UW Neurological Surgery Recent PubMed Publications

Extended lumbar drainage in idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis of diagnostic test accuracy.

Br J Neurosurg. 2020 Jul 09;:1-7

Authors: Nunn AC, Jones HE, Morosanu CO, Singleton WGB, Williams MA, Nagel SJ, Luciano MG, Zwimpfer TJ, Holubkov R, Wisoff JH, McKhann GM, Hamilton MG, Edwards RJ

Abstract
BACKGROUND: When appropriately selected, a high proportion of patients with suspected idiopathic normal pressure hydrocephalus (iNPH) will respond to cerebrospinal fluid diversion with a shunt. Extended lumbar drainage (ELD) is regarded as the most accurate test for this condition, however, varying estimates of its accuracy are found in the current literature. Here, we review the literature in order to provide summary estimates of sensitivity, specificity, positive- and negative predictive value for this test through meta-analysis of suitably rigorous studies.
METHODS: Studies involving a population of NPH patients with predominantly idiopathic aetiology (>80%) in which the intention of the study was to shunt patients regardless of the outcome of ELD were included in the review. Various literature databases were searched to identify diagnostic test accuracy studies addressing ELD in the diagnosis of iNPH. Those studies passing screening and eligibility were assessed using the QUADAS-2 tool and data extracted for bivariate random effects meta-analysis.
RESULTS: Four small studies were identified. They showed disparate results concerning diagnostic test accuracy. The summary estimates for sensitivity and specificity were 94% (CI 41-100%) and 85% (CI 33-100%), respectively. The summary estimates of positive and negative predictive value were both 90% (CIs 65-100% and 48-100%, respectively).
CONCLUSION: Large, rigorous studies addressing the diagnostic accuracy of ELD are lacking, and little robust evidence exists to support the use of ELD in diagnostic algorithms for iNPH. Therefore, a large cohort study, or ideally an RCT, is needed to determine best practice in selecting patients for shunt surgery.

PMID: 32643967 [PubMed - as supplied by publisher]

Safety, pharmacokinetics and causal prophylactic efficacy of KAF156 in a Plasmodium falciparum human infection study.

Clin Infect Dis. 2020 Jul 09;:

Authors: Kublin JG, Murphy SC, Maenza J, Seilie AM, Jain JP, Berger D, Spera D, Zhao R, Soon RL, Czartoski JL, Potochnic MA, Duke E, Chang M, Vaughan A, Kappe SHI, Leong FJ, Pertel P, Prince WT

Abstract
BACKGROUND: KAF156 is a novel antimalarial drug that is active against both liver- and blood- stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model.
METHODS: In Part 1, healthy, malaria-naïve participants received 800 mg KAF156 or placebo three hr before CHMI with Pf-infected mosquitoes. In Part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hr post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7-14 subjects were enrolled to KAF156 treatment and up to four subjects to placebo.
RESULTS: KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported - both resolved without sequelae and neither was considered related to KAF156. In Part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In Part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3/14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure-response analysis suggested that a 24-hr post-dose concentration of KAF156 of 21·5 ng/mL (90% CI 17.66 to 25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection.
CONCLUSIONS: KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy.

PMID: 32644127 [PubMed - as supplied by publisher]

Changes in the Preterm Heart From Birth to Young Adulthood: A Meta-analysis.

