UW Neurological Surgery Recent PubMed Publications

Pay-it-forward gonorrhea and chlamydia testing among men who have sex with men in China: a study protocol for a three-arm cluster randomized controlled trial.

Infect Dis Poverty. 2019 Aug 16;8(1):76

Authors: Zhang TP, Yang F, Tang W, Alexander M, Forastiere L, Kumar N, Li K, Zou F, Yang L, Mi G, Wang Y, Huang W, Lee A, Zhu W, Vickerman P, Wu D, Yang B, Christakis NA, Tucker JD

Abstract
BACKGROUND: Gonorrhea and chlamydia testing rates are poor among Chinese men who have sex with men (MSM). A quasi-experimental study suggested that a pay-it-forward strategy increased dual gonorrhea/chlamydia testing among MSM. Pay-it-forward offers an individual a gift (e.g., a free test) and then asks the same person if they would like to give a gift to another person. This article reports the protocol of a randomized controlled trial to evaluate dual gonorrhea/chlamydia test uptake and other outcomes among MSM in three arms - a pay-it-forward arm, a pay-what-you-want arm, and a standard of care arm.
METHODS: Three hundred MSM will be recruited at three HIV testing sites in Guangzhou and Beijing. Testing sites include two hospital-based MSM sexually transmitted diseases clinics and one MSM community-based organization. Eligible participants will be born biologically male, aged 16 years or older, reporting previous anal sex with another man, having never participated in the pay-it-forward program, without previous gonorrhea and chlamydia testing in the past 12 months, and residing in China. Following a cluster randomized design, every cluster of ten participants will be randomly allocated into one of three arms: (1) a pay-it-forward arm in which men are offered free gonorrhea and chlamydia testing and then asked whether they would like to donate ("pay it forward") toward testing for future testers; (2) a pay-what-you-want arm in which men are offered free testing and told to decide how much to pay after receiving the test; (3) a standard of care arm in which men can pay the full price for dual gonorrhoea and chlamydia testing. The primary outcome is dual gonorrhoea/chlamydia testing as verified by administrative records. Secondary outcomes include incremental cost per test, incremental cost per diagnosis, community connectedness, and social cohesion. Primary outcome will be calculated for each arm using intention-to-treat and compared using one-sided 95% confidence intervals with a margin of 20% increase defined as superiority.
DISCUSSION: This study will examine the pay-it-forward strategy in comparison to the standard of care in improving test uptake for gonorrhea and chlamydia. We will leverage the cluster randomized controlled trial to provide scientific evidence on the potential effect of pay-it-forward. Findings from this study will shed light on novel intervention methods for increasing preventive health service utilization and innovate ways to finance it among communities.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT03741725 . Registered on 12 November 2018.

PMID: 31426869 [PubMed - indexed for MEDLINE]

Progressive Multifocal Leukoencephalopathy After Carboplatin and Paclitaxel Chemotherapy for Ovarian Carcinoma.

J Oncol Pract. 2019 10;15(10):554-555

Authors: Menon PJ, McKenna MC, Murphy S

PMID: 31425008 [PubMed - indexed for MEDLINE]

GRP78 regulates CD44v membrane homeostasis and cell spreading in tamoxifen-resistant breast cancer.

Life Sci Alliance. 2019 08;2(4):

Authors: Tseng CC, Stanciauskas R, Zhang P, Woo D, Wu K, Kelly K, Gill PS, Yu M, Pinaud F, Lee AS

Abstract
GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.

PMID: 31416894 [PubMed - indexed for MEDLINE]

Radiological and clinical predictors of scoliosis in patients with Chiari malformation type I and spinal cord syrinx from the Park-Reeves Syringomyelia Research Consortium.

