bluuebunny/crossref_metadata_2025 huggingface dataset:
Foveal blur-boosted segmentation of nuclei in histopathology images with shape prior knowledge and probability map constraints
Authors: Duanmu Hongyi , Wang Fusheng , Teodoro George , Kong Jun
Published: June 2021

Motivation

In most tissue-based biomedical research, the lack of sufficient pathology training images with well-annotated ground truth inevitably limits the performance of deep learning systems. In this study, we propose a convolutional neural network with foveal blur enriching datasets with multiple local nuclei regions of interest derived from original pathology images. We further propose a human-knowledge boosted deep learning system by inclusion to the convolutional neural network new loss function terms capturing shape prior knowledge and imposing smoothness constraints on the predicted probability maps.

Results

Our proposed system outperforms all state-of-the-art deep learning and non-deep learning methods by Jaccard coefficient, Dice coefficient, Accuracy and Panoptic Quality in three independent datasets. The high segmentation accuracy and execution speed suggest its promising potential for automating histopathology nuclei segmentation in biomedical research and clinical settings.

Availability and implementation

The codes, the documentation and example data are available on an open source at: https://github.com/HongyiDuanmu26/FovealBoosted.

Supplementary information

Supplementary data are available at Bioinformatics online.
Assessing consistency across functional screening datasets in cancer cells
Authors: Cai Ling , Liu Hongyu , Minna John D , DeBerardinis Ralph J , Xiao Guanghua , Xie Yang
Published: June 2021

Motivation

Many high-throughput screening studies have been carried out in cancer cell lines to identify therapeutic agents and targets. Existing consistency assessment studies only examined two datasets at a time, with conclusions based on a subset of carefully selected features rather than considering global consistency of all the data. However, poor concordance can still be observed for a large part of the data even when selected features are highly consistent.

Results

In this study, we assembled nine compound screening datasets and three functional genomics datasets. We derived direct measures of consistency as well as indirect measures of consistency based on association between functional data and copy number-adjusted gene expression data. These results have been integrated into a web application—the Functional Data Consistency Explorer (FDCE), to allow users to make queries and generate interactive visualizations so that functional data consistency can be assessed for individual features of interest.

Availability and implementation

The FDCE web tool and we have developed and the functional data consistency measures we have generated are available at https://lccl.shinyapps.io/FDCE/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Transcriptomic analysis of human brains with Alzheimer’s disease reveals the altered expression of synaptic genes linked to cognitive deficits
Authors: Williams Jamal B , Cao Qing , Yan Zhen
Published: June 2021

Alzheimer’s disease is a progressive neurodegenerative disorder associated with memory loss and impaired executive function. The molecular underpinnings causing cognitive deficits in Alzheimer’s disease are loosely understood. Here, we performed cross-study large-scale transcriptomic analyses of postmortem prefrontal cortex derived from Alzheimer’s disease patients to reveal the role of aberrant gene expression in this disease. We identified that one of the most prominent changes in prefrontal cortex of Alzheimer’s disease humans was the downregulation of genes in excitatory and inhibitory neurons that are associated with synaptic functions, particularly the SNARE-binding complex, which is essential for vesicle docking and neurotransmitter release. Comparing genomic data of Alzheimer’s disease with proteomic data of cognitive trajectory, we found that many of the lost synaptic genes in Alzheimer’s disease encode hub proteins whose increased abundance is required for cognitive stability. This study has revealed potential molecular targets for therapeutic intervention of cognitive decline associated with Alzheimer’s disease.
Differential effect of ethanol intoxication on peripheral markers of cerebral injury in murine blunt traumatic brain injury
Authors: Li Zhenghui , Zhang Jin , Halbgebauer Steffen , Chandrasekar Akila , Rehman Rida , Ludolph Albert , Boeckers Tobias , Huber-Lang Markus , Otto Markus , Roselli Francesco , Heuvel Florian olde
Published: June 2021

Background

Blood-based biomarkers have proven to be a reliable measure of the severity and outcome of traumatic brain injury (TBI) in both murine models and patients. In particular, neuron-specific enolase (NSE), neurofilament light (NFL) and S100 beta (S100B) have been investigated in the clinical setting post-injury. Ethanol intoxication (EI) remains a significant comorbidity in TBI, with 30–40% of patients having a positive blood alcohol concentration post-TBI. The effect of ethanol on blood-based biomarkers for the prognosis and diagnosis of TBI remains unclear. In this study, we investigated the effect of EI on NSE, NFL and S100B and their correlation with blood–brain barrier integrity in a murine model of TBI.

Methods

We used ultra-sensitive single-molecule array technology and enzyme-linked immunosorbent assay methods to measure NFL, NSE, S100B and claudin-5 concentrations in plasma 3 hours post-TBI.

Results

We showed that NFL, NSE and S100B were increased at 3 hours post-TBI. Interestingly, ethanol blood concentrations showed an inverse correlation with NSE but not with NFL or S100B. Claudin-5 levels were increased post-injury but no difference was detected compared to ethanol pretreatment. The increase in claudin-5 post-TBI was correlated with NFL but not with NSE or S100B.