Pediatrics. 2020 08;146(2):

Authors: Telles F, McNamara N, Nanayakkara S, Doyle MP, Williams M, Yaeger L, Marwick TH, Leeson P, Levy PT, Lewandowski AJ

Abstract
CONTEXT: Preterm birth is associated with incident heart failure in children and young adults.
OBJECTIVE: To determine the effect size of preterm birth on cardiac remodeling from birth to young adulthood.
DATA SOURCES: Data sources include Medline, Embase, Scopus, Cochrane databases, and clinical trial registries (inception to March 25, 2020).
STUDY SELECTION: Studies in which cardiac phenotype was compared between preterm individuals born at <37 weeks' gestation and age-matched term controls were included.
DATA EXTRACTION: Random-effects models were used to calculate weighted mean differences with corresponding 95% confidence intervals.
RESULTS: Thirty-two observational studies were included (preterm = 1471; term = 1665). All measures of left ventricular (LV) and right ventricular (RV) systolic function were lower in preterm neonates, including LV ejection fraction (P = .01). Preterm LV ejection fraction was similar from infancy, although LV stroke volume index was lower in young adulthood. Preterm LV peak early diastolic tissue velocity was lower throughout development, although preterm diastolic function worsened with higher estimated filling pressures from infancy. RV longitudinal strain was lower in preterm-born individuals of all ages, proportional to the degree of prematurity (R 2 = 0.64; P = .002). Preterm-born individuals had persistently smaller LV internal dimensions, lower indexed LV end-diastolic volume in young adulthood, and an increase in indexed LV mass, compared with controls, of 0.71 g/m2 per year from childhood (P = .007).
LIMITATIONS: The influence of preterm-related complications on cardiac phenotype could not be fully explored.
CONCLUSIONS: Preterm-born individuals have morphologic and functional cardiac impairments across developmental stages. These changes may make the preterm heart more vulnerable to secondary insults, potentially underlying their increased risk of early heart failure.

PMID: 32636236 [PubMed - indexed for MEDLINE]

Evaluation of the Patient-Practitioner Consultation on Surgical Treatment Options for Patients With Craniosynostosis.

J Craniofac Surg. 2020 Jul-Aug;31(5):1186-1190

Authors: Pfeifauf KD, Said AM, Naidoo SD, Skolnick GB, Kestle JRW, Lee A, Birgfeld C, Anderson RCE, Gociman B, Siddiqi FA, Pollack IF, Goldstein JA, Tamber M, Imahiyerobo T, Smyth MD, Patel KB, Synostosis Research Group

Abstract
INTRODUCTION: Endoscope-assisted craniectomy and spring-assisted cranioplasty with post-surgical helmet molding are minimally invasive alternatives to the traditional craniosynostosis treatment of open cranial vault remodeling. Families are often faced with deciding between techniques. This study aimed to understand providers' practice patterns in consulting families about surgical options.
METHODS: An online survey was developed and distributed to 31 providers. The response rate was 84% (26/31).
RESULTS: Twenty-six (100%) respondents offer a minimally invasive surgical option for sagittal craniosynostosis, 21 (81%) for coronal, 20 (77%) for metopic, 18 (69%) for lambdoid, and 12 (46%) for multi-suture. Social issues considered in determining whether to offer a minimally invasive option include anticipated likelihood of compliance (23 = 88%), distance traveled for care (16 = 62%) and financial considerations (6 = 23%). Common tools to explain options include verbal discussion (25 = 96%), 3D reconstructed CT scans (17 = 65%), handouts (13 = 50%), 3D models (12 = 46%), hand drawings (11 = 42%) and slides (10 = 38%). Some respondents strongly (7 = 27%) or somewhat (3 = 12%) encourage a minimally invasive option over open repair. Others indicate they remain neutral (7 = 27%) or tailor their approach to meet perceived needs (8 = 31%). One (4%) somewhat encourages open repair. Despite this variation, all completely (17 = 65%), strongly (5 = 19%) or somewhat agree (4 = 15%) they use shared decision making in presenting surgical options.
CONCLUSION: This survey highlights the range of practice patterns in presenting surgical options to families and reveals possible discrepancies in the extent providers believe they use shared decision making and the extent it is actually used.

PMID: 32634133 [PubMed - indexed for MEDLINE]

Staphylococcus epidermidis protease EcpA can be a deleterious component of the skin microbiome in atopic dermatitis.

