bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models
Authors: Savel Hélène , Barbier Sandrine , Proust-Lima Cécile , Rondeau Virginie , Thiébaut Rodolphe , Meyer-Losic Florence , Richert Laura
Published: April 2023

In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models.

Mixed and joint models were compared in a real MCT (N = 225 mice) to estimate the effect of a chemotherapy and a simulation study. Mixed models assume that death is predictable by observed tumor volumes (data missing at random, MAR) while the joint models assume that death depends on nonobserved tumor volumes (data missing not at random, MNAR).

In the real dataset, of 103 deaths, 97 mice were sacrificed when reaching a predetermined tumor size (MAR data). Joint and mixed model estimates of tumor growth slopes differed significantly [0.24 (0.13;0.36)log(mm3)/week for mixed model vs. −0.02 [−0.16;0.11] for joint model]. By disrupting the MAR process of mice deaths (inducing MNAR process), the estimate of the joint model was 0.24 [0.04;0.45], close to mixed model estimation for the original dataset. The simulation results confirmed the bias in the slope estimate from the joint model.

Using a MCT example, we show that joint model can provide biased estimates under MAR mechanisms of dropout. We thus recommend to carefully choose the statistical model according to nature of mice deaths.
Significance:
This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models.
Data from A PRRX1 Signature Identifies TIM-3 and VISTA as Potential Immune Checkpoint Targets in a Subgroup of Microsatellite Stable Colorectal Cancer Liver Metastases
Authors: Nygaard Vigdis , Ree Anne Hansen , Dagenborg Vegar Johansen , Børresen-Dale Anne-Lise , Edwin Bjørn , Fretland Åsmund Avdem , Grzyb Krzysztof , Haugen Mads H. , Mælandsmo Gunhild M. , Flatmark Kjersti
Published: April 2023

Disease recurrence and drug resistance are major challenges in the clinical management of patients with colorectal cancer liver metastases (CLM), and because tumors are generally microsatellite stable (MSS), responses to immune therapies are poor. The mesenchymal phenotype is overrepresented in treatment-resistant cancers and is associated with an immunosuppressed microenvironment. The aim of this work was to molecularly identify and characterize a mesenchymal subgroup of MSS CLM to identify novel therapeutic approaches. We here generated a mesenchymal gene expression signature by analysis of resection specimens from 38 patients with CLM using ranked expression level of the epithelial-to-mesenchymal transition–related transcription factor PRRX1. Downstream pathway analysis based on the resulting gene signature was performed and independent, publicly available datasets were used to validate the findings. A subgroup comprising 16% of the analyzed CLM samples were classified as mesenchymal, or belonging to the PRRX1high group. Analysis of the PRRX1 signature genes revealed a distinct immunosuppressive phenotype with high expression of immune checkpoints HAVCR2/TIM-3 and VISTA, in addition to the M2 macrophage marker CD163. The findings were convincingly validated in datasets from three external CLM cohorts. Upregulation of immune checkpoints HAVCR2/TIM-3 and VISTA in the PRRX1high subgroup is a novel finding, and suggests immune evasion beyond the PD-1/PD-L1 axis, which may contribute to poor response to PD-1/PD-L1–directed immune therapy in MSS colorectal cancer. Importantly, these checkpoints represent potential novel opportunities for immune-based therapy approaches in a subset of MSS CLM.
Significance:
CLM is an important cause of colorectal cancer mortality where the majority of patients have yet to benefit from immunotherapies. In this study of gene expression profiling analyses, we uncovered novel immune checkpoint targets in a subgroup of patients with MSS CLMs harboring a mesenchymal phenotype.
Data from Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis
Authors: Benwell Christopher J. , Johnson Robert T. , Taylor James A.G.E. , Price Christopher A. , Robinson Stephen D.
Published: April 2023

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known coreceptors for VEGFRs, core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathologic angiogenesis. Here we demonstrate, using NRP1ECKO, NRP2ECKO, and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumor development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that codepleting NRP1 and NRP2 in mouse-microvascular endothelial cells stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumor angiogenesis.
Significance:
The findings presented in this study demonstrate that tumor angiogenesis and growth can be arrested completely by cotargeting endothelial NRP1 and NRP2. We provide new insight into the mechanisms of action regulating NRP-dependent tumor angiogenesis and signpost a novel approach to halt tumor progression.
Data from Characterization of Novel Derivatives of MBQ-167, an Inhibitor of the GTP-binding Proteins Rac/Cdc42
Authors: Medina Julia I. , Cruz-Collazo Ailed , Maldonado Maria del Mar , Matos Gascot Tatiana , Borrero-Garcia Luis D. , Cooke Mariana , Kazanietz Marcelo G. , Hernandez O'Farril Eliud , Vlaar Cornelis P. , Dharmawardhane Suranganie
Published: April 2023

Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 promotes loss of cancer cell polarity to result in disorganization of the actin cytoskeleton and detachment from the substratum. In lung cancer cells, MBQ-168 is more effective than MBQ-167 or EHop-097 at reducing ruffle formation in response to EGF. Comparable with MBQ-167, MBQ-168 significantly inhibits HER2-positive tumor growth and metastasis to lung, liver, and spleen. Both MBQ-167 and MBQ-168 inhibit the cytochrome P450 (CYP) enzymes 3A4, 2C9, and 2C19. However, MBQ-168 is approximately 10× less potent than MBQ-167 at inhibiting CYP3A4, thus demonstrating its utility in relevant combination therapies. In conclusion, the MBQ-167 derivatives MBQ-168 and EHop-097 are additional promising antimetastatic cancer compounds with similar and distinct mechanisms.
Significance:
Targeting the related GTPases Rac and Cdc42 that regulate cancer metastasis is a viable strategy to impede metastasis of solid cancers. Herein, we describe new Rac and Cdc42 inhibitors with unique mechanisms and varying potency in different cancer cell lines. The MBQ-167 derivatives MBQ-168 and EHop-097 show promise as potential antimetastatic cancer agents.
Data from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy
Authors: Paillasse Michael R. , Esquerré Michael , Bertrand Florie A. , Poussereau-Pomié Céline , Pichery Mélanie , Visentin Virgile , Gueguen-Dorbes Geneviève , Gaujarengues Florence , Barron Pauline , Badet Gaelle , Briaux Anne , Ancey Pierre-Benoit , Sibrac David , Erdociain Eric , Özcelik Dennis , Meneyrol Jérôme , Martin Valérie , Gomez-Brouchet Anne , Selves Janik , Rochaix Philippe , Battistella Maxime , Lebbé Céleste , Delord Jean-Pierre , Dol-Gleizes Frédérique , Bono Françoise , Blanc Isabelle , Alam Antoine , Hunneyball Ian , Whittaker Mark , Fons Pierre
Published: April 2023

The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e., sorafenib and pazopanib). As monotherapy, EVT801 showed a potent antitumor effect in VEGFR-3–positive tumors, and in tumors with VEGFR-3–positive microenvironments. EVT801 suppressed VEGF-C–induced human endothelial cell proliferation in vitro and tumor (lymph)angiogenesis in different tumor mouse models. In addition to reduced tumor growth, EVT801 decreased tumor hypoxia, favored sustained tumor blood vessel homogenization (i.e., leaving fewer and overall larger vessels), and reduced important immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSC) in circulation. Furthermore, in carcinoma mouse models, the combination of EVT801 with immune checkpoint therapy (ICT) yielded superior outcomes to either single treatment. Moreover, tumor growth inhibition was inversely correlated with levels of CCL4, CCL5, and MDSCs after treatment with EVT801, either alone or combined with ICT. Taken together, EVT801 represents a promising anti(lymph)angiogenic drug for improving ICT response rates in patients with VEGFR-3 positive tumors.
Significance:
The VEGFR-3 inhibitor EVT801 demonstrates superior selectivity and toxicity profile than other VEGFR-3 tyrosine kinase inhibitors. EVT801 showed potent antitumor effects in VEGFR-3–positive tumors, and tumors with VEGFR-3–positive microenvironments through blood vessel homogenization, and reduction of tumor hypoxia and limited immunosuppression. EVT801 increases immune checkpoint inhibitors’ antitumor effects.
Data from Mechanistic Modeling of the Interplay Between Host Immune System, IL-7 and UCART19 Allogeneic CAR-T Cells in Adult B-cell Acute Lymphoblastic Leukemia
Authors: Derippe Thibaud , Fouliard Sylvain , Marchiq Ibtissam , Dupouy Sandra , Almena-Carrasco Maria , Geronimi Julia , Declèves Xavier , Chenel Marylore , Mager Donald E.
Published: April 2023

Chimeric antigen receptor (CAR)-T cell therapies have shown tremendous results against various hematologic cancers. Prior to cell infusion, a host preconditioning regimen is required to achieve lymphodepletion and improve CAR-T cell pharmacokinetic exposure, leading to greater chances of therapeutic success. To better understand and quantify the impact of the preconditioning regimen, we built a population-based mechanistic pharmacokinetic-pharmacodynamic model describing the complex interplay between lymphodepletion, host immune system, homeostatic cytokines, and pharmacokinetics of UCART19, an allogeneic product developed against CD19+ B cells. Data were collected from a phase I clinical trial in adult relapsed/refractory B-cell acute lymphoblastic leukemia and revealed three different UCART19 temporal patterns: (i) expansion and persistence, (ii) transient expansion with subsequent rapid decline, and (iii) absence of observed expansion. On the basis of translational assumptions, the final model was able to capture this variability through the incorporation of IL-7 kinetics, which are thought to be increased owing to lymphodepletion, and through an elimination of UCART19 by host T cells, which is specific to the allogeneic context. Simulations from the final model recapitulated UCART19 expansion rates in the clinical trial, confirmed the need for alemtuzumab to observe UCART19 expansion (along with fludarabine cyclophosphamide), quantified the importance of allogeneic elimination, and suggested a high impact of multipotent memory T-cell subpopulations on UCART19 expansion and persistence. In addition to supporting the role of host cytokines and lymphocytes in CAR-T cell therapy, such a model could help optimizing the preconditioning regimens in future clinical trials.
Significance:
A mathematical mechanistic pharmacokinetic/pharmacodynamic model supports and captures quantitatively the beneficial impact of lymphodepleting patients before the infusion of an allogeneic CAR-T cell product. Mediation through IL-7 increase and host T lymphocytes decrease is underlined, and the model can be further used to optimize CAR-T cell therapies lymphodepletion regimen.
Data from Combination of a New Oral Demethylating Agent, OR2100, and Venetoclax for Treatment of Acute Myeloid Leukemia
Authors: Kamachi Kazuharu , Ureshino Hiroshi , Watanabe Tatsuro , Yoshida-Sakai Nao , Fukuda-Kurahashi Yuki , Kawasoe Kazunori , Hoshiko Toshimi , Yamamoto Yuta , Kurahashi Yuki , Kimura Shinya
Published: April 2023

