bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolomics in Clinical Practice: Improving Diagnosis and Informing Management
Authors: Odom John D , Sutton V Reid
Published: September 2021

Background

Metabolomics is the study of small molecules to simultaneously identify multiple low molecular weight molecules in a system. Broadly speaking, metabolomics can be subdivided into targeted and untargeted types of analysis, each type having advantages and drawbacks. Targeted metabolomics can quantify analytes but only looks for known or expected analytes related to particular disease(s), whereas untargeted metabolomics is typically nonquantitative but can detect thousands of analytes from an agnostic or nonhypothesis driven perspective, allowing for novel discoveries.

Content

One application of metabolomics is the study of inborn errors of metabolism (IEM). The biochemical hallmark of IEMs is decreased concentrations of analytes distal to the enzymatic defect and buildup of analytes proximal to the defect. Metabolomics can detect these changes with one test and is effective in screening for and diagnosis of IEMs. Metabolomics has also been used to study many nonmetabolic diseases such as autism spectrum disorder, various cancers, and multiple congenital anomalies syndromes. Metabolomics has led to the discovery of many novel biomarkers of disease. Recent publications demonstrate how metabolomics can be useful clinically in the diagnosis and management of patients, as well as for research and clinical discovery.

Metabolomics has proved to be a useful tool clinically for screening and diagnostic purposes and from a research perspective for the detection of novel biomarkers. In the future, metabolomics will likely become a routine part of the evaluation for many diseases as either a supplementary test or it may simply replace historical analyses that require several individual tests and sample types.
Lateral Flow Assays in Infectious Disease Diagnosis
Authors: Boehringer Hans R , O’Farrell Brendan J
Published: September 2021

Background

Lateral flow immunoassays are widely used as diagnostic tests in many applications in human and other diagnostic areas. Assays for human applications have been commercially available since the 1980s and initially were primarily used to identify pregnancy by measuring human chorionic gonadotropin in urine and serum/plasma.

Content

The first infectious disease lateral flow assays were commercialized in the late 1980s identifying the presence of Group A Streptococcus pyogenes collected with throat swabs; innumerable other applications followed in the intervening decades. The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) pandemic has brought a vast number of new assays for which emergency use authorization (EUA) has been requested in the USA. These assays have been designed for detection of the antibody response to an infection and viral antigens in respiratory samples. In view of the onslaught of new tests, this review will focus on the use of rapid lateral flow immunoassays for infectious diseases. Principles of lateral flow assays and approaches to the production of high-sensitivity point-of-care assays are presented. Market trends, customer requirements, and future directions of lateral flow assay technology and its applications in the infectious disease diagnostic space are discussed.

Lateral flow immunoassays play an important role in infectious disease diagnostics. Advancements in technology have led to improved performance of these assays and acceptance by professional users. With the advent of the SARS-CoV-2 pandemic, the market has reached new levels requiring hundreds of millions of tests per year for professional and even home use.
Gender aspects in cardiooncology
Authors: Hohneck Anna , Custodis Florian , Rosenkaimer Stephanie , Hofheinz Ralf , Maier Sandra , Akin Ibrahim , Borggrefe Martin , Gerhards Stefan
Published: September 2021

Background

Cardiooncology is a relatively new subspeciality, investigating the side effects of cytoreductive therapies on the cardiovascular (CV) system. Gender differences are well known in oncological and CV diseases, but are less elucidated in cardiooncological collectives.

Methods

Five hundred and fifty-one patients (278 male, 273 female) with diagnosed cancer who underwent regular cardiological surveillance were enrolled in the ‘MAnnheim Registry for CardioOncology’ and followed over a median of 41 (95% confidence interval: 40–43) months.

Results

Female patients were younger at the time of first cancer diagnosis [median 60 (range 50–70) vs. 66 (55–75), P = 0.0004], while the most common tumour was breast cancer (49.8%). Hyperlipidaemia was more often present in female patients (37% vs. 25%, P = 0.001). Male patients had a higher cancer susceptibility than female patients. They suffered more often from hypertension (51% vs. 67%, P = 0.0002) or diabetes (14% vs. 21%, P = 0.02) and revealed more often vitamin D deficiency [(U/l) median 26.0 (range 17–38) vs. 16 (9–25), P = 0.002] and anaemia [(g/dl) median 11.8 (range 10.4–12.9) vs. 11.7 (9.6–13.6), P = 0.51]. During follow-up, 140 patients died (male 77, female 63; P = 0.21). An increased mortality rate was observed in male patients (11.4% vs. 14%, P = 0.89), with even higher mortality rates of up to 18.9% vs. 7.7% (P = 0.02) considering tumours that can affect both sexes compared.

