bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid eruption of the Emeishan continental flood basalts: New paleomagnetic and geochronologic constraints
Authors: Xu Yingchao , Zheng Liandi , Yang Zhenyu , Tong Ya-Bo , Wang Bin , Yuan Wei , Jing Xianqing
Published: November 2021

The duration of the eruption of the Emeishan large igneous province is hotly debated. We conducted a magnetostratigraphic and geochronological study of the core area of the large igneous province in the Binchuan area of Yunnan Province, southwestern China, in order to constrain the duration of the eruption. The results of detailed thermal demagnetization experiments revealed two remanent magnetic components from the volcanic rocks of 11 composite sections. A low-temperature component separated below 300 °C is interpreted as a recent viscous remanence. Additionally, reliable characteristic remanent magnetizations were revealed above 400 °C, with unblocking temperatures up to 580−680 °C, which passed the fold test and record three magnetozones. Zircons from the felsic ignimbrites exposed in the final stage of the mafic volcanism are dated to 258.2 ± 0.7 Ma (n = 15; mean square of weighted deviates = 1.3) by sensitive high-resolution ion microprobe. Stratigraphic and magnetostratigraphic correlations of the Emeishan basalts in the Binchuan sections indicate that the eruption of the mafic rocks of the Emeishan large igneous province can be clearly divided into early (reverse polarity subzone), middle (normal polarity subzone), and late (reverse polarity subzone) stages, with a total duration of less than 1.7 m.y. (260.8−259.1 Ma). However, by combining this chronology with previously reported conodont biostratigraphic results from locations around the Emeishan large igneous province, and comparing the dominant normal-reverse polarity sequence in the Emeishan large igneous province with the geomagnetic polarity time scale, we obtain a much shorter duration of the main eruptive stage of <0.8 m.y. (260.4−259.6 Ma). About three quarters of the basalts of the Emeishan large igneous province record have a normal polarity and erupted within 0.4 m.y., while the other quarter, mainly distributed in the central zone, shows a reverse polarity and much shorter duration. Given the short duration of the eruption, gas volatiles would have been released into the atmosphere at high rates, which might provide a causal link between the rapid eruption and the end-Guadalupian mass extinction. Before the mantle plume eruption, localized eruptions probably occurred. After eruption of the mafic Emeishan flood basalts, an acid volcanic eruption occurred in the early Wuchiapingian, which was sporadically distributed in the Emeishan large igneous province.
Pathologically confirmed diffuse alveolar haemorrhage in lymphangioleiomyomatosis
Authors: Kobylianskii Jane , Hutchinson-Jaffe Adam , Cabanero Michael , Thenganatt John
Published: November 2021

A 40-year-old woman was referred to pulmonology after presenting with dyspnoea and self-limiting haemoptysis. Chest CT revealed diffuse ground glass opacities and small thin-walled cysts. Bronchoalveolar lavage cultures were negative and cytology revealed haemosiderin-laden macrophages. Transthoracic echocardiogram was normal. Connective tissue disease and vasculitis work-up were negative. Vascular endothelial growth factor-D level was indeterminate. Lung function was normal. She underwent video-assisted thoracoscopic lung biopsy. In addition to findings consistent with lymphangioleiomyomatosis, histopathological examination identified haemosiderosis without capillaritis, confirming a diagnosis of diffuse alveolar haemorrhage in the context of the associated clinical and radiographic features. Follow-up imaging after 5 months showed resolution of the diffuse ground glass opacities. Pharmacotherapy with sirolimus was not initiated due to absence of deterioration in pulmonary function. Diffuse alveolar haemorrhage in patients with lymphangioleiomyomatosis is a rare but important presentation. The few previously reported cases progressed to respiratory failure requiring mechanical ventilation.
Suspected acute rheumatic fever in a young man in England
Authors: Wilson Zak Michael , Craster Katie
Published: November 2021

A 24-year-old fit and well Caucasian man was referred to acute hospital via his General Practitioner with chest pain, palpitations, shortness of breath and an antecedent sore throat. Investigations revealed pericardial and pleural effusions, pericardial thickening on MRI, mild mitral regurgitation on echocardiogram and a raised Antistreptolysin O (ASO) titre.

He was treated as acute rheumatic fever (ARF) with a prolonged course of penicillin, supportive therapy with bisoprolol and colchicine with lansoprazole cover. The patient made a full recovery and subsequent cardiac MRI showed resolution of all changes.
Rare sacral extradural grade II ependymoma: a comprehensive review of literature
Authors: Fernández-de Thomas Ricardo J , Amaral-Nieves Natalie , De Jesus Orlando , Pastrana Emil A
Published: November 2021