The standard treatment for elderly patients with acute myeloid leukemia (AML) is venetoclax (Ven), a BCL-2–selective inhibitor, combined with hypomethylating agents (HMA) such as azacitidine or decitabine. This regimen results in low toxicity, high response rates, and potentially durable remission; however, because of low oral bioavailability, these conventional HMAs must be administered intravenously or subcutaneously. A combination of oral HMAs and Ven would provide a therapeutic advantage over parenteral administration of drugs and improve quality of life by reducing the number of hospital visits. Previously, we showed the promising oral bioavailability and antileukemia effects of a new HMA, OR2100 (OR21). Here, we investigated the efficacy and underlying mechanism of OR21 when used in combination with Ven to treat AML. OR21/Ven showed synergistic antileukemia effects in vitro, and significantly prolonged survival without increasing toxicity in a human leukemia xenograft mice model. RNA sequencing following combination therapy revealed downregulation of VAMP7, which is involved in autophagic maintenance of mitochondrial homeostasis. Combination therapy led to accumulation of reactive oxygen species, leading to increased apoptosis. The data suggest that the combination of OR21 plus Ven is a promising candidate oral therapy for AML.
Significance:
The standard treatment for elderly patients with AML is Ven combined with HMAs. OR21, a new oral HMA plus Ven showed synergistic antileukemia effects in vitro and vivo, suggesting that the combination of OR2100 plus Ven is a promising candidate oral therapy for AML.
Data from Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue
Authors: Cheng Ting-Yuan David , Zhang Runzhi , Gong Zhihong , Qin Bo , Cannioto Rikki A. , Datta Susmita , Zhang Weizhou , Omilian Angela R. , Yao Song , Khoury Thaer , Hong Chi-Chen , Bandera Elisa V. , Ambrosone Christine B.
Published: April 2023

Physical activity (PA) is associated with decreased signaling in the mTOR pathway in animal models of mammary cancer, which may indicate favorable outcomes. We examined the association between PA and protein expression in the mTOR signaling pathway in breast tumor tissue. Data on 739 patients with breast cancer, among which 125 patients had adjacent-normal tissue, with tumor expression for mTOR, phosphorylated (p)-mTOR, p-AKT, and p-P70S6K were analyzed. Self-reported recreational PA levels during the year prior to diagnosis were classified using the Centers for Disease Control and Prevention guideline as sufficient (for moderate or vigorous) PA or insufficient PA (any PA but not meeting the guideline) or no PA. We performed linear models for mTOR protein and two-part gamma hurdle models for phosphorylated proteins. Overall, 34.8% of women reported sufficient PA; 14.2%, insufficient PA; 51.0%, no PA. Sufficient (vs. no) PA was associated with higher expression for p-P70S6K [35.8% increase; 95% confidence interval (CI), 2.6–80.2] and total phosphoprotein (28.5% increase; 95% CI, 5.8–56.3) among tumors with positive expression. In analyses stratified by PA intensity, sufficient versus no vigorous PA was also associated with higher expression levels of mTOR (beta = 17.7; 95% CI, 1.1–34.3) and total phosphoprotein (28.6% higher; 95% CI, 1.4–65.0 among women with positive expression) in tumors. The study found that guideline-concordant PA levels were associated with increased mTOR signaling pathway activity in breast tumors. Studying PA in relation to mTOR signaling in humans may need to consider the complexity of the behavioral and biological factors.
Significance:
PA increases energy expenditure and limits energy utilization in the cell, which can influence the mTOR pathway that is central to sensing energy influx and regulating cell growth. We studied exercise-mediated mTOR pathway activities in breast tumor and adjacent-normal tissue. Despite the discrepancies between animal and human data and the limitations of our approach, the findings provide a foundation to study the mechanisms of PA and their clinical implications.
Data from Tumor-derived GCSF Alters Tumor and Systemic Immune System Cell Subset Composition and Signaling
Authors: Matos Israel , Barvalia Maunish , Chehal Manreet K. , Robertson A. Gordon , Kulic Iva , Silva Jessica A.F.D. , Ranganathan Abhinandan , Short Amy , Huang Yu-Hsuan , Long Erin , Priatel John J. , Dhanji Salim , Nelson Brad H. , Krebs Danielle L. , Harder Kenneth W.
Published: April 2023

