bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic radiological examinations and risk of intracranial tumours in adults—findings from the Interphone Study
Authors: Auvinen Anssi , Cardis Elisabeth , Blettner Maria , Moissonnier Monika , Sadetzki Siegal , Giles Graham , Johansen Christoffer , Swerdlow Anthony , Cook Angus , Fleming Sarah , Berg-Beckhoff Gabriele , Iavarone Ivano , Parent Marie-Elise , Woodward Alistair , Tynes Tore , McBride Mary , Krewski Dan , Feychting Maria , Takebayashi Toru , Armstrong Bruce , Hours Martine , Siemiatycki Jack , Lagorio Susanna , Larsen Signe Benzon , Schoemaker Minouk , Klaeboe Lars , Lönn Stefan , Schüz Joachim ,   and the INTERPHONE study group, Salminen Tiina , Lahkola Anna , McKinney Patricia , Yamaguchi Naohito
Published: July 2021

Background

Exposure to high doses of ionizing radiation is among the few well-established brain tumour risk factors. We used data from the Interphone study to evaluate the effects of exposure to low-dose radiation from diagnostic radiological examinations on glioma, meningioma and acoustic neuroma risk.

Methods

Brain tumour cases (2644 gliomas, 2236 meningiomas, 1083 neuromas) diagnosed in 2000–02 were identified through hospitals in 13 countries, and 6068 controls (population-based controls in most centres) were included in the analysis. Participation across all centres was 64% for glioma cases, 78% for meningioma cases, 82% for acoustic neuroma cases and 53% for controls. Information on previous diagnostic radiological examinations was obtained by interviews, including the frequency, timing and indication for the examinations. Typical brain doses per type of examination were estimated based on the literature. Examinations within the 5 years before the index date were excluded from the dose estimation. Adjusted odds ratios were estimated using conditional logistic regression.

Results

No materially or consistently increased odds ratios for glioma, meningioma or acoustic neuroma were found for any specific type of examination, including computed tomography of the head and cerebral angiography. The only indication of an elevated risk was an increasing trend in risk of meningioma with the number of isotope scans, but no such trends for other examinations were observed. No gradient was found in risk with estimated brain dose. Age at exposure did not substantially modify the findings. Sensitivity analyses gave results consistent with the main analysis.

Conclusions

There was no consistent evidence for increased risks of brain tumours with X-ray examinations, although error from selection and recall bias cannot be completely excluded. A cautious interpretation is warranted for the observed association between isotope scans and meningioma.
A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear
Authors: Hagsäter Sven Melker , Pettersson Robert , Pettersson Christopher , Atanasovski Daniela , Näslund Jakob , Eriksson Elias
Published: July 2021

Background

Though drugs binding to serotonergic 5-HT2A receptors have long been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety promoting or anxiety dampening. Whereas conditioned fear expressed as freezing in rats is modified by application of 5-HT2A–acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behavior remain sparse.

Methods

We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI)—per se or in combination—on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they received foot shocks 7 days earlier.

Results

The 5-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect.

Conclusions

The results indicate that 5-HT2A receptor activation is not a prerequisite for normal conditioned freezing in rats but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.
Snaking without subcriticality: grain boundaries as non-topological defects
Authors: Subramanian Priya , Archer Andrew J , Knobloch Edgar , Rucklidge Alastair M
Published: July 2021

Non-topological defects in spatial patterns such as grain boundaries in crystalline materials arise from local variations of the pattern properties such as amplitude, wavelength and orientation. Such non-topological defects may be treated as spatially localized structures, i.e. as fronts connecting distinct periodic states. Using the two-dimensional quadratic-cubic Swift–Hohenberg equation, we obtain fully nonlinear equilibria containing grain boundaries that separate a patch of hexagons with one orientation (the grain) from an identical hexagonal state with a different orientation (the background). These grain boundaries take the form of closed curves with multiple penta-hepta defects that arise from local orientation mismatches between the two competing hexagonal structures. Multiple isolas occurring robustly over a wide range of parameters are obtained even in the absence of a unique Maxwell point, underlining the importance of retaining pinning when analysing patterns with defects, an effect omitted from the commonly used amplitude-phase description. Similar results are obtained for quasiperiodic structures in a two-scale phase-field model.
Research on obstetric ward planning combining lean thinking and mixed-integer programming
Authors: Mu Dongmei , Li Hua , Zhao Danning , Ju Yuanhong , Li Yuewei
Published: July 2021

Background

In recent years, there are many studies on scheduling methods of patient flow, nurse scheduling, bed allocation, operating room scheduling and other problems, but there is no report on the research methods of how to plan ward allocation from a more macroscopic perspective.

Objective

Refine and stratify the obstetric ward to provide more accurate medical service for pregnant women and improve the work efficiency of obstetricians and midwives. The problem of how to allocate the number of each type of ward is modeled as a mixed integer programming problem, which maximizes the patient flow of pregnant women in obstetric hospitals.