Sacral spinal cord ependymoma is an uncommon pathology. Most of the reported cases are consistent with a myxopapillary ependymoma histopathologic subtype. Non-myxopapillary ependymomas rarely occur in the sacral region. Most lesions are intradural; however, rare extradural cases can occur. We present the case of a 46-year-old female patient diagnosed with a grade II sacral extradural ependymoma, emphasising the importance of an interdepartmental case approach for diagnosis and management. Even though grade II ependymomas are considered low grade, the potential for recurrence and metastatic disease has been reported. There are no treatment guidelines for these rare tumours besides gross total resection.
Prevalence of Alcohol Consumption in Emergency department presentations (PACE) in Queensland, Australia, using alcohol biomarkers ethanol and phosphatidylethanol: an observational study protocol
Authors: Vuong Kim A , Manzanero Silvia , Ungerer Jacobus P J , Mitchell Gary , McWhinney Brett , Vallmuur Kirsten , Warren Jacelle , McCreanor Victoria , Howell Tegwen , Pollard Clifford , Schuetz Michael , Zournazi Anna , Cameron Cate M
Published: November 2021

Introduction

Alcohol use in patients presenting to the emergency department (ED) is a significant problem in many countries. There is a need for valid and reliable surveillance of the prevalence of alcohol use in patients presenting to the ED, to provide a more complete picture of the risk factors and inform targeted public health interventions. This PACE study will use two biomarkers, blood ethanol and phosphatidylethanol (PEth), to determine the patterns, presence and level of alcohol use in patients presenting to an Australian ED.

Methods and analysis

This is an observational prevalence study involving the secondary use of routinely collected blood samples from patients presenting to the Royal Brisbane and Women’s Hospital (RBWH) Emergency and Trauma Centre (ETC). Samples will be tested for acute and medium-term alcohol intake using the two biomarkers blood ethanol and PEth respectively, over one collection period of 10–12 days. Descriptive statistics such as frequencies, percentages, means, SD, medians and IQRs, will be used to describe the prevalence, pattern and distribution of acute and medium-term alcohol intake in the study sample. The correlation between acute and medium-term alcohol intake levels will also be examined.

Ethics and dissemination

This study has been approved by the RBWH Human Research Ethics Committee (reference, LNR/2019/QRBW/56859). Findings will be disseminated to key stakeholders such as RBWH ETC, Australasian College for Emergency Medicine, Royal Australasian College of Surgeons, Statewide Clinical Networks, and used to inform clinicians and hospital services. Findings will be submitted for publication in peer-reviewed journals and presentation at appropriate conferences.
Psychometric properties of the traditional Chinese version of the youth attitude to noise scale: a cross-sectional study in a large representative sample
Authors: Chen Ningjing , Fong Daniel Yee Tak , Li Sha , Wong Janet Yuen Ha
Published: November 2021

Objectives

This study aimed to examine the psychometric properties of the traditional Chinese version of the Youth Attitude to Noise Scale (YANS) in a large representative sample.

Design

Cross-sectional study.

Setting

15 secondary schools in Hong Kong, China.

Participants

2842 adolescents aged 12–20 years participated in this study between April and July 2016.

Methods

The standard forward–backward validation procedures were followed to obtain the traditional Chinese version of the YANS. Prior to the formal investigation, the YANS was evaluated by cognitive debriefing. The sample was randomly divided into two halves for exploratory factor analyses (EFAs) and confirmatory factor analyses (CFAs), respectively. The number of factors was determined by comparison data approach using EFAs, and the factor structure was confirmed by CFAs using the one-factor, four-factor and bifactor models. The scale’s internal reliability, dimensionality and measurement invariance across gender and age groups were also examined.

Results

EFAs (n=1338) showed that four factors were extracted, and CFAs (n=1337) demonstrated the bifactor model fitted better to the sample than the other models. Additionally, the traditional Chinese version of the YANS showed high reliability (ω=0.84), a general factor, scale multidimensionality, and gender and age invariance.

Conclusions

The findings of the current study indicate that the traditional Chinese version of the YANS is a feasible instrument to assess attitude to noise in Chinese adolescents, regardless of their gender and age. Given the presence of a general factor, the YANS is not merely multidimensional, and whether to use the total or subscale scores is recommended to rely on research objectives.
Infertility-related distress and clinical targets for psychotherapy: a qualitative study
Authors: Dube Loveness , Nkosi-Mafutha Nokuthula , Balsom Ashley A , Gordon Jennifer L
Published: November 2021

Objectives

An estimated 30%–40% of women attending infertility tertiary care facilities experience clinically significant depression and anxiety. However, current psychological interventions for infertility are only modestly effective in this population. In this study, we aimed to identify the specific psychological components of infertility-related distress to assist in the development of a more targeted and effective therapeutic intervention. To our knowledge, this study is the first of its kind to include the views and opinions of mental health professionals who specialise in the field of infertility and the first to explore therapies currently used by mental health professionals.

Design

A qualitative approach using semistructured individual interviews and focus group interviews with women who have experience with infertility and also mental health professionals specialising in the field of infertility. Thematic analysis was used to identify patterns and themes emerging from the data.

Participants

Twenty-one women (aged 25–41 years) struggling to conceive for ≥12 months and 14 mental health professionals participated in semistructured interviews about the psychological challenges related to infertility.

Results

Five themes, each divided into subthemes, emerged from the data and these were developed into a model of infertility-related distress. These five themes are: (1) anxiety, (2) mood disturbance, (3) threat to self-esteem, identity and purpose, (4) deterioration of the couple and (5) weakened support network. In addition, therapeutic techniques used by mental health professionals were identified.