While immunotherapies such as immune checkpoint blockade and adoptive T-cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DC), monocytes, and macrophages (MF) orchestrate innate and adaptive immune responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, and activity. Using Cytometry by Time-of-Flight, we found that tumor-derived GCSF altered myeloid cell distribution both locally and systemically. We distinguished a large number of GCSF-induced immune cell subset and signal transduction pathway perturbations in tumor-bearing mice, including a prominent increase in immature neutrophil/myeloid-derived suppressor cell (Neut/MDSC) subsets and tumor-resident PD-L1+ Neut/MDSCs. GCSF expression was also linked to distinct tumor-associated MF populations, decreased conventional DCs, and splenomegaly characterized by increased splenic progenitors with diminished DC differentiation potential. GCSF-dependent dysregulation of DC development was recapitulated in bone marrow cultures in vitro, using medium derived from GCSF-expressing tumor cell cultures. Importantly, tumor-derived GCSF impaired T-cell adoptive cell therapy effectiveness and was associated with increased tumor volume and diminished survival of mice with mammary cancer. Treatment with neutralizing anti-GCSF antibodies reduced colonic and circulatory Neut/MDSCs, normalized colonic immune cell composition and diminished tumor burden in a spontaneous model of mouse colon cancer. Analysis of human colorectal cancer patient gene expression data revealed a significant correlation between survival and low GCSF and Neut/MDSC gene expression. Our data suggest that normalizing GCSF bioactivity may improve immunotherapy in cancers associated with GCSF overexpression.
Significance:
Tumor-derived GCSF leads to systemic immune population changes. GCSF blockade restores immune populations, improves immunotherapy, and reduces tumor size, paralleling human colorectal cancer data. GCSF inhibition may synergize with current immunotherapies to treat GCSF-secreting tumors.
Data from Predicting Cancer Risk from Germline Whole-exome Sequencing Data Using a Novel Context-based Variant Aggregation Approach
Authors: Guan Zoe , Begg Colin B. , Shen Ronglai
Published: April 2023

Many studies have shown that the distributions of the genomic, nucleotide, and epigenetic contexts of somatic variants in tumors are informative of cancer etiology. Recently, a new direction of research has focused on extracting signals from the contexts of germline variants and evidence has emerged that patterns defined by these factors are associated with oncogenic pathways, histologic subtypes, and prognosis. It remains an open question whether aggregating germline variants using meta-features capturing their genomic, nucleotide, and epigenetic contexts can improve cancer risk prediction. This aggregation approach can potentially increase statistical power for detecting signals from rare variants, which have been hypothesized to be a major source of the missing heritability of cancer. Using germline whole-exome sequencing data from the UK Biobank, we developed risk models for 10 cancer types using known risk variants (cancer-associated SNPs and pathogenic variants in known cancer predisposition genes) as well as models that additionally include the meta-features. The meta-features did not improve the prediction accuracy of models based on known risk variants. It is possible that expanding the approach to whole-genome sequencing can lead to gains in prediction accuracy.
Significance:
There is evidence that cancer is partly caused by rare genetic variants that have not yet been identified. We investigate this issue using novel statistical methods and data from the UK Biobank.
On the Design of an Algorithm for Mobility Management Over Fog Geographical Allocation for Healthcare Applications
Authors: Aldosary Saad , Hussien Doaa Abo , Amoon Mohammed , El- Sisi Ashraf , Khaled Haitham , El-Bahnasawy Nirmeen A.
Published: April 2023

Healthcare applications need an immediate response with minimal latency. Fog computing provides real-time monitoring and computation at the network edge so the data collected by Internet of Things (IoT) devices can be analyzed with minimal cost in real-time. However, dealing with end-user
mobility becomes even more challenging with fog-assisted IoT healthcare frameworks because low latency in mobility support and fog node locating is a vital prerequisite. In this paper, we propose a fog node (FN) allocation and mobility-adapted fog computing architecture. The architecture is
based on an algorithm that offers low latency for location-sensitive operations and service stability with high data broadcast quality for user mobility in fog computing. In our proposed architecture, it is no longer obligatory to either carry out a job on, or redirect it to, the cloud but
instead connect with other FNs to continue with a request for a new job. The proposed architecture minimizes average network lateness by 40%–50%, bandwidth by 30%–40%, and end-to-end communication by 35%–55%. Additionally, the utilization of the FN computational resources
is maximized.
Sources of Drag in Estuarine Meanders: Momentum Redistribution, Bottom Stress Enhancement, and Bend-Scale Form Drag
Authors: Bo Tong , Ralston David K. , Geyer W. Rockwell
Published: April 2023

Curvature can create secondary circulation and flow separation in tidal channels, and both have important consequences for the along-channel momentum budget. The North River is a sinuous estuary where drag is observed to be higher than expected, and a numerical model is used to investigate the influence of curvature-induced processes on the momentum distribution and drag. The hydrodynamic drag is greatly increased in channel bends compared to that for straight channel flows. Drag coefficients are calculated using several approaches to identify the different factors contributing to the drag increase. Flow separation creates low-pressure recirculation zones on the lee side of the bends and results in form drag. Form drag is the dominant source of the increase in total drag during flood tides and is less of a factor during ebb tides. During both floods and ebbs, curvature-induced secondary circulation transports higher-momentum fluid to the lower water column through vertical and lateral advection. Consequently, the streamwise velocity profile deviates from the classic log profile and vertical shear becomes more concentrated near the bed. This redistribution by the lateral circulation causes an overall increase in bottom friction and contributes to the increased drag. Additionally, spatial variations in the depth-averaged velocity field due to the curvature-induced flow are nonlinearly correlated with the bathymetric structure, leading to increased bottom friction. In addition to affecting the tidal flow, the redistributed momentum and altered bottom shear stress have clear implications for channel morphodynamics.
The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD
Authors: Gbotosho Oluwabukola T , Li Wei , Joiner Clinton H , Brown Lou Ann S , Hyacinth Hyacinth I
Published: April 2023