Methods

The obstetric wards are divided into observation ward, cesarean section ward and natural delivery ward according to lean thinking. CPLEX is used to solve the mixed-integer programming problem of ward allocation. In R software, multivariate Generalized Linear Models (GLM) regression model is used to analyze the influence of each factor on patient flow.

Results

The maximum patient flow of each case was obtained by CPLEX, which was 19–25% higher than that of patients without refinement, stratification and planning. GLM regression analysis was carried out on the abovementioned data, and the positive and negative correlation factors were obtained.

Conclusion

According to lean thinking, obstetric wards are divided into three types of wards. Obstetricians and midwives work more efficiently and get more rest time. Pregnant women also enjoy more detailed medical services. By modeling the delivery ward allocation problem as a mixed-integer programming problem, we can improve the capacity of the service in obstetric hospitals from a macro perspective. Through GLM regression model analysis, it is conducive to improve the obstetric hospital capacity from the perspective of positive and negative correlation factors.
Mobile health applications for older adults: a systematic review of interface and persuasive feature design
Authors: Liu Na , Yin Jiamin , Tan Sharon Swee-Lin , Ngiam Kee Yuan , Teo Hock Hai
Published: July 2021

Objective

Mobile-based interventions have the potential to promote healthy aging among older adults. However, the adoption and use of mobile health applications are often low due to inappropriate designs. The aim of this systematic review is to identify, synthesize, and report interface and persuasive feature design recommendations of mobile health applications for elderly users to facilitate adoption and improve health-related outcomes.

Materials and Methods

We searched PubMed, Embase, PsycINFO, CINAHL, and Scopus databases to identify studies that discussed and evaluated elderly-friendly interface and persuasive feature designs of mobile health applications using an elderly cohort.

Results

We included 74 studies in our analysis. Our analysis revealed a total of 9 elderly-friendly interface design recommendations: 3 recommendations were targeted at perceptual capabilities of elderly users, 2 at motor coordination problems, and 4 at cognitive and memory deterioration. We also compiled and reported 5 categories of persuasive features: reminders, social features, game elements, personalized interventions, and health education.

Discussion

Only 5 studies included design elements that were based on theories. Moreover, the majority of the included studies evaluated the application as a whole without examining end-user perceptions and the effectiveness of each single design feature. Finally, most studies had methodological limitations, and better research designs are needed to quantify the effectiveness of the application designs rigorously.

Conclusions

This review synthesizes elderly-friendly interface and persuasive feature design recommendations for mobile health applications from the existing literature and provides recommendations for future research in this area and guidelines for designers.
Pre-release dietary supplements of methoprene and raspberry ketone increase field abundance of sterile Queensland fruit flies (Diptera: Tephritidae)
Authors: Biswas Md Jamil Hossain , Mainali Bishwo P , Inskeep Jess R , Cross Dominic , Benelli Maurizio , Allen Andrew P , Taylor Phillip W , Rempoulakis Polychronis
Published: July 2021

The sterile insect technique (SIT) is a sustainable pest management tool based on the release of millions of sterile insects that suppress reproduction in targeted populations. Success of SIT depends on survival, maturation, dispersal, and mating of released sterile insects. Laboratory and field cage studies have demonstrated that dietary supplements of methoprene and raspberry ketone (RK) promote sexual maturation of adult Queensland fruit fly, Bactrocera tryoni (Froggatt), and may hence shorten the delay between release and maturity in the field. We investigated the effects of methoprene and RK dietary supplements on field abundance of sexually mature sterile Q-flies relative to untreated flies fed only sugar and yeast hydrolysate before release at 2 d of age. Compared with untreated flies, more methoprene- and RK-treated flies were recaptured in cuelure traps to which only sexually mature males are attracted. At distances of 100 and 200 m from the release point, recapture rates were higher for methoprene- and RK-treated flies than for untreated flies, but at 300 m recapture rates were low and were similar for treated and untreated flies. Rainfall, relative humidity, wind speed, and wind direction did not affect recapture rates, but temperature was positively correlated with recapture rates for all treatments. There was a strong correlation between the number of sterile and wild flies caught in traps, indicating co-location in the field. Dietary supplements of methoprene and RK can substantially increase abundance of sexually mature sterile male Q-flies in the field following release as 2-d-old immature adults.
Swirl sign in post-Roux-en-Y gastric bypass patients: a case series
Authors: Al-Mulla Ahmad E , Sultan Abdulla E , Imam Ehab S , Al-Huzaim Raghad A
Published: July 2021

Bariatric surgeries have been increasing with the rising numbers of obese patients. Roux-en-Y is one of the safest and effective bariatric procedures worldwide. Internal hernia is one of laparoscopic Roux-en-Y gastric bypass complications. Its vague symptoms and late presentation may lead to adverse outcomes. Swirl sign in computed tomography scan has proven to be a particular and sensitive finding to detecting internal hernia in patients with an ambiguous presentation.
Acetylcholine ameliorated hypoxia-induced oxidative stress and apoptosis in trophoblast cells via p38 MAPK/NF-κB pathway
Authors: Wang Zheng , Zhao Gongxiao , Zibrila Abdoulaye Issotina , Li Yubei , Liu Jinjun , Feng Weiyi
Published: July 2021