Conclusions

The results of this study suggest specific clinical targets that future interventions treating infertility-related distress should address.
7 Analytical comparison of a PD-L1 22C3 antibody laboratory-developed test protocol on the Benchmark XT and PD-L1 IHC 22C3 pharmDx: pan-tumor and triple-negative breast cancer samples
Authors: Vainer Gilad , Zatara Ghadeer , Huang Lingkang , Nuti Shanthy , Nuti Shanthy , Emancipator Kenneth
Published: November 2021

Background

PD-L1 IHC 22C3 pharmDx is an FDA-approved companion diagnostic for pembrolizumab across multiple tumor types designed for use on the Autostainer Link 48 (AL48). Many pathology laboratories do not have access to the AL48 and therefore do not use PD-L1 IHC 22C3 pharmDx but instead assess PD-L1 using laboratory-developed tests (LDTs) on the Ventana BenchMark platform. We compared our PD-L1 22C3 antibody-based LDT on the BenchMark XT platform with PD-L1 IHC 22C3 pharmDx using cervical cancer (CC), head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma (UC), esophageal SCC (ESCC), and triple-negative breast cancer (TNBC) samples.

Methods

Tumor specimens from patients with CC, HNSCC, UC, ESCC, and TNBC were stained with the 22C3 antibody, scored using the LDT on the BenchMark XT as previously described,1 and compared with PD-L1 IHC 22C3 pharmDx scored by a trained pathologist, who measured PD-L1 with the use of combined positive score (CPS) and standard cutoffs (HNSCC and CC, ≥1; UC, ESCC, and TNBC, ≥10). Agreement in PD-L1 CPS as determined using the LDT and the PD-L1 IHC 22C3 pharmDx was evaluated.

Results

423 samples with CC (n = 77), HNSCC (n = 126), UC (n = 121), ESCC (n = 80), and TNBC (n = 19) were evaluated in this study. The pan-tumor (CC, HNSCC, UC, and ESCC) intraclass correlation coefficient (ICC) of PD-L1 CPS as a continuous variable was 0.95 (95% CI, 0.94%–0.96%); Spearman correlations were 0.95. ICC (95% CI) was 0.92 (0.88–0.95) for CC, 0.97 (0.96–0.98) for HNSCC, 0.95 (0.92–0.97) for UC, and 0.92 (0.88–0.95) for ESCC; Spearman correlation was 0.93, 0.96, 0.92, and 0.89, respectively. The overall percentage agreement at the respective CPS cutoff was 96% (CC), 96% (HNSCC), 96% (UC), and 90% (ESCC). Staining patterns by 22C3 LDT and PD-L1 IHC 22C3 pharmDx were also very similar in our TNBC pilot study; however, correlation was not calculated because of the small sample numbers.

Conclusions

The PD-L1 22C3 antibody-based LDT on the BenchMark XT demonstrated high concordance with PD-L1 IHC 22C3 pharmDx. These findings suggest the comparability of PD-L1 IHC 22C3 pharmDx with an LDT based on the 22C3 antibody across several tumor types. Further validation for TNBC is ongoing to confirm the data from the pilot run.

Reference

Neuman T, et al. J Thorac Oncol. 2016;11:1863–1868.
8 Multiparameter characterization of CAR T cells
Authors: Wang Xueting , Pitzka Christina , Rheindorf Daniela , Mockel-Tenbrinck Nadine , Holzer Tatjana , Richter Anne , Cathomen Toni , Evaristo Cesar
Published: November 2021

Background

Adoptive cell transfer of chimeric antigen receptor (CAR) modified T cells has demonstrated great therapeutic success against certain hematological malignancies. However, a substantial number of patients experienced relapse at some point after treatment with the underlying mechanisms not fully understood. Emerging data suggest that the undesired clinical outcome is related to different aspects, which include: the tumor heterogeneity, the tumor microenvironment, as well as intrinsic characteristics of the CAR T cells. In this work, we aimed to understand the diversity of CAR T cells generated from different donors, using multiparameter in vitro characterization.

Methods

Leukapheresis from healthy donors were collected to generate CAR T cells using the GMP-compliant CliniMACS Prodigy® platform, enabling an automated and closed engineering of CAR T cells in a highly reproducible manner. We performed an in-depth characterization of the resulting CAR T cells by exploring differences in the immunophenotype, cell fitness and effector function of the freshly prepared as compared to frozen CAR T cell samples. Specifically, we designed several flow cytometry panels for the extensive characterization of immunophenotypes of interest such as: proliferative capacity, differentiation, activation and exhaustion. Cell fitness status was determined by the rate at which cells undergo apoptosis following stress. Finally, effector function was determined by the ability of the activated CAR T cells to secrete proinflammatory cytokines including IFN-g, TNF-a and IL-2. The associations between these different parameters were analyzed using comprehensive statistical approaches.

Results

With our established workflow, over 20 healthy-donor derived CAR T cells were generated and characterized. We have observed donor-dependent variations and responses for most of the explored parameters. In general, the freezing and thawing process negatively affected cell fitness and effector function of the CAR T cells and resulted in altered immunophenotypes. Additionally, correlations between certain immunophenotypes and cell fitness/effector function were identified.