The lung microenvironment plays a crucial role in maintaining lung homeostasis as well as the initiation and resolution of both acute and chronic lung injury. Acute chest syndrome (ACS) is a complication of sickle cell disease (SCD) like acute lung injury. Both the endothelial cells and peripheral blood mononuclear cells are known to secrete proinflammatory cytokines elevated during ACS episodes. However, in SCD, the lung microenvironment that may favor excessive production of proinflammatory cytokines and the contribution of other lung resident cells, such as alveolar macrophages and alveolar type 2 epithelial (AT-2) cells, to ACS pathogenesis is not completely understood. Here, we sought to understand the pulmonary microenvironment and the proinflammatory profile of lung alveolar macrophages (LAMs) and AT-2 cells at steady state in Townes sickle cell (SS) mice compared to control mice (AA). In addition, we examined lung function and micromechanics molecules essential for pulmonary epithelial barrier function in these mice. Our results showed that bronchoalveolar lavage (BAL) fluid in SS mice had elevated protein levels of pro-inflammatory cytokines interleukin (IL)-1β and IL-12 (p ⩽ 0.05) compared to AA controls. We showed for the first time, significantly increased protein levels of inflammatory mediators (Human antigen R (HuR), Toll-like receptor 4 (TLR4), MyD88, and PU.1) in AT-2 cells (1.4 to 2.2-fold) and LAM (17-21%) isolated from SS mice compared to AA control mice at steady state. There were also low levels of anti-inflammatory transcription factors (Nrf2 and PPARy) in SS mice compared to AA controls (p ⩽ 0.05). Finally, we found impaired lung function and a dysregulated composition of surfactant proteins (B and C). Our results demonstrate that SS mice at steady state had a compromised lung microenvironment with elevated expression of proinflammatory cytokines by AT-2 cells and LAM, as well as dysregulated expression of surfactant proteins necessary for maintaining the alveolar barrier integrity and lung function.
DNAfusion: an R/Bioconductor package for increased sensitivity of detecting gene fusions in liquid biopsies
Authors: Maansson Christoffer Trier , Andersen Emma Roger , Ulhoi Maiken Parm , Meldgaard Peter , Sorensen Boe Sandahl
Published: April 2023

Background

EML4-ALK gene fusions are oncogenic drivers in non-small cell lung cancer (NSCLC), and liquid biopsies containing EML4-ALK fragments can be used to study tumor dynamics using next-generation sequencing (NGS). However, the sensitivity of EML4-ALK detection varies between pipelines and analysis tools.

Results

We developed an R/Bioconductor package, DNAfusion, which can be applied to BAM files generated by commercially available NGS pipelines, such as AVENIO. Forty-eight blood samples from a training cohort consisting of 41 stage IV EML4-ALK-positive NSCLC patients and seven healthy controls were used to develop DNAfusion. DNAfusion detected EML4-ALK in significantly more samples (sensitivity = 61.0%) compared to AVENIO (sensitivity = 36.6%). The newly identified EML4-ALK-positive patients were verified using droplet digital PCR. DNAfusion was subsequently validated in a blinded validation cohort comprising 24 EML4-ALK-positive and 24 EML4-ALK-negative stage IV NSCLC patients. DNAfusion detected significantly more EML4-ALK individuals in the validation cohort (sensitivity = 62.5%) compared to AVENIO (sensitivity = 29.2%). DNAfusion demonstrated a specificity of 100% in both the training and validation cohorts.

Conclusion

Here we present DNAfusion, which increases the sensitivity of EML4-ALK detection in liquid biopsies and can be implemented downstream of commercially available NGS pipelines. The simplistic method of operating the R package makes it easy to implement in the clinical setting, enabling wider expansion of NGS-based diagnostics.
Survey on the management of childhood epilepsy among general practitioners in the area of Marrakech
Authors: Lahmini Widad , Gyamfi Samuel Opoku , Bourrous Mounir
Published: April 2023

Background

Epilepsy is a common chronic neurological disorder in the pediatric population and its evolution can be fatal. It represents a major public health problem as well as an economic burden for the families of affected children, health systems and the overall economies of countries. This further accentuates the role that general practitioners can play in the management of childhood epilepsy in the face of the persistent lack of neurologists and neuro-pediatricians in our country.

Methods

In order to assess the knowledge and therapeutic habits of general practitioners, we carried out a descriptive and cross-sectional study with general practitioners practicing in the two healthcare sectors: public and private, and in two settings: urban and rural, during the year 2018. The data was collected through a pre-established survey.