J Allergy Clin Immunol. 2020 Jul 04;:

Authors: Cau L, Williams MR, Butcher AM, Nakatsuji T, Kavanaugh JS, Cheng JY, Shafiq F, Higbee K, Hata TR, Horswill AR, Gallo RL

Abstract
BACKGROUND: S. aureus and S. epidermidis are the most abundant bacteria found on the skin of patients with atopic dermatitis (AD). S. aureus is known to exacerbate AD while S. epidermidis was considered as a beneficial commensal organism.
OBJECTIVE: In this study, we hypothesized that S. epidermidis could promote skin damage in AD by the production of a protease that damages the epidermal barrier.
METHODS: Protease activity of S. epidermidis isolates was compared with other staphylococcal species. The capacity of S. epidermidis to degrade the barrier and induce inflammation was examined using human keratinocyte tissue culture and mouse models. Skin swabs from atopic and healthy adult subjects were analyzed for the presence of S. epidermidis genomic DNA and mRNA.
RESULTS: S. epidermidis strains were observed to produce strong cysteine protease activity when grown at high density. The enzyme responsible for this activity was identified to be EcpA, a cysteine protease under quorum sensing control. EcpA was shown to degrade desmoglein-1 and LL-37 in vitro and disrupted the physical barrier and induced skin inflammation in mice. The abundance of S. epidermidis and expression of ecpA mRNA were increased on the skin of some patients with AD and this correlated with disease severity. Another commensal skin bacterial species, S. hominis, can inhibit EcpA production by S. epidermidis.
CONCLUSION: S. epidermidis was commonly regarded as a beneficial skin microbe while S. aureus considered to be deleterious. This study suggests that the overabundance of S. epidermidis found on some atopic patients can act similarly to S. aureus and damage the skin by expression of a cysteine protease.

PMID: 32634452 [PubMed - as supplied by publisher]

In Reply: Three-Vessel Anastomosis for Direct Bihemispheric Cerebral Revascularization.

Oper Neurosurg (Hagerstown). 2020 09 15;19(4):E458-E460

Authors: Sekhar LN, Zeeshan Q, Natarajan SK

PMID: 32629481 [PubMed - indexed for MEDLINE]

Rapid Improvement in Gemcitabine-associated Thrombotic Microangiopathy After a Single Dose of Eculizumab: Case Report and Review of the Literature.

Anticancer Res. 2020 Jul;40(7):3995-4000

Authors: Burns ST, Damon L, Akagi N, Laszik Z, Ko AH

Abstract
We present here the case of a 39-year-old man with metastatic pancreatic carcinoma receiving chemotherapy with the combination of gemcitabine and nab-paclitaxel as part of a clinical trial. Despite an impressive response to therapy, he ultimately developed profound anasarca, renal insufficiency, progressive cytopenias, and malignant hypertension 6 months into his treatment course. The diagnosis of gemcitabine-associated thrombotic microangiopathy (G-TMA) was made based on renal biopsy, and receipt of the anti-C5 monoclonal antibody eculizumab proved successful at reversing his deteriorating clinical course and improving his laboratory parameters. This case illustrates the importance of recognizing this rare but serious complication, and highlights one potential therapeutic option that can be used in the appropriate clinical context.

PMID: 32620643 [PubMed - indexed for MEDLINE]

Multimodal single-cell analysis reveals distinct radioresistant stem-like and progenitor cell populations in murine glioma.

Glia. 2020 Jul 04;:

Authors: Alexander J, LaPlant QC, Pattwell SS, Szulzewsky F, Cimino PJ, Caruso FP, Pugliese P, Chen Z, Chardon F, Hill AJ, Spurrell C, Ahrendsen D, Pietras A, Starita LM, Hambardzumyan D, Iavarone A, Shendure J, Holland EC

Abstract
Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells. In these analyses, mouse models of glioma have been used to understand the biology of this disease and therapeutic responses, including the radiation response. We present combined SP analysis and single-cell RNA sequencing of genetically-engineered mouse models of glioma to show a time course of cellular response to radiation. We identify and characterize two distinct tumor cell populations that are inherently radioresistant and also distinct effects of radiation on immune cell populations within the tumor microenvironment.