Conclusions

Collectively, we established a workflow for multiparameter characterization of CAR T cells and assessed the intrinsic variability of CAR T cells for both research and clinical application.
29 Elevated Flt3L predicts long-term survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms
Authors: Detjen Katharina , Otto Raik , Giesecke Yvonne , Geisler Lukas , Riemer Pamela , Jann Henning , Grötzinger Carsten , Sers Christine , Luedde Tom , Leser Ulf , Wiedenmann Bertram , Sigal Michael , Tacke Frank , Roderburg Christoph , Hammerich Linda
Published: November 2021

Background

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a rare and heterogeneous family of tumors arising from the disseminated neuroendocrine system of the gastrointestinal tract and pancreas. Clinical management of high-grade GEP-NEN is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable stratification of patients with otherwise comparable tumor features.

Methods

We used RNAseq data from human foregut-derived pancreatic and gastric GEP-NEN to evaluate Flt3L gene expression in tumor tissue. The data set (n=54) represented the full range of NEN grades and differentiation, and expression levels were compared to healthy control tissue as well. We also analyzed circulating Flt3L levels in serum samples of a separate cohort of G2/G3 GEP-NEN (n=59) an healthy controls (n=4). The study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.

Results

We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted disease related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients´ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.

Conclusions

Our results suggest Flt3L as a surrogate marker of an inflammatory tumor microenvironment. Therefore, we propose Flt3L as a prognostic biomarker for high grade GEP-NEN. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, may hold the promise to guide patient stratification and tailor treatment decisions and should be further evaluated, especially in the context of immunotherapies.

Ethics Approval

The study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.
50 In-situ visualization and measurement of tumor-infiltrating lymphocytes (TILs) on intact FFPE renal cell carcinoma (RCC) tissue using the spatial molecular imager (SMI)
Authors: Newell Evan , Kim Youngmi , Ryu Heeju , Li Shamin , Leon Michael , Kim Sean , Gregory Mark , Danaher Patrick , Beechem Joseph
Published: November 2021

Background

Although cancer immunotherapies can effectively restore T cell-mediated immunity leading to sustained clinical responses, these responses are unpredictable partly due to highly heterogeneous phenotypes of tumor-infiltrating lymphocytes (TILs) between patients. Thus, understanding such TILs and their roles in the context of tumor microenvironments (TME) may lead to developing better immunotherapy solutions. The spatial molecular imager (SMI) is a novel spatial transcriptomics platform that allows spatially resolved high-dimensional cellular phenotyping for comprehensive TIL profiling. SMI uses fluorescent molecular barcodes to enable in-situ measurement of biological targets on an intact tissue sample. Here, we characterize comprehensive TIL phenotypes and visualize landscape of TILs directly on intact formalin-fixed paraffin-embedded (FFPE) tissues using a 1000+-plex RNA panel.

Methods

To build multi-omics TIL profiling data sets for renal cell carcinoma (RCC) tissues, we employed scRNA-seq, mass cytometry (CyTOF) and SMI. Peripheral blood mononuclear cells and dissociated cells from matched RCC tumor and adjacent normal tissues were analyzed by CyTOF and single-cell sequencing. Then, SMI profiling of matching FFPE tissues was used to visualize TILs in the context of the TME and to understand relationships between high-dimensional cellular heterogeneity and the spatial organization of cells within a tumor tissue.

Results

CyTOF and scRNA-seq analysis of dissociated cells was used to determine the gene expression profiles of numerous cellular subsets. TCR sequencing was also used to assess the extent of clonal expansion and clonotypic relationships between blood and tumor. Consistent with our previous reports, T cell populations could be segregated based on markers associated with chronic T cell receptor signaling and many T cells with an exhausted phenotype were clonally expanded in the tumor but not the blood. In contrast, T cell clonotypes with bystander phenotypes in the tumor were readily detected as expanded clones in the blood, supporting notion that not all tumor-infiltrating T cells are specific for tumor antigens. SMI analysis of matched tumor tissue was used to accurately quantify the densities and to determine the spatial organization of all T cell subsets. In addition, computational methods were used to describe distinct cellular niches within tumors with accurately defined cellular compositions.

Conclusions

High dimensional cellular profiling highlights the abundance of bystander T cell infiltration of RCC tumors. Comprehensive spatial profiling by SMI provides spatial context to the highly diverse immune cell composition of tumor infiltrates.

Ethics Approval

Fully anonymous human material was obtained from Northwest Biotrust and given IRB designation of non-human subjects research.
75 Comprehensive profiling of the tumor-immune microenvironment using an augmented transcriptome
Authors: Levy Eric , Milani Pamela , Navarro Fabio , Bartha Gabor , Abbott Charles , Jacob Jose , McClory Rena , Li Robin , West John , Lyle John , Boyle Sean , Chen Richard
Published: November 2021

Background

Comprehensive profiling of both the tumor and tumor microenvironment (TME) can help further our understanding of tumor progression and response to treatment. Many immune features can be extracted from transcriptomic data, including characterization of the immune infiltrate and profiling the diversity of immune receptors. To address this, we have developed multiple TME profiling features as part of the ImmunoID NeXT Platform®, an augmented, immuno-oncology-optimized exome/transcriptome platform designed to provide comprehensive information regarding the tumor and TME from a single FFPE tumor sample. These features including quantification of immune cell infiltration and profiling of the T-cell receptor (TCR) and B-cell receptor (BCR).