Conclusions

Although female patients were younger at the time of first cancer diagnosis, male patients had both higher cancer susceptibility and an increased mortality risk. Concomitant CV diseases were more common in male patients.
Two sides of every coin: individuals’ experiences of undergoing colorectal cancer screening by faecal immunochemical test and colonoscopy
Authors: Wangmar Johanna , Wengström Yvonne , Jervaeus Anna , Fritzell Kaisa
Published: September 2021

Background

Acceptability of the recommended screening procedure represents a crucial determinant of the impact of colorectal cancer (CRC) screening programmes. This study aims to explore how individuals in CRC screening experience the screening procedure.

Methods

Study participants (n = 44), aged 60–62 years, screened by faecal immunochemical test (FIT) and/or colonoscopy, were recruited from the Screening of Swedish Colons (SCREESCO) study. Data were collected through six focus group discussions and 20 individual telephone interviews and analyzed using qualitative content analysis.

Results

The analysis resulted in 30 subcategories together forming four categories describing individuals’ experiences of the CRC screening procedure: From no worries to bothering emotions; Varying logistical concerns; Being well treated, but inconsistently informed and involved and Expectations not matching reality. Some subcategories only applied to either FIT or colonoscopy screening, while others applied to both screening procedures.

Conclusions

Undergoing CRC screening by FIT or colonoscopy is an individual experience. Strategies to improve patient experiences may include using one-sample FITs and optimizing bowel preparation and scheduling of colonoscopies according to individual preferences. Ensuring that needs for emotional support are acknowledged, together with clear and adequate information delivered at right time are further important aspects to consider.
Growth and structural changes in Swiss uneven-aged forests over 100 years, and comparisons between 15 uneven-aged forest types of Europe, North America and Australia
Authors: Forrester David I , Schmid Hubert , Nitzsche Jens
Published: September 2021

Long-term changes in growth, physiology and stand structure, as well as differences due to species composition, were examined in six types of Swiss plenter forests: (1) Picea abies dominated, (2) mixtures of P. abies and Abies alba, (3) mixtures of P. abies, A. alba and Fagus sylvatica, (4) mixtures of Larix decidua, Pinus cembra/sylvatica and P. abies, (5) F. sylvatica dominated and (6) species diverse stands. Long-term changes were examined using 19 plots measured for an average of 94 years. These data were then combined with the literature plenter forest data to compare the growth and structure of 15 species compositions from Europe, North America and Australia. Over the past 100 years, common trends included increases in growth, maximum tree sizes, species diversity, and increasingly convex diameter distributions with fewer medium sized trees and more very large trees. Differences in growth between species compositions were generally consistent with their light-use efficiency, transpiration and water-use efficiency, which were calculated using a process-based model. Stand volume of each forest type was negatively correlated with the shade tolerance (but not crown architectures) of the species it contained, but no such correlations existed for stand basal area. This reflects the high structural variability of these forests (through time and between sites) as well as the high tree neighbourhood variability within plots, which appear to buffer the effects of stand density on regeneration and recruitment. This study shows that despite significant temporal and spatial variability in structure, the negative exponentially shaped diameter distributions were maintained in the long term by applying simple silvicultural principles rather than requiring a very specific stand structure, i.e. a certain stand density, or that all diameter classes strictly lie on the curve of a negative exponentially shaped diameter distribution. The values of stand structural characteristics reported in this study could be used as a guide for the conversion of relatively simply structured forests into plenter forests.
Impact of early genomic prediction for recurrent selection in an upland rice synthetic population
Authors: Baertschi Cédric , Cao Tuong-Vi , Bartholomé Jérôme , Ospina Yolima , Quintero Constanza , Frouin Julien , Bouvet Jean-Marc , Grenier Cécile
Published: September 2021

Population breeding through recurrent selection is based on the repetition of evaluation and recombination among best-selected individuals. In this type of breeding strategy, early evaluation of selection candidates combined with genomic prediction could substantially shorten the breeding cycle length, thus increasing the rate of genetic gain. The objective of this study was to optimize early genomic prediction in an upland rice (Oryza sativa L.) synthetic population improved through recurrent selection via shuttle breeding in two sites. To this end, we used genomic prediction on 334 S0 genotypes evaluated with early generation progeny testing (S0:2 and S0:3) across two sites. Four traits were measured (plant height, days to flowering, grain yield, and grain zinc concentration) and the predictive ability was assessed for the target site. For days to flowering and plant height, which correlate well among sites (0.51–0.62), an increase of up to 0.4 in predictive ability was observed when the model was trained using the two sites. For grain zinc concentration, adding the phenotype of the predicted lines in the nontarget site to the model improved the predictive ability (0.51 with two-site and 0.31 with single-site model), whereas for grain yield the gain was less (0.42 with two-site and 0.35 with single-site calibration). Through these results, we found a good opportunity to optimize the genomic recurrent selection scheme and maximize the use of resources by performing early progeny testing in two sites for traits with best expression and/or relevance in each specific environment.
Effect of physical distancing on Covid-19 incidence in Brazil: does the strictness of mandatory rules matter?
Authors: Guimarães Raphael Mendonça , Monteiro da Silva José Henrique Costa , Brusse Gustavo Pedroso de Lima , Martins Thalyta Cássia de Freitas
Published: September 2021