Hypoxia-induced oxidative stress and apoptosis of trophoblast are involved in the pathogenesis of preeclampsia (PE). Extensive research reports that the principal vagal neurotransmitter acetylcholine (ACh) shows anti-oxidative and anti-apoptotic effects in various diseases models. However, the role of ACh in hypoxic trophoblast remains unknown. Here, we examined the apoptotic levels of human placenta and explored the role(s) of ACh on cobalt chloride (CoCl2)-treated (trophoblast-derived) HTR-8/SVneo cells for mimicking hypoxic injuries. Cell counting kit-8 (CCK-8), dihydroethidium (DHE) probe, western blotting, immunofluorescence staining, migration and invasion assay were employed in the current study. Our data showed that placentas from PE women exhibited increased level of reactive oxygen species (ROS) and apoptotic index than those in normal pregnancy. Our in vitro study showed that CoCl2 enhanced ROS generation and apoptosis in HTR-8/SVneo cells through the activation of the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor-κB (NF-κB) pathway. ACh significantly decreased hypoxia-induced ROS generation and the resulting apoptosis, accompanied by lowered phosphorylation of p38 MAPK and NF-κB. Western blotting analysis further confirmed that ACh decreased the ratio of pp38 MAPK/p38 MAPK, p-NF-κB/NF-κB, Bax/Bcl-2 and cleaved Caspase-3/Caspase-3. Besides, ACh promoted cell invasion and migration ability under hypoxic conditions. Atropine, the muscarinic receptor antagonist, abolished ACh’s effects mentioned above. Overall, our data showed that ACh exerted protective effects on hypoxia-induced oxidative stress and apoptosis in trophoblast cells via muscarinic receptors, indicating that improved vagal activity may be of therapeutic value in PE management.
ECOA-2. Immuno-sensitization of Glioblastoma to NY-ESO-1 Targeting via Promoter Demethylation
Authors: Lai Thomas , Treger Janet , Rao Jingyou , Li Tie , Lai Albert , Prins Robert , Everson Richard
Published: July 2021

Introduction

The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Mechanisms governing the expression of CTA have been explored in other cancers; however, neither the prevalence of NY-ESO-1 downregulation in GBM patient tumors nor the presumed mechanism of downregulation by promoter methylation in GBM has been formally established.

Methods

We characterized baseline CpG methylation of NY-ESO-1 in 30 bulk patient GBM samples, 10 patient-derived gliomaspheres, and three established tumor cell lines using bisulfite sequencing. We induced NY-ESO-1 expression in vitro in U251 human GBM cells using the hypomethylating agent decitabine (DAC). We investigated the epigenetic response of DAC-treated U251 with bisulfite sequencing and NY-ESO-1 expression with quantitative real-time PCR. Lastly, we performed single-cell RNA sequencing on DAC-treated GBM U251 to evaluate tumor subpopulations that upregulate NY-ESO-1 and other co-expressed CTA after DAC treatment.

Results

Baseline NY-ESO-1 expression is associated with promoter methylation in the majority of GBM. Treatment of cells with 1 µM DAC every day for 4 days explicitly demethylated the promoter region of NY-ESO-1 and resulted in a 1000-fold increase in mRNA expression. DAC treatment upregulates NY-ESO-1 coordinately with other cancer/testis antigens CTAG2 and MAGEA4 as demonstrated by single-cell RNA sequencing.

Conclusion

Exposure of U251 to DAC results in promoter demethylation in NY-ESO-1 and increased expression of CTA. DAC treatment may therefore render GBM susceptible to targeting of these antigens by T-cells, revealing a feasible strategy of NY-ESO-1 and co-expressed CTA promoter demethylation to sensitize GBM to immunotherapy.
OMRT-8. Precision targeting of cellular pathways with complementary diagnostics
Authors: Siddaway Robert , Nobre Liana , Milos Scott , Johnson Monique , Ryall Scott , Sheth Javal , Ku Michelle , Tabori Uri , Hawkins Cynthia
Published: July 2021