Methods

To develop our immune infiltrate quantification method, we profiled the transcriptomes of eight purified immune cell types using ImmunoID NeXT™ to develop platform-specific gene sets, and compared our transcriptome quantification to immune cell quantification with IHC. For TCR and BCR methods, we analyzed the reproducibility of clone results, and compared top clones to standalone TCR and BCR sequencing approaches. In addition, we characterized the immune content of over 800 tumor samples across 14 cancer types. Finally, we analyzed the immune features in a cohort of melanoma patients who underwent PD-1 blockade.

Results

We observe significant concordances between cell fractions by IHC and ImmunoID NeXT’s transcriptome-based scores in tumor FFPE samples for B cells, CD8+ T cells, and macrophages (R2>0.82, R2>0.75, and R2>0.52, respectively). For TCR and BCR methods, abundances of clones shared between subsequent curls of a tumor FFPE sample have very high concordances (R2>0.89, R2>0.92, and R2>0.76 for TRB, IgG, and IgA, respectively). Compared to the standalone approaches, we identify 100% of the top 500 TRB clones and 95% of the top 500 IgG clones, with highly concordant abundances (R2>0.94 and R2>0.82 for TRB and IgG, respectively) in a PBMC sample. We identify biologically-relevant immune signatures across tumor types by characterizing the immune features across over 800 tumor samples. Finally, in a melanoma cohort, TRB clonality and CD8+ T cell scores are significantly different in responders to checkpoint inhibition.

Conclusions

RNA sequencing can be used as a scalable approach to profile the immune composition in tumors. Such analysis can add to our understanding of the tumor-immune interaction, including studies of response to immunotherapy. We show that immune infiltrate quantification and TCR and BCR profiling – all part of the ImmunoID NeXT Platform – are able to accurately and effectively evaluate the composition and diversity of tumor-infiltrating immune cells.
92 Single cell and spatial multiplex profiling of immune cell markers in FFPE tumor tissues using the novel RNAscope™ HiPlex v2 in situ hybridization assay
Authors: Basak Sayantani , Dikshit Anushka , Yu Ming , Ji HaYeun , Chang Ching-Wei , Zhang Bingqing
Published: November 2021

Background

The tumor microenvironment (TME) is highly complex, comprised of tumor cells, immune cells, stromal cells, and extracellular matrix. Understanding spatial interactions between various cell types and their activation states in the TME is crucial for implementing successful immunotherapy strategies against various types of cancer. This study demonstrates a highly sensitive and specific multiplexed technique, the RNAscope HiPlex v2 in situ hybridization (ISH) assay for spatial and transcriptomic profiling of target genes to assess immune regulation in human lung, breast, cervical and ovarian FFPE tumor tissues.

Methods

We have expanded our current RNAscope HiPlex assay capability of iteratively multiplexing up to 12 targets in fixed and fresh frozen samples to include formalin fixed paraffin embedded (FFPE) tissues. The novel FFPE reagent effectively reduces background autofluorescence, improving the signal to noise ratio. We have leveraged this technology to investigate spatial expression of 12 oncology and immuno-oncology target genes, including tumor markers, immune checkpoint markers, immunosuppression markers, immune cell markers and secreted chemokine RNA expression profile within the TME. The targets were simultaneously registered using HiPlex image registration software v2 that enables background subtraction.

Results

We visualized T cell infiltration and identified T cell subsets within tumors using CD3and CD8 expression and activated T cells by IFNG expression. We further identified subsets of pro- and anti-inflammatory macrophages by CD68 and CD163 expression as well effector cells which secrete chemokines and cytokine. We also detected the hypoxia markers HIF1A and VEGF to elucidate the immunosuppressive state of tumor cells. Preliminary analysis and quantification of the HIF1A expression using HALO® image analysis software showed higher copy numbers in the lung tumor as compared to the other tumors, demonstrating the sensitivity of the assay through differential expression. We additionally showed the differential expression of immune checkpoint markers PDCD1, and CD274 within the TME.

Conclusions

Using a highly sensitive multiplexed RNAscope HiPlex v2 ISH assay, we have demonstrated the capability of this technique to spatially resolve 12 targets in four different tumor types. The FFPE reagent efficiently quenched background autofluorescence in the tissues and identified immune cell signatures within the TME. Quantification of immunosuppressive markers further depicted a differential expression among various tumors. This technology is highly beneficial for investigating complex and spatial tumor-stroma interactions in basic science and translational research. The assay can also provide valuable understanding of the biological crosstalk among various cell types in complex and heterogeneous tissues.
306 Decr2 regulates tumor cell ferroptosis and is required for immunotherapy efficacy
Authors: Li Shuyin , Gajewski Thomas , Li Shuyin , Higgs Emily
Published: November 2021

Background

Checkpoint blockade therapies have transformed the landscape of cancer care. Durable clinical responses have been observed in a subset of patients. However, many patients do not respond, and understanding the mechanisms underlying tumor resistance to checkpoint blockade drugs could potentially expand clinical benefit. We therefore performed an unbiased CRISPR library screen to identify novel gene alterations sufficient to mediate resistance to T cell-mediated killing.