Results

In total, 155 general practitioners responded to the survey. For 85.2% of physicians, the diagnosis of childhood epilepsy was based on interrogation, physical examination, and EEG. While brain imaging would be systematic regardless of the type of epilepsy for 45.2% of doctors. Only 6 doctors (3.9%) had knowledge of the latest classifications of the “ILAE”. For treatment, the majority of physicians (65.5%) adopted first-line monotherapy with valproate in leading position. Almost half of the doctors (48.4%) found that education of parents and children was always necessary. None of the GPs interviewed in our series assessed the academic impact of epilepsy. Only 32% of doctors had received continuing education on epilepsy.

Conclusion

The data from our study demonstrates that continuing education on the management of childhood epilepsy and the greater involvement of general practitioners were essential elements in improving care.
Date and doum palm natural fibers as renewable resource for improving interface damage of cement composites materials
Authors: Bendahane Khaled , Belkheir Mohammed , Mokaddem Allel , Doumi Bendouma , Boutaous Ahmed
Published: April 2023

Background

Various recent studies have investigated the use of traditional fibers (metallic or synthetic) as reinforcement in mortar. In recent times, there has been growing interest in using natural fibers as reinforcement in cement composites. This study was conducted to assess the impact of date palm, doum palm, and sisal fibers on the mechanical properties of cement composites. Genetic modeling was chosen to find the shear damage at the fiber-matrix interface of the three cement composites using genetic crossing operator, which allows us to calculate the damage at the interface using two damages of the matrix and the fibers, respectively.

Results

Our objective is to examine and evaluate the interface damage of date palm/mortar, doum palm/mortar and sisal/mortar under different mechanical tensile stresses ranging from 25 to 37 MPa with fiber volume fraction from 1 to 5%. It was found that the interface damage of date palm/mortar and doum palm/mortar cement composites was minimal compared to that of sisal/mortar. However, several researchers found that an increase in fiber volume fraction leads to decrease in mechanical properties and density in cement composites what we confirmed in this study that interface damage increases when the volume fraction increases.

Conclusions

The results are in line with the findings of a recent experimental study on the use of other plant fibers. Their results showed that incorporating ramie fibers resulted in a 27% increase in compressive strength, whereas the use of synthetic fibers resulted in 4% decrease in tensile strength in compression. It is recommended the use of doum and date palm natural fibers in the composition of mortars with a fiber volume fraction of 1 to 5% in order to reduce and avoid interface damage and limit the negative impact of synthetic fibers on the environment.
Glenway Wescott's Narratives of Queer Drift
Authors: Kindig Patrick
Published: April 2023

This essay argues that Glenway Wescott — an American author widely read in the early twentieth century but virtually unknown to literary scholars today — poses a problem for many of the narratives we tell ourselves about both queer identity and modernist literary history. On the one hand, the wandering, nonlinear plots of much of his fiction run counter to the narratives of urban migration, rural stasis, and ex-urban return that shape most scholarship on sexual geography. On the other, Wescott's tendency to borrow aesthetic practices from a wide range of literary schools and movements makes it difficult to locate him within the narrative of American literary history. Reading Wescott's writings — particularly those in his short story collection Good-Bye Wisconsin (1928) — as examples of what the essay terms queer drift, the author argues that Wescott's life and corpus destabilize the narratives we often use to make sense of both modern sexual identity and modernist literary aesthetics. In fact, this is why his work warrants more critical attention than it has traditionally received: it provides us with new ways of thinking about the relationship between queerness, geography, and narrative form.
INSTRUMENTO AVALIATIVO DE OBJETOS DIGITAIS DE APRENDIZAGEM PARA A MATEMÁTICA: A USABILIDADE EM FOCO
Authors: Alexandre Mariana Dos Reis , Barros Daniela Melare Vieira
Published: April 2023

Os Objetos Digitais de Aprendizagem (ODA) estão disponíveis em repositórios e são utilizados pelos professores nas aulas de matemática dos anos iniciais do Ensino Fundamental (ALEXANDRE, 2015). Todavia não havia um instrumento avaliativo para a avaliação sistemática dos ODA, por isso após a elaboração de um instrumento avaliativo, as questões que realizamos são: o que pensam os professores e futuros professores sobre o instrumento? Facilita a seleção dos ODA? Oferece uma orientação em relação ao potencial que o ODA possui e o que pode ser ampliado conforme a utilização? Neste viés, o objetivo deste estudo consiste em testar a usabilidade do instrumento avaliativo de ODA e promover reflexões mediante as perspectivas dos participantes. Realizamos a testagem de usabilidade de um instrumento por meio de três oficinas de formação inicial e continuada que contou com 44 participantes. Os resultados apontam a importância do instrumento para conhecimento da qualidade do ODA em seus aspectos pedagógicos; a necessidade de parcerias para o aprimoramento da acessibilidade do instrumento aos professores de diferentes realidades; a ampliação da temática nas formações iniciais e continuadas e reflexões indispensáveis para o contexto atual.
O lugar docente na política curricular: um debate a partir dos Institutos Federais
Authors: Hentz Isabel Cristina , Thiesen Juares Da Silva
Published: April 2023