PMID: 32621641 [PubMed - as supplied by publisher]

Head and Brain Postmortem Computed Tomography-Autopsy Correlation in Hospital Deaths.

Am J Forensic Med Pathol. 2020 Sep;41(3):163-175

Authors: Serinelli S, Richardson TE, Destian S, Mirchia K, Williams M, Medina-Perez M, Gitto L

Abstract
The use of postmortem computed tomography (PMCT) to support autopsy pathology has increased in recent decades. To some extent, PMCT has also been contemplated as a potential alternative to conventional postmortem examination. The purpose of this study was to investigate the ability of PMCT to detect specific pathologic findings in the head and brain in natural hospital deaths.We examined postmortem CT images and autopsy data from 31 subjects who died at SUNY (State University of New York) Upstate University Hospital between 2013 and 2018. Each subject underwent a noncontrast PMCT and a traditional autopsy. A neuroradiologist analyzed PMCT images for head and brain abnormalities. The autopsies were performed by pathologists who were aware of the radiology results.In our series, PMCT was able to detect the majority of the significant space-occupying lesions, although it was not always reliable in ascertaining their nature. Postmortem computed tomography revealed findings usually challenging to detect at autopsy. Unfortunately, there were also situations in which PMCT was misleading, showing changes that were difficult to interpret, or that could be related to postmortem events. Therefore, we conclude PMCT should be used as an adjunct rather than a substitute to autopsy.

PMID: 32618580 [PubMed - indexed for MEDLINE]

"It's Not the Shunt": An Algorithm for the Assessment of Other Medically Actionable Causes of Vomiting in Children With Craniofacial Malformations.

Cleft Palate Craniofac J. 2019 07;56(6):814-816

Authors: Maxey D, Lee A, Wenger T

Abstract
BACKGROUND: After shunt malfunction has been ruled out in children with craniofacial malformations with vomiting, it can be challenging to effectively communicate with front-line providers about their unique medically actionable causes of vomiting as compared to children whose shunts were placed for other reasons (eg, prematurity/intraventricular hemorrhage).
SOLUTION: An algorithm to facilitate communication "What we did that is new": We developed an algorithm to facilitate communication regarding emergent evaluation of vomiting in this population.

PMID: 30587011 [PubMed - indexed for MEDLINE]

The Synaptic Scaling Literature: A Systematic Review of Methodologies and Quality of Reporting.

Front Cell Neurosci. 2020;14:164

Authors: Moulin TC, Rayêe D, Williams MJ, Schiöth HB

Abstract
The maintenance of the excitability of neurons and circuits is a fundamental process for healthy brain functions. One of the main homeostatic mechanisms responsible for such regulation is synaptic scaling. While this type of plasticity is well-characterized through a robust body of literature, there are no systematic evaluations of the methodological and reporting features from these studies. Our review yielded 168 articles directly investigating synaptic scaling mechanisms, which display relatively high impact, with a median impact factor of 7.76 for the publishing journals. Our methodological analysis identified that 86% of the articles made use of inhibitory interventions to induce synaptic scaling, while only 41% of those studies contain excitatory manipulations. To verify the effects of synaptic scaling, the most assessed outcome was miniature excitatory postsynaptic current (mEPSC) recordings, performed in 71% of the articles. We could also observe that the field is mostly focused on mechanistic studies of the synaptic scaling pathways (70%), rather than the interaction with other types of plasticity, such as Hebbian processes (4%). We found that more than half of the articles failed to describe simple features, such as regulatory compliance statements, ethics committee approval, or statements of conflict of interests. In light of these results, we discuss the strengths and pitfalls existing in synaptic scaling literature.