Methods

B16.SIY cells were transduced with a genome-scale gRNA lentivirus to generate loss of function mutants. In vitro-primed CD8+ T cells isolated from 2C/Rag2–/– TCR transgenic mice specific for the SIY antigen were co-cultured with transduced B16.SIY tumor cells. Resistant cells were collected and targeted genes were identified by sequencing the gRNAs. The gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase, was identified. To investigate the role of Decr2 in tumor growth and immune responses in vivo, the Decr2 knock-down or Decr2 overexpressed tumors were transplanted into C57BL/6 mice for studies of anti-PD-L1 efficacy and immune response analysis. Based on a hypothesized role in ferroptosis, RNA-seq was performed and lipid reactive oxygen species were quantified.

Results

Decr2 mutants were relatively resistant to CD8+ T cell killing in vitro. In vivo, Decr2 knock-down tumors showed almost complete loss of anti-PD-L1 efficacy, without affecting early T cell priming or immune cell infiltration. However, tumor-infiltrating T cells failed to expand following anti-PD-L1 therapy in Decr2 knock-down tumors. RNA-seq analysis revealed upregulation of ferroptosis-related genes in Decr2-deficient tumor cells, and these tumor cells were relatively resistant to ferroptosis-inducers in vitro. Decr2 knock-down cells also showed defective induction of lipid ROS in response to CD8+ T cells in vitro, or when analyzed following anti-PD-L1 treatment ex vivo. Analysis of tumor RNA-seq data from human melanoma patients treated with checkpoint blockade revealed decreased Decr2 levels in non-responding patients.

Conclusions

Our results identify tumor cell-expressed Decr2 as novel regulator of ferroptosis and implicate the process of ferroptosis as a major mechanism of immune-mediated tumor cell killing in vivo. Pharmacologic strategies to facilitate tumor cell ferroptosis could have therapeutic utility.
Polar bear (Ursus maritimus) use of the Cape Bathurst polynya and flaw lead
Authors: Henderson Erin M. , Derocher Andrew E.
Published: November 2021

The Cape Bathurst polynya and flaw lead (CBP) are major, predictable habitat features with ≤15% ice cover in an otherwise ice-covered Beaufort Sea, and thought to provide hunting opportunities for polar bears (Ursus maritimus Phipps, 1774). We assessed 78 adult (female; with and without cubs) and subadult (male and female) polar bears’ use of the CBP from October to June 2007–2014. The CBP was up to 725 km wide in autumn, ice-covered in winter, and <306 km wide in spring. Seventy-nine percent (n = 62) of the bears used the CBP (≥1 location <2.4 km, or one 4 h step length, from the CBP). Use was higher for solitary adult females and subadult males, which travelled faster with low turning angles along wider sections than females with offspring and subadult females. Bears were closest to the CBP during the spring hyperphagia season. Although a wider CBP did not prevent crossing, bears primarily crossed from the coast towards pack ice at locations 53% narrower than areas not crossed. Bears might avoid crossing when it would require a long-distance swim. The CBP affects polar bear ecology by providing hunting habitat and a corridor that could increase prey encounters but may affect movement.
Integrating acceleration signal processing and image segmentation for condition assessment of asphalt roads
Authors: Sprague William , Rezazadeh Azar Ehsan
Published: November 2021

A proactive road maintenance system enables agencies to better allocate resources to manage their road networks. An inventory of the roads’ conditions is an essential component of such a maintenance program. This research project proposes a hybrid system to assess the condition of the asphalt roads, which uses a dashboard-mounted smartphone to simultaneously collect the acceleration response of a vehicle and the video footage of the road surface while driving. The system analyzes acceleration data for anomalous events that could indicate a defect. Then the computer vision module of the system applies semantic segmentation in the corresponding frame to the detected anomaly to identify defects. This system demonstrated 84% recall and 88% precision rates in detection of anomalies in two road segments. Despite these promising results, the system can only detect the defects that are passed over and it could miss some defects with small acceleration responses, such as traverse cracks.
Rapid advancement of spring migration and en route adjustment of migration timing in response to weather during fall migration in Vaux’s Swifts (Chaetura vauxi)
Authors: Prytula E.D. , McKellar A.E. , Schwitters L. , Reudink M.W.
Published: November 2021