This study aims to examine the association between physical distancing measures and coronavirus disease 2019 (COVID-19) incidence among Brazilian states. We divided the methodology was divided into three steps. In the first step, we used nationwide global positioning system daily data to estimate country and state-level physical distancing and examined the association with COVID-19 incidence through a Generalized Additive Model. Secondly, using National Household Sample Survey COVID19 data, a cluster analysis categorized the Brazilian states into different categories of physical distancing policies promoting adoption and political inclination of their governments. Finally, through a Poisson Regression Model, we examined the association of state physical distancing with variables related to the socio-economic situation, test coverage and early adoption of policies promoting physical distancing of each state. Physical distancing effects on reduction of COVID-19 spread are heterogeneous among states. Estimation of incidence rate ratio (IRR) suggests that in a scenario of 100% of social isolation incidence of COVID-19 will have reached approximately only 2.6% of the magnitude compared to when there is no social isolation for Brazil [95% confidence interval (CI) 0.8–8.3]. Only a 10% increase in Social Isolation Index in the country could have reflected in a 30.5% decrease in number of cases in 14 days. Adoption of physical distancing was associated with test coverage (IRR 0.976, 95% CI 0.973–0.979), home office (IRR 1.042, 95% CI 1.039–1.046), informal work proportion (IRR 0.961, 95% CI 0.958–0.965), political spectrum (IRR 0.961, 95% CI 0.958–0.965) and early moment of restrictive politics implementation (IRR 1.017, 95% CI 1.013–1.021). Physical distancing measures play a crucial role in mitigating the pandemic’s spread. These analyses are crucial to support government decisions and improve the community’s adherence to preventive measures.
Use of antidepressants and endometrial-cancer risk: a nationwide nested case–control study
Authors: Sperling Cecilie D , Aalborg Gitte L , Dehlendorff Christian , Friis Søren , Mørch Lina S , Kjaer Susanne K
Published: September 2021

Background

Preclinical studies have suggested that antidepressant drugs may possess antineoplastic properties. In a nationwide case–control study, we examined the association between use of antidepressants and endometrial-cancer risk with a particular focus on selective serotonin reuptake inhibitors (SSRIs).

Methods

From the Danish Cancer Registry, we identified all women with a histologically verified diagnosis of endometrial cancer between 2000 and 2016, and, for each woman, 15 age-matched controls. We obtained information on use of SSRIs, tricyclic antidepressants (TCAs) and other antidepressants based on records of filled prescriptions from the National Prescription Register. Using conditional logistic regression, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between use of antidepressants and endometrial-cancer risk compared with non-use. In active comparator analyses, SSRI use was compared with TCA use.

Results

The study population comprised 8164 cases and 122 432 controls. Compared with non-use, SSRI use was associated with an OR of 0.88 (95% CI 0.82–0.96) for endometrial cancer, whereas the association with TCA use was close to unity (OR 1.05, 95% CI 0.90–1.22). Use of other antidepressants yielded an OR of 0.86 (95% CI 0.71–1.03). We observed no apparent trends in associations according to cumulative amount. The inverse association with SSRI use persisted when compared with TCA use (OR 0.81, 95% CI 0.66–0.99).

Conclusions

Use of SSRIs was associated with a decreased risk of endometrial cancer, whereas no inverse association appeared with use of TCAs. The antineoplastic potential of SSRIs should be investigated in future studies.
The quality of social determinants data in the electronic health record: a systematic review
Authors: Cook Lily A , Sachs Jonathan , Weiskopf Nicole G
Published: September 2021

Objective

The aim of this study was to collect and synthesize evidence regarding data quality problems encountered when working with variables related to social determinants of health (SDoH).

Materials and Methods

We conducted a systematic review of the literature on social determinants research and data quality and then iteratively identified themes in the literature using a content analysis process.

Results

The most commonly represented quality issue associated with SDoH data is plausibility (n = 31, 41%). Factors related to race and ethnicity have the largest body of literature (n = 40, 53%). The first theme, noted in 62% (n = 47) of articles, is that bias or validity issues often result from data quality problems. The most frequently identified validity issue is misclassification bias (n = 23, 30%). The second theme is that many of the articles suggest methods for mitigating the issues resulting from poor social determinants data quality. We grouped these into 5 suggestions: avoid complete case analysis, impute data, rely on multiple sources, use validated software tools, and select addresses thoughtfully.

Discussion

The type of data quality problem varies depending on the variable, and each problem is associated with particular forms of analytical error. Problems encountered with the quality of SDoH data are rarely distributed randomly. Data from Hispanic patients are more prone to issues with plausibility and misclassification than data from other racial/ethnic groups.