PMID: 32612512 [PubMed]

Predicting the Trajectory of Any COVID19 Epidemic From the Best Straight Line.

medRxiv. 2020 Jun 28;:

Authors: Levitt M, Scaiewicz A, Zonta F

Abstract
A pipeline involving data acquisition, curation, carefully chosen graphs and mathematical models, allows analysis of COVID-19 outbreaks at 3,546 locations world-wide (all countries plus smaller administrative divisions with data available). Comparison of locations with over 50 deaths shows all outbreaks have a common feature: H(t) defined as loge(X(t)/X(t 1)) decreases linearly on a log scale, where X(t) is the total number of Cases or Deaths on day, t (we use ln for loge). The downward slopes vary by about a factor of three with time constants (1/slope) of between 1 and 3 weeks; this suggests it may be possible to predict when an outbreak will end. Is it possible to go beyond this and perform early prediction of the outcome in terms of the eventual plateau number of total confirmed cases or deaths? We test this hypothesis by showing that the trajectory of cases or deaths in any outbreak can be converted into a straight line. Specifically , is a straight line for the correct plateau value N, which is determined by a new method, Best-Line Fitting (BLF). BLF involves a straight-line facilitation extrapolation needed for prediction; it is blindingly fast and amenable to optimization. We find that in some locations that entire trajectory can be predicted early, whereas others take longer to follow this simple functional form. Fortunately, BLF distinguishes predictions that are likely to be correct in that they show a stable plateau of total cases or death (N value). We apply BLF to locations that seem close to a stable predicted N value and then forecast the outcome at some locations that are still growing wildly. Our accompanying web-site will be updated frequently and provide all graphs and data described here.

PMID: 32607515 [PubMed]

An American Physiological Society cross-journal Call for Papers on "Deconstructing Organs: Single-Cell Analyses, Decellularized Organs, Organoids, and Organ-on-a-Chip Models".

Am J Physiol Lung Cell Mol Physiol. 2020 08 01;319(2):L266-L272

Authors: Adams JC, Bell PD, Bodine SC, Brooks HL, Bunnett N, Joe B, Keehan KH, Kleyman TR, Marette A, Morty RE, Ramírez JM, Thomsen MB, Yates BJ, Zucker IH

PMID: 32609556 [PubMed - indexed for MEDLINE]

Spasm, stenosis and shelves: balloon-assisted tracking techniques in endovascular interventions.

J Cerebrovasc Endovasc Neurosurg. 2020 Mar;22(1):26-30

Authors: Walker M, Kim LJ, Levitt MR, Ghodke B

Abstract
The technique of balloon-assisted tracking (BAT) has been demonstrated in transradial cardio-angiographic procedures. Using three commonly encountered clinical scenarios, we outline the technical details of BAT for managing peripheral and cerebral interventions with challenging vascular access. We describe methods used to overcome vasospasm, stenosis and vascular shelves during interventions for acute ischemic stroke, but these issues are not unique to neuroendovascular cases and the techniques can be applied across all endovascular interventions. We present three acute stroke interventions where anatomic challenges were overcome with the use of endovascular BAT. This article describes a novel application for BAT techniques in endovascular interventions to assist with access in peripheral, cervical and intracranial vessels. These methods can also be used to improve access during diagnostic cerebral angiography. BAT is a useful adjunct when navigating catheters through vasospasm, tortuous anatomy, vascular step-offs or intraluminal plaques.

PMID: 32596141 [PubMed]

The feasibility and safety of early ileostomy reversal: a systematic review and meta-analysis.

