD-10 data cubes from the Australian Institute of Health and Welfare were analysed to determine the number of inguinal hernia repairs performed, open or laparoscopically, between 2000/2001 and 2014/2015 financial years. These data were combined with the Australian Bureau of Statistics population data estimates for the corresponding years, to give a procedure per 100 000 estimates.
RESULTS: Incidence of IHRs within Australia decreased from 217 to 194 per 100 000 population over the 15-year study period. There was a clear shift towards increased uptake of laparoscopic surgery with a subsequent fall in rates of open IHRs. Males accounted for the majority of IHR procedures. Unilateral repair was more common; however, the incidence of unilateral repair rates decreased while bilateral IHR rates increased over the study period.
CONCLUSION: Laparoscopic techniques are increasingly being used within public and private institutions across the country for inguinal hernia repair. There has also been a decrease in the incidence of IHR procedures performed per year over the 15-year period studied, consistent with published literature from Europe and the USA.

PMID: 32734711 [PubMed - as supplied by publisher]

Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer.

Mol Ther. 2020 Jul 21;:

Authors: Ko AH, Jordan AC, Tooker E, Lacey SF, Chang RB, Li Y, Venook AP, Tempero M, Damon L, Fong L, O'Hara MH, Levine BL, Melenhorst JJ, Plesa G, June CH, Beatty GL

Abstract
B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence.

PMID: 32730744 [PubMed - as supplied by publisher]

A comparison of subgaleal versus subperiosteal dissection in open cranial vault expansion for sagittal craniosynostosis.

World Neurosurg. 2020 Jul 22;:

Authors: Cho DY, Birgfeld CB, Lee A, Ellenbogen RG, Susarla SM

Abstract
OBJECTIVE: The aim of this study is to evaluate surgical outcomes for patients with sagittal craniosynostosis undergoing open cranial vault remodeling with a modified pi procedure comparing subgaleal versus subperiosteal dissection.
METHODS: A retrospective chart review was performed for children between the ages of 3 and 7 months with sagittal craniosynostosis undergoing open cranial vault expansion at Seattle Children's Hospital. Patient demographics, operative variables, and post-operative outcomes including the surface area of bony cranial defects at 2-year follow up were evaluated.
RESULTS: Over a 3-year period, 35 patients between the ages of 3-7 months underwent surgical correction of sagittal craniosynostosis using our institutional adaptation of the modified pi technique. Twenty-five patients underwent exposure via a sub-galeal (SG) approach, 10 patients had a sub-pericranial (SP) exposure. Compared to the SP group, the SG group had significant lower estimated blood loss and a shorter operating time (p < 0.05). There were no significant differences with regard to hospital length of stay or post-operative complications (p > 0.48). At two-years post-operatively, there were no significant differences in the size of the largest cranial defects (SG: 1.1 + 0.1 cm2 versus 3.7 + 0.1 cm2, p = 0.40); no patients required a secondary cranioplasty.
CONCLUSIONS: Open posterior and middle cranial vault expansion is a safe and efficient method of open cranial vault expansion in sagittal craniosynostosis regardless of the plane of dissection. Elevation of the scalp flaps in the subgaleal plane is a minor technical modification that can reduce blood loss and operative times.

PMID: 32711139 [PubMed - as supplied by publisher]

Reexamining the categorical exclusion of pediatric participants from controlled human infection trials.

Bioethics. 2020 Jul 26;:

Authors: Murphy SC, Duenas DM, Richie TL, Shah SK

Abstract
Controlled human infection (CHI) models have been developed for numerous pathogens in order to better understand disease processes and accelerate drug and vaccine testing. In the past, some researchers conducted highly controversial CHIs with vulnerable populations, including children. Ethical frameworks for CHIs now recommend vulnerable populations be excluded because they cannot consent to high risk research. In this paper we argue that CHI studies span a wide spectrum of benefit and risk, and that some CHI studies may involve minimal risk. The categorical exclusion of children from CHIs therefore departs from the standard approach to evaluating research risks, as international regulations and ethical guidance for pediatric research generally permit non-beneficial research with low risks. The paradigm in research ethics has also shifted from focusing on protecting vulnerable participants to recognizing that inclusion can be important as a matter of justice, providing new reasons to question this default exclusion of children from CHIs. Recognizing that pediatric CHIs can raise complex ethical issues and are easy to sensationalize in ways that may threaten the public's trust in research and sponsor institutions, we conclude by describing additional complexities that must be addressed before pediatric CHIs beyond licensed vaccine studies might be ethically acceptable.