J Neurosurg Pediatr. 2019 Aug 16;:1-8

Authors: Strahle JM, Taiwo R, Averill C, Torner J, Shannon CN, Bonfield CM, Tuite GF, Bethel-Anderson T, Rutlin J, Brockmeyer DL, Wellons JC, Leonard JR, Mangano FT, Johnston JM, Shah MN, Iskandar BJ, Tyler-Kabara EC, Daniels DJ, Jackson EM, Grant GA, Couture DE, Adelson PD, Alden TD, Aldana PR, Anderson RCE, Selden NR, Baird LC, Bierbrauer K, Chern JJ, Whitehead WE, Ellenbogen RG, Fuchs HE, Guillaume DJ, Hankinson TC, Iantosca MR, Oakes WJ, Keating RF, Khan NR, Muhlbauer MS, McComb JG, Menezes AH, Ragheb J, Smith JL, Maher CO, Greene S, Kelly M, O'Neill BR, Krieger MD, Tamber M, Durham SR, Olavarria G, Stone SSD, Kaufman BA, Heuer GG, Bauer DF, Albert G, Greenfield JP, Wait SD, Van Poppel MD, Eskandari R, Mapstone T, Shimony JS, Dacey RG, Smyth MD, Park TS, Limbrick DD

Abstract
OBJECTIVE: Scoliosis is frequently a presenting sign of Chiari malformation type I (CM-I) with syrinx. The authors' goal was to define scoliosis in this population and describe how radiological characteristics of CM-I and syrinx relate to the presence and severity of scoliosis.
METHODS: A large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°).
RESULTS: Based on available imaging of patients with CM-I and syrinx, 260 of 825 patients (31%) had a clear diagnosis of scoliosis based on radiographs or coronal MRI. Forty-nine patients (5.9%) did not have scoliosis, and in 516 (63%) patients, a clear determination of the presence or absence of scoliosis could not be made. Comparison of patients with and those without a definite scoliosis diagnosis indicated that scoliosis was associated with wider syrinxes (8.7 vs 6.3 mm, OR 1.25, p < 0.001), longer syrinxes (10.3 vs 6.2 levels, OR 1.18, p < 0.001), syrinxes with their rostral extent located in the cervical spine (94% vs 80%, OR 3.91, p = 0.001), and holocord syrinxes (50% vs 16%, OR 5.61, p < 0.001). Multivariable regression analysis revealed syrinx length and the presence of holocord syrinx to be independent predictors of scoliosis in this patient cohort. Scoliosis was not associated with sex, age at CM-I diagnosis, tonsil position, pB-C2 distance (measured perpendicular distance from the ventral dura to a line drawn from the basion to the posterior-inferior aspect of C2), clivoaxial angle, or frontal-occipital horn ratio. Average curve magnitude was 29.9°, and 37.7% of patients had a left thoracic curve. Older age at CM-I or syrinx diagnosis (p < 0.0001) was associated with greater curve magnitude whereas there was no association between syrinx dimensions and curve magnitude.
CONCLUSIONS: Syrinx characteristics, but not tonsil position, were related to the presence of scoliosis in patients with CM-I, and there was an independent association of syrinx length and holocord syrinx with scoliosis. Further study is needed to evaluate the nature of the relationship between syrinx and scoliosis in patients with CM-I.

PMID: 31419800 [PubMed - as supplied by publisher]

Chronic electrocorticography for sensing movement intention and closed-loop deep brain stimulation with wearable sensors in an essential tremor patient.

J Neurosurg. 2017 Sep;127(3):580-587

Authors: Herron JA, Thompson MC, Brown T, Chizeck HJ, Ojemann JG, Ko AL

Abstract
Deep brain stimulation (DBS) has become a widespread and valuable treatment for patients with movement disorders such as essential tremor (ET). However, current DBS treatment constantly delivers stimulation in an open loop, which can be inefficient. Closing the loop with sensors to provide feedback may increase power efficiency and reduce side effects for patients. New implantable neuromodulation platforms, such as the Medtronic Activa PC+S DBS system, offer important data sources by providing chronic neural sensing capabilities and a means of investigating dynamic stimulation based on symptom measurements. The authors implanted in a single patient with ET an Activa PC+S system, a cortical strip of electrodes on the hand sensorimotor cortex, and therapeutic electrodes in the ventral intermediate nucleus of the thalamus. In this paper they describe the effectiveness of the platform when sensing cortical movement intentions while the patient actually performed and imagined performing movements. Additionally, they demonstrate dynamic closed-loop DBS based on several wearable sensor measurements of tremor intensity.