Conclusion

Consideration of data quality and evidence-based quality improvement methods may help prevent bias and improve the validity of research conducted with SDoH data.
Determination of Sulphasalazine and Its Related Compounds by Simple, Smart, Validated, Green Spectrophotometric Methods
Authors: Abdelwhab Nada S , Habib Neven M , Abdelrahman Maha M , Mahmoud Hamada M , Emam Aml A
Published: September 2021

Background

Sulphasalazine (SZ) is a prodrug. Its active metabolite (mesalazine, MZ), which is also available in pharmaceutical formulations, and the major active metabolite of MZ (N-acetyl-5-aminosalicylic acid, AS) are commonly used for the treatment of inflammatory bowel diseases.

Objective

Two accurate, precise, sensitive, and specific spectrophotometric methods were developed and validated for determination of the studied components.

Methods

The first method is a modified ratio difference spectrophotometric method. In this method, SZ was determined by measuring the peak area from 410–500 nm, while MZ and AS were determined by measuring the difference of the selected amplitude values. The second method is a mean centering of ratio spectra spectrophotometric method.

Results

The developed methods were linear over the concentration ranges of 2–35, 2–30 and 1–25 µg/mL for SZ, MZ and AS, respectively.

Conclusion

The developed methods were validated according to International Conference on Harmonization guidelines. They were successfully applied for determination of studied analytes. A greenness assessment was undertaken using three different tools.

Highlights

Spectrophotometric methods were developed for determination of SZ and its related compounds for the first time. They were designated to be green and eco-friendly and their greenness profiles were evaluated using green solvents to keep the environment clean.
Epitope-dependent thermodynamic signature of single-domain antibodies against hen egg lysozyme
Authors: Akiba Hiroki , Tamura Hiroko , Caaveiro Jose M M , Tsumoto Kouhei
Published: September 2021

A substantial body of work has been carried out describing the structural features of the complex between single-domain antibodies (VHHs) and antigens, and the preeminence for epitopes located at concave surfaces of the antigen. However, the thermodynamic basis of binding is far less clear. Here, we have analysed the energetic profiles of five VHHs binding to the catalytic cleft or to a noncleft epitope of hen egg lysozyme. Various binding energetic profiles with distinctive enthalpic/entropic contributions and structural distribution of critical residues were found in the five antibodies analysed. Collectively, we suggest that from an energetic point of view the binding mechanism is influenced by the shape of the epitope. This information may be beneficial for the design of tailored epitopes for VHHs and their practical use.
When in Rome... On Local Norms and Sentencing Decisions
Authors: Abrams David , Galbiati Roberto , Henry Emeric , Philippe Arnaud
Published: September 2021

We study spatial variation in criminal sentencing. We show the existence of local sentencing practices varying widely even across geographically proximate areas. Using compulsory rotation of judges in North Carolina, we find that judges arriving in a new court gradually converge toward local sentencing practices. We provide evidence that convergence in sentencing corresponds to a process of learning about local practices, which is accelerated by the presence of senior judges in the district, and that these sentencing practices are correlated with local norms of behavior. Finally, we discuss the theoretical implications of these results for the optimal design of judicial systems.
Receptivity to a Nurse-Led Symptom Management Intervention Among Highly Symptomatic Patients With Cancer
Authors: Wintheiser Grant A , Ruddy Kathryn J , Herrin Jeph , Rahman Parvez A , Pachman Deirdre R , Leppin Aaron L , Rutten Lila J Finney , Lee Minji K , Griffin Joan M , Tofthagen Cindy , Chlan Linda L , Ridgeway Jennifer L , Mitchell Sandra A , Cheville Andrea L
Published: September 2021

Background

The symptom burden associated with cancer and its treatment can negatively affect patients’ quality of life and survival. Symptom-focused collaborative care model (CCM) interventions can improve outcomes, but only if patients engage with them. We assessed the receptivity of severely symptomatic oncology patients to a remote nurse-led CCM intervention.

Methods

In a pragmatic, cluster-randomized, stepped-wedge trial conducted as part of the National Cancer Institute IMPACT Consortium (E2C2, NCT03892967), patients receiving cancer care were asked to rate their sleep disturbance, pain, anxiety, emotional distress, fatigue, and limitations in physical function. Patients reporting at least 1 severe symptom (≥7/10) were offered phone consultation with a nurse symptom care manager (RN SCM). Initially, patients had to “opt-in” to receive a call, but the protocol was later modified so they had to “opt-out” if they did not want a call. We assessed the impact of opt-in vs opt-out framing and patient characteristics on receptiveness to RN SCM calls. All statistical tests were 2-sided.

Results

Of the 1204 symptom assessments (from 864 patients) on which at least 1 severe symptom was documented, 469 (39.0%) indicated receptivity to an RN SCM phone call. The opt-out period (odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.12 to 2.32, P = .01), receiving care at a tertiary care center (OR = 3.59, 95% CI = 2.18 to 5.91, P < .001), and having severe pain (OR = 1.80, 95% CI = 1.24 to 2.62, P = .002) were associated with statistically significantly greater willingness to receive a call.