PMID: 32715497 [PubMed - as supplied by publisher]

Inotropic and lusitropic, but not arrhythmogenic, effects of adipocytokine resistin on human atrial myocardium.

Am J Physiol Endocrinol Metab. 2020 09 01;319(3):E540-E547

Authors: Aitken-Buck HM, Babakr AA, Fomison-Nurse IC, van Hout I, Davis PJ, Bunton RW, Williams MJA, Coffey S, Jones PP, Lamberts RR

Abstract
The adipocytokine resistin is released from epicardial adipose tissue (EAT). Plasma resistin and EAT deposition are independently associated with atrial fibrillation. The EAT secretome enhances arrhythmia susceptibility and inotropy of human myocardium. Therefore, we aimed to determine the effect of resistin on the function of human myocardium and how resistin contributes to the proarrhythmic effect of EAT. EAT biopsies were obtained from 25 cardiac surgery patients. Resistin levels were measured by ELISA in 24-h EAT culture media (n = 8). The secretome resistin concentrations increased over the culture period to a maximal level of 5.9 ± 1.2 ng/mL. Coculture with β-adrenergic agonists isoproterenol (n = 4) and BRL37344 (n = 13) had no effect on EAT resistin release. Addition of resistin (7, 12, 20 ng/mL) did not significantly increase the spontaneous contraction propensity of human atrial trabeculae (n = 10) when given alone or in combination with isoproterenol. Resistin dose-dependently increased trabecula-developed force (maximal 2.9-fold increase, P < 0.0001), as well as the maximal rates of contraction (2.6-fold increase, P = 0.002) and relaxation (1.8-fold increase, P = 0.007). Additionally, the postrest potentiation capacity of human trabeculae was reduced at all resistin doses, suggesting that the inotropic effect induced by resistin might be due to altered sarcoplasmic reticulum Ca2+ handling. EAT resistin release is not modulated by common arrhythmia triggers. Furthermore, exogenous resistin does not promote arrhythmic behavior in human atrial trabeculae. Resistin does, however, induce an acute dose-dependent positive inotropic and lusitropic effect.

PMID: 32715745 [PubMed - in process]

Application of the sociology theory ethnomethodology to medical education: Utilization of small group learning to combat unconscious bias in patient care.

Ann Med Surg (Lond). 2020 Sep;57:17-19

Authors: Ghaffari-Rafi A, Ghaffari-Rafi S, Lee RE, Aforlabi-Logoh I, Ko AWK, Gadama Y, Mehdizadeh R, Leon-Rojas J

PMID: 32695334 [PubMed]

Three strikes? Failed vascular access in mechanical thrombectomy.

Clin Case Rep. 2020 Jul;8(7):1329-1330

Authors: Walker M, Levitt MR, Ghodke BV

Abstract
Anatomic variability in the posterior circulation and small, fragile, or otherwise treacherous origins of vertebral arteries can create a challenge to acute endovascular intervention. We report a case of unsuccessful reperfusion due to inability to access the posterior circulation in a patient with acute basilar artery occlusion.

PMID: 32695393 [PubMed]

Situational Intracranial Pressure Management: An Argument Against a Fixed Treatment Threshold.

Crit Care Med. 2020 Aug;48(8):1214-1216

Authors: Chesnut RM, Videtta W

PMID: 32697494 [PubMed - in process]

Cohort profile: BIOVASC-late, a prospective multicentred study of imaging and blood biomarkers of carotid plaque inflammation and risk of late vascular recurrence after non-severe stroke in Ireland.