Conclusions

Ethanol induces an effect on biomarker release in the bloodstream that is different from TBI not influenced by alcohol. This could be the basis of investigations into humans.
Mapping and quantification of the twitter footprint of cardiologists
Authors: Kalra Ankur , Kumar Ashish , Nowacki Amy S , Shahadat Amna , Khan Muhammad Shahzeb , Jabri Ahmad , Khan Safi U , Michos Erin D , Califf Robert M , Bhatt Deepak L
Published: June 2021

Aims

The increasing importance placed by medical journals for dissemination of published articles on social media, such as posting Altmetric scores, has further expedited the need for differentiating bona fide science from pseudo-science. The ‘Kardashian index’ (a.k.a., K-index) was suggested, which correlates the citations of a scientist with his/her Twitter followers.

Methods and results

From a list of top 100 cardiology hospitals in accordance with the most recent US News and World Report rankings, 1500 cardiologists were selected based on institutional physician profile pages complete with cardiologists’ headshots. The K-index of cardiologists, and variables like all-time posts, and posts for the past 12 months (1 June 2019 to 31 May 2020) from cardiologists were documented and analysed. The K-index of cardiologists in our study was stratified into the following categories (upper boundary inclusive); K-index 0–1 (n = 104); K-index 1–2 (n = 30); K-index 2–3 (n = 24); K-index 3–4 (n = 14); K-index 4–5 (n = 5); and K-index >5 (n = 22). There was no statistically significant difference (P = 0.94) in the citation number across the K-index categories (no consistent pattern observed, median citations ranging from 237 to 610). However, cardiologists with higher K-index categories had a higher number of 12-month posts (median 14 vs. 392 for K-index categories 0–1 and >5, respectively; P-value <0.001).

Conclusion

Considering no evidence of a difference in the number of citations across K-index categories, the stigma associated with higher K-index needs to be reconsidered.
The rise in inequality after pandemics: can fiscal support play a mitigating role?
Authors: Furceri Davide , Loungani Prakash , Ostry Jonathan D , Pizzuto Pietro
Published: June 2021

Major epidemics of the last two decades (SARS, H1N1, MERS, Ebola, and Zika) have been followed by increases in inequality [Furceri et al. (2020), COVID Economics, 12, 138–157]. In this article, we show that the extent of fiscal consolidation in the years following the onset of these pandemics has played an important role in determining the extent of the increase in inequality. Episodes marked by extreme austerity—measured using either the government’s fiscal balance, health expenditures, or redistribution—have been associated with an increase in the Gini measure of inequality three times as large as in episodes where fiscal policy has been more supportive. We survey the evidence thus far on the distributional impacts of the COVID-19 pandemic, which suggests that inequality is likely to increase in the absence of strong policy actions. We review the case made by many observers [IMF (2020), Fiscal Monitor; Stiglitz (2020), Finance & Development, Fall 2020; Sandbu (2020b), Financial Times, 26 November 2020)] that fiscal support should not be withdrawn prematurely despite understandable concerns about high public debt-to-GDP ratios.
Apathy and Anhedonia in Adult and Adolescent Cannabis Users and Controls Before and During the COVID-19 Pandemic Lockdown
Authors: Skumlien Martine , Langley Christelle , Lawn Will , Voon Valerie , Sahakian Barbara J
Published: June 2021

Background

COVID-19 lockdown measures have caused severe disruptions to work and education and prevented people from engaging in many rewarding activities. Cannabis users may be especially vulnerable, having been previously shown to have higher levels of apathy and anhedonia than non-users.

Methods

In this survey study, we measured apathy and anhedonia, before and after lockdown measures were implemented, in n = 256 adult and n = 200 adolescent cannabis users and n = 170 adult and n = 172 adolescent controls. Scores on the Apathy Evaluation Scale (AES) and Snaith-Hamilton Pleasure Scale (SHAPS) were investigated with mixed-measures ANCOVA, with factors user group, age group, and time, controlling for depression, anxiety, and other drug use.

Results

Adolescent cannabis users had significantly higher SHAPS scores before lockdown, indicative of greater anhedonia, compared with adolescent controls (P = .03, η p2 = .013). Contrastingly, adult users had significantly lower scores on both the SHAPS (P < .001, η p2 = .030) and AES (P < .001, η p2 = .048) after lockdown compared with adult controls. Scores on both scales increased during lockdown across groups, and this increase was significantly smaller for cannabis users (AES: P = .001, η p2 = .014; SHAPS: P = .01, η p2 = .008). Exploratory analyses revealed that dependent cannabis users had significantly higher scores overall (AES: P < .001, η p2 = .037; SHAPS: P < .001, η p2 = .029) and a larger increase in scores (AES: P = .04, η p2 =.010; SHAPS: P = .04, η p2 = .010), compared with non-dependent users.

Conclusions

Our results suggest that adolescents and adults have differential associations between cannabis use as well as apathy and anhedonia. Within users, dependence may be associated with higher levels of apathy and anhedonia regardless of age and a greater increase in levels during the COVID-19 lockdown.
Measuring the impacts of the Using Antibiotics Wisely campaign on Canadian community utilization of oral antibiotics for respiratory tract infections: a time-series analysis from 2015 to 2019
Authors: Rolf von den Baumen Teagan , Crosby Michael , Tadrous Mina , Schwartz Kevin L. , Gomes Tara
Published: June 2021

Background

On 1 November 2018, Choosing Wisely Canada launched their Using Antibiotics Wisely primary care campaign, which aimed to reduce unnecessary antibiotic prescriptions for respiratory tract infections (RTIs) through educational tools for patients and providers.