Conclusions

Many severely symptomatic patients were not receptive to an RN SCM phone call. Better understanding of reasons for refusal and strategies for improving patient receptivity are needed.
Rosette-Forming Glioneuronal Tumor in the Pineal Region: A Series of 6 Cases and Literature Review
Authors: Lin Chun-Chieh , Mansukhani Mahesh M , Bruce Jeffrey N , Canoll Peter , Zanazzi George
Published: September 2021

Resected lesions from the pineal region are rare specimens encountered by surgical pathologists, and their heterogeneity can pose significant diagnostic challenges. Here, we reviewed 221 pineal region lesions resected at New York-Presbyterian Hospital/Columbia University Irving Medical Center from 1994 to 2019 and found the most common entities to be pineal parenchymal tumors (25.3%), glial neoplasms (18.6%), and germ cell tumors (17.6%) in this predominantly adult cohort of patients. Six cases of a rare midline entity usually found exclusively in the fourth ventricle, the rosette-forming glioneuronal tumor, were identified. These tumors exhibit biphasic morphology, with a component resembling pilocytic astrocytoma admixed with variable numbers of small cells forming compact rosettes and perivascular pseudorosettes. Targeted sequencing revealed a 100% co-occurrence of novel and previously described genetic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways, suggesting a synergistic role in tumor formation. The most common recurrent mutation, PIK3CA H1047R, was identified in tumor cells forming rosettes and perivascular pseudorosettes. A review of the literature revealed 16 additional cases of rosette-forming glioneuronal tumors in the pineal region. Although rare, this distinctive low-grade tumor warrants consideration in the differential diagnosis of pineal region lesions.
Nuclear IMPDH Filaments in Human Gliomas
Authors: Ahangari Narges , Munoz David G , Coulombe Josee , Gray Douglas A , Engle Elizabeth C , Cheng Long , Woulfe John
Published: September 2021

The analysis of nuclear morphology plays an important role in glioma diagnosis and grading. We previously described intranuclear rods (rods) labeled with the SDL.3D10 monoclonal antibody against class III beta-tubulin (TUBB3) in human ependymomas. In a cohort of adult diffuse gliomas, we identified nuclear rods in 71.1% of IDH mutant lower-grade gliomas and 13.7% of IDH wild-type glioblastomas (GBMs). The presence of nuclear rods was associated with significantly longer postoperative survival in younger (≤65) GBM patients. Consistent with this, nuclear rods were mutually exclusive with Ki67 staining and their prevalence in cell nuclei inversely correlated with the Ki67 proliferation index. In addition, rod-containing nuclei showed a relative depletion of lamin B1, suggesting a possible association with senescence. To gain insight into their functional significance, we addressed their antigenic properties. Using a TUBB3-null mouse model, we demonstrate that the SDL.3D10 antibody does not bind TUBB3 in rods but recognizes an unknown antigen. In the present study, we show that rods show immunoreactivity for the nucleotide synthesizing enzymes inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase. By analogy with the IMPDH filaments that have been described previously, we postulate that rods regulate the activity of nucleotide-synthesizing enzymes in the nucleus by sequestration, with important implications for glioma behavior.
Research on the evaluation of museum website utility index based on analytic hierarchy process: a case study of China's national first-class museums
Authors: Ma Xintao , Hu Yuna
Published: September 2021

In order to better serve the construction and development of museum websites in developing countries, and based on the user's online experience perspective, an analytic hierarchy process suitable for the construction of a museum website for developing counties utility index evaluation system was used to measure the official websites of 115 national first-class museums in China, and reflect the level of museum website construction and service levels. The results revealed the following: there were obvious differences in the level of a Chinese museum construction sites, showing an overall Rugby-type distribution situation; content completeness and update speed are the most important factors that affect the measurement of the museum website's utility index, which fully reflects the importance of the comprehensiveness, accuracy and timeliness of the website information in the construction of a museum website; the influence is that museum websites are generally weak, with limited spread and power, and fails to form a large positive social influence; the construction problems are mainly concentrated in the two aspects of technology and operation. The display, safety and security technology of the museum website content is relatively backward, and most of the website backgrounds rarely have professionals for daily visitor interaction and operation, and maintenance. The results of the index measured by this system not only allows museum personnel to clearly understand the gaps in the development of museum websites, but also provides more clear requirements for future personnel to design, build and improve the overall usefulness of the website or a single utility index in a targeted manner, which has important guiding significance and practical value.
Exploring the similarity between Han’s and non-Han’s Yuan poetry: Resistance distance metrics over character co-occurrence networks
Authors: Yang Yi , Song Yue
Published: September 2021