O objetivo do artigo é identificar, no âmbito de diferentes tradições teóricas que tratam sobre currículo, espaços de atuação de professores na produção de políticas curriculares. Como finalidade mais específica, pretende-se trazer para a discussão o modo como os Institutos Federais organizam suas (micro)políticas curriculares e, nesse âmbito, situar a participação/atuação de seus docentes. O trabalho resulta de aprofundamento teórico feito sobre o recorte em pauta e trata-se de um estudo de corte bibliográfico, com alguma inserção no campo empírico relacionado a dois (02) IFs em Santa Catarina. Como resultado, avaliou-se que a teoria da resistência e as abordagens pós-críticas são as que parecem trazer referenciais com maior ênfase no protagonismo do trabalho docente na política curricular. Esses dois conjuntos de abordagem expressam e interpretam as correlações de força entre indivíduo e estrutura de forma a não ignorar a estrutura, mas também de evidenciar as possibilidades de ação dos sujeitos na produção do social. Quando tomam-se essas abordagens como referente para pensar os movimentos de produção da política curricular que são mobilizados nos Institutos Federais, percebe-se que se abre um interessante campo de pesquisa, especialmente em relação aos espaços para protagonismo docente e consequentes possibilidades de atuação desses sujeitos na política.
Risk factors and clinical manifestations of COVID-19 in pregnant women in Indonesia
Authors: Rahayu Heni Setyowati Esti , Wijayanti Kartika , Anggraeni Mekar Dwi , Poniman
Published: April 2023

Background/Aims

Pregnant women are at higher risk for severe illness from COVID-19 than non-pregnant women. Research investigating risk factors and clinical manifestations of COVID-19 in pregnant women is limited in Indonesia. Therefore, this study's aim was to investigate these clinical issues.

Methods

For this observational cross-sectional study, data were collected from Merah Putih Government Hospital. A total of 106 medical records were analysed using descriptive statistics and Pearson's Chi-squared test, to examine differences in risk factors or clinical manifestations in pregnant women with or without COVID-19.

Results

There were no significant differences between the two groups in terms of risk factors such as diabetes, bronchial asthma and cardiovascular disease. There were significant differences between the groups for clinical manifestations of fever, cough, dyspnea, ageusia, rapid antigen test and lymphocytopenia.

Conclusions

Coordinated care strategies should be initiated, particularly in the assessment of vulnerable pregnant women. Future pandemic preparedness studies should be considered to improve and protect maternal and child health in Indonesia.
Numerical investigations of heat transfer characteristics using oblong fins and circular fins in a wedge channel
Authors: Venkatesh Goveraiahgari , Meenakshi Reddy Reddygari , Mallikarjuna Rao Pabbisetty
Published: April 2023

Turbine inlet air temperatures are extremely high, which can result in blade material damage. As a result, cooling the turbine blades is required, and a variety of cooling techniques have been introduced. The majority of the previous research on pin fins has focused on circular fins using a wedge duct to apply a constant temperature and uniform heat flux to the end wall and pin fin surfaces. The present study compares seven oblong pin-fins to seven circular pin fins in a wedge duct with a Reynolds number range of 10,000–50,000 and a constant heat flux (surface) of 3280 W/m2 applied to the endwall and surfaces of the oblong pin fin. The results indicate that the friction factor for oblong fins is 14% lower than for circular pin fins. The thermal performance factor is increased by 11.4%. The thermal performance factor can be improved by using oblong pin fins with higher Reynolds numbers.
Analytic hierarchy process (AHP)-based materials selection system for natural fiber as reinforcement in biopolymer composites for food packaging
Authors: Salwa H. N. , Sapuan S. M. , Mastura M. T. , Zuhri M. Y. M.
Published: April 2023

The biodegradability of a material has been an important measure in packaging design. Green biocomposites, which are made of natural fiber and biopolymer matrix, are promising alternative materials in single-use packaging to replace conventional materials. Selection of the most suitable natural fiber for reinforcement in green biocomposites is an initial attempt towards reducing resources depletion and packaging waste dumping. A selection system of analytic hierarchy process (AHP)-based method is proposed. Food packaging materials’ requirements and production factors are the basis of selecting 13 vital characteristics of natural fibers as the selection criteria. Nine natural fibers were assessed based on data gathered from recent literature. From the results, ijuk obtained the highest priority score (14%). Whilst, sisal had the lowest rank with a score of 8.8%. Sensitivity analysis was then performed to further validate the results, and ijuk remained at the top rank in four out of the six scenarios tested. It was concluded that ijuk is the most suitable natural fiber for reinforcement in green biocomposites for food packaging design. Nonetheless, for future development, more comprehensive selection criteria, such as fiber specific properties, fiber processing, and fibre treatment, are suggested to be included in the framework for more comprehensive results.
Johan Ickx (ed.), L’Ostpolitik vaticana: L’Unione Sovietica e la Chiesa ortodossa russa (1945-1978), Libreria Editrice Vaticana (Col. Atti e documenti, 58), Città del Vaticano 2021, 335 pp.
Authors: Dulska Anna-K.
Published: April 2023