Precision medicine tailors treatment for each patient by identifying the molecular drivers of their disease. This can allow more effective tumour targeting, avoid harmful standard chemotherapeutic side-effects, and offer savings to the healthcare system through not treating patients who are unlikely to respond to a specific agent. Treatment regimes are usually designed by identifying DNA-level alterations and selecting drugs tailored to that mutation. However, cancer is not a one-pathway disease and not all patients with particular mutations will respond to treatment, while patients without canonical pathway-activating mutations are excluded from potentially life-saving treatment. To address this, we have developed a NanoString assay combining proteomic and transcriptomic profiles of 4 key actionable, cancer-related pathways (MAPK, PI3K, NFκB and JAK/STAT). We used RNA-Seq data from gold standard cell lines with defined pathway changes to identify minimal gene sets indicative of pathway activation, and integrated them with phospho protein measurements to generate a pathway activation score. The combined panel was run on isogenic cell lines as well as glioma samples with both known and unknown driving alterations. We found pathway activation to be more variable than expected based on DNA alterations alone, implying that consideration of proteomic and/or transcriptomic-level information is important for future therapeutic decision-making.
OMRT-14. Small molecule circadian clock compounds exhibit potential as a novel therapy paradigm for glioblastoma
Authors: Chan Priscilla , Hirota Tsuyoshi , Qu Meng , Zhang Guoxin , Shah Khalid , Wakimoto Hiroaki , Kamenecka Theodore , Solt Laura , Rich Jeremy , Kay Steve
Published: July 2021

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor type, claiming the lives of patients within 2 years of diagnosis. The major challenges in treating GBM are largely due to the biological characteristics of the tumor and the brain and pharmacokinetics of many drugs approved for other cancers. These tumors are located in areas that make it difficult to surgically resect without posing major issues and exposure to many drugs and therapies are limited due to the blood-brain barrier (BBB). GBMs also contain cancer stem cells, called GSCs, that have self-renewal and tumor initiating abilities, can secrete angiogenic factors, invade into the normal brain, and are chemoresistant and radioresistant. We found that GSCs have an exclusive dependence on core circadian clock transcription factors, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK). These results suggest the potential for small molecule modulators of the circadian clock as a novel therapy paradigm for GBM treatment following surgical resection to prevent GSC infiltration and reoccurrence of the primary tumor. Here we found that multiple classes of clock compounds (Cryptochrome (CRY) stabilizers, REV-ERB agonists, Casein Kinase 1 (CK1) inhibitors, and Casein Kinase 2 (CK2) inhibitors) have the ability to elongate circadian periods in a clock reporter cell line. They also selectively and potently target patient-derived GSCs that range in sensitivity to temozolomide (TMZ) chemotherapy treatment while having limited effects on control cells both as single agents and in combination with each other. This data provides a platform for further exploration of synergistic effects of combining clock compounds with each other or with current GBM therapies, such as chemotherapy and radiation, with the ultimate goal of developing a clinical model of treatment.
OTEH-6. Algorithmic approach to characterize post-treatment recurrent glioma using RNA sequencing and quantitative histopathology
Authors: Argenziano Michael , Save Akshay , Boyett Deborah , Grinband Jack , Yoon Hyunsoo , Li Jing , Banu Matei , McKhann Guy , Sisti Michael , Swanson Kristin , Bruce Jeffrey , Canoll Peter
Published: July 2021

Introduction

Distinguishing between tumor and treatment effect in post-treatment glioma, although crucial for clinical management, is difficult because contrast-enhancing regions are mixtures of recurrent tumor and reactive tissue, and definitive histopathological criteria do not exist. This study disentangles the marked intra-tumoral heterogeneity in the treatment-recurrent setting by developing an unsupervised framework to algorithmically categorize intraoperative MRI-localized biopsies into three clinically-relevant tissue clusters based on joint analysis of RNA sequencing and histopathological data.

Methods

A retrospective cohort of 84 MRI-localized biopsies from 37 patients with post-treatment recurrent glioblastoma underwent mRNA extraction and quantification via PLATEseq protocol. For 48 of 84 biopsies, a neighboring piece of tissue underwent quantitative histopathology based on labeling index (LI) for SOX2, CD68, NeuN, Ki67, and H&E. Correlation between LIs and gene expression for these 48 samples was performed. Genes significantly correlated (p<0.05) with ≥1 marker were used for hierarchical clustering of correlation matrix, identifying three mutually-exclusive tissue-specific gene sets. These sets were then used to perform ssGSEA to categorize each of 84 biopsies into one of three tissue types.

Results

Correlation analysis identified 7779 genes significantly correlated with ≥1 histopathological marker. Clustering revealed three gene sets associated with specific markers: SetA-3688 genes associated with SOX2/Ki67/H&E; SetB-2418 genes associated with CD68; SetC-1673 genes associated with NeuN. ssGSEA using these sets categorized each biopsy into one of three tissue types: 27 biopsies enriched in SetA, 28 in SetB, and 29 in SetC.