The Yuan dynasty is the first non-Han unified dynasty in ancient China. It is subtle to tell the similarities and differences between the classic Chinese poems in the Yuan dynasty written by the writers of Han nationality and non-Han minority nationalities. By graph theory and statistics, this article establishes a novel method for quantifying the similarity between the Han’s and non-Han’s Yuan poetry. First, we formulate the character co-occurrence networks (CCONs) of the Han’s and non-Han’s Yuan poem databases collected from ‘Database of Ancient Chinese Classics’. The resistance distance, a graph theory concept, is introduced to describe the lexical relation between a pair of characters in the CCONs. Then, we propose the similarity index as the coefficient of variation for the ratios of resistance distances in the CCONs of Han’s and non-Han’s poem databases, which measures the consistency between the usages of characters in the Han’s and non-Han’s poems. The calculation results indicate that the Han’s and non-Han’s poems share a high percentage of common high-frequency characters and there do not exist significantly different lexical features in terms of the usage of these high-frequency characters. The obtained results offer new insights into the quantitative features of this long-debated issue.
NLRP3 promotes endometrial receptivity by inducing epithelial–mesenchymal transition of the endometrial epithelium
Authors: Cheng Xi , Zhang Yu , Ma Jinzhao , Wang Shuxian , Ma Rujun , Ge Xie , Zhao Wei , Xue Tongmin , Chen Li , Yao Bing
Published: September 2021

Endometrial receptivity is crucial for successful embryo implantation. It is regulated by multiple factors which include ovarian steroid hormones and the immune microenvironment among others. Nod-Like Receptor Pyrins-3 (NLRP3) is a key intracellular pattern-recognition receptor and a critical component of the inflammasome, which plays an essential role in the development of inflammation and of immune responses. However, the physiological functions of NLRP3 in the endometrium remain largely unclear. This study investigated the physiological and pathological significance of NLRP3 in human endometrial epithelial cell during the implantation window. NLRP3 is highly expressed during the mid-proliferative and mid-secretory phases of the human endometrium and transcriptionally up-regulated by estradiol (E2) through estrogen receptor β (ERβ). In addition, NLRP3 promotes embryo implantation and enhances epithelial-mesenchymal transition (EMT) of Ishikawa (IK) cells via both inflammasome-dependent and inflammasome-independent pathways, which might provide a novel insight into endometrial receptivity and embryo implantation. Our findings suggest that NLRP3, which is transcriptionally regulated by E2, induces epithelial–mesenchymal transition of endometrial epithelial cells and promotes embryo adhesion.
PL03.4.A Factors associated with health-related quality of life (HRQoL) deterioration in glioma patients during the progression-free survival period
Authors: Coomans M , Dirven L , Aaronson N , Baumert B , van den Bent M , Bottomley A , Brandes A , Chinot O , Coens C , Gorlia T , Herrlinger U , Keime-Guibert F , Malmström A , Martinelli F , Stupp R , Talacchi A , Wick W , Reijneveld J , Taphoorn M
Published: September 2021

BACKGROUND

Maintenance of functioning and wellbeing during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period.

MATERIAL AND METHODS

We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period.

RESULTS

5539 patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9%-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8–5.4 months, and median time-to-deterioration between 8.2–11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period.

CONCLUSION

HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients’ functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signalled.
KS01.3.A Tumoral MHC class II expression in gliomas drives T cell exhaustion
Authors: Chih Y , Sahm K , Sadik A , Bunse T , Trautwein N , Pusch S , Stevanovic S , Opitz C , Deimling A , Wick W , Sahm F , Bunse L , Platten M
Published: September 2021

BACKGROUND

Neoepitopes are presented on major histocompatibility class II (MHCII) molecules. In glioma, for instance, the recurrent driver mutation IDH1R132H was shown to bear an MHCII-restricted epitope in preclinical and clinical vaccine studies. The general relevance of MHCII expression in glioma for antitumor immunity, however, remains unknown. Here we evaluate stromal and tumoral MHCII expression, functionality, and its association with survival in gliomas.

MATERIAL AND METHODS

Immunostaining of human glioma tissues was used to identify tumoral, endothelial, and microglial MHCII expression and to enumerate T cell infiltrates. To gain insights into tumoral MHCII expression, bulk transcriptomic data from TCGA and single-cell transcriptomic data from publicly available datasets were analyzed. MHC ligandome analyses of an MHCII+ glioma cell line and human glioma tissues were used to determine the functionality of MHCII in vitro and ex vivo. Functional in vitro co-culture assays with an HLA-DR-matched tetanus toxoid (TT) epitope-overexpressing glioma cell line and in vitro-expanded TT-reactive T cells from healthy donors were used to examine direct target recognition by T helper cells. CRISPR-Cas9-mediated knockout of MHCII in preclinical hypermutant glioblastoma cell line GL261 was employed to further validate the consequences of tumoral MHCII expression and to probe potential clinical intervention with existing therapies.