PMID: 27858575 [PubMed - indexed for MEDLINE]

Repression of ferritin light chain translation by human eIF3.

Elife. 2019 08 15;8:

Authors: Pulos-Holmes MC, Srole DN, Juarez MG, Lee AS, McSwiggen DT, Ingolia NT, Cate JH

Abstract
A central problem in human biology remains the discovery of causal molecular links between mutations identified in genome-wide association studies (GWAS) and their corresponding disease traits. This challenge is magnified for variants residing in non-coding regions of the genome. Single-nucleotide polymorphisms (SNPs) in the 5' untranslated region (5'-UTR) of the ferritin light chain (FTL) gene that cause hyperferritinemia are reported to disrupt translation repression by altering iron regulatory protein (IRP) interactions with the FTL mRNA 5'-UTR. Here, we show that human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor of FTL mRNA translation, and eIF3-mediated FTL repression is disrupted by a subset of SNPs in FTL that cause hyperferritinemia. These results identify a direct role for eIF3-mediated translational control in a specific human disease.

PMID: 31414986 [PubMed - indexed for MEDLINE]

Large Particle Fluorescence-Activated Cell Sorting Enables High-Quality Single-Cell RNA Sequencing and Functional Analysis of Adult Cardiomyocytes.

Circ Res. 2019 08 16;125(5):567-569

Authors: Kannan S, Miyamoto M, Lin BL, Zhu R, Murphy S, Kass DA, Andersen P, Kwon C

PMID: 31415233 [PubMed - indexed for MEDLINE]

Cooperation of oncolytic virotherapy with VEGF-neutralizing antibody treatment in IDH wildtype glioblastoma depends on MMP9.

Neuro Oncol. 2019 12 17;21(12):1607-1609

Authors: Wirsching HG, Arora S, Zhang H, Szulzewsky F, Cimino PJ, Quéva C, Houghton AM, Glorioso JC, Weller M, Holland EC

PMID: 31412117 [PubMed - indexed for MEDLINE]

Impact of Telephone-Based Problem-Solving Treatment on the Use of Medical and Psychological Services in the Military.

J Head Trauma Rehabil. 2018 Mar/Apr;33(2):E1-E6

Authors: Richardson JS, Fann JR, Bell KR, Temkin N

Abstract
OBJECTIVE: To explore the impact of problem-solving treatment (PST) for mild traumatic brain injury in active duty service members on the use of medical and psychological services.
PARTICIPANTS: Service members who had a mild traumatic brain injury during their last deployment and enrolled in the CONcussion Treatment After Combat Trauma (CONTACT) study.
DESIGN: Secondary analysis of a randomized clinical trial. Participants were assigned to telephone-based PST, or e-mailed or mailed education only over the course of 6 months.
MAIN MEASURE: Self-reported health service utilization from months 4 through 6 and 10 through 12 after initiation of treatment, using the Cornell Service Index.
RESULTS: In months 4 to 6, participants receiving PST had 6.17 times the odds of an emergency department visit or hospitalization than those receiving education only (95% confidence interval = 1.92-19.8; P value = .0023). These estimates, however, were not significant using a conservative Bonferroni correction (P value threshold < .0014). There were no other significant differences for other medical or psychological services received in months 4 to 6 or 10 to 12.
CONCLUSION: Telephone-based PST was designed to complement clinical care, and this study showed that it may increase emergency department utilization. Future evaluations of PST with more accurate and complete measures of health service utilization are needed.

PMID: 28422894 [PubMed - indexed for MEDLINE]

Improving Provider Readiness for Intimate Partner Violence Screening.