Conclusions

Using MRI-localized biopsies with both RNAseq and histopathological data, this algorithmic approach allows development of three orthogonal tissue-specific gene sets that can be applied to characterize the heterogeneity in post-treatment recurrent glioma: SetA: genes correlated with SOX2/Ki67/H&E, representing recurrent tumor; SetB: genes correlated with CD68 (microglia) representing reactive tissue consistent with treatment effect; SetC: genes correlated with NeuN (neurons), representing infiltrated brain.
OTEH-7. Molecular characterization of tumor stiffness in glioblastoma
Authors: Halldorsson Skarphedinn , Svensson Siri Fløgstad , Berg Henriette Engen , Wolrab Denise , Rise Frode , Wilkins Alistair , Wilson Steven Ray , Holcapek Michal , Emblem Kyrre Eeg , Vik-Mo Einar O
Published: July 2021

Tumor heterogeneity is one of the hallmarks of glioblastoma multiforme (GBM). Morphology within a given GBM tumor can be extremely variable where some regions of the tumor have a soft, gel-like structure while other areas are dense and fibrous. Abnormal mechanical stress and tissue stiffening caused by cancer proliferation are believed to affect vascularity by compressing structurally weak blood vessels and restricting the supply of nutrients and oxygen to the tissue. These effects contribute to a hypoxic microenvironment that promotes disease progression and chemoresistance. The genetic and molecular mechanisms that govern tissue stiffness within GBM tumors, however, are largely unknown. Magnetic Resonance Elastography (MRE) is an emerging technique for quantifying tissue stiffness non-invasively.

We have evaluated 10 GBM patients by MRE imaging obtained prior to surgical resection. During surgery, 2–7 stereotactically navigated biopsies were collected from locations within the tumor with varying degrees of measured stiffness. Biopsies were processed to extract RNA, proteins, polar metabolites and lipids. Biomolecules were analyzed on relevant -omics platforms (RNA sequencing, MS-proteomics and lipidomics, NMR of polar metabolites).

Differential expression and gene set enrichment analysis of patient paired biopsies indicate an overall increase in macrophage infiltration and extracellular matrix re-organization associated with increased tumor stiffness. Among the most highly upregulated genes in stiff tumor tissue were lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1) and macrophage receptor with collagenous structure (MARCO), both of which have been associated with immune cell infiltration and tissue stiffness.

Our preliminary findings offer novel insights into tumor morphology in GBM that can be inferred from imaging prior to surgery. This can be used to identify tumor regions with high risk of progression and infiltration, thereby informing and guiding surgical strategy and may ultimately lead to novel treatment strategies.
OTEH-8. Pathway-based approach reveals sensitivity to radiation when targeting E2F1 in Glioblastoma
Authors: Alvarado Alvaro , Tessema Kaleab , Muthukrishnan Sree , Kawaguchi Riki , Swarup Vivek , Goldman Steven , Kornblum Harley
Published: July 2021

The great phenotypic heterogeneity of glioblastoma (GBM) – both inter and intratumorally – has hindered therapeutic efforts. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has not translated to a significant extension of patient survival. We hypothesize that, rather than gene expression as a whole, analysis of targetable pathways could yield important insights into the development of novel classification schemes and, most importantly, to targeted therapeutics. Here, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. The Cancer Genome Atlas samples were clustered using gene set enrichment analysis and the resulting 3 clusters were informative of patient survival and only modestly overlapped with prior molecular classification. We validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity, proliferation and in vivo tumor growth when E2F1, our top target, was silenced. Consistent with our theory, E2F1 knockdown had little or no effect on the growth of the non-enriched lines, despite their ability to proliferate in vitro and in vivo. We similarly analyzed single cell RNAseq datasets and correlated cell cycle and stemness signatures with the gene lists we generated, concluding that cells with stem cell signatures were depleted of E2F1 and its downstream targets. Finally, we confirmed a connection between E2F1 and cellular inhibitor of PP2A (CIP2A) in a cluster of samples. Loss of function studies reveal a diminished capacity for DNA damage regulation in E2F1 activated samples. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.
OTEH-11. Single Cell RNA Sequencing to identify cellular heterogeneity with in Pituitary Adenomas
Authors: Jain Saket , Babikir Husam , Shamardani karin , Diaz Aaron , Aghi Manish
Published: July 2021

Pituitary adenomas (PA) are one of the most common primary brain tumors and comprise approximately 15% of brain neoplasms. Most PA are histologically benign, but can cause significant morbidity. Previous studies utilized whole genome and exome sequencing to identify a few somatic variants, but no recurrent mutations were observed. Further studies are warranted to identify driver mutations occurring at low frequencies. We used single-cell RNA sequencing (10X Genomics) to investigate cellular heterogeneity in 12 non-functioning pituitary adenomas. Our analysis identified discrete clusters of cells associated with specific functional pathways. One of these clusters corresponded to cells expressing genes related to metabolic pathways, primarily lipid metabolism. Another cluster consistent amongst the three patients comprised cells involved in antigen presentation and processing. In addition, the copy number variation analysis highlighted distinct chromosomal alterations within our samples. Interestingly, we were able to identify clonal variations within each tumor based on chromosomal aberrations. For example, in our first patient we observed a gain of chromosome 19 and loss of chromosome 2. Our analysis showed three different clonal populations within this tumor. All three populations harbored the loss of chromosome 2, one population exhibited gain of chromosome 19, while a third population exhibited loss of chromosome 19. These early results indicate the loss of chromosome 2 as an early event in tumorigenesis and gain/loss of chromosome 19 as late events. We are currently in a process of identifying somatic variations within these tumors by variant calling. Currently we are expanding our analysis to 20 non-functional PA. Mapping the single-cell gene expression profiles with mutational phylogeny will reveal the differences in clonal evolution within the tumor subtypes. This study will help us define the molecular fingerprint of pituitary adenomas and provide insights which could be utilized in the clinic for better management of these tumors.
OTME-9. Comprehensive Metabolic Profiling Of high MYC Medulloblastoma Reveals Key Differences Between In Vitro And In Vivo Glucose And Glutamine Usage
Authors: Pham Khoa , Poore Brad , Hanaford Allison , Maxwell Micah J , Sweeney Heather , Parthasarathy Akhila , Alt Jesse , Rais Rana , Slusher Barbara S , Eberhart Charles G , Raabe Eric H
Published: July 2021