RESULTS

MHCII is expressed in the majority of gliomas and associated with increased infiltration of T cells. In 10% of the analyzed glioma tissues and a subset of single cells, tumoral MHCII expression is detected. Clinical and transcriptomic data reveal that tumoral MHCII is associated with poor prognosis, cytokine responses, immune inhibition and T cell differentiation. Ligandome analyses evidence presentation of peptides by MHCII molecules on glioma cells. In in vitro assays, TT-reactive T helper cells specifically produce IFNg when co-cultured with MHCII+ glioma cells upon the presence of co-stimulation. In agreement with the clinical data, preclinical murine models demonstrate that tumoral MHCII expression leads to reduced survival. Co-culture assay shows that tumoral MHCII results in upregulation of PD-1 on T helper cells antigen-specifically. Concordantly, immune checkpoint blockade (ICB) therapy slows the disease progression of mice carrying MHCII+ tumors.

CONCLUSION

MHCII is expressed in gliomas by a subset of tumor cells. Although tumoral MHCII is functional, it is associated with poor survival in both clinical data and preclinical models. T cell exhaustion induced by tumoral MHCII expression can, in part, be overcome by ICB in vivo. Further experiments are required to decipher tumor cell intrinsic and microenvironmental consequences of tumoral MHCII expression.
OS03.5.A Corelation between longitudinal t2 MRI radiomic primary texture feature values and radiation dose in non-tumoral regions of the brain in paediatric brain tumours
Authors: Sakhavalkar P , Avula S , Pizer B , Thorp N , Jenkinson M
Published: September 2021

BACKGROUND

Paediatric brain tumour survivors may have treatment toxicity associated with signal change on follow-up MRI. Quantitative MRI texture features can potentially be used as surrogates of the underlying tissue changes following radiation therapy.

MATERIAL AND METHODS

Longitudinal retrospective study in 51 paediatric primary brain tumours treated with photon (N=30) and proton (N=21) radiotherapy (RT). T2 MRI scans at baseline and multiple time point from the date of surgery to 2 years following radiotherapy were selected for the textural analysis. Scans were bias corrected, registered with the CT dose maps and with baseline scan for each patient using 3Dslicer. Regions of interest (ROI) of fixed diameter were drawn in 11 predetermined non-tumoral regions of brain including in peri-tumoural region (PTV). ROIs were placed in homogenous white/grey matter. Radiation dose was calculated in each of these 11 ROIs and texture features were extracted using pyradiomics. Data were analysed using machine learning and statistical analysis. General linear multivariate model was used to corelate primary texture features over period of 24 months and radiation dose, time, effect of dose*time together at each ROI separately.

RESULTS

There were Brainstem 4, Cerebellar19, Hemispheric cerebral 7 and Supratentorial midline 10 tumours. Median age at diagnosis was 8.26 years (range: 0–20). Median RT treatment dose was 28.52Gy (0-60Gy). Multivariate analysis shows significant corelation (p < 0.001) between radiation dose and longitudinal primary texture features in all 11ROIs. Time showed corelation with feature values only in 3 ROIs and dose* time showed corelation in 5ROIs. Primary (statistical) feature values showing consistent correlation with dose in all 11 ROIs over 24 months are total energy, 10%, 90%, energy, entropy, mean, median, and minimum.

CONCLUSION

Radiomic texture analysis is a promising modality to understand dose related textural changes in the normal part of brain in paediatric brain tumour patients treated with radiation therapy. Radiomic changes need to be related to neurological outcomes in future research.
P06.01 Pediatric non-pontine diffuse midline glioma H3K27M mutant: a monoinstitutional experience
Authors: Schiavello E , Biassoni V , De Cecco L , Pecori E , Filippo S , Gandola L , Massimino M
Published: September 2021

BACKGROUND

The new entity “diffuse-midline-glioma H3K27M-mutant”(DMG) was defined in the 2016 WHO classification. This tumor subtype, regardless of histological features, is associated with an aggressive clinical behavior and poor prognosis, sharing the same outcome as DIPG.

MATERIAL AND METHODS

We report our experience from 2016 to 2018 in treating patients with radiotherapy and concomitant Nimotuzumab/Vinorelbine, as already published for DIPG’s patients (DOI10.1007/s11060-014-1428-z). All patients’ parents provided written informed consent for treatment.

RESULTS

Patients were 9: 7/9 females, median age at diagnosis 13 years (range 1–26); 8 with localized disease, 1 with spinal fluid (CSF) dissemination. Five patients had thalamic disease (1 bithalamic), 2 ponto-cerebellar (one with 2 lesions), 1 pineal gland and one with disseminated CSF disease at diagnosis. 3/9 were biopsed in thalamus, the others had partial resection. Central neuropathological review with confirmed histopathological diagnosis of DMG mutated was necessary for inclusion. At the first pathological evaluation tumors had been classified according to the fourth edition of the WHO 2007 as glioblastoma (n=4), anaplastic astrocytoma grade III (n=1), diffuse astrocytoma grade II (n=1), and 1 glial tumor with oligodendroglial features; 2 patients already had DMG at the first pathological evaluation. Immunohistochemical analysis revealed p53 mutation in 3 patients. All 9 patients were evaluated on serial plasma samples with NGS targeted panel (Pan-Cancer) and 6/9 presented p53 mutation in at least one of the samples. 8/9 expressed MAP2K1 gain of function at liquid biopsy. The small number of patients did not allow correlations with the prognosis. Two patients completed the scheduled 2 years of treatment: one had a local relapse at 37 months after diagnosis, the other is alive without evidence of progression at 30 months. With a median follow up of 14.4 months, PFS and OS were 33% and 77% at 1 year; OS was 22% at 2 years, with 2 patients long survivors at 36 and 40 months after diagnosis.