Worldviews Evid Based Nurs. 2019 Jun;16(3):204-210

Authors: Lee ASD, McDonald LR, Will S, Wahab M, Lee J, Coleman JS

Abstract
BACKGROUND: Intimate partner violence (IPV) is a significant public health issue. Healthcare providers (e.g., nurses, advanced practice nurses, physicians, social workers) have a unique opportunity to prevent and reduce IPV through screening and referral. The objective of this project was to determine the impact of education and a brief screening tool integrated into the electronic medical record (EMR) on readiness to screen for IPV.
METHODS: An intervention was implemented that included the EMR integration of a screening tool, creation of an automated resource telephone system and healthcare provider IPV screening and response education. Readiness for screening was evaluated pre- and postintervention using the Domestic Violence Health Care Provider Survey Scale (DVHCPSS), which is scored cumulatively and by each of six domains. An unpaired Student's t test was performed.
RESULTS: Mean age (31-40 years of age) and years of clinical practice (11-15 years) was the same for pre- (n = 96) and postintervention (n = 83) survey respondents. There was an overall significant increase in screening readiness (p = .003) with significant improvement in "professional role resistance/fear of offending the patient" (p < .0001), "blame victim items" (p = .0029), "perceived self-efficacy" (p = .0064), and "victim/provider safety" (p = .003).
LINKING EVIDENCE TO ACTION: Adopting and integrating a validated IPV screening tool into the EMR combined with education was associated with an improvement in overall readiness for IPV screening. Reducing and preventing IPV through universal screening and referral can be accomplished by embedding a standardized readily accessible validated IPV screening tool in the EMR.

PMID: 31012540 [PubMed - indexed for MEDLINE]

Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome.

Elife. 2019 08 12;8:

Authors: Bolea I, Gella A, Sanz E, Prada-Dacasa P, Menardy F, Bard AM, Machuca-Márquez P, Eraso-Pichot A, Mòdol-Caballero G, Navarro X, Kalume F, Quintana A

Abstract
Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.

PMID: 31403401 [PubMed - indexed for MEDLINE]

Mischaracterization of Spaceflight-Associated Neuro-ocular Syndrome.

JAMA Neurol. 2019 Aug 12;:

Authors: Williams MA, Malm J

PMID: 31403660 [PubMed - as supplied by publisher]

In Reply: The Spectrum of Trigeminal Neuralgia Without Neurovascular Compression.

Neurosurgery. 2019 10 01;85(4):E800-E801

Authors: Magown P, Ko AL, Burchiel KJ

PMID: 31407009 [PubMed - indexed for MEDLINE]

Dual recombinase fate mapping reveals a transient cholinergic phenotype in multiple populations of developing glutamatergic neurons.

J Comp Neurol. 2019 Aug 09;:

Authors: Nasirova N, Quina LA, Agosto-Marlin IM, Ramirez JM, Lambe EK, Turner EE

Abstract
Cholinergic transmission shapes the maturation of glutamatergic circuits, yet the developmental sources of acetylcholine have not been systematically explored. Here we have used Cre-recombinase mediated genetic labeling to identify and map both mature and developing CNS neurons that express choline acetyltransferase (ChAT). Correction of a significant problem with a widely used ChatCre transgenic line ensures that this map does not contain expression artifacts. ChatCre marks all known cholinergic systems in the adult brain, but also identifies several brain areas not usually regarded as cholinergic, including specific thalamic and hypothalamic neurons, the subiculum, the lateral parabrachial nucleus, the cuneate/gracilis nuclei, and the pontocerebellar system. This ChatCre fate map suggests transient developmental expression of a cholinergic phenotype in areas important for cognition, motor control, and respiration. We therefore examined expression of ChAT and the vesicular acetylcholine transporter (VAChT) in the embryonic and early postnatal brain to determine the developmental timing of this transient cholinergic phenotype, and found that it mirrored the establishment of relevant glutamatergic projection pathways. We then used an intersectional genetic strategy combining ChatCre with Vglut2Flp to show that these neurons adopt a glutamatergic fate in the adult brain. The transient cholinergic phenotype of these glutamatergic neurons suggests a homosynaptic source of acetylcholine for the maturation of developing glutamatergic synapses. These findings thus define critical windows during which specific glutamatergic circuits may be vulnerable to disruption by nicotine in utero, and suggest new mechanisms for pediatric disorders associated with maternal smoking, such as sudden infant death syndrome. This article is protected by copyright. All rights reserved.