BMJ Open. 2020 Jul 19;10(7):e038607

Authors: McCabe JJ, Giannotti N, McNulty J, Collins S, Coveney S, Murphy S, Barry M, Harbison J, Cronin S, Williams D, Horgan G, Dolan E, Cassidy T, McDonnell C, Kavanagh E, Foley S, O'Connell M, Marnane M, Kelly P

Abstract
PURPOSE: Inflammation is important in stroke. Anti-inflammatory therapy reduces vascular events in coronary patients. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) identifies plaque inflammation-related metabolism. However, long-term prospective cohort studies investigating the association between carotid plaque inflammation, identified on 18F-FDG PET and the risk of recurrent vascular events, have not yet been undertaken in patients with stroke.
PARTICIPANTS: The Biomarkers Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease (BIOVASC) study and Dublin Carotid Atherosclerosis Study (DUCASS) are two prospective multicentred observational cohort studies, employing near-identical methodologies, which recruited 285 patients between 2008 and 2016 with non-severe stroke/transient ischaemic attack and ipsilateral carotid stenosis (50%-99%). Patients underwent coregistered carotid 18F-FDG PET/CT angiography and phlebotomy for measurement of inflammatory cytokines. Plaque 18F-FDG-uptake is expressed as maximum standardised uptake value (SUVmax) and tissue-to-background ratio. The BIOVASC-Late study is a follow-up study (median 7 years) of patients recruited to the DUCASS/BIOVASC cohorts.
FINDINGS TO DATE: We have reported that 18F-FDG-uptake in atherosclerotic plaques of patients with symptomatic carotid stenosis predicts early recurrent stroke, independent of luminal narrowing. The incorporation of 18F-FDG plaque uptake into a clinical prediction model also improves discrimination of early recurrent stroke, when compared with risk stratification by luminal stenosis alone. However, the relationship between 18F-FDG-uptake and late vascular events has not been investigated to date.
FUTURE PLANS: The primary aim of BIOVASC-Late is to investigate the association between SUVmax in symptomatic 'culprit' carotid plaque (as a marker of systemic inflammatory atherosclerosis) and the composite outcome of any late major vascular event (recurrent ischaemic stroke, coronary event or vascular death). Secondary aims are to investigate associations between: (1) SUVmax in symptomatic plaque, and individual vascular endpoints (2) SUVmax in asymptomatic contralateral carotid plaque and SUVmax in ipsilateral symptomatic plaque (3) SUVmax in asymptomatic carotid plaque and major vascular events (4) inflammatory cytokines and vascular events.

PMID: 32690537 [PubMed - in process]

Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus.

J Cyst Fibros. 2020 Jul 17;:

Authors: De Jong E, Garratt LW, Looi K, Lee AHY, Ling KM, Smith ML, Falsafi R, Sutanto EN, Hillas J, Iosifidis T, Martinovich KM, Shaw NC, Montgomery ST, Kicic-Starcevich E, Lannigan FJ, Vijayasekaran S, Hancock REW, Stick SM, Kicic A, WAERP, Arest CF

Abstract
BACKGROUND: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection.
METHODS: Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively.
RESULTS: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection.
CONCLUSIONS: Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies.

PMID: 32684439 [PubMed - as supplied by publisher]

Traumatic Fetal Subdural Hematoma and Unstable Maternal Spine Fracture.

World Neurosurg. 2020 10;142:368-370

Authors: Young CC, Hofstetter CP

Abstract
We present a remarkable image of a woman, 24 weeks pregnant, who sustained polytrauma after a high-speed motor vehicle collision. Evaluation revealed traumatic bilateral subdural hematoma in the fetus and an unstable T12-L1 fracture in the patient. The standard of care for her unstable fracture was surgical fixation; however, this was hampered by the desire to continue the pregnancy in the interest of the premature fetus. This case presented a unique additional consideration in the management of the polytrauma neurosurgery patient and underscores the importance of coordinated team work and patient counseling to achieve the optimal patient outcome.

PMID: 32683009 [PubMed - indexed for MEDLINE]

Percutaneous cervical cordotomy for cancer-related pain: national data (response to letter by Professor S Mercadante).

BMJ Support Palliat Care. 2020 12;10(4):414

Authors: Poolman M, Makin M, Briggs J, Scofield K, Campkin N, Williams M, Sharma ML, Laird B, Mayland CR, INPIC Group

PMID: 32680892 [PubMed - indexed for MEDLINE]

Managing central venous access during a health care crisis.