Climate change has generated earlier springs, later falls, and different weather patterns. These changes may prove challenging to migratory species if they are unable to adjust their migratory timing. We analyzed changes in migratory timing of Vaux’s Swifts (Chaetura vauxi (J.K. Townsend, 1839)) by examining first arrivals (date the first swift arrived) and peak roost occupancy (date the maximum number of swifts were observed) at migratory roosts in both spring and fall from the citizen science organization Vaux’s Happening. First arrivals and peak occupancy date in Vaux’s Swifts advanced over time from 2008 to 2017, and the timing of first arrivals advanced with an increase in local wind gust speeds. In contrast, fall migration timing did not change over time from 2008 to 2016, but higher temperatures were associated with later fall migration (both first arrival and peak roost occupancy) and higher local wind speeds were associated with earlier fall migration (peak roost occupancy only). Like many other migratory birds, Vaux’s Swifts may be tracking earlier spring phenology, and may also be altering their migratory timing in response to local weather conditions, especially during fall migration. Our results indicate that swifts may be able to adjust their migration to a changing climate, at least in the short term.
Shell evolution for neutron-rich 46–54Ar isotopes in the full and truncated fp neutron model spaces
Authors: Bahr Hussam A. , Alzubadi Ali A.
Published: November 2021

The shell evolution of even–even drip line argon isotopes [Formula: see text] has been investigated via the shell model calculations using SDPF-U and SDPF-NR two-body effective interactions in two different shell model spaces [Formula: see text] and [Formula: see text]. In this work, the energy of first [Formula: see text], reduced transition probability [Formula: see text], excitation energy levels as well as how the proton shells evolve with [Formula: see text] have been studied. Excellent agreements were obtained for the first [Formula: see text] level along the investigated isotopes within [Formula: see text] and [Formula: see text] model spaces.
Agile Support Vector Machine for Energy-efficient Resource Allocation in IoT-oriented Cloud using PSO
Authors: Junaid Muhammad , Sohail Adnan , Turjman Fadi Al , Ali Rashid
Published: November 2021

Over the years cloud computing has seen significant evolution in terms of improvement in infrastructure and resource provisioning. However the continuous emergence of new applications such as the Internet of Things (IoTs) with thousands of users put a significant load on cloud infrastructure. Load balancing of resource allocation in cloud-oriented IoT is a critical factor that has a significant impact on the smooth operation of cloud services and customer satisfaction. Several load balancing strategies for cloud environment have been proposed in the past. However the existing approaches mostly consider only a few parameters and ignore many critical factors having a pivotal role in load balancing leading to less optimized resource allocation. Load balancing is a challenging problem and therefore the research community has recently focused towards employing machine learning-based metaheuristic approaches for load balancing in the cloud. In this paper we propose a metaheuristics-based scheme
Data Format Classification using Support Vector Machine (DFC-SVM),
to deal with the load balancing problem. The proposed scheme aims to reduce the online load balancing complexity by offline-based pre-classification of raw-data from diverse sources (such as IoT) into different formats e.g. text images media etc. SVM is utilized to classify “n” types of data formats featuring audio video text digital images and maps etc. A one-to-many classification approach has been developed so that data formats from the cloud are initially classified into their respective classes and assigned to virtual machines through the proposed modified version of
Particle Swarm Optimization (PSO)
which schedules the data of a particular class efficiently. The experimental results compared with the baselines have shown a significant improvement in the performance of the proposed approach. Overall an average of 94% classification accuracy is achieved along with 11.82% less energy 16% less response time and 16.08% fewer SLA violations are observed.
STEMUR: An Automated Word Conflation Algorithm for the Urdu Language
Authors: Fatima Tayyaba , Islam Raees Ul , Anwar Muhammad Waqas , Jamal M. Hasan , Chaudhry M. Tayyab , Gillani Zeeshan
Published: November 2021

Stemming is a common word conflation method that perceives stems embedded in the words and decreases them to their stem (root) by conflating all the morphologically related terms into a single term, without doing a complete morphological analysis. This article presents STEMUR, an enhanced stemming algorithm for automatic word conflation for Urdu language. In addition to handling words with prefixes and suffixes, STEMUR also handles words with infixes. Rather than using a totally unsupervised approach, we utilized the linguistic knowledge to develop a collection of patterns for Urdu infixes to enhance the accuracy of the stems and affixes acquired during the training process. Additionally, STEMUR also handles English loan words and can handle words with more than one affix. STEMUR is compared with four existing Urdu stemmers including Assas-Band and the template-based stemmer that are also implemented in this study. Results are processed on two corpora containing 89,437 and 30,907 words separately. Results show clear improvements regarding strength and accuracy of STEMUR. The use of maximum possible infix rules boosted our stemmer's accuracy up to 93.1% and helped us achieve a precision of 98.9%.
Revisiting Behavioral Integrity: Progress and New Directions After 20 Years
Authors: Simons Tony , Leroy Hannes , Nishii Lisa
Published: November 2021