Book Review
Iuliu-Marius Morariu, Repere ale autobiografiei spirituale din spaţiul ortodox în secolele XIX şi XX-Ioan de Kronstadt, Siluan Athonitul şi Nicolae Berdiaev, Lumen, Iași 2019, 536 pp.
Authors: Rus Anca-Ioana
Published: April 2023

Book Review
Reflections on Resistance to Pesticides in Relation to Application Techniques
Authors: Matthews Graham
Published: April 2023

A wide range of pesticides have been developed, but these have mostly been formulated to mix with water as the diluents and are applied as a spray, either with ground equipment or from aircraft using hydraulic nozzles. The effectiveness of any technique is a function of the interaction of various factors, including plant size, volume of spray applied, spectrum of droplets sprayed, distribution of droplets relative to location of pests on plants, timing of an application relative to crop monitoring and subsequent persistence of the deposits of pesticide, especially after rain.
The Impact of the EU Neonicotinoid Ban on UK Carrot and Lettuce Production and Prospects for Future Aphid Management
Authors: Whatty Megan , Collier Rosemary
Published: April 2023

Since their introduction in the 1990s, neonicotinoid insecticides have become the most widely used group of insecticides in the world, effective against a wide range of agricultural pests, and used on over 140 crops in 120 countries. However, in 2013, the European Union (EU) implemented a moratorium on the use of pesticides containing three neonicotinoid active substances ‐ clothianidin, imidacloprid and thiamethoxam, banning their use initially on flowering crops such as oilseed rape and sunflowers. These restrictions were further extended in 2018, resulting in a complete ban on the outdoor use of these three active substances including crops such as cereals and sugar beet, and vegetables such as carrots and lettuce. Despite the restrictions affecting a wide range of crops, research into the impact of these restrictions on crop production has focussed mainly on oilseed rape (OSR) cultivation, with little attention being paid to other crop sectors, which have also had to adapt to the loss of neonicotinoids. In the United Kingdom (UK), neonicotinoids were mainly used in OSR, cereal and sugar beet production, but also on soft fruit, potatoes, vegetable crops such as carrot, and salad production. It has been widely documented that the ‘perfect storm’ of losing neonicotinoids, coupled with a warm winter, resulted in devastating impacts to the UK sugar beet industry in 2020 due to high numbers of overwintering aphids. Nevertheless, these same factors have also led to impacts on the UK carrot and lettuce industries, although far less is documented about how these sectors have responded to the neonicotinoid restrictions. This article examines how the loss of neonicotinoids has impacted carrot and lettuce production in the UK, and the future options for Integrated Pest Management of aphids on these crops. It is based partly on an online grower survey and interviews with agronomists conducted in 2021. It is argued that despite the neonicotinoid restrictions having adverse impacts on the UK agricultural sector, the trend of increasing bans on plant protection products is unlikely to slow, thus growers must be supported to adapt to this loss by strengthening their armoury of Integrated Pest Management (IPM) options.
Analyze the fluctuation of hoarfrost in Son La to propose some coping solutions
Authors: Nguyen Van Minh
Published: April 2023

Hoarfrost is an extreme weather phenomenon that is a sign of climate change. The article analyzes the changes of hoarfrost in Son La with a time series of 40 years, including 10 years and a long time to see the degree of change in the trend of the hoarfrost. Besides, it also mentioned the harmful effects of hoarfrost in Son La and proposed solutions to cope. Research on hoarfrost in a mountainous province like Son La (which is identifying fruit tree agriculture as its strength), has both scientific and practical value.
Serum IgE and absolute eosinophil count-A valuable serological markers in childhood urticaria
Authors: Smith A Nirmal , B Poorana , M Sucindar , Chidambaranathan S , Kaviarasan PK
Published: April 2023

: Urticaria is the most common skin disorder in children presenting to the paediatric department. Sometimes it can also present with angioedema which is an emergency condition requiring immediate treatment. Hence this study signifies the importance of Absolute eosinophil count and serum IgE in childhood urticaria and its correlation with disease severity and management.

To analyse the Absolute eosinophil count and serum IgE in children with urticaria from age group of 1-12 years and its correlation with disease severity.

An observational study on 49 children with urticaria and measurement of Absolute eosinophil count and serum IgE and categorised based on urticaria activity score.

Most common age group affected was 5-12 years and mean age was 6.75±3.47. Out of 49 children, 97.95% of the affected children have raised serum IgE levels, 39% of the affected children have raised Absolute Eosinophil Count. There was also increase in serum IgE levels with increase in AEC levels were found.

The disease severity increases with increasing levels of absolute eosinophil count and serum IgE in children with urticaria. Hence this study suggests that absolute eosinophil count and serum IgE should be regareded as a valuable markers in childhood urticaria.
LANGUAGE USE IN INTER-ETHNIC MARRIAGES IN TURKESTAN
Authors: Abdinassir Nazira
Published: April 2023

The current paper intends to answer the following questions: What is the rule of the language use in the case of an interethnic marriage in Turkestan? What the features of sociocultural environment like and how these specificities make impact on the language use in interethnic marriages? Furthermore, what are the sociolinguistic aspect of the study concerning the interpretation if interethnic language use in mixed marriages? The whole research is based on a database which consists of 40 interviews.