Reprograming of cellular metabolism is a hallmark of cancer. The metabolic alterations in cancer cells is not only defined by series of genetic mutations, but also reflecting the crosstalk between cancer cells and other factors in the microenvironment. Altering metabolism allows cancer cells to overcome unfavorable conditions, to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in different environments – in vitro, in flank xenografts and in orthotopic xenografts. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and the high-MYC medulloblastoma cells in culture. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of nucleotide, hexosamine biosynthetic pathway (HBP), TCA cycle, and amino acid and glutathione pathways. There was significantly higher glucose up taking and usage in orthotopic xenograft tumor compared to flank xenograft and cells in culture. The data demonstrated that glucose was the main carbon source for the glutamate, glutamine and glutathione synthesis through the TCA cycle. The glutaminase ii pathway was the main pathway utilizing glutamine in MYC-amplified medulloblastoma in vivo. Glutathione was found as the most abundant upregulated metabolite. Glutamine derived glutathione was mainly synthesized through glutamine transaminase K (GTK) enzyme in vivo. In conclusion, we demonstrated that high MYC medulloblastoma adapt to different environments by altering its metabolic pathways despite carrying the same genetic mutations. Glutamine antagonists may have therapeutic applications in human patients.
OTME-10. Integrated analysis of human gliomas at the single cell level identifies S100A4 as a novel immunotherapy target
Authors: Abdelfattah Nourhan , Kumar Parveen , Leu Jia-Shiun , Flynn William , Baskin David , Ptichumani Kumar , Ijare Omkar , George Joshy , Yun Kyuson
Published: July 2021

Understanding the immune composition of a given tumor is critical to assess its potential responsiveness to cancer immunotherapy. This is especially true for tumors that are intrinsically resistant to immunotherapies, such as GBM. Unfortunately, studies on the functional heterogeneity and associated molecular targets of immune-suppressive cells in vivo have been lacking. Here we report an integrated multi-dimensional analysis of the mutational profiles and single-cell transcriptomics of 60,024 glioma and stromal cells from 16 human samples. We identified molecular signatures of seven distinct macrophage subtypes, each with prognostic clinical value. The three inflammatory subtypes showed hallmarks of TNF/NFκB pathway enrichment and are associated with good outcomes; in contrast, four immunosuppressive subtypes with metabolic pathway hallmarks (oxidative phosphorylation, PI3K/AKT/mTOR, fatty acid metabolism) are associated with poor survival. In addition, we resolved an ongoing controversy in the field regarding the roles of brain resident macrophages, microglia, vs. bone marrow derived macrophages (BMDM) in gliomas. Our data show compelling evidence that microglia are pro-inflammatory and are associated with good survival while BMDMs are mostly immune-suppressive and associated with poor survival. In addition, deciphering immune-suppressive macrophage and Treg molecular signatures enabled us to identify previously unknown immunotherapy targets. In a proof of principle study, we showed that S100A4, a calcium binding protein previously shown to mediate metastasis, was universally upregulated in both innate and adaptive immune suppressor cells, and implantation of gliomas in S100a4-/- host mice significantly extended survival and resulted in pro-inflammatory immune landscape, compared to same glioma cells implanted in B6 control hosts. This functional validation study shows that S100A4 is a highly promising therapeutic target for GBM immunotherapy.
The association between sugar intake during pregnancy and allergies in offspring: a systematic review and a meta-analysis of cohort studies
Authors: Gupta Adyya , Singh Ankur , Fernando Roshan L , Dharmage Shyamali C , Lodge Caroline J , Waidyatillake Nilakshi T
Published: July 2021

Context

It has been hypothesized that a mother’s diet during pregnancy may modulate her offspring’s immune system development and lead to development of allergic diseases among offspring. However, the evidence for this is unclear and inconclusive.

Objective

This systematic review was undertaken to examine the weight of evidence for causality from cohort studies on the association between maternal free sugar intake during pregnancy and development of allergies in offspring.

Data Sources

Using a systematic search strategy, PubMed, SCOPUS, and Web of Science databases were searched from inception to May 2020.