Objectives

We explored the impact of this campaign on antibiotic utilization in Canada.

Methods

We conducted a population-based study in Canada between January 2015 and December 2019. We used interventional autoregressive integrated moving average models to study the impact of the Using Antibiotics Wisely campaign on the prescribing rate (prescriptions per 1000 population) of RTI-indicated antibiotics. We analysed prescription rates overall and stratified by age group, drug class and province, in each month over the study period.

Results

There was a 1.5% reduction in the annual prescribing rate of RTI-indicated antibiotics over the study period, which was generally consistent across age groups and provinces. Following the 2018 Using Antibiotics Wisely clinician toolkit release, we observed no significant change in RTI-indicated antibiotic prescribing rates nationally (P = 0.13). This was consistent by age group (children, P = 0.91; adults, P = 0.58; and older adults, P = 0.67) and drug class (narrow-spectrum penicillins, P = 0.88; macrolides, P = 0.85; broad-spectrum penicillins, P = 0.60; cephalosporins, P = 0.45; tetracyclines, P = 0.55; and fluoroquinolones, P = 0.98). In our secondary analysis of prescription rates in provinces that self-identified as prioritizing Using Antibiotics Wisely, we observed no significant change following the launch of the campaign.

Conclusions

The introduction of the Using Antibiotics Wisely campaign in Canada has not caused a significant change in short-term antibiotic prescribing patterns. Community antibiotic stewardship campaigns that include components beyond education may be more impactful.
A Method That Precisely Pressurizes the Local Limb
Authors: Zhou Jinfeng , Fu Chen , Yang Wengbo , Gu Wenhua
Published: June 2021

Pressure garment treatment (PGT) is currently recognized as an effective method to prevent scar formation or treat scar hyperplasia. Research on PGT remains controversial. These controversies indicate that PGT lacks reliable evidence of evidence-based medicine. Different studies on PGT need to be conducted under the same “gold standard” so that different studies can be compared. We consider this “gold standard” to be that the pressure remains stable within a confidence interval during treatment. We calibrated and verified the reference value of the sensor using a cuff of sphygmomanometer. A pressure-adjustable pressure system was obtained by installing a soft tissue expander on the pressure garment. Local pressure was adjusted by charging and releasing air. Subsequently, the flexible pressure sensor was placed on the upper arm of the healthy volunteers. We validated the compression system on healthy volunteers’ forearms and AO standard prostheses (forearms). The reference value of the sensor was calibrated on Volunteer 1. Measuring repeated on Volunteers 2 and 3. The measurement was very reproducible. The test results in the experimental group showed that the local pressure gradually increased with the increase of the inflation of the airbag. However, the pressure at the opposite position of the forearm changed little. Real-time pressure monitoring and pressure adjustment enable the pressure to be maintained at a certain value. Our study provides a new idea for the production of elastic clothing with the function of pressure measurement and pressure regulation, which may promote the accuracy and reliability of PGT.
How to manage emotional problems
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

It is important to address your loved one’s emotional problems. Learn to recognize the signs of depression and anxiety. Common symptoms of depression include feelings of sadness, worthlessness or guilt; fixating on past failures; being tearful; irritability or frustration, even over small matters; memory difficulties; trouble concentrating; sleep difficulties; daytime fatigue and lack of energy; changes in appetite; often wanting to stay home; physical slowing; physical aches or pains; loss of interest in activities; loss of interest in sex; loss of interest in living; hopelessness about the future; frequent thoughts of death. Help them to deal with the sadness and frustration that often come with declining abilities. Start by improving your loved one’s abilities and adjust tasks to make them easier. Treat depression and anxiety with aerobic exercise, meditation, relaxation, and talk therapy.
Introduction
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This introduction outlines the structure of the Managing Cancer and Living Meaningfully (CALM) book and presents an overview of core CALM concepts and research. Part I of the book outlines the theoretical framework and research that has informed the development of CALM. Part II contains the CALM manual, which presents the specific content and process of CALM. Our path to the development of CALM is described and the four CALM domains are introduced alongside the CALM evidence base.
Military Medical Ethics and Just War
Authors: Gross Michael L.
Published: June 2021

The goal of military medicine is to conserve the fighting force necessary to prosecute just wars. Just wars are defensive or humanitarian. A defensive war protects one’s people or nation. A humanitarian war rescues a foreign, persecuted people or nation from grave human rights abuse. To provide medical care during armed conflict, military medical ethics supplements civilian medical ethics with two principles: military-medical necessity and broad beneficence. Military-medical necessity designates the medical means required to pursue national self-defense or humanitarian intervention. While clinical-medical necessity directs care to satisfy urgent medical needs, military-medical necessity utilizes medical care to satisfy the just aims of war. Military medicine may, therefore, attend the lightly wounded before the critically wounded or use medical care to win hearts and minds. The underlying principle is broad, not narrow, beneficence. The latter addresses private interests, while broad beneficence responds to the collective welfare of the political community.
Sleep Hygiene
Authors: Patel Smita
Published: June 2021