Behavioral integrity (BI) describes the extent to which an observer believes that an actor's words tend to align with their actions. It considers whether the actor is seen as keeping promises and enacting the same values they espouse. Although the construct of BI was introduced in 1999 and developed more fully in 2002, it builds on the work of earlier scholars that discussed related notions of hypocrisy, credibility, and gaps between espousal and enactment. Since the 2002 paper, a growing literature has established the BI construct, largely but not exclusively in the leadership realm, as a critical antecedent to positive attitudes such as trust and commitment, positive behaviors such as turnover and performance, and as a moderator of the effectiveness of leadership initiatives. BI is by definition subjectively assessed, and perceptions of BI are susceptible to various forms of perceptual biases. A variety of factors appear to affect whether observers interpret a particular word-action alignment or gap as an indication of the actor's high or low BI. In this article, we examine and synthesize this literature and suggest directions for future research. We discuss the early history of BI research and then examine contemporary research at the individual, group, and organizational levels of analysis. We assess what we have learned and what methodological challenges and theoretical questions remain to be addressed. We hope in this way to stimulate further research on this consequential construct.
Efficacy and Prognostic Factors of Androgen Deprivation Therapy Combined with Radiation Therapy for Prostate Cancer
Authors: Zeng Siping , Guan Gangyun , Qin Qiuwei , Xie Huadong , Meng Yongyan , Zhao Qiyue
Published: November 2021

Objective. To analyze the efficacy of androgen deprivation therapy (ADT) combined with radiation therapy (also known as radiotherapy) for prostate cancer. Methods. The clinical data of 94 prostate cancer patients treated in the Oncology Department of Xiangzhou People’s Hospital from January 2017 to January 2018 were retrospectively analyzed, and the patients were divided into the combined group and the reference group according to their admission order, with 47 cases each. The patients in the reference group only received the radiotherapy, and on this basis, those in the combined group accepted ADT, so as to evaluate the efficacy of different treatment methods by comparing the patients’ serum total prostate-specific antigen (T-PSA), vascular endothelial growth factor (VEGF), and other indicators and analyze the relevant factors affecting patients’ prognosis by Cox single-factor and multi-factor regression models. Results. Compared with the reference group after treatment, the patients in the combined group obtained significantly lower T-PSA and VEGF levels (

P
<
0.001

), significantly higher objective remission rate and disease control rate (

P
<
0.05

), and remarkably longer modified progression-free survival (mPFS) and overall survival (OS) (

P
<
0.001

), and after the multi-factor research, it was found that the Gleason score of 8–10, positive lymphatic metastasis, and single radiotherapy were the factors affecting the clinical prognosis of prostate cancer. Conclusion. Combining ADT with radiotherapy ensures a better survival benefit for prostate cancer patients and has a fairly well efficacy. Further study will be conducive to establishing a better solution for such patients.
Comparison of China Reference with Different National and International References: The Prevalence of High Blood Pressure in 695,302 Children and Adolescents in a Metropolis of Yangtze River Delta, China
Authors: Zhang Min , Zhang Hai-Tao , Zha Ri-Sheng , Gui Guo-Ping , Han Di , Hu Jia , Yang Hai-bing , Shen Hui
Published: November 2021

Objectives. This study aimed to compare performances of China reference and different national references on high blood pressure (HBP). Methods. A cross-sectional study including 695,302 children and adolescents aged 7 to 17 years in Suzhou, China, was conducted to determine the prevalence of HBP based on U.S., international, Europe, and China references in 2016. Results. Different percentiles of height and blood pressure were found among four references. Referring to U.S. reference, the prevalence of HBP was the highest with 26.0%, followed by International reference with 20.0%, Europe reference with 19.5%, and China reference with 19.2%. McNemar tests indicated statistically significant differences between HBP prevalence comparing China reference with the other 3 references (

P
<
0.001

). The area under the curve was 0.947, 0.851, and 0.949 for U.S., international, and Europe reference, respectively. U.S. reference showed the highest sensitivity (98.2%), but the lowest specificity (91.2%), and Europe reference showed the highest kappa value (0.893). Conclusions. The prevalence of HBP varied among these four references, and the appropriate choice of reference would be important to recognize high-risk children and judge the trends of HBP prevalence in the targeted population.
Comparison of Canal Transportation and Centering Ability of One-G, EdgeGlidePath, and Neolix: A MicroComputed Tomography Study of Curved Root Canals
Authors: Shojaeian Shiva , Mortezapour Niloofar , Soltaninejad Fatemeh , Zargar Nazanin , Zandi Babak , Shantiaee Yazdan , Bidaki Amin
Published: November 2021

Aims. A glide path is created prior to root canal instrumentation by nickel-titanium (NiTi) rotary files to increase the efficiency and safety of cleaning and shaping. This study aimed to assess root canal transportation in use of different glide path files in curved canals. Materials and Methods. 30 sound mesiobuccal root canals of mandibular molars with 20° to 40° curvature were selected and randomly assigned to 3 groups of EdgeGlidePath (EGP, EdgeEndo), One-G (Micro-Mega), and Neolix (Neoniti). The specimens were scanned before and after glide path creation by microcomputed tomography (micro-CT). The pre- and postoperative micro-CT scans were superimposed, and the degree of canal transportation and centering ratio were measured at 1, 3, 5, and 7 mm distances from the apical foramen. Statistical Analysis. The data were analyzed by two-way and one-way ANOVA. Results. The effects of distance from the apical foramen and instrument type and the interaction effect of the two were not significant on the centering ability of the files or canal transportation. Conclusion. EdgeGlidePath, One-G, and Neolix files fabricated from the conventional NiTi alloy or heat-treated M-Wire alloy showed similar performance regarding centering ability and canal transportation in glide path preparation in curved canals.