Data Extraction

For the reporting of this systematic review, the PRISMA guideline was followed. Studies examining maternal sugar consumption during pregnancy (using self-reported data) and the development of allergic diseases among offspring (infancy to 5 years) were included.

Data Analysis

The Newcastle–Ottawa Scale quality assessment tool was used to assess the study quality. Meta-analysis was conducted using a random-effects model to synthesize the findings. Of 159 publications identified from the search, 5 articles with 4 unique cohort studies were included in this systematic review. The limited meta-analysis showed that a mother’s increased free sugar intake during pregnancy was associated with an increased risk of developing asthma in offspring (odds ratio 1.07 [95% CI, 1.00 to 1.14; I2 = 0%]). High free sugar intake by the mother during pregnancy was also associated with increased odds of offspring (to age 7.7 years) developing other common allergies, including allergic rhinitis, atopy and eczema, wheeze, and food allergies .

Conclusion

From the limited evidence, this review suggests that high free sugar consumption during pregnancy may be associated with the development of allergies in offspring. Clinical guidelines and public health policy recommendations for maternal diet in pregnancy should include advice about reducing free sugar intake due to a possible association with allergies in offspring. However, recommendations should be made with caution considering other maternal and fetal risk factors.
Evaluation of rice research: An alternate method to capture outcomes
Authors: Samal Parshuram , Mondal Biswajit , Jambhulkar Nitiprasad N , Singh Onkar N , Verma Ramlakhan , Dash Sushant K , Das Anup K , Pathak Himanshu
Published: July 2021

Policy-makers, research managers, and donors are interested in knowing the outputs, outcomes, and impacts of investment in agricultural research. Several institutions are engaged in rice research and impact assessment of rice research requires area coverage information for rice varieties. The area coverage information for individual varieties is not available at the national level in many developing countries as the conventional household survey method is expensive and time-consuming. This article aims to find a cost-effective and quick method to estimate the area under popular rice varieties in India and their spread in different states. Secondary data collected from 27 states and 1 union territory of India were used to estimate the area. The results of the new method compared well with some of the studies conducted at the state level. The most important varieties identified using the new method were Swarna, Cottondora Sannalu, Samba Mahsuri, Vijetha, IR-64, and Ranjeet, which covered more than 1 million ha each in the country. On geographical coverage, IR-64 has spread to 17 states followed by Swarna, Cottondora Sannalu, Samba Mahsuri, Vijetha, IR-36, and Swarna Sub-1 which covered 14, 14, 12, 11, 11, and 10 states, respectively. The area information can be used to compute returns to rice research by different research institutions and study dynamics of varietal change over time. The popular varieties identified should be used in future breeding programs and biotechnological studies for the development of superior varieties.
Ultrasound in osteoarthritis of the hand: a comparison to computed tomography and histology
Authors: Husic Rusmir , Finzel Stephanie , Stradner Martin H , Dreu Manuel , Hofmeister Alexander , Beham-Schmid Christine , Graninger Winfried B , Fessler Johannes , Dejaco Christian
Published: July 2021

Objective

To compare structural findings between US, micro-CT (µCT) and histology in people with OA of the hands.

Methods

We analysed DIP and PIP joints of 31 fingers from 15 dissecting-room cadavers with OA of the hands. The occurrence of bone erosions and osteophytes were recorded by US, µCT and histology at 16 regions for each joint and compared for each method.

Results

In total, US (n = 558, 56.2% of 992 examined regions) and µCT (n = 493, 49.7%) detected a higher frequency of osteophytes at PIP and DIP joints than histology (n = 161, 23.4% of 689 histological examined regions; P = 0.01). We found a comparable number of erosions with each method [US, n = 52 (5.2%); µCT, n = 43 (4.3%); histology, n = 35 (5.2%)]. Both imaging techniques correlated moderately with each other regarding the detection of osteophytes (r = 0.54, P = 0.002) and erosions (r = 0.43, P = 0.017). Neither US nor µCT correlated with histology regarding erosions or osteophytes. With histology as the reference, US had a sensitivity of 80% and a specificity of 32% to detect osteophytes, whereas µCT had a sensitivity of 73% and a specificity of 27%. For erosions, sensitivities (US 10% and µCT 6%, respectively) were much lower. Microscopically, erosions contained fibrous myxoid tissue extending from subcortical cavities through the breach of cortical bone.

Conclusions

The ability of US to identify osteophytes was comparable to that of µCT, yielding a good sensitivity when histology was used as the gold standard. The sensitivity of US and µCT to detecting erosions was low compared with histology.
Neonatal Nurse and Midwife Competence Regarding Pain Management in Neonates
Authors: Mala Onanong , Forster Elizabeth M. , Kain Victoria J.
Published: July 2021

Background:

Neonates in need of intensive care are often subjected to numerous painful procedures. Despite the growing scientific research, hospitalized neonates continue to experience unrelieved pain. Enhancing the competence of neonatal intensive care nurses is an integral component of effective pain management.