An important aspect of maintaining a healthy mental state and good quality of life is maintaining proper sleep hygiene. A lack of sleep, a disrupted sleeping pattern, or a disordered sleep routine can make a huge impact on well-being and daytime alertness. Inadequate sleep hygiene behaviors may precipitate an episode of insomnia and may perpetuate insomnia. When these behaviors are identified and addressed, it can positively impact sleep. Good sleep habits are behaviors and conditions that can be consciously changed to improve an individual’s quality and quantity of sleep. While sleep hygiene alone is not considered a primary therapy for chronic insomnia, it can be an important adjunctive measure to improve sleep quality along with cognitive behavioral therapy and therapeutics. Sleep is essential, and an improved quality of sleep achieved on a regular basis is optimal for all.
Sleep and Cannabis
Authors: Dedhia Param , Kole Alison
Published: June 2021

With the rising interest in cannabis, the concept of medicinal cannabis for sleep has quickly grown. The chemistry of cannabis and its medicinal effects are becoming known. Within sleep science, cannabis research has noted a connection to circadian rhythm and sleep staging. Early research has looked at insomnia, obstructive sleep apnea, restless leg syndrome, rapid eye movement behavior disorder, posttraumatic stress disorder, and chronic pain. At this time, there is encouragement for future research based on available studies. However, rigorous studies are needed before the medicinal use of cannabis for sleep can be supported by medical literature. Nevertheless, cannabis is being self-administered, and patients are looking for education. The healthcare provider has a unique opportunity to partner with patients through education and guidance, making it important for medical experts to learn about cannabis.
Hypnotic Medication Use
Authors: Revolorio Kaddy , Martin Jennifer L.
Published: June 2021

Hypnotic medications are widely prescribed for the treatment of insomnia, and, either due to patient preference or medical necessity, some patients must discontinue use of hypnotics after using these medications for long periods of time. Helping patients to discontinue use of hypnotics can be clinically challenging. Hypnotic taper interventions as well as hypnotic taper interventions combined with cognitive behavior therapy for insomnia (CBT-I) are generally useful in helping patients discontinue use without significant disruption to sleep. Interventions that include CBT-I seem to have greater long-term benefits as patients experience improvements in sleep that are long-lasting and are better able to abstain from hypnotic use in the future. Additional research to incorporate motivational enhancement strategies and better understand the optimal timing and structure of hypnotic medication tapering interventions with CBT-I are needed.
Transradial Approach for Stroke
Authors: Chen Stephanie H. , Jabbour Pascal M. , Peterson Eric C.
Published: June 2021

Performing a mechanical thrombectomy via the radial approach is a critical skill to be learned in the armamentarium of the neurointerventionalist. In addition to potential safety advantages, patient anatomy often renders femoral access to the internal carotid artery impossible. Morbid obesity, severe aortic arch tortuosity, or aortofemoral occlusive disease can cause significant delays in accessing the target vessel or even complete failure. There are unique challenges to performing mechanical thrombectomy via the radial approach, given the need for speed and qualified metrics of technical success. The technical nuances and pearls of performing a mechanical thrombectomy via the radial approach are reviewed.
Drug Treatments
Authors: Taylor Eric
Published: June 2021

This chapter describes the use of medication in alleviating the problems of young people with neurodevelopmental disorders. It gives special emphasis to its use in multiple overlapping conditions and to the long-term impact on functioning. Stimulant and non-stimulant medications for the control of inattention and hyperactivity are reviewed. Antipsychotics for control of agitation and aggression, as well as for the treatment of psychosis, are considered. Pharmacological management of mood and anxiety problems is covered in the context of people with neurodevelopmental disorders. Control of tics, other movement disorders, and sleep problems are included. Practical considerations of prescribing are covered, and cautions about safety include descriptions of adverse events and how to reduce them.
Properties of cold molecular gas in four type-1 active galaxies hosting outflows
Authors: Runnoe Jessie C , Gültekin Kayhan , Rupke David , López-Sepulcre Ana
Published: June 2021

Feedback from active galactic nuclei (AGN) has proven to be a critical ingredient in the current picture of galaxy assembly and growth. However, observational constraints on AGN-driven outflows face technical challenges and as a result, the cold molecular gas outflow properties of type-1 AGN are not well known. We present new IRAM NOrthern Extended Millimeter Array observations of CO$\, (1{-}0)$ in F07599+6508, Z11598 − 0112, F13342 + 3932, and PG1440 + 356, all nearby type-1 AGN and ultraluminous infrared galaxies. We achieve spatial resolution of 1–3 arcsec corresponding to physical scales of 2–8 kpc and spectral resolution of 15–60  km s−1, which enables updated CO$\, (1{-}0)$ redshifts and a detailed morphological view of the cold molecular gas in these sources. The CO$\, (1{-}0)$ luminosities, $L_{CO}^{\prime }$, are in the range 2–12 × 109 K km s−1 pc2 and inferred molecular gas masses, M(H2), are in the range 2–9 × 109 M⊙. The velocity fields and gas distributions do not unambiguously identify any of these sources as having outflows. However, Z11598 − 0112 has signs of infalling material and after the subtraction of a rotating disc model PG 1440 + 356 shows complex kinematics in the residuals that may indicate an outflow or warped disc.
On the Nitrogen variation in ∼2 Gyr old massive star clusters in the large Magellanic Cloud
Authors: Martocchia S , Lardo C , Rejkuba M , Kamann S , Bastian N , Larsen S , Cabrera-Ziri I , Chantereau W , Dalessandro E , Kacharov N , Salaris M
Published: June 2021