CONCLUSION

The molecular and phenotypic pattern of DMG allows to include patients in clinical trials/registry shared with patients suffering from DIPG. Our knowledge is still limited about this entity; new insights into molecular profile should help us to study new drugs directed against the effects of the H3K27M mutations and to define new diagnostic/prognostic approach as liquid biopsy able to correlate treatments and prognosis
P10.03 Establishment and validation of clinical prediction model in WHO grade II glioma
Authors: Xue X , Gao Q
Published: September 2021

OBJECTIVE

WHO grade II glioma has the characteristics of heterogeneity, and this disease progresses rapidly in some patients, in whom the malignant degree is equivalent to that of high-grade glioma. In order to accurately predict the prognosis of patients, an effective clinical prediction model based on relevant risk factors is needed which could provide a theoretical basis for optimization of clinical individualized treatment.

METHODS

According to the inclusion and exclusion criteria, eligible patients from January 2010 to December 2018 in our hospital were selected, and those who met the criteria were randomly assigned 4:1 to the training group and the validation group, respectively. The predictors were screened by univariate and multivariate Cox regression analysis, the prediction model was established, and the model was verified and evaluated.

RESULTS

A total of 258 patients with WHO grade II glioma were recruited, including 208 patients as the training group and 50 patients as the validation group. Six independent risk factors, including patient age, preoperative Karnofsky performance status (KPS) score, preoperative seizure symptoms, surgical resection range, tumor size and IDH status, were selected and included into the prediction model by univariate and multivariate Cox regression analysis, and were visualized in the form of Nomogram. The concordance index (C index) was used to evaluate the predictive ability of the model. Results showed that the C-index was 0.832 in the training group and 0.853 in the validation group, respectively, indicating good performance for the prediction model. The calibration charts were drawn in both groups respectively, which showed that the calibration lines were in good agreement with the standard lines, indicating good consistency between the two groups.

CONCLUSIONS

In this study, a clinical prediction model for WHO grade II glioma was established, and it was verified that the model has good predictive ability, which may be beneficial for clinical work.
P11.03 Sleep analysis of accelerometer data from High Grade Glioma patients in the BrainWear study
Authors: George M , Dadhania S , Williams M
Published: September 2021

BACKGROUND

Sleep disturbance is a common symptom in patients with high grade glioma (HGG). Existing self-reported and uni-dimensional data from questionnaires are of limited value. The observational phase 2 trial, BrainWear (ISRCTN 34351424) provides the first objective analysis of sleep in HGG patients.

MATERIAL AND METHODS

Patients with HGG were asked to wear an AX3 Axivity tri-axial accelerometer throughout treatment. The study employed a wear-as-long-as-possible approach to accelerometry data collection, and we used age-sex matched controls from the UK Biobank as comparators. Baseline was established as a 7 day period of wear prior to surgery or at least 7 days post-surgery. The dataset for this analysis consists of 21 patients with data at baseline and 15 patients during chemo-radiation. Only 16 of the 21 HGG patients at baseline were included for initial comparisons with healthy controls due to age limitations of the UK Biobank cohort for matching. Raw accelerometer data was processed using the GGIR package, with non-imputation of missing data, exclusion of days with <16 hours of wear time and removal of algorithm-identified problematic data. Mann-Whitney U-tests and unpaired T-tests were used to compare 7 sleep-related features between HGG patients and healthy controls at baseline, with choice of statistical test based on shapiro-wilk derived normality. Secondly, to assess changes in sleep in HGG patients across treatment period, K-means clustering of 5 sleep parameters, available longitudinally, was conducted to explore sleep behaviours at baseline (n = 21) and during chemo-radiation.

RESULTS

HGG patients (n = 16) exhibited greater daytime inactivity than healthy controls (n = 32) (p < 0.0001, 2.2 vs 0.5 hrs) and more variation in their 24 hour activity rhythm from day to day (p < 0.0001, 0.12 vs 0.18). We identified 5 sleep features which allowed us to cluster patients’ sleep behaviour, and most (62.5%) of HGG patients have a poor sleep profile. This sleep profile was characterised by an average of 5.4 hours of night-time sleep, 2.1 hours of daytime inactivity and disturbed sleep quality. However, evaluation of HGG patient sleep cluster designation at baseline and during chemoradiation, showed HGG patients with data at both timepoints (n = 9) demonstrate stability or improvement in sleep profile.

CONCLUSION

Patients with HGG have objective evidence of poor sleep compared to healthy matched controls. Further work will explore changes in sleep over time.