PMID: 31396962 [PubMed - as supplied by publisher]

Multicenter validation of automated trajectories for selective laser amygdalohippocampectomy.

Epilepsia. 2019 09;60(9):1949-1959

Authors: Vakharia VN, Sparks RE, Li K, O'Keeffe AG, Pérez-García F, França LGS, Ko AL, Wu C, Aronson JP, Youngerman BE, Sharan A, McKhann G, Ourselin S, Duncan JS

Abstract
OBJECTIVE: Laser interstitial thermal therapy (LITT) is a novel minimally invasive alternative to open mesial temporal resection in drug-resistant mesial temporal lobe epilepsy (MTLE). The safety and efficacy of the procedure are dependent on the preplanned trajectory and the extent of the planned ablation achieved. Ablation of the mesial hippocampal head has been suggested to be an independent predictor of seizure freedom, whereas sparing of collateral structures is thought to result in improved neuropsychological outcomes. We aim to validate an automated trajectory planning platform against manually planned trajectories to objectively standardize the process.
METHODS: Using the EpiNav platform, we compare automated trajectory planning parameters derived from expert opinion and machine learning to undertake a multicenter validation against manually planned and implemented trajectories in 95 patients with MTLE. We estimate ablation volumes of regions of interest and quantify the size of the avascular corridor through the use of a risk score as a marker of safety. We also undertake blinded external expert feasibility and preference ratings.
RESULTS: Automated trajectory planning employs complex algorithms to maximize ablation of the mesial hippocampal head and amygdala, while sparing the parahippocampal gyrus. Automated trajectories resulted in significantly lower calculated risk scores and greater amygdala ablation percentage, whereas overall hippocampal ablation percentage did not differ significantly. In addition, estimated damage to collateral structures was reduced. Blinded external expert raters were significantly more likely to prefer automated to manually planned trajectories.
SIGNIFICANCE: Retrospective studies of automated trajectory planning show much promise in improving safety parameters and ablation volumes during LITT for MTLE. Multicenter validation provides evidence that the algorithm is robust, and blinded external expert ratings indicate that the trajectories are clinically feasible. Prospective validation studies are now required to determine if automated trajectories translate into improved seizure freedom rates and reduced neuropsychological deficits.

PMID: 31392717 [PubMed - indexed for MEDLINE]

Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study.

Br J Ophthalmol. 2020 04;104(4):493-499

Authors: Gale RP, Pearce I, Eter N, Ghanchi F, Holz FG, Schmitz-Valckenberg S, Balaskas K, Burton BJL, Downes SM, Eleftheriadis H, George S, Gilmour D, Hamilton R, Lotery AJ, Patel N, Prakash P, Santiago C, Thomas S, Varma D, Walters G, Williams M, Wolf A, Zakri RH, Igwe F, Ayan F

Abstract
BACKGROUND/AIMS: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity.
METHODS: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed.
RESULTS: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified.
CONCLUSION: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

PMID: 31383649 [PubMed - indexed for MEDLINE]

Letter to the Editor. Microsurgery for basilar apex aneurysms in the modern era.

J Neurosurg. 2017 12;127(6):1468-1469

Authors: Morton RP, Kim LJ, Sekhar LN

PMID: 28799878 [PubMed - indexed for MEDLINE]

The benefit zone of full-endoscopic spine surgery.