We present ESO/VLT FORS2 low resolution spectroscopy of red giant branch stars in three massive intermediate age (∼1.7–2.3 Gyr) star clusters in the Large Magellanic Cloud. We measure CH and CN index bands at 4300 Å  and 3883 Å, as well as [C/Fe] and [N/Fe] abundance ratios for 24, 21, and 12 member stars of NGC 1978, NGC 1651, and NGC 1783, respectively. We find a significant intrinsic spread in CN in NGC 1978 and NGC 1651, a signal of multiple stellar populations (MPs) within the clusters. On the contrary, we report a null CN spread in NGC 1783 within our measurement precision. For NGC 1978, we separated the two populations in the CN distribution and we translated the CN spread into an internal N variation Δ[N/Fe] = 0.63 ± 0.49 dex. For NGC 1651 and NGC 1783, we put upper limits on the N abundance variations of Δ[N/Fe] ≤ 0.2, 0.4 dex, respectively. The spectroscopic analysis confirms previous results from HST photometry, where NGC 1978 was found to host MPs in the form of N spreads, while slightly younger clusters (e.g. NGC 1783, < 2 Gyr old) were not, within the limits of the uncertainties. It also confirms that intermediate age massive clusters show lower N abundance variations with respect to the ancient globular clusters, although this is in part due to the effect of the first dredge up at these stellar masses, as recently reported in the literature. We stress the importance of future studies to estimate the initial N abundance variations, free of stellar evolutionary mixing processes, by observing unevolved stars in young clusters.
ATRT-06. RESULTS OF MULTICENTER TRIAL CONCERNING THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMORS OF THE CENTRAL NERVOUS SYSTEM UNDER 3 YEARS OLD
Authors: Olga Zheludkova , Liudmila Olkhova , Ludmilla Zubarovskaya , Julia Dinikina , Anna Smirnova , Yuri Kushel’ , Armenak Melikyan , Shavkat Kadyrov , Marina Ryzhova , Liudmila Shishkina , Alexey Kislyakov , Evgeniy Shultz , Svetlana Gorbatykh , Olga Polushkina , Eugenia Inyushkina , Natalia Yudina , Asmik Gevorgian , Liudmila Privalova , Liudmila Minkina , Artem Zaichikov , Ivan Fisyun , Daniil Sakun , Vyacheslav Mitrofanov , Sergey Kovalenko , Ekaterina Grishina , Nadezhda Pishchaeva , Nikolay Vorob’ev , Nadezhda Plakhotina , Natalia Popova , Dmitriy Pogorelov , Alexander Shapochnik , Andrey Korchunov
Published: June 2021

Objective

To evaluate the prognostic factors in children with AT/RT aged under 3 years. Patients and methods: The prognostic factors were analyzed in 106patients under 3 years who got treatment and follow-up from 2008 to 2020.There were 41children younger than 12 months and 65patients older than 12 months. The location of the tumor was infratentorial in 58 patients, supratentorial in 46, and spinal cord in 2. There were 54 boys and 52 girls. Among the patients,57 had stage M0,36 had stage М+ or a multifocal tumor, and 13 had stage Mx. All the patients had undergone surgical treatment: total tumor removal in 27, subtotal-33, partial-42, biopsy - 4;67patients had got chemoradiotherapy according to the ATRT-2006(IRS III) protocol; 15, MUV-ATRT protocol; 3, CWS protocol; 9, EU-RHAB protocol; 6, HIT-SKK protocol; and 6 according to individual treatment schemes.12 patients received HDC with AuHCR.

Results

47 are alive,1 was lost to follow-up, and 58 died:52 of progressive disease,6 of chemotherapy complications. The five-year PFS was 0.27; the five-year OS was 0.40. The PFS was significantly better in patients older than 12months old compared to patients under 12months: 0.33 and 0.17, respectively; p=0.0047. The PFS after total resection was higher than after subtotal resection, partial resection, and tumor biopsy: 0.51, 0.29, 0.09, and 0%, respectively (p=0.025).The PFS after radiotherapy was markedly higher compared to patients without radiotherapy: 0.63 and 0.0, respectively (р<0.001). The tumor location, stage, and gender did not affect the PFS. The survival rate was statistically significantly higher among the patients who had got treatment according to the ATRT-2006 protocol compared to MUV-ATRT,EU-RHAB, individual therapeutic regimens, CWS, and HIT-SKK: 0.33, 0.26, 0.11, 0.30, and 0.0, respectively; p=0.0020. The PFS was higher among the patients who had got intraventricular/intrathecal chemotherapy; p=0.0002. HDC with AuHCR did not statistically affect the PFS; p=0.0546.In multivariate analysis, the PFS was influenced by the age, tumor location, extent of surgery, radiotherapy, regional chemotherapy, HDC with AuHCR.