Purpose:

The purpose of this article is to identify and synthesize the existing evidence on nurses' and midwives' competence regarding neonatal pain management internationally.

Methods/Search Strategy:

The review was guided by Whittemore and Knafl's 5-stage framework, with 8 databases searched in June 2020 including PubMed, CINAHL Complete (via EBSCOhost), MEDLINE (via EBSCOhost), PsycINFO (via Ovid), EMBASE, Scopus, Cochrane Library, and Google Scholar. Reference lists of selected articles were also hand-searched. Studies were reviewed independently for methodology and inclusion and exclusion criteria. The initial search yielded 3037 articles; 19 met the inclusion criteria and were included for analysis: qualitative (n = 5) and quantitative (n = 14).

Findings/Results:

Nurses' and midwives' competence regarding neonatal pain management in the neonatal intensive care unit is discussed in relation to knowledge, attitudes, behaviors, and perceptions of competence by most studies. The barriers to effective neonatal pain management were found to relate to nurses' and midwives' factors, underutilized pain assessment tools, and organizational factors. Potential facilitators to effective neonatal pain management included clear evidence-based guidelines/protocols, adequate training, and the use of appropriate and accurate pain assessment tools. Parent involvement and a team approach to neonatal pain management were also identified.

Implications for Practice and Research:

These findings suggest that further research is necessary to address the barriers and promote facilitators to improve neonatal pain management.
Comparison of preoperative and postoperative radiation therapy for extremity soft-tissue sarcoma: a randomized clinical trial
Authors: Mahmoudi Hamideh , Arefpour Amir Mohammad , Jamshidi Khodamorad , Fadavi Pedram , Mirzaei Alireza
Published: July 2021

Background:

The optimal sequencing of radiotherapy and surgery for the treatment of soft-tissue sarcoma (STS) is an ongoing source of controversy. In this study, the authors compared preoperative and postoperative radiotherapy in patients with extremity STS.

Methods:

Eighty patients with localized extremity STS were randomly assigned to either preoperative or postoperative radiotherapy group. Baseline characteristics of the patients were not significantly different between the two study groups. Primary outcome measures were pain, acute complications (wound dehiscence and infection), and late complications (limb edema, subcutaneous fibrosis, and joint stiffness). The severity of late complications was evaluated using the radiation therapy oncology group criteria. Secondary outcome measures were oncologic outcomes, including local recurrence and distant metastasis.

Results:

The mean pain level was not significantly different between the two groups (P=0.1). Infection was not seen in any of the patients. The rate of wound dehiscence and infection was not significantly different between the two groups (P=0.32 for both). Of the late complications, the rate of limb edema and subcutaneous fibrosis was similar in the two groups (P=0.16 and P=0.35, respectively). In contrast, the rate of joint stiffness was significantly more in the postoperative radiotherapy group (P<0.001). The severity of all three late complications also was more in the postoperative radiotherapy group at 6 and 12 mo. There were no significant differences between the two groups regarding local recurrence and distant metastasis (P=0.99 and P=0.77, respectively).

Conclusions:

The authors suggest preoperative radiotherapy in patients with localized extremity STS because of its lower rate of and less severe complications, particularly joint stiffness.

Level of Evidence:

Level I.
Descriptors of Sepsis Using the Sepsis-3 Criteria: A Cohort Study in Critical Care Units Within the U.K. National Institute for Health Research Critical Care Health Informatics Collaborative*
Authors: Shah Anoop D. , MacCallum Niall S. , Harris Steve , Brealey David A. , Palmer Edward , Hetherington James , Shi Sinan , Perez-Suarez David , Ercole Ari , Watkinson Peter J. , Jones Andrew , Ashworth Simon , Beale Richard , Brett Stephen J. , Singer Mervyn
Published: July 2021

OBJECTIVES:

To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records.

DESIGN:

Retrospective cohort study using electronic health records.

SETTING:

Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative.

PATIENTS:

A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical).

MEASUREMENTS AND MAIN RESULTS:

Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9–25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5–19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1–13.6%) (p for comparison less than 0.0001).

CONCLUSIONS:

We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding.
The Use of Thiazide Diuretics for the Treatment of Hypertension in Patients With Advanced Chronic Kidney Disease
Authors: Pham Ngoc-Yen T. , Owen Jonathan G. , Singh Namita , Shaffi Saeed Kamran
Published: July 2021

The use of thiazide diuretics for the treatment of hypertension in patients with advance chronic kidney disease. Thiazides have been recommended as the first-line for the treatment of hypertension, yet their use has been discouraged in advanced chronic kidney disease (CKD), as they are suggested to be ineffective in advanced CKD. Recent data suggest that thiazide diuretics may be beneficial blood pressure control in addition to natriuresis in existing CKD. This review discusses the commercially available thiazides with a focus on thiazide pharmacology, most common adverse effects, clinical uses of thiazide diuretic, and the evidence for efficacy of thiazide use in advanced CKD.