ANZ J Surg. 2020 Jun 28;:

Authors: Ng ZQ, Levitt M, Platell C

Abstract
BACKGROUND: Recent evidence supports the safety of early reversal of a temporary stoma, within 14 days of construction. The aim of this systematic review and meta-analysis was to evaluate the post-operative morbidity and overall feasibility of early stoma reversal.
METHODS: Medline and Cochrane databases were searched for studies up to June 2019 that investigated the outcomes of early stoma reversal (EC, defined as closure ≤14 days from the index operation) versus late stoma reversal (LC, ≥8 weeks from the index operation). Meta-analysis was performed on the respective rates of post-operative morbidity, anastomotic leak, wound infection, bleeding, sepsis, small bowel obstruction and ileus.
RESULTS: Nine studies were included (667 patients analysed). Meta-analysis showed no significant difference in the post-operative morbidity rate, anastomotic leak rate, rates of small bowel obstruction, bleeding and ileus between EC and LC. However, the wound infection rate was significantly higher after EC than LC; relative difference 0.10 (95% confidence interval 0.00-0.19, P = 0.047). The stoma-related complication rate was significantly higher after LC than EC; relative difference -0.28 (95% confidence interval -0.45 to -0.11, P = 0.001).
CONCLUSION: The concept of early stoma reversal is appealing, and this meta-analysis confirms the safety of early stoma closure with an associated reduction in stoma-related complications despite higher wound infection rates. However, the results need to be interpreted with caution due to the heterogeneity of the studies included, especially in respect of the definition of complications that were used. Further well-designed prospective studies are required prior to confident adoption of early stoma closure into clinical practice.

PMID: 32597018 [PubMed - as supplied by publisher]

The Future of Skull Base Surgery: A View Through Tinted Glasses.

World Neurosurg. 2020 10;142:29-42

Authors: Sekhar LN, Juric-Sekhar G, Qazi Z, Patel A, McGrath LB, Pridgeon J, Kalavakonda N, Hannaford B

Abstract
In the present report, we have broadly outlined the potential advances in the field of skull base surgery, which might occur within the next 20 years based on the many areas of current research in biology and technology. Many of these advances will also be broadly applicable to other areas of neurosurgery. We have grounded our predictions for future developments in an exploration of what patients and surgeons most desire as outcomes for care. We next examined the recent developments in the field and outlined several promising areas of future improvement in skull base surgery, per se, as well as identifying the new hospital support systems needed to accommodate these changes. These include, but are not limited to, advances in imaging, Raman spectroscopy and microscopy, 3-dimensional printing and rapid prototyping, master-slave and semiautonomous robots, artificial intelligence applications in all areas of medicine, telemedicine, and green technologies in hospitals. In addition, we have reviewed the therapeutic approaches using nanotechnology, genetic engineering, antitumor antibodies, and stem cell technologies to repair damage caused by traumatic injuries, tumors, and iatrogenic injuries to the brain and cranial nerves. Additionally, we have discussed the training requirements for future skull base surgeons and stressed the need for adaptability and change. However, the essential requirements for skull base surgeons will remain unchanged, including knowledge, attention to detail, technical skill, innovation, judgment, and compassion. We believe that active involvement in these rapidly evolving technologies will enable us to shape some of the future of our discipline to address the needs of both patients and our profession.

PMID: 32599213 [PubMed - indexed for MEDLINE]

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

PLoS Genet. 2020 06;16(6):e1008725

Authors: Ferreira MAR, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, Lu Y, Grosche S, Rüschendorf F, Granell R, Brumpton BM, Fritsche LG, Bhatta L, Gabrielsen ME, Nielsen JB, Zhou W, Hveem K, Langhammer A, Holmen OL, Løset M, Abecasis GR, Willer CJ, Emami NC, Cavazos TB, Witte JS, Szwajda A, 23andMe Research Team, collaborators of the SHARE study, Hinds DA, Hübner N, Weidinger S, Magnusson PK, Jorgenson E, Karlsson R, Paternoster L, Boomsma DI, Almqvist C, Lee YA, Koppelman GH

Abstract
Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

PMID: 32603359 [PubMed - indexed for MEDLINE]

A Phase 2 Study of Allogeneic GM-CSF Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer.