Conclusions

The survival of patients with CNS AT/RT aged under 3years significantly depended on the patients’ age, extent of surgery, chemotherapy protocol, radiotherapy, and regional administration of chemotherapeutic drugs.
BIOL-06. MIR-1253 POTENTIATES CISPLATIN RESPONSE IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA BY REGULATING FERROPTOSIS
Authors: Kanchan Ranjana , Khan Parvez , Perumal Naveenkumar , Atri Pranita , Venkata Ramakanth Chirravuri , Thapa Ishwor , Doss David , Nasser Mohd Wasim , Batra Surinder , Mahapatra Sidhartha
Published: June 2021

Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, i.e. SHH (sonic hedgehog), WNT (wingless), and non-SHH/WNT groups 3 and 4, the latter representing high-risk MB. Haploinsufficiency of 17p13.3, which houses the tumor suppressor gene miR-1253, characterizes high-risk tumors. Despite improvements in targeted therapies, a limited proportion of these patients survive the disease. Capitalizing on the tumor suppressive properties of miRNAs as adjuncts to chemotherapy provides a promising alternative to current therapeutic strategies. In this study, we explored the potentiating effects of miR-1253 on cisplatin cytotoxicity in group 3 MB. First, in silico and in vitro analyses revealed an upregulation of ABCB7, a mitochondrial iron transporter and putative target of miR-1253, in MB cell lines and group 3 MB tumors. Overexpression of miR-1253 resulted in downregulation of ABCB7 and GPX4, a critical ferroptosis regulator, which consequently increased labile mitochondrial iron pool and, in turn, mitochondrial ROS (mtROS). Complementarily, we demonstrated, using CRISPR knockdown of ABCB7, ferroptosis induction with downregulation of GPx4 expression, liberation of free iron, mtROS generation and lipid peroxidation. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. Therapeutically, the combination of miR-1253 and cisplatin led to an additive effect on cell viability, colony formation, apoptosis, and ROS generation. In turn, treatment with mtROS inhibitor (MnTBAP) and ferroptosis inhibitor (Ferrostatin) lead to partial recovery from the cytotoxic effects of this combination therapy. These studies identify an miR-1253-induced ferroptosis pathway targeting the ABCB7/GPX4/mtROS axis in group 3 MB. They further provide proof-of-concept in using miR-based therapeutics to augment treatment efficacy of current chemotherapeutics in the treatment of high-risk tumors.
BIOL-08. IGFBP2 PROMOTES TUMOR METASTASIS IN SHH MEDULLOBLASTOMA
Authors: Kunhiraman Haritha , Kenney Anna
Published: June 2021

Medulloblastoma (MB) is the most common pediatric brain malignancy. MB comprises 5 major subgroups known as WNT, SHH p53wt, SHH p53mut, Group 3 and Group 4. Among the four MB subgroups SHH group is the most dominant molecular subgroup in infants and adults. These tumors are proposed to arise from cerebellar granule neuron precursors (CGNPs), whose developmental expansion requires SHH signaling from the neighboring Purkinje neurons. Previous reports suggest that SHH group features a unique tumor microenvironment compared with other MB groups. Recently, we performed cytokine array analysis of culture media from different MB cell lines. Interestingly, our data showed increased levels of IGFBP2 produced by SHH MB cell lines compared to others. We confirmed these results using ELISA and Western blotting from 3 human SHH MB cell lines, and Smo/A1 mouse tumor cells. IGFBP2 is a member of IGFBP super family of proteins; it plays important roles in tumor cell proliferation, metastasis and drug resistance. We analyzed the role of IGFBP2 in SHH group medulloblastoma tumor growth and metastasis. IGFBP2 knock-down stable cell lines showed phenotypic changes including reduced cell proliferation, cell migration and colony size. Our preliminary in vitro data suggest IGFBP2 exerts it metastasis-promoting role in SHH MB by regulating the expression of EMT marker proteins such as N cadherin, slug etc. and matrix remodeling proteins like MMPs and TIMPs. We are currently performing functional studies in organotypic tumor slice cultures to validate these findings and establish IGFBP2 as a novel regulator of aggressive tumor growth and spread in SHH MB.
EMBR-03. PINEOBLASTOMA: A POOLED OUTCOME STUDY OF NORTH AMERICAN AND AUSTRALIAN THERAPEUTIC DATA
Authors: Hansford Jordan , Huang Jie , Dodgshun Andrew , Li Bryan , Hwang Eugene , Leary Sarah , Gajjar Amar , Von Hoff Katja , Endersby Raelene , Wells Olivia , Wray Alison , Kotecha Rishi , Raleigh David , Stoller Schuyler , Mueller Sabine , Schild Steven , Bandopadhayay Pratiti , Fouladi Maryam , Bouffet Eric , Huang Annie , Onar Arzu , Gottardo Nicholas
Published: June 2021

Background

Pineoblastoma (PB) is a rare embryonal brain tumour most often diagnosed in young children. To date, no clinical trials have been conducted specific to pediatric PB. Collaborative studies performed over the past 30 years have included PB in studies accruing for other embryonal tumours, primarily medulloblastoma (MB), but also including the entity formerly known as CNS-PNET and atypical teratoid rhabdoid tumors. Each of these studies have included only a small number of children with PB, making clinical features difficult to interpret and determinants of outcome difficult to ascertain.

Patients and Methods

Published centrally reviewed series with sufficient treatment and outcome data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact and Wilcoxon-Mann-Whitney tests, and Spearman correlations were used as appropriate. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analysis.