J Vasc Surg. 2020 Oct;72(4):1184-1195.e3

Authors: Chun TT, Judelson DR, Rigberg D, Lawrence PF, Cuff R, Shalhub S, Wohlauer M, Abularrage CJ, Anastasios P, Arya S, Aulivola B, Baldwin M, Baril D, Bechara CF, Beckerman WE, Behrendt CA, Benedetto F, Bennett LF, Charlton-Ouw KM, Chawla A, Chia MC, Cho S, Choong AMTL, Chou EL, Christiana A, Coscas R, De Caridi G, Ellozy S, Etkin Y, Faries P, Fung AT, Gonzalez A, Griffin CL, Guidry L, Gunawansa N, Gwertzman G, Han DK, Hicks CW, Hinojosa CA, Hsiang Y, Ilonzo N, Jayakumar L, Joh JH, Johnson AP, Kabbani LS, Keller MR, Khashram M, Koleilat I, Krueger B, Kumar A, Lee CJ, Lee A, Levy MM, Lewis CT, Lind B, Lopez-Pena G, Mohebali J, Molnar RG, Morrissey NJ, Motaganahalli RL, Mouawad NJ, Newton DH, Ng JJ, O'Banion LA, Phair J, Rancic Z, Rao A, Ray HM, Rivera AG, Rodriguez L, Sales CM, Salzman G, Sarfati M, Savlania A, Schanzer A, Sharafuddin MJ, Sheahan M, Siada S, Siracuse JJ, Smith BK, Smith M, Soh I, Sorber R, Sundaram V, Sundick S, Tomita TM, Trinidad B, Tsai S, Vouyouka AG, Westin GG, Williams MS, Wren SM, Yang JK, Yi J, Zhou W, Zia S, Woo K

Abstract
OBJECTIVE: During the COVID-19 pandemic, central venous access line teams were implemented at many hospitals throughout the world to provide access for critically ill patients. The objective of this study was to describe the structure, practice patterns, and outcomes of these vascular access teams during the COVID-19 pandemic.
METHODS: We conducted a cross-sectional, self-reported study of central venous access line teams in hospitals afflicted with the COVID-19 pandemic. To participate in the study, hospitals were required to meet one of the following criteria: development of a formal plan for a central venous access line team during the pandemic; implementation of a central venous access line team during the pandemic; placement of central venous access by a designated practice group during the pandemic as part of routine clinical practice; or management of an iatrogenic complication related to central venous access in a patient with COVID-19.
RESULTS: Participants from 60 hospitals in 13 countries contributed data to the study. Central venous line teams were most commonly composed of vascular surgery and general surgery attending physicians and trainees. Twenty sites had 2657 lines placed by their central venous access line team or designated practice group. During that time, there were 11 (0.4%) iatrogenic complications associated with central venous access procedures performed by the line team or group at those 20 sites. Triple lumen catheters, Cordis (Santa Clara, Calif) catheters, and nontunneled hemodialysis catheters were the most common types of central venous lines placed by the teams. Eight (14%) sites reported experience in placing central venous lines in prone, ventilated patients with COVID-19. A dedicated line cart was used by 35 (59%) of the hospitals. Less than 50% (24 [41%]) of the participating sites reported managing thrombosed central lines in COVID-19 patients. Twenty-three of the sites managed 48 iatrogenic complications in patients with COVID-19 (including complications caused by providers outside of the line team or designated practice group).
CONCLUSIONS: Implementation of a dedicated central venous access line team during a pandemic or other health care crisis is a way by which physicians trained in central venous access can contribute their expertise to a stressed health care system. A line team composed of physicians with vascular skill sets provides relief to resource-constrained intensive care unit, ward, and emergency medicine teams with a low rate of iatrogenic complications relative to historical reports. We recommend that a plan for central venous access line team implementation be in place for future health care crises.

PMID: 32682063 [PubMed - indexed for MEDLINE]

Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis.

Genes Dev. 2020 Jul 16;:

Authors: Szulzewsky F, Arora S, Hoellerbauer P, King C, Nathan E, Chan M, Cimino PJ, Ozawa T, Kawauchi D, Pajtler KW, Gilbertson RJ, Paddison PJ, Vasioukhin V, Gujral TS, Holland EC

Abstract
YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

PMID: 32675324 [PubMed - as supplied by publisher]

Glucose promotes epithelial-mesenchymal transitions in bladder cancer by regulating the functions of YAP1 and TAZ.