J Spine Surg. 2019 Jun;5(Suppl 1):S41-S56

Authors: Hasan S, Härtl R, Hofstetter CP

Abstract
Minimally invasive spine procedures have undergone rapid development during the last decade. Efforts to decrease muscle crush injuries during prolonged retraction, avoid significant soft tissue stripping and minimize bony resection are surgical principles that are employed to prevent iatrogenic instability and provide patients with decreased post-operative pain and disability. Full-endoscopic spine surgery represents a tool for the spine surgeon to provide targeted access to spinal pathology utilizing these principles. Endoscopic techniques have seen over 30 years of evolution and innovation, however, early iterations of these techniques largely focused on transforaminal lumbar microdiscectomies. Currently, endoscopic techniques are utilized for approaching pathology in the cervical, thoracic and lumbar spine. There has been a growing body of literature that not only confirms the efficacy of these procedures but also underscores the advantages these procedures offer with respect to less morbidity and safer complication profiles. Endoscopic decompressions have been utilized in the settings of degenerative spinal stenosis, spondylolisthesis, scoliosis, previous fusion, tumor and infection. Furthermore, endoscopic interbody fusion has also been utilized in the lumbar spine as technology continues to advance. As technological innovation continues to facilitate reproducible surgical technique and expand the indications for use, we believe that endoscopic spine surgical techniques will provide surgeons with a more powerful and less morbid approach to spinal pathology that ultimately elevates the standard of care when treating our patients. We present a brief review of the history of endoscopic spine surgery, an overview of current techniques and review current outcomes of endoscopic spine surgical procedures in the context of an invasiveness/complexity index to elucidate the benefit zone of these newer techniques.

PMID: 31380492 [PubMed]

Influence of Commercial and Laboratory Diets on Growth, Body Composition, and Reproduction in the Zebrafish Danio rerio.

Zebrafish. 2019 12;16(6):508-521

Authors: Fowler LA, Williams MB, Dennis-Cornelius LN, Farmer S, Barry RJ, Powell ML, Watts SA

Abstract
The value of the zebrafish (Danio rerio) as a model organism continues to expand. In developing the model, current feeding practice in zebrafish laboratories includes the use of commercially available diets. In this study, we compared outcomes in growth, body composition, and reproduction among zebrafish fed five highly utilized commercial diets and one formulated chemically defined reference diet. Wild-type zebrafish larvae were raised on live feed until 21 days postfertilization and then fed diets for 16 weeks. All fish received a daily ration of >5% of body weight (adjusted biweekly). Growth varied among diets throughout the feeding trial, and at study termination (week 16), significant differences among diets were observed for terminal weight gain, body condition index, body fat deposition, and reproductive outcomes. In addition, the proportion of viable embryos produced from females fed the formulated reference diet was high relative to the commercial diets. These data suggest that metabolic profiles, most likely reflecting nutrient/energy availability, utilization, and allocation, vary relative to diet in zebrafish. Undefined differences in metabolic profiles could result in erroneous predictions of health outcomes and make comparisons among laboratories more challenging. We recommend that dietary standards should be defined for zebrafish to support their common utility in biomedical research.

PMID: 31381491 [PubMed - indexed for MEDLINE]

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Nat Cell Biol. 2019 08;21(8):1003-1014

Authors: Kofuji S, Hirayama A, Eberhardt AO, Kawaguchi R, Sugiura Y, Sampetrean O, Ikeda Y, Warren M, Sakamoto N, Kitahara S, Yoshino H, Yamashita D, Sumita K, Wolfe K, Lange L, Ikeda S, Shimada H, Minami N, Malhotra A, Morioka S, Ban Y, Asano M, Flanary VL, Ramkissoon A, Chow LML, Kiyokawa J, Mashimo T, Lucey G, Mareninov S, Ozawa T, Onishi N, Okumura K, Terakawa J, Daikoku T, Wise-Draper T, Majd N, Kofuji K, Sasaki M, Mori M, Kanemura Y, Smith EP, Anastasiou D, Wakimoto H, Holland EC, Yong WH, Horbinski C, Nakano I, DeBerardinis RJ, Bachoo RM, Mischel PS, Yasui W, Suematsu M, Saya H, Soga T, Grummt I, Bierhoff H, Sasaki AT

Abstract
In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

PMID: 31371825 [PubMed - indexed for MEDLINE]