Results

We describe a 30-year review of the reported clinical features of PB and a pooled centrally reviewed, cohort analysis of cases (n=178) from the Children’s Oncology Group (COG) (n=82) groups and several published, centrally reviewed institutional series (n=96). We find young children <3 years of age have a dramatically poorer outlook compared to older children (5-year OS 16.2% +/- 5.3% vs 67.3% +/- 5%) confirming new and novel approaches are needed in future clinical trials for this at risk group. Interestingly, male gender was predictive of worse outcome possibly suggestive of gender specific subgroup risks that needs validation in future studies. Assessment of radiation therapy is not possible as the vast majority of children under age three did not receive any form of radiation therapy.

Conclusion

Given the relative scarcity of this tumor and the emerging data on subgroups of pineoblastoma, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.
EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION
Authors: Badodi Sara , Pomella Nicola , Zhang Xinyu , Morrison Gillian , Pollard Steve M , Bennett Christopher D , Clifford Steven C , Peet Andrew , Marino Silvia
Published: June 2021

Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further subdivided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes plays an essential role in MB, particularly in the G4 subgroup, the least understood of all subgroups, despite being the most common and associated with poor prognosis. A BMI1High; CHD7Low molecular signature identifies patients with poor survival within this subgroup. We show that BMI1High; CHD7Low mediates a novel epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display hyperactivation of the AKT/mTOR pathway which leads to energetic rewiring characterized by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration, impairs MB proliferation in vitro and significantly extends survival in an in vivo pre-clinical model. Moreover, inositol synergises with cisplatin, a chemotherapy agent currently used in MB treatment, enhancing its therapeutic effect in vivo. Importantly, cerebellar neural stem cells bearing the BMI1High; CHD7Low signature do not show metabolic adaptation and are thus resistant to inositol treatment, highlighting a fundamental difference between normal and neoplastic metabolism in the developing cerebellum. In summary, we have identified an actionable vulnerability in a pre-clinical setting modelling a molecularly defined group of MB patients, the translational value of which can now be explored in signature-matched clinical trials in MB.
EMBR-14. INFLUENCE OF MRI FEATURES ON THE SURVIVAL AND IMPACT ON INDIVIDUAL MOLECULAR SUBGROUPS: RESULT FROM 171 PATIENTS WITH MEDULLOBLASTOMA
Authors: Dasgupta Archya , Maitre Madan , Kalra Babusha , Chatterjee Abhishek , Krishnatry Rahul , Goda Jayant , Shirsat Neelam , Epari Sridhar , Sahay Ayusi , Janu Amit , Pungavkar Sona , Chinnaswamy Girish , Moiyadi Aliasgar , Shetty Prakash , Gupta Tejpal , Jalali Rakesh
Published: June 2021

Background

To investigate the influence of different MRI features on survival in patients with medulloblastoma.

Methods

A total of 171 patients were included in the study, including 131 pediatric and 40 adults (> 18 years). A set of 16 pre-defined semantic MRI features was analyzed using T1W (pre and post-contrast), T2W, and diffusion-weighted imaging (additional sequences as available). Patients with a definitive event (recurrence) or a minimum follow up of 12 months (in case of no recurrence) were included in the current analysis. All patients were treated and followed up according to standard institutional practice. Log-rank test was used for univariate analysis (UVA) and Cox regression for multivariate analysis (MVA).

Results

The molecular subgroups were as follows: WNT-27 children, 7 adults; SHH-31 children, 29 adults; group 3–32 children, 3 adults; and group 4–41 children, 1 adult. The median follow up was 45 months (range 1 to 137 months). For all the patients, on UVA the recurrence-free survival (RFS) was significantly (p<0.05) influenced by location-vertical, brainstem involvement, contrast uptake area, contrast heterogeneity, necrosis, and calcification. Similar factors (T2W homogeneity instead of area of contrast) impacted overall survival (OS). On MVA, location-vertical, brainstem involvement, and calcification were significant features for both RFS and OS. Tumor location-vertical was the only feature influencing RFS and OS within the SHH subgroup. For group 3 tumors, contrast uptake area (RFS and OS) and calcification (RFS alone) had a significant influence (MVA). Within group 4, contrast pattern (RFS) and T2W homogeneity (RFS and OS) were significant factors on UVA, none on MVA.

Conclusion

Several MRI features can be linked with survival in patients with medulloblastoma, with a specific impact on individual molecular subgroups. Considering the entire population, non-central location on the vertical aspect, tumors away from brainstem, calcification are risk factors associated with inferior outcomes.
EMBR-23. KIF11 DEPENDENCY ON P53 MUTATIONAL STATUS IN MEDULLOBLASTOMA
Authors: Huang Shiying , Karthik Sekar , Lin Qi , Du YuChen , Lau Ching C , Adekunle Adesina , Su Jack M F , Major Angela , Elghetany M Tarek , Hui Kam-Man , Li Xiaonan , Teo Wan-Yee
Published: June 2021

Introduction

KIF11, a mitotic kinesin, is a component responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11. Inhibition of KIF11 results monopolar spindle formation, resulting in monoastral mitosis in cells. This activates the spindle assembly checkpoint, cells are arrested and prevented from entering cell cycle, resulting in cell death via apoptosis or necrosis, cell division with aneuploidy or mitotic slippage without division into tetraploid G1 phase.

Methods

We hypothesized that the effect of KIF11 inhibition on medulloblastoma (MB) is dependent of its p53 mutational status.