J Cell Mol Med. 2020 Jul 17;:

Authors: Li S, Zhu H, Chen H, Xia J, Zhang F, Xu R, Lin Q

Abstract
Glucose levels and type 2 diabetes (T2D) are both associated with tumorigenesis and epithelial-mesenchymal transitions (EMTs). EMTs facilitate bladder cancer (BC) metastasis development, but the mechanism by which high-glucose levels promote these EMTs in BC remains unclear. Therefore, we sought to elucidate the mechanism underlying EMT promotion due to increased glucose levels. T24 and UMUC-3 cells were cultured in media containing different glucose concentrations. YAP1, TAZ, GLUT1 and EMT-associated marker expression was analysed via Western blotting and qPCR. BC cell proliferation and invasion were assessed using MTT and Transwell assays, respectively. A xenograft nude mouse model of diabetes was used to evaluate tumour growth and metastasis in vivo. T2D was positively associated with pathologic grade (P = .016) and TNM stage (P < .001) in BC. High glucose triggered BC cell proliferation and invasion in both in vitro and in vivo conditions. High-glucose levels also promoted EMTs in BC cells and increased YAP1 and TAZ expression. YAP1 or TAZ knockdown altered EMT marker expression and decreased GLUT1 expression. Overall, our results suggest that high-glucose levels promote EMTs in BC cells via YAP1 and TAZ regulation. These effector molecules may be promising therapeutic targets for BC cases comorbid with T2D.

PMID: 32678516 [PubMed - as supplied by publisher]

Prenatal exposure to PCBs in Cyp1a2 knock-out mice interferes with F1 fertility, impairs long-term potentiation, reduces acoustic startle and impairs conditioned freezing contextual memory with minimal transgenerational effects.

J Appl Toxicol. 2019 04;39(4):603-621

Authors: Hufgard JR, Sprowles JLN, Pitzer EM, Koch SE, Jiang M, Wang Q, Zhang X, Biesiada J, Rubinstein J, Puga A, Williams MT, Vorhees CV

Abstract
Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three-coplanar/five-noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2-/- ::Ahrb1 C57BL6/J mice compared with wild-type mice (Ahrb1  = high AHR affinity). Here we exposed gravid Cyp1a2-/- ::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2 ). PCB-exposed F1 mice exhibited increased open-field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long-term potentiation with no change in spatial learning or memory. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild-type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de-/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.

PMID: 30561030 [PubMed - indexed for MEDLINE]

Factors Associated With Medication Adherence in Vascular Surgery Patients.

Vasc Endovascular Surg. 2020 Oct;54(7):625-632

Authors: Minami HR, Zemela MS, Ring AC, Williams MS, Smeds MR

Abstract
INTRODUCTION: Patients with vascular disease have higher mortality rates than age-matched peers and medical management of coexisting diseases may alter these outcomes. We sought to understand factors associated with medication nonadherence in vascular surgery patients at a single University vascular surgery clinic over a 3-month period.
MATERIALS AND METHODS: Consecutive vascular surgery patients were surveyed from June to August 2019. The survey included demographic questions, the validated Morisky Medication Adherence Scale, the 4-item Patient Health Questionnaire for Anxiety and Depression scales, and other medication-related questions. Medical and surgical histories were retrospectively collected from charts. Univariate and multivariate analyses were used to compare among high, intermediate, and low adherence.
RESULTS: A total of 128 (74%) of 174 patients met study inclusion criteria. On univariate analysis, lower medication adherence was associated with younger age (P = .004), anxiety and depression (P = .001), higher daily pain (P < .001), and patients who believed their medications were less important for treating their vascular disease (P < .001). Adherence was not associated with symptomatic vascular disease, gender, education level, marital status, employment, insurance, or the use of medication usage reminders. Multivariate analysis significantly predicted high adherence relative to low adherence with 5-year increase in age (odds ratio [OR] = 1.252, P = .021) and low adherence relative to high adherence with greater perceived pain (OR = 0.839, P = .016).
CONCLUSIONS: Younger age and high level of pain were associated with lower medication adherence. Informing patients of the importance of prescribed medication and addressing anxiety or depression symptoms may improve adherence.

PMID: 32666902 [PubMed - indexed for MEDLINE]