Clin Cancer Res. 2020 Jun 26;:

Authors: Wu AA, Bever KM, Ho WJ, Fertig EJ, Niu N, Zheng L, Parkinson RM, Durham JN, Onners BL, Ferguson A, Wilt C, Ko AH, Wang-Gillam A, Laheru DA, Anders RA, Thompson ED, Sugar EA, Jaffee EM, Le DT

Abstract
PURPOSE: This phase 2 study tested granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting.
METHODS: Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for 4 doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.
RESULTS: Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median overall survival (OS) was 9.38 months (95% CI: 5.0, 12.2) for Arm A and 14.7 months (95% CI: 11.6, 20.0) for Arm B (HR 1.75, p=0.019). Using immune related-response criteria, 2 partial responses (5.7%) were observed in Arm A and 4 (13.8%) in Arm B. GVAX + ipilimumab promoted T cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor.
CONCLUSIONS: GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

PMID: 32591464 [PubMed - as supplied by publisher]

Mathematical modeling of PDGF-driven glioma reveals the dynamics of immune cells infiltrating into tumors.

Neoplasia. 2020 Jun 22;22(9):323-332

Authors: Niu B, Zeng X, Phan TA, Szulzewsky F, Holte S, Holland EC, Tian JP

Abstract
BACKGROUND: Tumor-infiltrated immune cells compose a significant component of many cancers. They have been observed to have contradictory impacts on tumors. Although the primary reasons for these observations remain elusive, it is important to understand how immune cells infiltrating into tumors is regulated. Recently our group conducted a series of experimental studies, which showed that muIDH1 gliomas have a significant global reduction of immune cells and suggested that the longer survival time of mice with CIMP gliomas may be due to the IDH mutation and its effect on reducing of the tumor-infiltrated immune cells. However, to comprehend how IDH1 mutants regulate infiltration of immune cells into gliomas and how they affect the aggressiveness of gliomas, it is necessary to integrate our experimental data into a dynamical system to acquire a much deeper understanding of subtle regulation of immune cell infiltration.
METHODS: The method is integration of mathematical modeling and experiments. According to mass conservation laws and assumption that immune cells migrate into the tumor site along a chemotactic gradient field, a mathematical model is formulated. Parameters are estimated from our experiments. Numerical methods are developed to solve the problem. Numerical predictions are compared with experimental results.
RESULTS: Our analysis shows that the net rate of increase of immune cells infiltrated into the tumor is approximately proportional to the 4/5 power of the chemoattractant production rate, and it is an increasing function of time while the percentage of immune cells infiltrated into the tumor is a decreasing function of time. Our model predicts that wtIDH1 mice will survive longer if the immune cells are blocked by reducing chemotactic coefficient. For more aggressive gliomas, our model shows that there is little difference in their survivals between wtIDH1 and muIDH1 tumors, and the percentage of immune cells infiltrated into the tumor is much lower. These predictions are verified by our experimental results. In addition, wtIDH1 and muIDH1 can be quantitatively distinguished by their chemoattractant production rates, and the chemotactic coefficient determines possibilities of immune cells migration along chemoattractant gradient fields.
CONCLUSIONS: The chemoattractant gradient field produced by tumor cells may facilitate immune cells migration to the tumor cite. The chemoattractant production rate may be utilized to classify wtIDH1 and muIDH1 tumors. The dynamics of immune cells infiltrating into tumors is largely determined by tumor cell chemoattractant production rate and chemotactic coefficient.

PMID: 32585427 [PubMed - as supplied by publisher]

Insights on cross-species transmission of SARS-CoV-2 from structural modeling.

bioRxiv. 2020 Jun 05;:

Authors: Rodrigues JP, Barrera-Vilarmau S, Teixeira JM, Seckel E, Kastritis P, Levitt M

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 6 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic, the question emerges whether human-to-animal transmission is possible and if so, which animal species are most at risk. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

PMID: 32577636 [PubMed]