Results

Our findings on Hoechst staining demonstrated a small molecule inhibitor of KIF11 which induced apoptosis in p53-wildtype MB cells at 48h (p<0.0001), was able to trigger mitotic catastrophe (p = 0.0010) in p53-mutant MB cells at 24h and subsequent necrosis (p=0.0039) at 48h. KIF11 inhibitor exerted anti-proliferative effects on five MB cell lines at nanomolar concentration range, independent of its p53 mutational status. Cells treated with KIF11 inhibitor were arrested in G2/M phase. Apoptosis was observed on Annexin V flow cytometry 24h after treatment, followed by necrosis after 48h in p53-wildtype cells. In contrast, treated p53-mutant cells underwent necrosis at 24h. Differences in cell death mechanisms upon KIF11 inhibition was confirmed on immunoblotting by upregulated p53 expression and presence of cleaved-PARP and DNA-damage marker in p53-wildtype cells, indicative of apoptosis. While inhibition of KIF11 and increased p53 expression were observed only after 48h, cleaved-PARP expression was detected as early as 24h in p53-wildtype, suggesting KIF11-independent, cleaved-PARP-mediated cell death at 24h. In contrast, treated p53-mutant cells showed decreased p53 expression and absence of cleaved-PARP and DNA-damage marker after 24h.

Conclusions

Our results suggest that when mitotic arrest is induced, p53-mutant MB cells undergo mitotic catastrophe and necrosis while p53-wildtype MB cells predominantly undergo apoptosis.
EMBR-27. NEOPLASTIC AND IMMUNE SINGLE CELL TRANSCRIPTOMICS DEFINE SUBGROUP-SPECIFIC INTRA-TUMORAL HETEROGENEITY OF CHILDHOOD MEDULLOBLASTOMA
Authors: Donson Andrew , Riemondy Kent , Venkataraman Sujatha , Willard Nicholas , Nellan Anandani , Sanford Bridget , Griesinger Andrea , Amani Vladimir , Mitra Siddhartha , Hankinson Todd , Handler Michael , Sill Martin , Ocasio Jennifer , Weir Seth , Malawsky Daniel , Gershon Timothy , Garancher Alexandra , Wechsler-Reya Robert , Hesselberg Jay , Foreman Nicholas , Vibhakar Rajeev
Published: June 2021

Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. To better understand cellular heterogeneity in MB we used single-cell RNA sequencing, immunohistochemistry and deconvolution of transcriptomic data to profile neoplastic and immune populations in childhood MB samples and MB genetically engineered mouse models (GEMM). Neoplastic cells clustered primarily according to individual sample of origin which is in part due to the effect of chromosomal copy number gains and losses. Harmony alignment of single cell transcriptomic data revealed novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes and are associated with clinical outcomes. This includes photoreceptor-like cells and glutamatergic lineage unipolar brush cells in both GP3 and GP4 subgroups of MB, and a SHH subgroup nodule-associated neuronally-differentiated cell subpopulation. We definitively chart the spectrum of MB immune cell infiltrates, which reveals unexpected degree of myeloid cell diversity. Myeloid subpopulations include subgroup/subtype-associated developmentally-related neuron-pruning as well as antigen presenting myeloid cells. Human MB cellular diversity is recapitulated in subgroup-specific MB GEMM, supporting the fidelity of these models. These findings provide a clearer understanding of both the neoplastic and immune cell heterogeneity in MB and how these impact subgroup/subtype classification and clinical outcome.
EMBR-31. DEVELOPMENT OF INJECTABLE POLYSACCHARIDE HYDROGEL TO ENHANCE DRUG PENETRATION IN PEDIATRIC BRAIN TUMORS
Authors: Patel Jenny , Barker Elizabeth
Published: June 2021

Improving unacceptable low response rates and reducing acute and long-term morbidities remain significant challenges in pediatric neuro-oncology. Chemotherapy is an effective primary or adjuvant treatment for pediatric disease, but current administration approaches hinder the pharmacological activity exerted by chemotherapy treatments. Barriers in the route of drug administration and in the tumor microenvironment limit anticancer drugs from penetrating tissue efficiently and reaching all cancer cells. Strategies have been proposed to overcome these barriers with hope of leading to sustained and elongated drug exposure in solid tumors. However, few methods have been explored to design drug delivery systems to circumvent these barriers with potential to enhance drug penetration and reduce adverse systemic side effects in treating pediatric brain tumors. In this study, we validate an injectable polysaccharide hydrogel capable of releasing drugs locally at tumor site, sustaining drug concentration, and eliciting tumor response. We synthesized a hydrogel with dimethyl sulfoxide (DMSO) incorporating amylopectin, a polysaccharide found in starch, loaded with doxorubicin. We determined the structure of doxorubicin is not altered when released from the hydrogel through characterization of drug-loaded and unloaded hydrogels, suggesting drug is encapsulated in the hydrogel network and is able to maintain structure to induce mechanism of action. We tested sustained release of drug and therapeutic efficacy in vitro with DAOY, a medulloblastoma cell line. Our approach demonstrates that local drug delivery presents potential to enhance drug penetration in pediatric brain tumors by sustaining drug concentration at tumor site for an extended period of time. Local drug delivery systems have been investigated for decades but few have been investigated for treatment of pediatric brain tumors. For researchers, physicians, and clinicians, this research can lead to a greater effort to improve current outcomes of conventional drug treatment and provide an opportunity to address current challenges in pediatric oncology.